warfarin and Cerebral-Hemorrhage

Infective endocarditis (IE) carries a high risk of vascular complications (e.g., cerebral embolism, intracerebral hemorrhage, and renal infarction), which are correlated with increased early and late mortality. Although anticoagulation is the cornerstone for management of thromboembolic complications, it remains controversial and challenging in patients with IE. An appropriate anticoagulation strategy is crucial to improving outcomes and requires a good understanding of the indication, timing, and regimen of anticoagulation in the setting of IE. Observational studies have shown that anticoagulant treatment failed to reduce the risk of ischemic stroke in patents with IE, supporting that IE alone is not an indication for anticoagulation. In the absence of randomized controlled trials and high-quality meta-analyses, however, current guidelines on IE were based largely on observational data and expert opinion, providing few specific recommendations on anticoagulation. A multidisciplinary approach and patient engagement are required to determine the timing and regimen of anticoagulation in patients with IE, especially in specific situations (e.g., receiving warfarin anticoagulation at the time of IE diagnosis, cerebral embolism or ischemic stroke, intracerebral hemorrhage, or urgent surgery). Collectively, individualized strategies on anticoagulation management of IE should be based on clinical evaluation, available evidence, and patient engagement, and ultimately be developed by the multidisciplinary team.

Topics: Anticoagulants; Blood Coagulation; Cerebral Hemorrhage; Endocarditis; Humans; Intracranial Embolism; Stroke; Warfarin

While anticoagulation and its reversal have been of clinical relevance for decades, recent academic and technological advances have expanded the repertoire of its application in neurological disease. The advent of direct oral anticoagulants provides effective, mechanistically elegant, and relatively safer therapeutic options than warfarin for eligible patients at risk for neurological sequelae of prothrombotic states, particularly given the recent availability of corresponding reversal agents. In this review, we examine the provenance, indications, safety, and reversal tools for anticoagulant medications in the context of neurological disease, with specific attention to acute ischemic stroke, cerebral venous sinus thrombosis, and intracerebral hemorrhage. We will use specific clinical scenarios to illustrate the complex factors that must be considered in the use of anticoagulation, including intracranial pathology such as intracerebral hemorrhage, traumatic brain injury, or malignancy; metabolic complications such as chronic kidney disease; pregnancy; and advanced age.

Topics: Anticoagulants; Brain Ischemia; Cerebral Hemorrhage; Humans; Stroke; Warfarin

Anticoagulant therapy increases the risk that cerebral microbleeds (CMBs) progress to intracerebral hemorrhage, but whether the therapy increases risk of CMB occurrence is unclear. We performed a systematic review and meta-analysis to investigate the potential association between anticoagulant use and CMB occurrence in stroke and stroke-free individuals.. We searched observational studies in PubMed, Ovid EMBASE, and Cochrane Library from their inception until September 2019. We calculated the pooled odds ratio (OR) and 95% confidence interval (CI) for the prevalence and incidence of CMBs in anticoagulant users relative to non-anticoagulant users.. Forty-seven studies with 25,245 participants were included. The pooled analysis showed that anticoagulant use was associated with CMB prevalence (OR 1.54, 95% CI 1.26-1.88). The association was observed in subgroups stratified by type of participants: stroke-free, OR 1.86, 95% CI 1.25-2.77; ischemic stroke/transient ischemic attack, OR 1.33, 95% CI 1.06-1.67; and intracerebral hemorrhage, OR 2.26, 95% CI 1.06-4.83. Anticoagulant use was associated with increased prevalence of strictly lobar CMBs (OR 1.68, 95% CI 1.22-2.32) but not deep/infratentorial CMBs. Warfarin was associated with increased CMB prevalence (OR 1.64, 95% CI 1.23-2.18), but novel oral anticoagulants were not. Anticoagulant users showed higher incidence of CMBs during long-term follow-up (OR 1.72, 95% CI 1.22-2.44).. Anticoagulant use is associated with higher prevalence and incidence of CMBs. This association appears to depend on location of CMBs and type of anticoagulants. More longitudinal investigations with adjustment for confounders are required to establish the causality.

Topics: Anticoagulants; Cerebral Hemorrhage; Humans; Ischemic Attack, Transient; Magnetic Resonance Imaging; Risk Factors; Stroke; Warfarin

Background and Purpose- There are scarce data regarding the safety of intravenous thrombolysis (IVT) in acute ischemic stroke among patients on direct oral anticoagulants (DOACs). Methods- We performed a systematic review and meta-analysis of the current literature. Data regarding all adult patients pretreated with DOAC who received IVT for acute ischemic stroke were recorded. Meta-analysis was performed by comparing the rate of symptomatic intracerebral hemorrhage in these patients with (1) stroke patients without prior anticoagulation therapy and (2) patients on warfarin with international normalized ratio <1.7. Meta-analyses were further conducted in subgroups as follows: (1) administration of DOAC within 48 hours versus an unknown interval before IVT, (2) consideration of symptomatic intracerebral hemorrhage outcome according to the National Institute of Neurological Disorders (NINDS) versus the European Cooperative Acute Stroke Study II (ECASS-II) criteria. Results- After reviewing 13 392 reports and communicating with certain authors of 12 published studies, a total of 52 823 acute ischemic stroke patients from 6 studies were enrolled in the present meta-analysis: DOACs: 366, warfarin: 2133, and 503 241 patients without prior anticoagulation. We detected no additional risk of symptomatic intracerebral hemorrhage following IVT among patients taking DOACs within 48 hours-DOACs-warfarin: NINDS (odds ratio [OR], 0.55 [95% CI, 0.19-1.59]), ECASS-II (OR, 0.77 [95% CI, 0.28-2.16]); DOACs-no-anticoagulation: NINDS (OR, 1.23 [95% CI, 0.46-3.31]), ECASS-II (OR, 0.87 [95% CI, 0.32-2.41]). Similarly, no additional risk was detected with no time limit between last DOAC intake-DOACs warfarin: NINDS (OR, 0.85 [95% CI, 0.49-1.45]), ECASS-II (OR, 1.11 [95% CI, 0.67-1.85]); DOACs-no-anticoagulation: NINDS (OR, 1.17 [95% CI, 0.43-3.15]), ECASS-II (OR, 0.87 [95% CI, 0.33-2.41]). There was no evidence of heterogeneity across included studies (

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cerebral Hemorrhage; Dabigatran; Female; Humans; Male; Middle Aged; Risk Factors; Stroke; Warfarin

As intracerebral hemorrahge becomes more frequent as a result of an aging population with greater comorbidities, rapid identification and reversal of precipitators becomes increasingly paramount. The aformentioned population will ever more likely be on some form of anticoagulant therapy. Understanding the mechanisms of these agents and means by which to reverse them early on is critical in managing the acute intracerebral hemorrhage.

Topics: Antibodies, Monoclonal, Humanized; Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Cerebral Hemorrhage; Coagulants; Factor VIIa; Factor Xa; Factor Xa Inhibitors; Humans; Plasma; Recombinant Proteins; Treatment Outcome; Vitamin K; Warfarin

Atrial fibrillation is one of the most common comorbid conditions in hemodialysis patients, and warfarin is widely prescribed anticoagulant to prevent thromboembolic complications in such patients. In the last decade, several epidemiological studies pointed out the risk of bleeding with the use of warfarin. So, this meta-analysis is aimed to assess the bleeding risk associated with the use of warfarin.. This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis guidelines. PubMed, Embase, Scopus, and Cochrane central databases were searched from inception to June 10, 2018. The primary outcome was to quantify the bleeding risk associated with warfarin use. The secondary outcome was to assess the bleeding risk based on different subgroups. Review Manager (RevMan) version 5.3 was used for performing statistical analysis.. A total of 15 studies, constituting a pooled sample of 53 581 patients (37.14% female), were included. Of these, 17 469 were warfarin users. We found that warfarin use had a significant association with the bleeding risk. The pooled relative risk (RR) of bleeding was estimated to be 1.35 (95% CI: 1.18-1.53, P = < 0.00001), and the pooled RR of major bleeding (five studies) was estimated to be 1.32 (95% CI: 1.07-1.63, P = 0.009). Subgroup analysis revealed a significant association of warfarin use with the intracranial hemorrhage/hemorrhagic stroke (nine studies) (pooled RR: 1.43 [95% CI: 1.20-1.71, P = < 0.0001]).. The results indicate that warfarin use increases the risk of bleeding in hemodialysis patients with atrial fibrillation.

Topics: Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Cohort Studies; Databases, Bibliographic; Female; Hemorrhage; Humans; Male; Renal Dialysis; Risk; Thromboembolism; Warfarin

The characteristics and natural history of acute non-vitamin K antagonists oral anticoagulants (NOAC)-associated intracerebral haemorrhage (ICH) are largely unknown. We performed a comprehensive systematic review and meta-analysis to compare baseline ICH volume, haematoma expansion and clinical outcomes between NOAC-ICH versus vitamin K antagonists-ICH (VKA-ICH).. We searched PubMed and conference abstracts for observational studies comparing baseline characteristics and outcomes in patients with NOAC-ICH versus VKA-ICH using an appropriate keyword/MeSH term search strategy. Data were extracted following PRISMA and MOOSE guidelines. The main outcome measures were mortality and unfavourable functional outcome (modified Rankin Score: 4-6) at discharge and at 3 months, as well as ICH volumes and haematoma expansion rates in the two groups. Random-effects models with DerSimonian-Laird weights were used for pooled estimates calculation.. Twelve studies including 393 NOAC-ICH and 3482 VKA-ICH were pooled in meta-analysis. There was no difference in mean ICH-volume between the two groups (standard mean difference: -0.24; 95% CI -0.52 to 0.04, p=0.093). The rates of haematoma expansion were comparable in NOAC-ICH versus VKA-ICH (OR: 0.76; 95% CI 0.49 to 1.19, p=0.236). We did not find any difference between patients with NOAC-ICH versus VKA-ICH in all-cause mortality at discharge (OR: 0.66; 95% CI 0.42 to 1.05, p=0.077) and unfavourable functional outcome at discharge (OR: 0.77; 95% CI 0.41 to 1.44, p=0.413). The 3-month outcome was also comparable between the two ICH groups. Moderate-to-substantial statistical heterogeneity was noted.. Our results confirm that ICH volume, haematoma expansion, mortality and functional outcome appear to be similar for NOAC-ICH versus VKA-ICH. Large prospective cohorts and updated meta-analyses are needed to provide more precise estimates.

Topics: Anticoagulants; Antithrombins; Cerebral Hemorrhage; Dabigatran; Factor Xa Inhibitors; Hematoma; Humans; Mortality; Odds Ratio; Phenprocoumon; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Severity of Illness Index; Thiazoles; Vitamin K; Warfarin

Topics: Anticoagulants; Brain; Cerebral Hemorrhage; Humans; Warfarin

Non-vitamin K antagonist oral anticoagulants (NOACs) have a half-life of around 12 h. We aimed to clarify if there was any effect modification by dosing (once- or twice-daily) regimens in Asian patients.. Phase III randomized controlled trials of NOACs compared with warfarin in Asian patients with atrial fibrillation (AF) were identified and extracted from PubMed, CENTRAL, and CINAHL databases through November 2016. Outcomes were pooled by dosing regimens with the Mantel-Haenszel fixed-effects model. The risk ratio (RR) and 95% confidence interval (CI) were calculated. Effect differences between once- and twice-daily NOACs were assessed with Bucher indirect comparisons using common estimates, once heterogeneity was low, and with the Bayesian method.. From 6 trials, there was no effect modification by dosing regimens in the risk of stroke or systemic embolism across ethnicities (all interaction P > 0.05). Both dosing regimens were associated with a greater reduction in the risk of major bleeding in Asian patients (RR, 0.63 (95% CI, 0.47-0.85) and 0.57 (95% CI, 0.43-0.75), for once- and twice-daily NOACs, respectively). In Asian patients, risks of hemorrhagic stroke and intracranial hemorrhage were lower with once- (RR, 0.41 (95% CI, 0.21-0.80) and 0.29 (95% CI, 0.16-0.53)) and twice-daily NOACs (RR, 0.25 (95% CI, 0.12-0.51) and 0.38 (95% CI, 0.23-0.65)), compared with warfarin. There was no effect difference favoring any of NOAC regimens evaluated by Bucher and Bayesian methods.. In Asian patients with AF, NOACs, regardless of dosing regimens, have a similar feature of preserved efficacy with improved safety compared with warfarin.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Drug Administration Schedule; Humans; Randomized Controlled Trials as Topic; Warfarin

The use of vitamin K antagonists (VKAs) in hemodialysis patients with atrial fibrillation (AF) is controversial. No randomized trials are available and observational studies have yielded conflicting results, engendering a large clinical practice variability and physician uncertainty. An unresolved but highly relevant question is whether AF poses a true risk of ischemic stroke in hemodialysis and whether any form of oral anticoagulation is therefore warranted.. We conducted a systematic review of studies that compared the incidence of ischemic stroke and bleeding in hemodialysis patients with AF taking VKA and those not taking VKA. When hemodialysis patients had been pooled with peritoneal dialysis, kidney transplant, or stage V chronic kidney disease patients, unpublished outcome data of the hemodialysis subgroup were obtained through personal communication. The main outcome measures were ischemic stroke/thromboembolic events, all-cause mortality, major bleeding, and hemorrhagic stroke. Combined hazard ratios (HRs) and 95% CIs were calculated using a random-effects model.. Twelve prospective or retrospective cohort studies were included in the meta-analysis, totaling 17,380 hemodialysis patients of whom 4,010 (23.1%) received VKA. In VKA-treated patients, mean CHADS. Our meta-analysis revealed a trend for a reduction of the risk of ischemic stroke in hemodialysis patients with AF treated with VKA. The true protective effect may have been underestimated, owing to inclusion of low-risk patients not expected to benefit from anticoagulation and to suboptimal anticoagulation. However, assessment of the overall effect of VKA in hemodialysis patients should also take into account the increased risk of bleeding, in particular of hemorrhagic stroke. Whether new oral anticoagulants provide a better benefit-risk ratio in hemodialysis patients should be the subject of future trials.

Topics: Anticoagulants; Atrial Fibrillation; Cause of Death; Cerebral Hemorrhage; Hemorrhage; Humans; Kidney Failure, Chronic; Mortality; Proportional Hazards Models; Renal Dialysis; Stroke; Thromboembolism; Vitamin K; Warfarin

Intracerebral hemorrhage (ICH) in patients with oral anticoagulation therapy is an increasingly prevalent problem in large part due to the aging population and the increased use of anticoagulants for patients at high risk of thrombosis. Warfarin has been virtually the only outpatient anticoagulant choice until fairly recently. The development of subcutaneously injected heparinoids, and more recently, of direct thrombin inhibitors, has made the treatment and prognostication of ICH in anticoagulated patients more difficult. In this review, we will review the current state of diagnosis, prognostication, and treatment for patients with this often-devastating type of bleeding. We will focus on warfarin therapy, because the preponderance of evidence comes from studies of warfarin treatment. Where there is evidence, we will contrast warfarin with some of the newer treatment modalities. We review the evidence of the 4 major reversal agents for warfarin, vitamin K, prothrombin complex concentrates, activated factor VII, and fresh frozen plasma as well as rational treatment choices. We offer possible treatments for the newer anticoagulants based on the limited evidence available. Finally, we review recommendations from the major societies and studies that support early and aggressive therapies in intensive care units with dedicated neurological specialists.

Topics: Administration, Oral; Age Factors; Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Critical Care; Factor VIIa; Humans; Plasma; Thrombosis; Tomography, X-Ray Computed; Vitamin K; Warfarin

Topics: Administration, Oral; Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Dabigatran; Gastrointestinal Hemorrhage; Humans; Intracranial Embolism; Morpholines; Postoperative Complications; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Thiophenes; Thrombosis; Vitamin K; Warfarin

For a long time, vitamin K antagonists (VKA) were the only available oral anticoagulants for clinical use. It is conceivable that the number of patients treated with novel direct oral anticoagulants (NOAC) will increase, due to the easy handling and the favorable risk-benefit profile compared with VKA. It is, therefore, expected that clinicians will be increasingly confronted with the question on how to treat acute ischemic stroke (AIS) if there is an indication for thrombolysis or how to manage intracranial bleedings.. In this review, we discuss controversies on thrombolysis in patients anticoagulated with NOAC, the dilemma of when to restart anticoagulation after AIS, and whether (and when) to re-institute oral anticoagulation after a brain hemorrhage. We provide suggestions for the management of these situations.. Thrombolysis for patients with ischemic stroke who were given warfarin at subtherapeutic International normalized ratio values (≤ 1.7) may be considered according to guideline. Thrombolysis is contraindicated if intake of NOAC is reported in a patient, but no other information is available on-time of last intake of NOAC. Prothrombin complex concentrate have been proposed as a plausible, but unproven therapy to reverse the anticoagulant effects of NOACs.

Topics: Administration, Oral; Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Blood Coagulation Tests; Cerebral Hemorrhage; Humans; Stroke; Thrombolytic Therapy; Warfarin

Topics: Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Blood Coagulation Factors; Cerebral Hemorrhage; Dabigatran; Factor Xa Inhibitors; Humans; Monitoring, Physiologic; Morpholines; Prodrugs; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Thrombin; Thromboembolism; Vitamin K; Warfarin

Systemic thrombolysis with alteplase is the only approved medical treatment for patients with acute ischaemic stroke. Thrombectomy is also increasingly used to treat proximal occlusions of the cerebral arteries, but has not shown superiority over systemic thrombolysis with alteplase. Many patients with acute ischaemic stroke are pretreated with antiplatelet or anticoagulant drugs, which can increase the bleeding risk of thrombolysis or thrombectomy. Pretreatment with aspirin monotherapy increases the bleeding risk of alteplase in both observational and randomised trials with no effect on clinical outcome, and the risk of intracerebral haemorrhage is increased with the combination of aspirin and clopidogrel. Antiplatelet drugs should not be given in the first 24 h after alteplase treatment. Data from pooled randomised trials and a large observational study show that thrombolysis can probably be done safely in patients given vitamin-K antagonists if the international normalised ratio is less than 1·7, although bleeding risk is slightly raised. Almost no data are available for the safety of alteplase in patients with atrial fibrillation who have been given novel oral anticoagulants (NOAC) for stroke prevention. Some coagulation parameters could help to identify patients treated with NOAC who might be eligible for thrombolysis. Thrombectomy can be done in patients given antiplatelets and probably in those given anticoagulants; however, conclusions about anticoagulants are based on findings from observational studies with small patient numbers.

Topics: Animals; Anticoagulants; Brain Ischemia; Cerebral Hemorrhage; Fibrinolytic Agents; Humans; Plasminogen Activators; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Stroke; Thrombectomy; Thrombolytic Therapy; Tissue Plasminogen Activator; Warfarin

Warfarin-related intracerebral haemorrhage (WRICH) has high mortality. Haematoma expansion is prolonged in WRICH and independently predicts worse outcomes. Guidelines recommend prompt reversal of the warfarin coagulopathy, but evidence of benefit is lacking.. To determine whether the introduction of a WRICH reversal protocol (late 2008), which includes prothrombin complex concentrates (PCC), improves outcomes. All patients presenting with WRICH between January 2004 and July 2010 were included. Retrospective case note and radiology review was performed, collecting data on intracerebral haemorrhage (ICH) severity, degree and timeliness of reversal, and patient outcomes. Cox's proportional hazards analysis was used to compare outcomes associated with and without PCC after controlling for ICH severity.. Eighty-eight patients were included (27 treated palliatively). Mean international normalised ratio was 2.9. Vitamin K, PCC and fresh frozen plasma were given alone or in combination to 68, 23 and 44 patients, and mean time from computed tomography scanning to administration was 2.2, 3.3 and 3.1 h respectively. Four patients received PCC pre-protocol (none before 2007), two during development and seventeen patients post-protocol. Those who received PCC had improved survival (P < 0.001). After controlling for ICH score, hazard ratio for death was 0.27 (P < 0.01) for use of PCC. Survival tended to be greater with earlier administration of PCC (P = 0.053). Despite improved survival, discharge domicile and function were not significantly worse.. PCC reversal was associated with improved survival without worsened disability. Delays in administration may have reduced the potential benefits.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Female; Humans; Kaplan-Meier Estimate; Male; Retrospective Studies; Treatment Outcome; Warfarin

The incidence of oral anticoagulation-associated intracerebral hemorrhage (OAC-ICH) is growing due to the increasing use of warfarin and the older age of treated patients. Recent population studies reveal that OAC-ICH currently occurs at a frequency comparable to that of subarachnoid hemorrhage. Most frequently, OAC-ICH are located in deep or lobar regions of the brain, although it may also occur in the brainstem. These hemorrhages are larger than spontaneous hematomas and may be fatal in at least 50% of cases. The primary cause of brain injury in patients with OAC-ICH is the direct mechanical disruption of the brain tissue but secondary damage may occur through the intervention of matrix metalloproteinases, glutamate, cytokines, heme, iron, and the chemical toxicity of products such as thrombin, which are released from the clot. The pathogenesis of OAC-ICH also includes the effects of aging, the level of anticoagulation, genetic factors, and a high prevalence of concurrent cerebrovascular conditions, such as cerebral amyloid angiopathy, leukoaraiosis or previous strokes. The treatment of OAC-ICH is challenging and involves rapid reversal of anticoagulation with hemostatic drug therapies such as vitamin K, fresh frozen plasma, prothrombin complex concentrates or recombinant factor VIIa. These therapies may not always be sufficient to stabilize the patient's clinical condition and lacking randomized controlled trials, the best hematological approach to reverse oral anticoagulation is debated. Other difficult decisions reviewed in this article are whether anticoagulation should be restarted after OAC-ICH, and when anticoagulant treatment should be resumed. The newer oral anticoagulants, which are increasingly being introduced for thromboembolism prevention, may confer a lower risk of intracranial bleeding than warfarin, although they do not have an antidote and their anticoagulant effect is difficult to monitor.

Topics: Administration, Oral; Anticoagulants; Cerebral Hemorrhage; Humans; Incidence; Warfarin

Intracerebral hemorrhage in patients with warfarin-associated coagulopathy is an increasingly common life-threatening condition that requires emergent management. The evolution of therapeutic options in this setting, as well as recently published guidelines, has resulted in some heterogeneity in recommendations by professional societies. This heterogeneity can be attributed to lack of evidence-based support for plasma therapy; the variability in availability of prothrombin complex concentrates; the variability in the coagulation factor levels and contents of prothrombin complex concentrates; ambiguity about the optimal dose and route of administration of vitamin K; and the lack of standardized clinical care pathways, particularly in community hospitals, for the management of these critical care patients. In this review, we summarize the relevant literature about these controversies and present recommendations for management of patients with warfarin-associated coagulopathy and intracerebral hemorrhage.

Topics: Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Cerebral Hemorrhage; Female; Humans; Male; Vitamin K; Warfarin

Cerebral microbleeds (MB) are potential risk factors for intracerebral hemorrhage (ICH), but it is unclear if they are a contraindication to using antithrombotic drugs. Insights could be gained by pooling data on MB frequency stratified by antithrombotic use in cohorts with ICH and ischemic stroke (IS)/transient ischemic attack (TIA).. We performed a systematic review of published and unpublished data from cohorts with stroke or TIA to compare the presence of MB in: (1) antithrombotic users vs nonantithrombotic users with ICH; (2) antithrombotic users vs nonusers with IS/TIA; and (3) ICH vs ischemic events stratified by antithrombotic use. We also analyzed published and unpublished follow-up data to determine the risk of ICH in antithrombotic users with MB.. In a pooled analysis of 1460 ICH and 3817 IS/TIA, MB were more frequent in ICH vs IS/TIA in all treatment groups, but the excess increased from 2.8 (odds ratio; range, 2.3-3.5) in nonantithrombotic users to 5.7 (range, 3.4-9.7) in antiplatelet users and 8.0 (range, 3.5-17.8) in warfarin users (P difference=0.01). There was also an excess of MB in warfarin users vs nonusers with ICH (OR, 2.7; 95% CI, 1.6-4.4; P<0.001) but none in warfarin users with IS/TIA (OR, 1.3; 95% CI, 0.9-1.7; P=0.33; P difference=0.01). There was a smaller excess of MB in antiplatelet users vs nonusers with ICH (OR, 1.7; 95% CI, 1.3-2.3; P<0.001), but findings were similar for antiplatelet users with IS/TIA (OR, 1.4; 95% CI, 1.2-1.7; P<0.001; P difference=0.25). In pooled follow-up data for 768 antithrombotic users, presence of MB at baseline was associated with a substantially increased risk of subsequent ICH (OR, 12.1; 95% CI, 3.4-42.5; P<0.001).. The excess of MB in warfarin users with ICH compared to other groups suggests that MB increase the risk of warfarin-associated ICH. Limited prospective data corroborate these findings, but larger prospective studies are urgently required.

Topics: Anticoagulants; Brain Ischemia; Cerebral Hemorrhage; Female; Fibrinolytic Agents; Humans; Male; Risk Factors; Stroke; Warfarin

Topics: Aged; Anticoagulants; Cerebral Hemorrhage; Craniocerebral Trauma; Evidence-Based Emergency Medicine; Female; Humans; International Normalized Ratio; Patient Discharge; Risk Assessment; Warfarin; Watchful Waiting

Topics: Anticoagulants; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Chronic Disease; Dabigatran; Humans; Pyrazoles; Pyridones; Recurrence; Risk Assessment; Venous Thromboembolism; Warfarin

Therapeutic anticoagulation with heparins, warfarin, and anti-Xa inhibitors carry an inherent risk of complications due to their multifaceted pharmacokinetic and pharmacodynamic properties as well as narrow therapeutic ranges. When an anticoagulated patient presents with a major or life-threatening bleed, immediate and effective therapy may be necessary to reverse the effects of the anticoagulant, minimize blood loss, and reduce patient morbidity and mortality. Optimal agents and strategies for anticoagulant reversal are limited, particularly for newer anticoagulants. The literature describing such strategies available to reverse the effects of anticoagulants in the setting of a bleed is limited, and therefore many controversies exist. Thus, as new anticoagulants become available, without a specific agent for reversal, the concerns and controversies related to this topic must be addressed. The purpose of this review is to discuss the management of major or life-threatening bleeds by addressing the following controversies: (1) the use of recombinant factor VIIa for rapid reversal of warfarin in patients with intracerebral hemorrhage, (2) the role of prothrombin complex concentrate in emergent warfarin reversal, and (3) the optimal approach to reverse newer anticoagulants such as low molecular weight heparins, fondaparinux, and direct thrombin inhibitors.

Topics: Adult; Anticoagulants; Cerebral Hemorrhage; Coagulants; Disease Progression; Factor VIIa; Female; Hemorrhage; Humans; Male; Recombinant Proteins; Warfarin

Warfarin is the most commonly used oral anticoagulant. Intracranial hemorrhage is the most serious complication of anticoagulation and the anticoagulant effect of warfarin has to be urgently reversed in this situation. Traditional methods of reversal of the anticoagulant effect of warfarin involving the use of vitamin K and fresh frozen plasma are slow and relatively ineffective and there is a need for alternative treatment approaches.. Agents such as prothrombin complex conjugates and recombinant activated factor VII are being increasingly used to emergently correct warfarin-associated coagulopathy. Over the last decade, several small case series have suggested that these agents may lead to more rapid correction of the INR, however, improved clinical outcome is yet to be proven. A recent small prospective trial has also demonstrated the safety of a prothrombin complex conjugate and its efficacy in rapidly correcting an elevated INR in these patients.. There is a need for well designed randomized clinical trials aimed at evaluating the efficacy of these agents in improving the outcome of patients with anticoagulant associated intracranial hemorrhage.

Topics: Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Disseminated Intravascular Coagulation; Factor VIIa; Humans; Plasma; Vitamin K; Vitamins; Warfarin

Intracerebral hemorrhage (ICH) is the most serious complication of oral anticoagulant therapy (OAT), with mortality in excess of 50%. Major risk factors are advanced patient age, elevated systolic blood pressure, intensity of anticoagulation, and previous cerebral ischemia. A number of acute treatments are available, but all have significant side effects and no randomized clinical trials assessing clinical outcome have been performed. Future trials will have to address choice and dose of agent, the timing of its administration, and the risk of side effects.

Topics: Age Factors; Aged; Anticoagulants; Cerebral Arteries; Cerebral Hemorrhage; Coagulants; Dose-Response Relationship, Drug; Early Diagnosis; Humans; Risk Factors; Warfarin

Clinical trials during the past 20 years have revolutionized the antithrombotic management of atrial fibrillation. Based on consideration of 30 randomized trials involving 29,017 participants, adjusted-dose warfarin remains the most efficacious prophylaxis against stroke for atrial fibrillation patients at moderate-to-high risk (compared with antiplatelet agents, warfarin reduces stroke by about 40%). The optimal INR for prevention of stroke for most atrial fibrillation patients is probably 2.0-2.5; INRs of 1.6-1.9 provide substantial protection, 80-90% of that afforded by higher intensities. Warfarin-associated intracerebral hemorrhage is an increasing problem as more elderly patients with atrial fibrillation are anticoagulated. Modest reductions in blood pressure results in large decreases in this most dreaded complication of warfarin; anticoagulation of elderly atrial fibrillation patients should be accompanied by a firm commitment to control hypertension. Warfarin-associated intracerebral hemorrhage has a 50% early mortality. A wide range of acute treatments to urgently reverse anticoagulation have been recommended by experts, but prevention is a far better option than treatment of this devastating problem.

Topics: Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Humans; Hypertension; Stroke; Warfarin

Anticoagulant-associated intracerebral hemorrhage (ICH) is a devastating disease, causing death in half of patients and permanent disability in the majority of survivors. The finding that patients often continue bleeding after hospital presentation offers the possibility that emergency warfarin reversal may improve outcomes. As no clinical trials have demonstrated the superiority of any one treatment strategy, various treatment options are available. Intravenous vitamin K is the definitive therapy; however, as monotherapy it can require many hours to take effect. Therefore, it is often considered an adjunct agent. Coagulation factors can be repleted with fresh frozen plasma (FFP), which is widely available and relatively low cost, but can require substantial time to deliver in real-world settings. A number of coagulation factor products collectively termed prothrombin complex concentrates (PCCs) are widely available that can rapidly provide many or all the vitamin K-dependent coagulation factors. Recombinant activated factor VII is used in many centers for this purpose, as it is thought to provide a procoagulant effect that may compensate for the lack of the other critical factors. Until clinical trials demonstrate the superiority of any one means of warfarin reversal, a number of expert guidelines from national organizations are available to help local providers guide therapy. At our institution, we have focused on improving the rapid and reliable delivery of a combination of intravenous vitamin K and FFP, with continued re-dosing until the desired INR lowering is achieved.

Topics: Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Factors; Cerebral Hemorrhage; Drug Interactions; Humans; Plasma; Practice Guidelines as Topic; Vitamin K; Warfarin

Warfarin-related intracerebral hemorrhage (WICH) is a medical and neurosurgical emergency with a 1-month mortality of approximately 50%. Warfarin is commonly is used in patients with atrial fibrillation to prevent ischemic stroke and to prevent progression of deep vein thrombosis to pulmonary embolism. Owing to the ageing population, and increased incidence of atrial fibrillation with age and warfarin use, the incidence of WICH is expected to rise in the future. When WICH occurs, immediate discontinuation of warfarin with rapid warfarin reversal remains the first-line intervention, often with neurosurgical intervention. The optimal agent for rapid warfarin anticoagulation reversal remains to be defined owing to the lack of prospective randomized trials. We review current literature and prospects for future research for this devastating neurologic emergency.

Topics: Animals; Anticoagulants; Cerebral Hemorrhage; Disease Management; Drug Interactions; Humans; International Normalized Ratio; Plant Preparations; Warfarin

We describe a 58-year old female patient with rapid development of arterial and venous thromboembolisms, including deep vein thrombosis (DVT) in the lower limbs, recurrent cerebral infarctions and bilateral pulmonary emboli. Her laboratory data on admission showed positive anticardiolipin antibody of IgG isotype (IgG aCL) and positive anti-beta2 glycoprotein-I antibody of IgG isotype (IgG abeta2-GPI), and decreased protein C activity and protein S antigen. Systemic examinations revealed the presence of an ovarian cancer. Surgical resection was attempted, but her cancer infiltrated the pelvic wall and could not be resected. Despite treatment with unfractionated heparin followed by warfarin, she died due to recurrent episodes of cerebral infarction. This case was considered as probable catastrophic antiphospholipid syndrome (CAPS), which might be associated with ovarian cancer. Known as Trousseau's syndrome, arterial and, more commonly, venous thrombosis is a frequent complication of cancer and sometimes a harbinger of occult cancer. Our case indicates that there is an overlap between antiphospholipid syndrome (APS) and Trousseau's syndrome. It is important to bear in mind that a thrombotic event associated with cancer can be the first manifestation of CAPS.

Topics: Adenocarcinoma, Clear Cell; Adolescent; Adult; Aged; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Antiphospholipid Syndrome; Carboplatin; Cerebral Hemorrhage; Cerebral Infarction; Docetaxel; Fatal Outcome; Female; Humans; Male; Middle Aged; Neoplasms; Neoplasms, Unknown Primary; Ovarian Neoplasms; Palliative Care; Paraneoplastic Syndromes; Protein C Deficiency; Protein S Deficiency; Pulmonary Embolism; Taxoids; Thrombophilia; Thrombophlebitis; Warfarin

Wider use of oral anticoagulants has led to an increasing frequency of warfarin-related intracerebral hemorrhage (ICH). The high early mortality of approximately 50% has remained stable in recent decades. In contrast to spontaneous ICH, the duration of bleeding is 12 to 24 hours in many patients, offering a longer opportunity for intervention. Treatment varies widely, and optimal therapy has yet to be defined. An OVID search was conducted from January 1996 to January 2006, combining the terms warfarin or anticoagulation with intracranial hemorrhage or intracerebral hemorrhage. Seven experts on clinical stroke, neurologic intensive care, and hematology were provided with the available information and were asked to independently address 3 clinical scenarios about acute reversal and resumption of anticoagulation in the setting of warfarin-associated ICH. No randomized trials assessing clinical outcomes were found on management of warfarin-associated ICH. All experts agreed that anticoagulation should be urgently reversed, but how to achieve it varied from use of prothrombin complex concentrates only (3 experts) to recombinant factor VIIa only (2 experts) to recombinant factor VIIa along with fresh frozen plasma (1 expert) and prothrombin complex concentrates or fresh frozen plasma (1 expert). All experts favored resumption of warfarin therapy within 3 to 10 days of ICH in stable patients in whom subsequent anticoagulation is mandatory. No general agreement occurred regarding subsequent anticoagulation of patients with atrial fibrillation who survived warfarin-associated ICH. For warfarin-associated ICH, discontinuing warfarin therapy with administration of vitamin K does not reverse the hemostatic defect for many hours and is inadequate. Reasonable management based on expert opinion includes a wide range of additional measures to reverse anticoagulation in the absence of solid evidence.

Topics: Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Factor VII; Factor VIIa; Humans; Hypertension; Iatrogenic Disease; Plasma; Recombinant Proteins; Warfarin

Intracerebral hemorrhage (ICH), which comprises 15 percent to 30 percent of all strokes, has an estimated incidence of 37,000 cases per year. One third of patients are actively bleeding when they present to the emergency department, and hematoma growth during the first hours after ICH onset is thought to be a prime determinant of clinical deterioration. Inflammation, as opposed to ischemia, also negatively affects patient condition. Recombinant activated factor VII is emerging as a potential first-line therapy, especially in warfarin-associated hemorrhage. Corticosteroid therapy is not supported by contemporary studies or by current management guidelines. Aggressive blood pressure reduction is under investigation. Surgical intervention has shown no statistically significant benefit over medical management for patients with ICH in general, although subgroup analysis in a large randomized trial suggested potential benefits from surgery for patients with lobar ICH. Not long ago, ICH was considered virtually untreatable. Diligent efforts in both bench and clinical research are generating hope for patients who experience this catastrophic event.

Topics: Anticoagulants; Blood Pressure; Cerebral Hemorrhage; Coagulants; Factor VII; Factor VIIa; Humans; Recombinant Proteins; Stroke; Warfarin

Elderly patients as a group may present more of a challenge in managing warfarin therapy because of alterations in pharmacokinetics from other medications, diet, and disease; pharmacodynamic changes; increased risk for hemorrhage; and difficulty in monitoring. The elderly, however, may derive the most benefit from warfarin therapy for certain indications, such as the prevention of stroke in atrial fibrillation or recurrent events following deep venous thrombosis. Warfarin can be managed as effectively as in other populations with careful attention to these issues.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Gastrointestinal Hemorrhage; Geriatric Assessment; Humans; Male; Maximum Tolerated Dose; Monitoring, Physiologic; Prothrombin Time; Risk Assessment; Treatment Outcome; Warfarin

The management of spontaneous intracerebral haemorrhage (ICH) can be challenging for hospital doctors. Although the management of ICH is covered in stroke guidelines, many difficult clinical questions remain. In this article the authors suggest approaches to ten common and difficult questions.

Topics: Anticoagulants; Aspirin; Brain Ischemia; Cerebral Hemorrhage; Hospitalization; Humans; Magnetic Resonance Angiography; Medical Records; Myocardial Infarction; Neurosurgical Procedures; Patient Education as Topic; Patient Selection; Platelet Aggregation Inhibitors; Pulmonary Embolism; Referral and Consultation; Terminology as Topic; Venous Thrombosis; Warfarin

Approximately 7000 intracerebral hemorrhages (ICHs) annually in the US are caused by use of antithrombotic therapies. We review the incidence, risk factors, and predictors of ICH in patients receiving long-term anticoagulation or antiplatelet therapy.. ICH rates range from 0.3% to 0.6% per year during oral anticoagulation in recent reports. Major risk factors are advanced patient age, elevated blood pressure, intensity of anticoagulation, and previous cerebral ischemia. Combining antiplatelet agents with anticoagulation and the combined use of aspirin plus clopidogrel appear to increase ICH risk. Modest blood pressure-lowering halves the frequency of ICH during antiplatelet therapy.. ICH is an uncommon, but often fatal, complication of antithrombotic therapy that particularly afflicts patients with previous stroke. Recent data support that keeping international normalized ratio < or =3.0, control of hypertension, and avoiding the combination of aspirin with warfarin reduce its frequency.

Topics: Administration, Oral; Age Factors; Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Blood Pressure; Brain Ischemia; Cerebral Hemorrhage; Clinical Trials as Topic; Clopidogrel; Female; Fibrinolytic Agents; Humans; International Normalized Ratio; Male; Middle Aged; Platelet Aggregation Inhibitors; Risk Factors; Ticlopidine; Warfarin

Atrial fibrillation (AF) is now regarded as the arrhythmia for which patients are hospitalized the most frequently, an arrhythmia that is responsible for significant morbidity and mortality. Of particular importance is that the arrhythmia is associated with a significant incidence of thromboembolism which may induce disabling and incapacitating strokes, sometimes fatal. In the past, it was thought that in patients with AF restoration and maintenance of sinus rhythm prevent the development of strokes, a presumption that has not been vindicated by controlled clinical trials. On the other hand, over many decades, it has been established that appropriate anticoagulation especially with warfarin can reduce stroke rate in nonvalvular AF by about 70%, and mortality by 26%. Aspirin reduces stroke rate by 26%, mortality by about 10%. Thus, in AF oral anticoagulants have become the focal point of therapy for the prevention of strokes and the safety and efficacy of such a therapy has been established by controlled clinical trials; moreover, the subsets of patients with AF in whom anticoagulation is mandatory have been defined on the basis of defined risk factors. Warfarin is now the anticoagulant of choice although its limitations are considerable in terms of drug-drug interactions, narrow range of therapeutic index requiring strict monitoring of intensity of anticoagulation, among other limitations which influence compliance of therapy with the agent. In this review, the continuing role of warfarin in the prevention of stroke in patients with AF is discussed as a background for the development of newer anticoagulants. The issue is of particular importance in the older patients, in whom the development of safer antithrombotic therapies remain a major challenge. In this context, the potential role of the direct thrombin inhibitors hold promise for the future and the evolving data on leading compounds of this class which may be competitive with warfarin are discussed.

Topics: Aged; Ambulatory Care Facilities; Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Cerebral Hemorrhage; Drug Design; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Prospective Studies; Randomized Controlled Trials as Topic; Risk Factors; Self Care; Stroke; Thrombin; Warfarin

Ischemic stroke, a major complication of atrial fibrillation (AF), is believed to result from atrial thrombus formation caused by ineffective atrial contraction. Oral anticoagulant therapy effectively reduces the risk of ischemic stroke in patients with AF; this therapy is recommended for patients with any frequency or duration of AF and other risk factors for stroke, such as increased age (>75 years), hypertension, prior stroke, left ventricular dysfunction, diabetes, or heart failure. Recently published data comparing rate-control and rhythm-control strategies in AF emphasized the importance of maintaining an international normalized ratio higher than 2.0 during warfarin therapy and the need for continuing anticoagulant therapy to prevent stroke in high-risk patients, even if the strategy is rhythm control. Hemorrhagic complications can be minimized by stringent control of the international normalized ratio (particularly in elderly patients) and appropriate therapy for comorbidities such as hypertension, gastric ulcer, and early-stage cancers. Undertreatment of patients with AF is a continuing problem, particularly in the elderly population. Patients perceived as likely to be noncompliant, such as the functionally impaired, are less likely to receive warfarin therapy. However, stroke prevention with anticoagulants is cost-effective and improves quality of life, despite the challenges of maintaining appropriate anticoagulation with monitoring and warfarin dose titration. New medications in development with more predictable dosing and fewer drug-drug interactions may reduce the complexities of achieving optimal anticoagulation and increase the practicality of long-term anticoagulant therapy for patients with AF at risk of stroke.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Humans; Stroke; Warfarin

To elucidate predisposing factors for enlargement of intracerebral hematoma (ICH) during warfarin therapy, we reviewed 47 patients on warfarin who developed acute ICH and determined relationships among ICH enlargement, INR reversal and clinical data. Among 36 patients treated to counteract the effects of warfarin within 24 h of onset, ICH increased in 10 patients (enlarged group), but remained unchanged in the remaining 26 (unchanged group), while ICH remained unchanged in another 11 patients in whom the effect of warfarin was reversed after 24 h. The international normalized ratio (INR) was counteracted immediately in 11 patients treated with prothrombin complex concentrate (PCC) but gradually in the other 36 treated by reducing the dose of warfarin, or by administering vitamin K or fresh frozen plasma. Multivariate analysis with a logistic regression model showed an INR value <2.0 at admission or for 24 h after immediate INR correction with PCC prevented ICH enlargement (OR 0.069, 95%CI 0.006-0.789, p = 0.031). An INR value of >2.0 within 24 h of ICH seems an important predisposing factor for ICH enlargement.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Comorbidity; Diabetes Mellitus; Disease Progression; Female; Humans; Hypercholesterolemia; Hypertension; International Normalized Ratio; Liver Diseases; Male; Middle Aged; Platelet Aggregation Inhibitors; Postoperative Complications; Retrospective Studies; Risk Factors; Tomography, X-Ray Computed; Vitamin K; Warfarin

To determine if anticoagulation therapy is effective for preventing progression of pediatric sinovenous thrombosis, to determine the safety of anticoagulation therapy in the pediatric population, and to outline risk factors and clinical presentation in the authors' population of patients with sinovenous thrombosis.. A retrospective chart review was conducted of 17 consecutive pediatric patients with sinovenous thrombosis at the authors' institution regardless of treatment option and outcome.. Fifteen children underwent anticoagulation therapy; two did not. Surgical intervention was undertaken in two patients. None of the children died. None had recurrence after anticoagulation was initiated. Of the patients who had follow-up studies performed, 33% had some resolution of the clot, 60% had complete resolution, and 13% had no change. Both children who did not undergo anticoagulation therapy had resolution of the thrombus. All of the children had improvement of their symptoms at presentation. No patient had worsening of radiologic findings during the follow-up period.. Anticoagulation therapy did not result in bleeding complications. Fifteen of 17 patients were safely anticoagulated. All children had improvement of their presenting symptoms. There was no worsening of radiologic findings in any patient, and there was improvement in 13 patients. One patient has long-term neurologic sequelae (a learning disability). This patient underwent extensive surgeries for subdural and epidural empyemas.

Topics: Anticoagulants; Brain Damage, Chronic; Cerebral Hemorrhage; Child; Child, Preschool; Cohort Studies; Combined Modality Therapy; Comorbidity; Drug Evaluation; Female; Heparin; Heparin, Low-Molecular-Weight; Humans; Infant; Infant, Newborn; Male; Retrospective Studies; Risk Factors; Safety; Seizures; Sinus Thrombosis, Intracranial; Treatment Outcome; Virginia; Warfarin

Oral anticoagulant therapy is very effective in preventing thromboembolism. Its major complication is hemorrhage. The rate of intracranial bleeding from randomized trials and observational studies ranges from 0.1 to 0.9% per year and largely depends on the International Normalized Ratio (INR) target range. Risk factors for this often-fatal complication include INR intensity, older age, cerebrovascular disease, and hypertension. Recent insights into the pathogenesis of intracerebral hemorrhage have focused on underlying arterial vasculopathies that predispose to bleeding, particularly in the elderly. The rate of major extracranial hemorrhage on oral anticoagulant therapy ranges from 0.4 to 2% per year. Different definitions of major hemorrhage, INR target ranges, age distribution, burden of comorbid illness, and type of coumarin challenge comparability of studies. Additional risk factors for major hemorrhage include history of gastrointestinal bleeding, concurrent use of antiplatelet or nonsteroidal anti-inflammatory drugs, genetic differences in warfarin metabolism, INR variability, type of coumarin, comorbid illnesses, and duration of oral anticoagulant therapy.

Topics: Administration, Oral; Anticoagulants; Cerebral Hemorrhage; Hemorrhage; Humans; Risk Factors; Warfarin

Topics: Aspirin; Atrial Fibrillation; Cerebral Hemorrhage; Cerebrovascular Disorders; Electric Countershock; Fibrinolytic Agents; Humans; Risk Factors; Warfarin

In comparison with the incidence of cerebrovascular accident in the general population, atrial fibrillation increases the risk by a factor of five. Although age is without doubt the main risk factor for cerebrovascular accidents in patients with permanent of paroxysmal non-valvular atrial fibrillation, other independent risk factors have been identified: a previous history of hypertension, cerebrovascular accident, heart failure or diabetes. These factors enable identification of a population at risk in which oral anticoagulation may be recommended with an excellent efficacy/risk ratio. Six large scale randomised controlled multicenter trials of primary prevention have been published with a total of over 2,800 patients with non-valvular atrial fibrillation. The combined results of these trials show that treatment with vitamin K antagonist (INR 2-3) leads to a significant reduction in the risk of an ischaemic cerebrovascular accident of 64% (95% CI [51-74]; p < 0.001) and in the risk of death from all causes of 28% (95% CI [12-47]; p = 0.038) with a slight increase in the risk of cerebral haemorrhage (+ 2.7% NS). Although the benefits of aspirin therapy are not as impressive (reduction of the risk of an ischaemic cerebrovascular accident of 22%; 95% CI [0-39]; p = 0.053), this alternative may be proposed in patients under 75 years of age without the previously mentioned risk factors. The value of combined aspirin-oral anticoagulant therapy, especially in high risk patients, has not yet been established and is under evaluation.

Topics: Adult; Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Cerebral Hemorrhage; Cerebrovascular Disorders; Humans; Middle Aged; Platelet Aggregation Inhibitors; Primary Prevention; Risk Factors; Treatment Outcome; Vitamin K; Warfarin

Warfarin is the standard anticoagulation therapy for valvular atrial fibrillation (AF); however, new oral anticoagulants have emerged as an alternative. We compared the efficacy and safety of dabigatran with conventional treatment in AF associated with left-sided valvular heart disease (VHD), including mitral stenosis (MS). Patients with AF and left-sided VHD were randomly assigned to receive dabigatran or conventional treatment. The primary end point was the occurrence of clinical stroke or a new brain lesion (silent brain infarct and microbleed) on 1-year follow-up brain magnetic resonance imaging. Patients in the dabigatran group were switched from warfarin (n = 52), antiplatelets alone (n = 5), or no therapy (n = 2) to dabigatran. In the conventional group, 53 used warfarin (including 42 MS patients), and 7 used antiplatelets. No death or clinical stroke event occurred in either group during follow-up. Silent brain infarct and microbleed occurred in 20 and 2 patients in the dabigatran group and 20 and 4 patients in the conventional treatment group. The incidence rate of the primary end point did not significantly differ between groups (34% vs 40%, relative risk 0.87, 95% confidence interval 0.59 to 1.29, p = 0.491). The primary end point rate was similar between groups in 82 patients (40 in the dabigatran group and 42 in the conventional group) with MS (32% vs 34%, relative risk 0.93, 95% confidence interval: 0.57 to 1.50, p = 0.759). In conclusion, primary end point rates after treatment with dabigatran were similar to conventional treatment in patients with significant VHD and AF. New oral anticoagulants could be a reasonable alternative to warfarin in patients with AF and VHD, which should be confirmed in future large-scale studies.

Topics: Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Dabigatran; Heart Valve Diseases; Humans; Stroke; Treatment Outcome; Warfarin

We determined associations of physiological abnormalities (systolic blood pressure, glucose, and body temperature) and warfarin use with outcomes in spontaneous intracerebral hemorrhage.. Post hoc analyses of INTERACT2 (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial) comparing systolic blood pressure control (<140 versus <180 mm Hg) in 2839 hypertensive patients with intracerebral hemorrhage (onset <6 hours). Multivariable logistic regression defined associations of baseline scores assigned as 0 to 6 per 10 mm Hg systolic blood pressure increase (range, 150-220 mm Hg) and 0 or 1 for serum glucose (≤6.5 versus >6.5 mmol/L), body temperature (≤37.5 °C versus >37.5 °C), and warfarin use (no versus yes) and death or major disability (modified Rankin Scale scores 3-6 at 90 days).. Baseline score distribution was 0 (7.7%), 1 (15.6%), 2 (19.0%), 3 (19.1%), 4 (15.2%), 5 (11.6%), 6 (8.9%), and 7 (2.9%). After adjustment for baseline neurological severity and potential confounders, significant linear associations were evident for increasing (per point) score and death or major disability (odds ratio, 1.12 [95% CI, 1.07-1.17]), death (odds ratio, 1.15 [95% CI, 1.07-1.23]), and major disability (odds ratio, 1.10 [95% CI, 1.05-1.15]).. Combination of abnormal physiological parameters and warfarin use is associated with poor outcomes in intracerebral hemorrhage. Effects of their early control is under investigation in INTERACT3 (Intensive Care Bundle With Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial). Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00716079.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Glucose; Blood Pressure; Body Temperature; Cerebral Hemorrhage; Disability Evaluation; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Prognosis; Treatment Outcome; Warfarin

Intracerebral hemorrhage (ICH) patients commonly have concomitant white matter lesions (WML) which may be associated with poor outcome. We studied if WML affects hematoma expansion (HE) and post-stroke functional outcome in a post hoc analysis of patients from randomized controlled trials.. In ICH patients from the clinical trials MISTIE II and CLEAR III, WML grade on diagnostic computed tomography (dCT) scan (dCT, < 24 h after ictus) was assessed using the van Swieten scale (vSS, range 0-4). The primary outcome for HE was > 33% or > 6 mL ICH volume increase from dCT to the last pre-randomization CT (< 72 h of dCT). Secondary HE outcomes were: absolute ICH expansion, > 10.4 mL total clot volume increase, and a subgroup analysis including patients with dCT < 6 h after ictus using the primary HE definition of > 33% or > 6 mL ICH volume increase. Poor functional outcome was assessed at 180 days and defined as modified Rankin Scale (mRS) ≥ 4, with ordinal mRS as a secondary endpoint.. Of 635 patients, 55% had WML grade 1-4 at dCT (median 2.2 h from ictus) and 13% had subsequent HE. WML at dCT did not increase the odds for primary or secondary HE endpoints (P ≥ 0.05) after adjustment for ICH volume, intraventricular hemorrhage volume, warfarin/INR > 1.5, ictus to dCT time in hours, age, diabetes mellitus, and thalamic ICH location. WML increased the odds for having poor functional outcome (mRS ≥ 4) in univariate analyses (vSS 4; OR 4.16; 95% CI 2.54-6.83; P < 0.001) which persisted in multivariable analyses after adjustment for HE and other outcome risk factors.. Concomitant WML does not increase the odds for HE in patients with ICH but increases the odds for poor functional outcome.. http://www.clinicaltrials.gov trial-identifiers: NCT00224770 and NCT00784134.

Topics: Cerebral Hemorrhage; Hematoma; Humans; Risk Factors; Warfarin; White Matter

The aim of this study is to examine the relationship between time in the therapeutic range (TTR) and clinical outcomes in heart failure patients in sinus rhythm treated with warfarin.. We used data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial to assess the relationship of TTR with the WARCEF primary outcome (ischemic stroke, intracerebral hemorrhage, or death), with death alone, ischemic stroke alone, major hemorrhage alone, and net clinical benefit (primary outcome and major hemorrhage combined). Multivariable Cox models were used to examine how the event risk changed with TTR and to compare the high TTR, low TTR, and aspirin-treated patients, with TTR being treated as a time-dependent covariate. A total of 2217 patients were included in the analyses; among whom 1067 were randomized to warfarin and 1150 were randomized to aspirin. The median (interquartile range) follow-up duration was 3.6 (2.0-5.0) years. Mean (±SD) age was 61±11.3 years, with 80% being men. The mean (±SD) TTR was 57% (±28.5%). Increasing TTR was significantly associated with reduction in primary outcome (adjusted P<0.001), death alone (adjusted P=0.001), and improved net clinical benefit (adjusted P<0.001). A similar trend was observed for the other 2 outcomes, but significance was not reached (adjusted P=0.082 for ischemic stroke and adjusted P=0.109 for major hemorrhage).. In patients with heart failure in sinus rhythm, increasing TTR is associated with better outcome and improved net clinical benefit. Patients in whom good quality anticoagulation can be achieved may benefit from the use of anticoagulants.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00041938.

Topics: Aged; Anticoagulants; Aspirin; Brain Ischemia; Cerebral Hemorrhage; Chi-Square Distribution; Double-Blind Method; Drug Monitoring; Female; Heart Failure; Heart Rate; Humans; Male; Middle Aged; Multivariate Analysis; Platelet Aggregation Inhibitors; Predictive Value of Tests; Proportional Hazards Models; Risk Factors; Stroke; Stroke Volume; Time Factors; Treatment Outcome; Ventricular Function, Left; Warfarin

Anticoagulants are widely used to prevent recurrence of ischemic stroke in patients with nonvalvular atrial fibrillation, but in some patients, they also cause bleeding, particularly intracranial hemorrhage. One of the independent predictors of intracerebral hemorrhage is the presence of cerebral microbleeds (CMBs); a high incidence of intracerebral hemorrhage is reported in warfarin-treated patients with multiple CMBs. Longitudinal study suggested that the presence of CMBs at baseline is a predictor of new CMBs in warfarin-treated patients. However, there has been no study on the progression of CMBs in patients receiving the non-vitamin K antagonist oral anticoagulants (NOACs).. This study tests the hypothesis that the incidence of hemorrhagic stroke is lower in patients receiving NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) than in those receiving warfarin, and this difference reflects the difference in the effects of warfarin and NOACs on the progression of CMBs.. We will enroll 200 patients with at least 1 CMB detected by 1.5 T magnetic resonance imaging (T2(∗)-weighted imaging) at baseline and who have received NOACs or warfarin for at least 12 months. Primary end point is the proportion of subjects with an increased number of CMBs at month 12 of treatment with NOACs or warfarin. If the results of this study support the efficacy of NOACs for preventing increase of CMBs, this would be of great interest to domestic and overseas clinicians, in view of the potential therapeutic impact, including that on primary prevention of ischemic stroke.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Pilot Projects; Stroke; Treatment Outcome; Warfarin

Because patients with warfarin-associated intracerebral hemorrhage (WAICH) have a high risk of ongoing bleeding, disability, and death, urgent coagulopathy reversal should be considered. On the other hand, thromboembolism may occur with reversal or withholding of anticoagulant therapy. The current status of acute hemostatic treatments and clinical outcomes in WAICH patients was investigated.. WAICH patients admitted within 3 days of onset were prospectively enrolled in 10 stroke centers. Thromboembolic and hemorrhagic complications and functional outcomes were followed-up for one year.. Of 50 WAICH patients (31 men, 73 ± 9 years old) enrolled, all stopped warfarin on admission. Elevated prothrombin time-international normalized ratios (PT-INR) were normalized in 43 (86%). Anticoagulant therapy was resumed with intravenous full-dose unfractionated heparin followed by warfarin in 9 (18%), intravenous low-dose unfractionated heparin followed by warfarin in 14 (28%) and warfarin alone in 14 (28%) at a median of 2.5 (IQR 1.25-9), 4 (2-5.5) and 6 (3-11) days after onset, respectively, after emergent admission. Onset-to-admission time (per 1-hour increase; OR 0.55, 95% CI 0.19-0.84) was inversely associated with hematoma expansion. Anticoagulant therapy was resumed with intravenous full-dose unfractionated heparin in 9 (18%), low-dose heparin in 14 (28%) and warfarin alone in 14 (28%) at a median of 2.5, 4 and 6 days after onset, respectively. During one-year follow-up (n=47), 11 thromboembolic and 6 hemorrhagic complications were documented. Twenty four patients showed unfavorable outcomes, corresponding to a modified Rankin Scale score of 4-6. Thromboembolic complications (OR, 10.62; 95% CI, 1.05-227.85), as well as advanced age (per 1 year; OR, 1.27; 95% CI, 1.10-1.61) and higher National Institutes of Health Stroke Scale (NIHSS) score (per 1 point; OR, 1.24; 95% CI 1.07-1.55), were independently associated with unfavorable outcome.. PT-INR normalization on admission and early anticoagulant resumption were common in WAICH patients. Thromboembolic complications were independently associated with unfavorable outcome.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Cohort Studies; Female; Hematoma; Humans; Male; Middle Aged; Observation; Tomography, X-Ray Computed; Treatment Outcome; Warfarin

Patients with intracerebral hemorrhage (ICH) who present with a spot sign on computed tomography angiography are at increased risk of hematoma expansion and poor outcome. Because primary ICH is the acute manifestation of chronic cerebral small vessel disease, we investigated whether different clinical or imaging characteristics predict spot sign presence, using ICH location as a surrogate for arteriolosclerosis- and cerebral amyloid angiopathy-related ICH.. Patients with primary ICH and available computed tomography angiography at presentation were included. Predictors of spot sign were assessed using uni- and multivariable regression, stratified by ICH location.. Seven hundred forty-one patients were eligible, 335 (45%) deep and 406 (55%) lobar ICH. At least one spot sign was present in 76 (23%) deep and 102 (25%) lobar ICH patients. In multivariable regression, warfarin (odds ratio [OR], 2.42; 95% confidence interval [CI], 1.01-5.71; P=0.04), baseline ICH volume (OR, 1.20; 95% CI, 1.09-1.33, per 10 mL increase; P<0.001), and time from symptom onset to computed tomography angiography (OR, 0.89; 95% CI, 0.80-0.96, per hour; P=0.009) were associated with the spot sign in deep ICH. Predictors of spot sign in lobar ICH were warfarin (OR, 3.95; 95% CI, 1.87-8.51; P<0.001) and baseline ICH volume (OR, 1.20; 95% CI, 1.10-1.31, per 10 mL increase; P<0.001).. The most potent associations with spot sign are shared between deep and lobar ICH, suggesting that the acute bleeding process that arises in the setting of different chronic small vessel diseases shares commonalities.

Topics: Anticoagulants; Cerebral Angiography; Cerebral Hemorrhage; Female; Humans; Male; Risk Factors; Tomography, X-Ray Computed; Warfarin

The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference in the primary outcome between warfarin and aspirin in 2305 patients with reduced left ventricular ejection fraction in sinus rhythm. However, it is unknown whether any subgroups benefit from warfarin or aspirin.. We used a Cox model stepwise selection procedure to identify subgroups that may benefit from warfarin or aspirin on the WARCEF primary outcome. A secondary analysis added major hemorrhage to the outcome. The primary efficacy outcome was time to the first to occur of ischemic stroke, intracerebral hemorrhage, or death. Only age group was a significant treatment effect modifier (P for interaction, 0.003). Younger patients benefited from warfarin over aspirin on the primary outcome (4.81 versus 6.76 events per 100 patient-years: hazard ratio, 0.63; 95% confidence interval, 0.48-0.84; P=0.001). In older patients, therapies did not differ (9.91 versus 9.01 events per 100 patient-years: hazard ratio, 1.09; 95% confidence interval, 0.88-1.35; P=0.44). With major hemorrhage added, in younger patients the event rate remained lower for warfarin than aspirin (5.41 versus 7.25 per 100 patient-years: hazard ratio, 0.68; 95% confidence interval, 0.52-0.89; P=0.005), but in older patients it became significantly higher for warfarin (11.80 versus 9.35 per 100 patient-years: hazard ratio, 1.25; 95% confidence interval, 1.02-1.53; P=0.03).. In patients <60 years, warfarin improved outcomes over aspirin with or without inclusion of major hemorrhage. In patients ≥60 years, there was no treatment difference, but the aspirin group had significantly better outcomes when major hemorrhage was included.

Topics: Adult; Age Factors; Aged; Anticoagulants; Aspirin; Brain Ischemia; Cerebral Hemorrhage; Double-Blind Method; Female; Heart Failure; Heart Rate; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Proportional Hazards Models; Risk Factors; Stroke; Stroke Volume; Time Factors; Treatment Outcome; Ventricular Function, Left; Warfarin

It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm.. We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause.. The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P=0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P=0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P=0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P=0.82).. Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized. (Funded by the National Institute of Neurological Disorders and Stroke; WARCEF ClinicalTrials.gov number, NCT00041938.).

Topics: Aged; Anticoagulants; Aspirin; Brain Ischemia; Cerebral Hemorrhage; Double-Blind Method; Female; Follow-Up Studies; Heart Failure; Hemorrhage; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Risk; Stroke; Stroke Volume; Treatment Outcome; Warfarin

Apixaban reduces stroke with comparable bleeding risks when compared with aspirin in patients with atrial fibrillation who are unsuitable for vitamin k antagonist therapy. This analysis explores patterns of bleeding and defines bleeding risks based on stroke risk with apixaban and aspirin.. The Apixaban versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin k Antagonist Treatment (AVERROES) trial randomized 5599 patients with atrial fibrillation and risk factors to receive either apixaban or aspirin. Bleeding events were defined as the first occurrence of either major bleeding or clinically relevant nonmajor bleeding.. The rate of a bleeding event was 3.8%/year with aspirin and 4.5%/year with apixaban (hazard ratio with apixaban, 1.18; 95% CI, 0.92-1.51; P=0.19). The anatomic site of bleeding did not differ between therapies. Risk factors for bleeding common to apixaban and aspirin were use of nonstudy aspirin>50% of the time and a history of daily/occasional nosebleeds. The rates of both stroke and bleeding increased with higher CHADS2 scores but apixaban compared with aspirin was associated with a similar relative risk of bleeding (P interaction 0.21) and a reduced relative risk of stroke (P interaction 0.37) irrespective of CHADS2 category.. Anatomic sites and predictors of bleeding are similar for apixaban and aspirin in these patients. Higher CHADS2 scores are associated with increasing rates of bleeding and stroke, but the balance between risks and benefits of apixaban compared with aspirin is favorable irrespective of baseline stroke risk. Clinical Trial Registration Information- www.clinicaltrials.gov. Unique identifier: NCT 00496769.

Topics: Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Brain Ischemia; Cerebral Hemorrhage; Contraindications; Female; Fibrinolytic Agents; Follow-Up Studies; Humans; Male; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Risk Factors; Stroke; Vitamin K; Warfarin

Concern exists that preadmission warfarin use may be associated with an increased risk of intracerebral hemorrhage in patients with ischemic stroke receiving intravenous tissue plasminogen activator, even in those with an international normalized ratio <1.7. However, evidence to date has been derived from a small single-center cohort of patients.. We used data from Phase 3 of the Registry of the Canadian Stroke Network. We compared the rates of post-tissue plasminogen activator hemorrhage, including any intracerebral hemorrhage, symptomatic intracerebral hemorrhage, and gastrointestinal hemorrhage in patients with and without preadmission warfarin use. For those receiving warfarin, we restricted the analysis to patients with an international normalized ratio <1.7 on presentation. Secondary outcomes included functional status and mortality. Multivariate analyses were performed to adjust for other prognostic factors.. Our cohort included 1739 patients with acute ischemic stroke treated with intravenous tissue plasminogen activator of whom 125 (7.2%) were receiving warfarin before admission and had an international normalized ratio <1.7. Preadmission warfarin use was not associated with any secondary intracerebral hemorrhage (OR, 1.2; 95% CI, 0.7 to 2.2), symptomatic intracerebral hemorrhage (OR, 1.1; 95% CI, 0.5 to 2.3), or gastrointestinal hemorrhage (OR, 1.1; 95% CI, 0.2 to 5.6). Multivariate analysis showed that preadmission warfarin use was independently associated with a reduced risk of poor functional outcome (OR, 0.6; 95 CI, 0.3 to 0.9), but not with in-hospital mortality (OR, 0.6; 95% CI, 0.3 to 1.0).. The results from the present study suggest that tissue plasminogen activator treatment appears to be safe in patients with acute ischemic stroke taking warfarin with an international normalized ratio <1.7 and may reduce the risk of poor functional outcome.

Topics: Aged; Aged, 80 and over; Anticoagulants; Brain Ischemia; Cerebral Hemorrhage; Cohort Studies; Drug Synergism; Drug Therapy, Combination; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Prospective Studies; Stroke; Tissue Plasminogen Activator; Warfarin

Warfarin use has rapidly increased with the aging of the population. We investigated the temporal trends in the incidence and outcome of warfarin-related intracerebral hemorrhages (ICHs) in a defined population.. We identified all subjects with first-ever primary ICH during 1993 to 2008 among the population of Northern Ostrobothnia, Finland. The number of warfarin users was obtained from the national register of prescribed medicines kept by the Social Insurance Institution of Finland. We calculated the annual incidence of warfarin-related ICHs, 28-day case fatality, and deaths from the primary bleed.. The proportion of warfarin users among the population increased 3.6-fold from 0.68% in 1993 to 2.28% in 2008. Of a total of 982 patients with ICH, 182 (18.5%) had warfarin-related ICH. One-year survival rate after onset of stroke was 35.2% among warfarin users and 67.9% among nonusers. The annual incidence (P=0.062) and 28-day case fatality of warfarin-related ICHs (P=0.002) decreased during the observation period. Warfarin users were older (mean difference 6.6; 95% CI, 5.0 to 8.1; P<0.001) than nonusers. Admission international normalized ratio values above the therapeutic range (2.0 to 3.0) decreased through the observation period, suggesting improved control of anticoagulant therapy over time.. The annual incidence and case fatality of warfarin-related ICHs decreased, although the proportion of warfarin users almost quadrupled in our population.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Finland; Humans; Incidence; International Normalized Ratio; Male; Middle Aged; Registries; Retrospective Studies; Warfarin

Published data suggest that patients with cerebral ischaemia and atrial fibrillation (CIAF) have higher inhospital mortality than patients with cerebral ischaemia of arterial origin (CIAO). Data on long term risks are scarce. We compared the long term risks of death and vascular events (VE) between these groups.. We extended the follow-up of 2473 patients from the Dutch TIA Trial (recruitment March 1986 to March 1989, all treated with aspirin; CIAO) and 186 Dutch participants of the European Atrial Fibrillation Trial (recruitment June 1988 to May 1992, 26% on anticoagulants during the trial; CIAF). Hazard ratios (HRs) for death and VE of CIAF versus CIAO were analysed by means of Cox regression analysis and adjusted for age, sex and several cardiovascular risk factors.. After a mean follow-up of 10.1 years, 1484 patients with CIAO had died and 1336 had suffered at least one VE (377 cardiac, 455 stroke). Mean follow-up of the CIAF patients was 6.8 years; 150 patients had died and 136 had suffered at least one VE (41 cardiac, 63 stroke). Adjusted HRs (CIAF vs CIAO) were 1.46 (95% CI 1.22 to 1.74) for death, 1.49 (1.24 to 1.79) for first VE, 1.94 (1.47 to 2.55) for first stroke and 1.41 (1.01 to 1.96) for first cardiac event. These HRs were essentially the same as those for the duration of the trials.. Our study shows that the long term risk of death or vascular events is 1.5 times higher in patients with CIAF than in those with CIAO, after adjustment for differences between the groups.

Topics: Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Cause of Death; Cerebral Hemorrhage; Cerebral Infarction; Cohort Studies; Death, Sudden, Cardiac; Disease-Free Survival; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Heart Failure; Hospital Mortality; Humans; Ischemic Attack, Transient; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Netherlands; Proportional Hazards Models; Risk Factors; Warfarin

In ACTIVE-W, oral anticoagulation (OAC) was more efficacious than combined clopidogrel plus aspirin (C+A) in preventing vascular events in patients with atrial fibrillation. However, because OAC carries important bleeding complications, risk stratification schemes have been devised to identify patients for whom the absolute benefits of OAC exceed its risks.. Participants were risk-stratified with the widely-used CHADS(2) scheme. Treatment-specific rates of stroke and major bleeding were calculated for patients with a CHADS(2)=1 and compared to those with a CHADS(2)>1.. Observed stroke rates for those with a CHADS(2)=1 were 1.25% per year on C+A and 0.43% per year on OAC (RR=2.96, 95% CI: 1.26 to 6.98, P=0.01). Among patients with a CHADS(2)>1, the stroke rates were 3.15% per year on C+A and 2.01% per year on OAC (RR=1.58, 95% CI: 1.11 to 2.24, P=0.01) (P for interaction between stroke risk category and efficacy of OAC=0.19). The risk of major bleeding during OAC was significantly lower among patients with CHADS(2)=1 (1.36% per year) compared with CHADS(2)>1 (2.75% per year) (RR=0.49, 95% CI 0.30 to 0.79, P=0.003).. In this clinical trial, patients with a CHADS(2)=1 had a low risk of stroke, yet still derived a modest (<1% per year) but statistically significant absolute reduction in stroke with OAC and had low rates of major hemorrhage on OAC.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Anticoagulants; Aspirin; Atrial Fibrillation; Biphenyl Compounds; Cerebral Hemorrhage; Clinical Protocols; Clopidogrel; Drug Combinations; Drug Therapy, Combination; Female; Humans; Irbesartan; Male; Middle Aged; Platelet Aggregation Inhibitors; Risk Assessment; Risk Factors; Stroke; Tetrazoles; Ticlopidine; Treatment Outcome; Warfarin

Although accumulating evidence suggests the presence of microbleeds as a risk factor for intracerebral hemorrhage (ICH), little is known about its significance in anticoagulated patients. The aim of this study was to determine whether the presence of microbleeds is associated with recurrent hemorrhagic stroke in patients who had received warfarin following atrial fibrillation-associated cardioembolic infarction.. A total of 87 consecutive patients with acute recurrent stroke, including 15 patients with ICH and 72 patients with cerebral infarction, were enrolled in this study. International normalized ratios (INRs), vascular risk factors, and imaging characteristics, including microbleeds on T2*-weighted MR images and white matter hyperintensity (WMH) on T2-weighted MR images, were compared in the 2 groups.. Microbleeds were noted more frequently in patients with ICH than in patients with cerebral infarction (86.7% versus 38.9%, P = .0007). The number of microbleeds was larger in patients with ICH than in patients with cerebral infarction (mean, 8.4 versus 2.1; P = .0001). INR was higher in patients with ICH than in patients with cerebral infarction (mean, 2.2 versus 1.4; P < .0001). The frequency of hypertension was higher in patients with ICH than in patients with cerebral infarction (86.7% versus 45.8%, P = .0039). Multivariate analysis revealed that the presence of cerebral microbleeds (odds ratio, 7.383; 95% confidence interval, 1.052-51.830) was associated with ICH independent of increased INR and hypertension.. The presence of cerebral microbleeds may be an independent risk factor for warfarin-related ICH, but more study is needed because of strong confounding associations with elevated INR and hypertension.

Topics: Aged; Anticoagulants; Brain Ischemia; Cerebral Hemorrhage; Female; Humans; Male; Recurrence; Statistics as Topic; Stroke; Treatment Outcome; Warfarin

Warfarin prevents stroke in atrial fibrillation (AF); however, concerns regarding international normalized ratio control and hemorrhage limit its use in the elderly. The oral direct thrombin inhibitors (DTIs) are potential alternatives to warfarin, offering fixed dosing without drug and dietary interactions and the need for international normalized ratio monitoring. Although ximelagatran, a DTI studied in the Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation trials, has been withdrawn, development of other DTIs continues. We report our experience in elderly high-risk AF patients on ximelagatran compared with warfarin therapy.. Data from patients with AF and stroke risk factors randomized in Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation III and V trials to ximelagatran or warfarin were analyzed for stroke/systemic emboli, bleeding, and raised alanine aminotransferase levels in those >or=75 (n=2804) and <75 (n=4525) years.. Ximelagatran was as effective as warfarin in reducing stroke/systemic emboli in the elderly (2.23%/y with ximelagatran vs 2.27%/y with warfarin) as in younger patients (1.25%/y vs 1.28%/y). Total bleeds were significantly lower with ximelagatran compared with warfarin in elderly (40% vs 45%, P=0.01) and younger (27% vs 35%, P<0.001) patients. Raised alanine aminotransferase values (>3-fold elevation) among ximelagatran patients were more common in older (7.5% old vs 5.3% young) patients, particularly women (9.5% elderly women vs 6.1% elderly men).. In high-risk elderly AF patients, ximelagatran is as effective as warfarin with less bleeding, but alanine aminotransferase elevations are common, particularly in elderly women. Oral DTIs for stroke prevention show promise in elderly patients.

Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Alanine Transaminase; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Cerebral Hemorrhage; Double-Blind Method; Embolism; Female; Humans; Intracranial Thrombosis; Male; Middle Aged; Sex Characteristics; Sex Factors; Stroke; Thrombin; Treatment Outcome; Up-Regulation; Warfarin

We performed a combination of prespecified and exploratory subgroup analyses to detect any treatment differences among various baseline subgroups in the Warfarin-Aspirin Recurrent Stroke Study (WARSS) cohort.. The WARSS compared the efficacy of adjusted-dose warfarin (INR 1.4-2.8) to aspirin (325 mg/day) for recurrent ischemic stroke or death within 2 years. The effect of warfarin and aspirin was compared among prespecified and exploratory subgroups with respect to sociodemographic and vascular risk factors, stroke subtype, arterial territory, and infarct topography. Hazard ratios and 95% confidence intervals comparing warfarin to aspirin were calculated using Cox proportional hazards models. Differences in hazard ratios were tested using interaction terms.. No treatment differences between warfarin and aspirin were found across multiple prespecified subgroups. In a multivariate model, warfarin was associated with greater hazard among patients with moderate stroke severity (HR 1.63, 95% CI 1.005-2.64, p = 0.047) and a greater benefit among those with posterior circulation location without brainstem infarction (HR 0.54, 95% CI 0.33-0.88, p = 0.013). In post-hoc analyses of the cryptogenic subgroup, warfarin was associated with worse outcomes among patients with moderate stroke severity and better outcomes among those without baseline hypertension or with posterior circulation infarcts sparing the brainstem.. In the WARSS, the majority of subgroup analyses showed no benefit of warfarin over aspirin. Warfarin benefit was limited to brainstem-sparing posterior circulation infarcts and select cryptogenic stroke subgroups. Pending future clinical trial evidence to the contrary, antiplatelets are recommended for survivors of noncardioembolic stroke.

Topics: Aged; Anticoagulants; Aspirin; Cerebral Hemorrhage; Cohort Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Secondary Prevention; Stroke; Treatment Outcome; Warfarin

We conducted a retrospective, multicenter study to compare the efficacy of warfarin with aspirin for the prevention of major vascular events (ischemic stroke, myocardial infarction, or sudden death) in patients with symptomatic stenosis of a major intracranial artery. Patients with 50 to 99% stenosis of an intracranial artery (carotid; anterior, middle, or posterior cerebral; vertebral; or basilar) were identified by reviewing the results of consecutive angiograms performed at participating centers between 1985 and 1991. Only patients with TIA or stroke in the territory of the stenotic artery qualified for inclusion in the study. Patients were prescribed warfarin or aspirin according to local physician preference and were followed by chart review and personal or telephone interview. Seven centers enrolled 151 patients; 88 were treated with warfarin and 63 were treated with aspirin. Median follow-up was 14.7 months (warfarin group) and 19.3 months (aspirin group). Vascular risk factors and mean percent stenosis of the symptomatic artery were similar in the two groups, yet the rates of major vascular events were 18.1 per 100 patient-years of follow-up in the aspirin group (stroke rate, 10.4/100 patient-years; myocardial infarction or sudden death rate, 7.7/100 patient-years) compared with 8.4 per 100 patient-years of follow-up in the warfarin group (stroke rate, 3.6/100 patient-years; myocardial infarction or sudden death rate, 4.8/100 patient-years). Kaplan-Meier analysis showed a significantly higher percentage of patients free of major vascular events among patients treated with warfarin (p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aspirin; Cerebral Angiography; Cerebral Hemorrhage; Cerebrovascular Disorders; Cohort Studies; Constriction, Pathologic; Female; Guinea Pigs; Humans; Male; Middle Aged; Retrospective Studies; Risk Factors; Vascular Diseases; Warfarin

Nonrheumatic atrial fibrillation is common among the elderly and is associated with an increased risk of stroke. We investigated whether anticoagulation with warfarin would reduce this risk.. We conducted a randomized, double-blind, placebo-controlled study to evaluate low-intensity anticoagulation with warfarin (prothrombin-time ratio, 1.2 to 1.5) in 571 men with chronic nonrheumatic atrial fibrillation; 525 patients had not previously had a cerebral infarction, whereas 46 patients had previously had such an event. The primary end point was cerebral infarction; secondary end points were cerebral hemorrhage and death.. Among the patients with no history of stroke, cerebral infarction occurred in 19 of the 265 patients in the placebo group during an average follow-up of 1.7 years (4.3 percent per year) and in 4 of the 260 patients in the warfarin group during an average follow-up of 1.8 years (0.9 percent per year). The reduction in risk with warfarin therapy was 0.79 (95 percent confidence interval, 0.52 to 0.90; P = 0.001). The annual event rate among the 228 patients over 70 years of age was 4.8 percent in the placebo group and 0.9 percent in the warfarin group (risk reduction, 0.79; P = 0.02). The only cerebral hemorrhage occurred in a 73-year-old patient in the warfarin group. Other major hemorrhages, all gastrointestinal, occurred in 10 patients: 4 in the placebo group, for a rate of 0.9 percent per year, and 6 in the warfarin group, for a rate of 1.3 percent per year. There were 37 deaths that were not preceded by a cerebral end point--22 in the placebo group and 15 in the warfarin group (risk reduction, 0.31; P = 0.19). Cerebral infarction was more common among patients with a history of cerebral infarction (9.3 percent per year in the placebo group and 6.1 percent per year in the warfarin group) than among those without such a history.. Low-intensity anticoagulation with warfarin prevented cerebral infarction in patients with nonrheumatic atrial fibrillation without producing an excess risk of major hemorrhage. This benefit extended to patients over 70 years of age.

Topics: Aged; Atrial Fibrillation; Cerebral Hemorrhage; Cerebrovascular Disorders; Double-Blind Method; Follow-Up Studies; Gastrointestinal Hemorrhage; Humans; Male; Research Design; Warfarin

In a non-randomized controlled study carried out on 238 hospitalized patients with cerebral infarction, anticoagulant treatment (AC) was compared with the natural course in the prevention of transient ischemic attacks (TIA), cerebral infarction, stroke, stroke or death. 137 patients were allocated to AC, mean follow-up 30.5 months, and 101 patients were allocated to the controls (untreated group), mean follow-up 25.2 months. There were no statistically significant differences among the patients in the group who had suffered TIA (AC treated group 10.2%, untreated group 5.9%), cerebral infarction (AC treated group 10.2%, untreated group 11.9%), stroke (AC treated group 14.6%, untreated group 12.9%), stroke or death (AC treated group 22.6%, untreated group 19.8%). Minor bleedings occurred significantly more frequently (P less than 0.01) in the treated group. Severe bleedings occurred in 8 patients in the treated group (5.8%) compared to 1 of the controls (1%). It is concluded from the trial that AC can only seldom be recommended as prophylactic against new strokes in patients with cerebral infarction due to arterial thromboembolism.

Topics: Adult; Aged; Brain Ischemia; Cerebral Hemorrhage; Cerebral Infarction; Clinical Trials as Topic; Drug Therapy, Combination; Female; Heparin; Humans; Male; Middle Aged; Warfarin

Elderly patients with nonvalvular atrial fibrillation (NVAF) might have a higher risk of intracerebral hemorrhage. To investigate this, we compared the incidence of intracranial hemorrhage (ICH) and its subtypes, as well as ischemic stroke, in patients taking direct oral anticoagulants (DOACs) compared with warfarin in a real-world setting. We also determined the baseline characteristics associated with both ICH and ischemic stroke.. Patients aged ⩾ 75 years with documented NVAF enrolled in the prospective, multicenter, observational All Nippon Atrial Fibrillation in the Elderly Registry between October 2016 and January 2018 were evaluated. The co-primary endpoints were the incidence of ischemic stroke and ICH. Secondary endpoints included subtypes of ICH.. Of 32,275 patients (13,793 women; median age, 81.0 years) analyzed, 21,585 (66.9%) were taking DOACs and 8233 (25.5%) were taking warfarin. During the median 1.88-year follow-up, 743 patients (1.24/100 person-years) developed ischemic stroke and 453 (0.75/100 person-years) developed ICH (intracerebral hemorrhage, 189; subarachnoid hemorrhage, 72; subdural/epidural hemorrhage, 190; unknown subtype, 2). The incidence of ischemic stroke (adjusted hazard ratio (aHR) 0.82, 95% confidence interval (CI) 0.70-0.97), ICH (aHR 0.68, 95% CI 0.55-0.83), and subdural/epidural hemorrhage (aHR 0.53, 95% CI 0.39-0.72) was lower in DOAC users versus warfarin users. The incidence of fatal ICH and fatal subarachnoid hemorrhage was also lower in DOAC users versus warfarin users. Several baseline characteristics other than anticoagulants were also associated with the incidence of the endpoints. Of these, history of cerebrovascular disease (aHR 2.39, 95% CI 2.05-2.78), persistent NVAF, (aHR 1.90, 95% CI 1.53-2.36), and long-standing persistent/permanent NVAF (aHR 1.92, 95% CI 1.60-2.30) was strongly associated with ischemic stroke; severe hepatic disease (aHR 2.67, 95% CI 1.46-4.88) was strongly associated with overall ICH; and history of fall within 1 year was strongly associated with both overall ICH (aHR 2.29, 95% CI 1.76-2.97) and subdural/epidural hemorrhage (aHR 2.90, 95% CI 1.99-4.23).. Patients aged ⩾ 75 years with NVAF taking DOACs had lower risks of ischemic stroke, ICH, and subdural/epidural hemorrhage than those taking warfarin. Fall was strongly associated with the risks of intracranial and subdural/epidural hemorrhage.. The individual de-identified participant data and study protocol will be shared for up to 36 months after the publication of the article. Access criteria for data sharing (including requests) will be decided on by a committee led by Daiichi Sankyo. To gain access, those requesting data access will need to sign a data access agreement. Requests should be directed to yamt-tky@umin.ac.jp.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Female; Humans; Intracranial Hemorrhages; Ischemic Stroke; Prospective Studies; Registries; Stroke; Subarachnoid Hemorrhage; Treatment Outcome; Warfarin

4-F PCC is administered for reversal of factor Xa inhibitor-associated coagulopathy despite a lack of quality evidence demonstrating hemostatic efficacy. The aim of this study was to evaluate the hemostatic efficacy of 4-F PCC in intracerebral hemorrhage patients who received factor Xa inhibitors versus warfarin.. This was a multi-center, retrospective, observational cohort study at a large healthcare system. Patients taking warfarin received 4-F PCC 25-50 units/kg based on the presenting INR, while patients taking a factor Xa inhibitor received 35 units/kg. The primary outcome was the percentage of patients with good or excellent hemostatic efficacy as assessed by modified Sarode scale, with neurologic outcomes assessed as a secondary endpoint. Patients were included in the primary outcome population if they had a repeat CT scan within 24 h.. One hundred fifty-seven patients were included in the primary outcome population; [warfarin (n = 76), factor Xa inhibitors (n = 81)]. Hemostatic efficacy was 83 % in the warfarin group versus 75 % in the factor Xa inhibitor group (p = 0.24). The hemostatic efficacy risk difference between the groups was 7.6 % (95 % CI 5.1 %, 20.2 %). Good neurologic outcome (mRS 0-2) at discharge was 17 % in warfarin patients versus 12 % in the factor Xa inhibitor patients (p = 0.40).. There was no significant difference in hemostatic efficacy or clinical outcomes between patients taking warfarin or a factor Xa inhibitor following reversal with 4-F PCC. This study provides further support that 4-F PCC can be used for the reversal of factor Xa inhibitor-associated coagulopathy.

Topics: Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Factors; Cerebral Hemorrhage; Factor IX; Factor Xa; Factor Xa Inhibitors; Hemostatics; Humans; Retrospective Studies; Warfarin

Data on the use of activated prothrombin complex concentrate (aPCC) for the management of warfarin associated major bleeding is sparse. The objective of the study was to assess the achievement of effective clinical hemostasis using aPCC in patients presenting with major bleeding while on warfarin. We also assessed the safety of the drug. This retrospective study was conducted at a tertiary care teaching center in the USA where patients with major bleeding while receiving warfarin, and received aPCC were included. Efficacy of aPCC in achieving effective hemostasis was assessed according to the International Society of Thrombosis and Hemostasis Scientific and Standardization Subcommittee criteria. Efficacy was also assessed by achieving INR < 1.5 after treatment. The primary safety endpoint was the occurrence of any thromboembolic complications. A total of 67 patients were included in the study. The most common site for bleeding was intracerebral hemorrhage (n = 37, 55.2%), followed by gastrointestinal bleed (n = 26, 38.8%). Clinical hemostasis was achieved in 46 (68.7%) patients and of the 21 (31.3%) patients who did not achieve clinical hemostasis, 16 died. Thirty nine (58.2%) patients achieved INR < 1.5. Five (7.5%) patients developed thromboembolic complications. This study suggests that the use of aPCCs is effective in achieving effective hemostasis in patients on warfarin presenting with major bleeding.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Coagulants; Female; Gastrointestinal Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Retrospective Studies; Thromboembolism; Time Factors; Treatment Outcome; Vitamin K; Warfarin

 Intracranial hemorrhage (ICH) is one of the major devastating complications of anticoagulation. Matrix metalloproteinase (MMP) inhibition has been proposed as a novel pharmacological approach for ICH treatment..  We evaluated the effects of CM-352 (MMP-fibrinolysis inhibitor) in an experimental ICH model associated with oral anticoagulants as compared with clinically used prothrombin complex concentrate (PCC)..  ICH was induced by collagenase injection into the striatum of wild type (C57BL/6J) anticoagulated mice (warfarin or rivaroxaban) and.  Only PCC reduced hemorrhage volume and improved functional outcome in warfarin-ICH, but both PCC and CM-352 treatments diminished hemorrhage volume (46%,.  CM-352 treatment, by diminishing MMPs and rivaroxaban-associated fibrinolytic effects, might be a novel antihemorrhagic strategy for rivaroxaban-associated ICH.

Topics: Animals; Anticoagulants; Benzamides; Blood Coagulation Factors; Cerebral Hemorrhage; Disease Models, Animal; Hydroxamic Acids; Interleukin-6; Intracranial Hemorrhages; Matrix Metalloproteinase 10; Mice; Mice, Inbred C57BL; Plasminogen Activator Inhibitor 1; Rivaroxaban; Warfarin

Background To investigate the effectiveness and safety of withholding or restarting antithrombotic agents, and different antithrombotic therapies among patients with atrial fibrillation post-intracranial hemorrhage. Methods and Results This is a nationwide retrospective cohort study involving patients with atrial fibrillation receiving antithrombotic therapies who subsequently developed intracranial hemorrhage between January 1, 2011 and December 31, 2017. The risk of ischemic stroke (IS), recurrent intracerebral hemorrhage (ICH), and all-cause mortality were investigated between patients receiving no treatment versus patients reinitiating oral anticoagulants (OACs) or antiplatelet agents, and warfarin versus non-vitamin K antagonist OACs. We applied inverse probability of treatment weighting to balance the baseline characteristics and Cox proportional hazards model to estimate the hazard ratios (HRs) of different outcomes of interest. Compared with no treatment, OACs reduced the risk of IS (HR, 0.61; 0.42-0.89), without increase in the risk of ICH (1.15, 0.66-2.02); antiplatelet agent users showed a similar risk of IS (1.13, 0.81-1.56) and increased risk of ICH (1.81, 1.07-3.04). Use of OACs or antiplatelet agents did not reduce the risk of all-cause mortality (0.85, 0.72-1.01; and 0.88, 0.75-1.03, respectively). Compared with warfarin, non-vitamin K antagonist OAC users showed a similar risk of IS (0.92, 0.50-1.70), non-significantly reduced risk of ICH (0.53, 0.22-1.30), and significantly reduced all-cause mortality (0.60, 0.43-0.84). Conclusions OACs are recommended in patients with atrial fibrillation and intracranial hemorrhage because they reduced the risk of IS with no increase in the risk of subsequent ICH. Non-vitamin K antagonist OACs are recommended over warfarin owing to their survival benefits.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Fibrinolytic Agents; Humans; Intracranial Hemorrhages; Platelet Aggregation Inhibitors; Retrospective Studies; Stroke; Warfarin

Anticoagulant treatment increases the risk of intracerebral hemorrhage (ICH), but whether the treatment, more specifically non-vitamin K oral anticoagulants (NOACs), increases the risk of cerebral microbleeds (CMBs) remains uncertain. We performed this study to investigate the development of new CMBs due to NOACs or warfarin treatment in patients with atrial fibrillation (AF).We prospectively recruited AF patients before anticoagulation from June 2016 to June 2018. We performed susceptibility-weighted imaging (SWI) examinations on all enrolled AF patients and re-examined SWI 1 year later. We compared demographic features and new CMBs between the NOACs group and the warfarin group. Univariate analysis of clinical factors was performed according to the development of new CMBs; and age, a HAS-B(L)ED score, warfarin use, and the presence of baseline CMBs were then selected for inclusion in the multivariate logistic regression model.A total of 72 AF patients were recruited, 29 of whom were assigned to the NOACs group and 43 to the warfarin group. Finally, 1 patient in the NOACs group (3.4%) and 9 patients (20.9%) in the warfarin group developed new CMBs after 1 year follow-up (P = .08). Univariate analysis showed that age, a HAS-B(L)ED score ≥4, the presence of baseline CMBs were associated with the development of new CMBs (P < .05). And multivariate regression analysis showed baseline CMBs (P = .03, odds ratio = 6.37, 95% confidence interval 1.15-35.36) was independently related to the increase in new CMBs.AF patients treated with NOACs may have a decreased trend in the development of new CMBs compared with those treated with warfarin. Baseline CMBs increased the frequency of new CMBs during anticoagulant treatment. The development of new CMBs in AF patients with anticoagulation requires further longitudinal studies with longer follow-up in larger samples.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Follow-Up Studies; Humans; Vitamin K; Warfarin

Topics: Anticoagulants; Cerebral Hemorrhage; Heart Valve Prosthesis; Heart Valves; Humans; Warfarin

There is limited evidence describing the mortality benefit of utilizing 4-factor prothrombin complex concentrate (4F-PCC) in patients presenting with a warfarin-associated intracerebral hemorrhage (ICH) and a Glasgow Coma Scale (GCS) of ≤8. The aim of this study is to determine the potential mortality benefit of 4F-PCC in this patient population.. This was a retrospective chart review, performed at a comprehensive stroke center from October 2013 through August 2020. Patients were included if they were ≥ 18 years of age, experienced a spontaneous ICH with baseline GCS ≤ 8, treated with warfarin prior to admission, had a baseline INR ≥ 1.7, and received 4F-PCC for INR normalization due to warfarin-associated ICH. The primary outcome was in-hospital mortality at 30 days.. A total of 252 patients received 4F-PCC in the specified time period. Of those patients, 25 patients met inclusion criteria. Sixteen patients (64%) experienced in-hospital mortality. When compared to a historical estimated 80% mortality rate in the studied patient population, there was no statistically significant difference (p = 0.208) in mortality when 4F-PCC was utilized to reverse INR.. The administration of 4F-PCC in patients presenting with warfarin-related ICH and GCS ≤ 8 did not result in statistically significant mortality benefit. Our results are limited by study design and sample size. Thus, larger studies are needed to determine if a benefit exists for 4F-PCC in this patient population. Although the results are not statistically significant, our small study suggests that there may be a clinically significant mortality benefit when 4F-PCC is utilized.

Topics: Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Glasgow Coma Scale; Humans; International Normalized Ratio; Retrospective Studies; Warfarin

Direct oral anticoagulants have been evaluated in the general population, but proper evidence for their safe use in the geriatric population is still missing. We compared the bleeding risk of a direct oral anticoagulant (rivaroxaban) and vitamin K antagonists (VKAs) among French geriatric patients with non-valvular atrial fibrillation (AF) aged ≥80 years.. We performed a sequential observational prospective cohort study, using data from 33 geriatric centres. The sample comprised 908 patients newly initiated on VKAs between September 2011 and September 2014 and 995 patients newly initiated on rivaroxaban between September 2014 and September 2017. Patients were followed up for up to 12 months. One-year risks of major, intracerebral, gastrointestinal bleedings, ischaemic stroke and all-cause mortality were compared between rivaroxaban-treated and VKA-treated patients with propensity score matching and Cox models.. Major bleeding risk was significantly lower in rivaroxaban-treated patients (7.4/100 patient-years) compared with VKA-treated patients (14.6/100 patient-years) after multivariate adjustment (HR 0.66; 95% CI 0.43 to 0.99) and in the propensity score-matched sample (HR 0.53; 95% CI 0.33 to 0.85). Intracerebral bleeding occurred less frequently in rivaroxaban-treated patients (1.3/100 patient-years) than in VKA-treated patients (4.0/100 patient-years), adjusted HR 0.59 (95% CI 0.24 to 1.44) and in the propensity score-matched sample HR 0.26 (95% CI 0.09 to 0.80). Major lower bleeding risk was largely driven by lower risk of intracerebral bleeding.. Our study findings indicate that bleeding risk, largely driven by lower risk of intracerebral bleeding, is lower with rivaroxaban than with VKA in stroke prevention in patients ≥80 years old with non-valvular AF.

Topics: Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Factor Xa Inhibitors; Female; France; Hemorrhage; Humans; Ischemic Stroke; Male; Mortality; Outcome and Process Assessment, Health Care; Risk Assessment; Rivaroxaban; Warfarin

Although the use of factor Xa (FXa) inhibitors has increased substantially over the past decade, there are limited data on characteristics and outcomes of FXa inhibitor-associated intracerebral hemorrhage (ICH).. To investigate the association between prior oral anticoagulant use (FXa inhibitors, warfarin, or none) and in-hospital outcomes among patients with nontraumatic ICH.. This is a cohort study of 219 701 patients with nontraumatic ICH admitted to 1870 hospitals in the Get With The Guidelines-Stroke registry between October 2013 and May 2018. Data analysis was performed in December 2019.. Anticoagulation therapy before ICH.. The primary outcome was in-hospital mortality. Secondary outcomes were a composite measure of in-hospital mortality or discharge to hospice, discharge home, independent ambulation, and modified Rankin Scale (mRS) score at discharge.. Of 219 701 patients (mean [SD] age, 68.2 [15.3] years; 104 940 women [47.8%]), 9202 (4.2%) were taking FXa inhibitors, 21 430 (9.8%) were taking warfarin, and 189 069 (86.0%) were not taking any oral anticoagulant before ICH. Patients taking FXa inhibitors or warfarin were older and had higher prevalence of cardiovascular risk factors. Compared with those not taking an oral anticoagulant (42 660 of 189 069 patients [22.6%]), the in-hospital mortality risk was higher for both FXa inhibitors (2487 of 9202 patients [27.0%]; adjusted odds ratio [aOR], 1.27; 95% CI, 1.20-1.34; P < .001) and warfarin (7032 of 21 430 patients [32.8%]; aOR, 1.67; 95% CI, 1.60-1.74; P < .001). Both FXa inhibitors (3478 of 9202 patients [37.8%]; aOR, 1.19; 95% CI, 1.13-1.26; P < .001) and warfarin (9151 of 21 430 patients [42.7%]; aOR, 1.50; 95% CI, 1.44-1.56; P < .001) were associated with higher odds of death or discharge to hospice compared with not taking oral anticoagulation (58 022 of 189 069 patients [30.7%]). Although the rates of discharge home, independent ambulation, mRS scores of 0 or 1, and mRS scores of 0 to 2 were numerically lower among patients taking FXa inhibitors, these differences were not significant compared with patients not taking oral anticoagulants. In contrast, patients taking FXa inhibitors were less likely to die (aOR, 0.76; 95% CI, 0.72-0.81; P < .001) or to experience death or discharge to hospice (aOR, 0.79; 95% CI, 0.75-0.84; P < .001), more likely to be discharged home (aOR, 1.18; 95% CI, 1.10-1.26; P < .001), and had better mRS scores at discharge (eg, mRS scores of 0-1: aOR, 1.24; 95% CI, 1.09-1.40; P < .001) than those treated with warfarin. Concomitant warfarin and antiplatelet therapy (either single or dual) was associated with worse outcomes compared with taking warfarin alone (eg, in-hospital mortality for dual-antiplatelet agents: aOR, 2.07; 95% CI, 1.72-2.50; P < .001). However, such incremental risk was not significant in patients taking FXa inhibitors.. In this cohort study, FXa inhibitor-associated ICH was associated with higher risk of mortality or death or discharge to hospice than not taking an oral anticoagulant, but patients taking FXa inhibitors had better outcomes than those with warfarin-related ICH.

Topics: Aged; Aged, 80 and over; Anticoagulants; Case-Control Studies; Cerebral Hemorrhage; Cohort Studies; Dependent Ambulation; Drug Therapy, Combination; Dual Anti-Platelet Therapy; Factor Xa Inhibitors; Female; Functional Status; Hospices; Hospital Mortality; Humans; Male; Middle Aged; Odds Ratio; Patient Discharge; Platelet Aggregation Inhibitors; Registries; Risk Factors; Warfarin

Current guidelines allow the administration of intravenous recombinant tissue plasminogen activator (IV r-tPA) to warfarin-treated patients with acute ischemic stroke (AIS) who have an international normalized ratio (INR) of ≤1.7. However, concerns remain about the safety of using IV r-tPA in this situation due to a conceivable risk of symptomatic intracranial hemorrhage (sICH), lack of dedicated randomized controlled trials and the conflicts in the available data. We aimed to determine the risk of sICH in warfarin-treated patients with subtherapeutic INR who received IV r-tPA for AIS in our large volume comprehensive center.. Patients who had received IV r-tPA for AIS in a 9.6-year period were retrospectively investigated (n = 834). Patients taking warfarin prior to presentation were identified (n = 55). One patient was excluded due to elevated INR beyond the acceptable range for IV r-tPA treatment. Because of the significant difference in the sample size (54 vs 779), warfarin group was matched with 54 non-warfarin patients adjusted for independent risk factors for sICH (age, admission NIHSS, history of diabetes). Good outcome was defined as mRS of 0-2 on discharge and sICH was defined as an ICH causing increase in NIHSS ≥4 or death. Warfarin-treated group was further dichotomized based on INR (1-1.3 vs 1.3-1.7) and safety and outcome measures were compared between resultant groups.. No significant difference was found between warfarin-treated and the non-warfarin groups in terms of chance of good outcome on discharge (27.8% in warfarin group vs 26.4% in non-warfarin group; p-value >0.05), or the rate of occurrence of sICH (3.7% in warfarin group vs 11.1% in non-warfarin group; p-value >0.05). Furthermore, rate of sICH (5.1% in patients with INR <1.3 versus 0.0% in patients with INR 1.3-1.7; p-value >0.05) or chance of good outcome on discharge (28.2% of patients with INR <1.3 versus 26.7% in patients with INR 1.3-1.7; p-value >0.05) were not found to be different after the warfarin-treated group was dichotomized.. Administration of IV r-tPA for AIS in warfarin-treated patients with subtherapeutic INR <1.7 does not increase the risk of sICH.

Topics: Administration, Intravenous; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Clinical Decision-Making; Databases, Factual; Drug Monitoring; Female; Fibrinolytic Agents; Humans; International Normalized Ratio; Ischemic Stroke; Male; New York; Predictive Value of Tests; Retrospective Studies; Risk Assessment; Risk Factors; Thrombolytic Therapy; Time Factors; Tissue Plasminogen Activator; Treatment Outcome; Warfarin

Management of warfarin-associated intracerebral hemorrhage (ICH) necessitates rapid reversal of anticoagulation. Guideline-based management of warfarin-associated ICH includes timely administration of prothrombin complex concentrate (PCC) and intravenous (IV) vitamin K. In 2017, our hospital implemented an order set for warfarin reversal to facilitate computerized provider order entry (CPOE), and the pharmacy department began prospective verification and dispensing of all PCC orders for anticoagulant reversal. We sought to compare the proportion of patients who received timely, guideline-based therapy for warfarin-associated ICH before and after these changes. We conducted a single-center, retrospective cohort study of all warfarin-associated ICH patients who had an order for PCC. A total of 66 patients were included; 32 patients (pre-intervention cohort) were evaluated in the 2 year period prior to the process improvement changes, while 34 patients (post-intervention cohort) were evaluated in the 2 year period following these changes. Baseline characteristics were similar between groups. The proportion of patients receiving timely guideline-based therapy was significantly higher in the post-intervention cohort compared to the pre-intervention cohort (76.5% vs 34.4%, p < 0.001), primarily driven by increased ordering of vitamin K 10 mg IV in conjunction with PCC in the post-intervention cohort. Our results indicate that implementation of an order set to assist with CPOE, in addition to prospective pharmacist verification of PCC orders, leads to increased adherence to guideline-based management of warfarin-associated ICH.

Topics: Anticoagulants; Anticoagulation Reversal; Blood Coagulation Factors; Cerebral Hemorrhage; Humans; International Normalized Ratio; Pharmacists; Prospective Studies; Retrospective Studies; Vitamin K; Warfarin

Direct oral anticoagulants (DOACs) are increasingly used in place of warfarin, but evidence about their effectiveness and safety in patients with valvular atrial fibrillation (AF) remains limited.. To assess the effectiveness and safety of DOACs compared with warfarin in patients with valvular AF.. New-user retrospective propensity score-matched cohort study.. U.S.-based commercial health care database from 1 January 2010 to 30 June 2019.. Adults with valvular AF who were newly prescribed DOACs or warfarin.. The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial or gastrointestinal bleeding.. Among a total of 56 336 patients with valvular AF matched on propensity score, use of DOACs (vs. warfarin) was associated with lower risk for ischemic stroke or systemic embolism (hazard ratio [HR], 0.64 [95% CI, 0.59 to 0.70]) and major bleeding events (HR, 0.67 [CI, 0.63 to 0.72]). The results for the effectiveness and safety outcomes remained consistent for apixaban (HRs, 0.54 [CI, 0.47 to 0.61] and 0.52 [CI, 0.47 to 0.57], respectively) and rivaroxaban (HRs, 0.74 [CI, 0.64 to 0.86] and 0.87 [CI, 0.79 to 0.96], respectively); with dabigatran, results were consistent for the major bleeding outcome (HR, 0.81 [CI, 0.68 to 0.97]) but not for effectiveness (HR, 1.03 [CI, 0.81 to 1.31]).. Relatively short follow-up; inability to ascertain disease severity.. In this comparative effectiveness study using practice-based claims data, patients with valvular AF who were new users of DOACs had lower risks for ischemic stroke or systemic embolism and major bleeding than new users of warfarin. These data may be used to guide risk-benefit discussions regarding anticoagulant choices for patients with valvular AF.. None.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Comparative Effectiveness Research; Dabigatran; Embolism; Female; Follow-Up Studies; Gastrointestinal Hemorrhage; Humans; Ischemic Stroke; Male; Propensity Score; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Treatment Outcome; Warfarin

Thalassemia is an inherited disease associated with thromboembolic events (TEE) and cerebral artery disease. Here, we report a patient with beta-thalassemia presenting with intracerebral hemorrhage due to cerebral venous sinus thrombosis (CVST), and intracranial aneurysms were found after examination. We believe that it is very rare for this patient to have two kinds of cerebrovascular diseases.. A 25-year-old woman suffered from headache for nine days. She had a history of thalassemia and splenectomy nine years prior.. Intracranial hemorrhage, Cerebral venous sinus thrombosis, Intracranial aneurysm and double heterozygous beta-thalassemia major.. The patient was treated with low-molecular-weight heparin sodium injection (4100IU sc q12 h) and then switched to warfarin after four days of overlap with low-molecular-weight heparin sodium injection. Oral hydroxyurea was prescribed before discharged from the hospital.. The patient's headache was relieved significantly within 48 h, and re-examination of CT showed that the hemorrhage was completely absorbed one week later.. CVST and intracranial aneurysms are associated with the pathological mechanism of thalassemia, and patients with beta-thalassemia should be monitored and educated for long-term prevention, especially those with risk factors.

Topics: Adult; Angiography, Digital Subtraction; beta-Thalassemia; Cerebral Hemorrhage; Cranial Sinuses; Drug Therapy, Combination; Female; Headache; Heparin, Low-Molecular-Weight; Heterozygote; Humans; Intracranial Aneurysm; Magnetic Resonance Imaging; Sinus Thrombosis, Intracranial; Treatment Outcome; Warfarin

Background and Purpose- The risk of arterial ischemic events after intracerebral hemorrhage (ICH) is poorly understood given the lack of a control group in prior studies. This study aimed to evaluate the risk of acute ischemic stroke and myocardial infarction (MI) among patients with and without ICH. Methods- We performed a retrospective cohort study using claims data from Medicare beneficiaries from 2008 to 2014. Our exposure was acute ICH, identified using validated

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cerebral Hemorrhage; Female; Humans; Male; Myocardial Infarction; Stroke; United States; Warfarin

Patients with mechanical heart valves are at high thrombotic risk and require warfarin. Among those developing intracranial hemorrhage, limited data are available to guide clinicians with antithrombotic reinitiation. This 13-patient case series of warfarin-associated intracranial hemorrhages found the time to reinitiate antithrombotic therapy (17 days, interquartile range 21.5 days), and changes to international normalized ratio targets were variable and neither correlated with the type, location, or etiology of bleed, nor the valve and associated thromboembolic risk. The initial presentation significantly impacted prognosis, and diligent assessment and follow-up may support positive long-term outcomes.

Topics: Aged; Anticoagulants; Antifibrinolytic Agents; Aortic Valve; Aspirin; Blood Coagulation Factors; Cerebral Hemorrhage; Female; Heart Valve Prosthesis; Hematoma, Subdural; Humans; International Normalized Ratio; Intracranial Hemorrhages; Male; Middle Aged; Mitral Valve; Plasma; Platelet Aggregation Inhibitors; Pregnancy; Retrospective Studies; Subarachnoid Hemorrhage; Subarachnoid Hemorrhage, Traumatic; Thromboembolism; Vitamin K; Warfarin

Topics: Adult; Anticoagulants; Basal Ganglia Hemorrhage; Betacoronavirus; Brain; Cerebral Angiography; Cerebral Hemorrhage; Comorbidity; Computed Tomography Angiography; Coronavirus Infections; COVID-19; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Frontal Lobe; Heparin, Low-Molecular-Weight; Humans; Hypertension; Magnetic Resonance Imaging; Male; Middle Aged; Myocardial Ischemia; Pandemics; Pneumonia, Viral; Pulmonary Embolism; Retrospective Studies; Risk Factors; SARS-CoV-2; Severity of Illness Index; Tomography, X-Ray Computed; Venous Thrombosis; Warfarin

Cerebral microbleeds (CMBs) are a magnetic resonance imaging (MRI) marker for cerebral small vessel disease. Existing CMBs and those that newly develop are associated with the risks of stroke incidence and recurrence. The purpose of the present study was to investigate the association of oral anticoagulant (OAC) use and the development of new CMBs in cardioembolic stroke patients with atrial fibrillation.. We prospectively followed cardioembolic stroke patients with atrial fibrillation who had been hospitalized in the stroke center of our hospital, had been prescribed anticoagulants at discharge, and underwent repeated brain MRI with an interval of at least one year from the baseline MRI. Assessing the presence, number and location of CMBs using T2*-weighted gradient-recalled echo MRI, we used logistic regression models to investigate the associations between OAC use and the incidence of new CMBs. We also examined associations of subsequent stroke with OACs and CMBs during the follow-up.. A total of 81 patients, consisting of 45 patients receiving direct oral anticoagulants (DOACs) and 36 patients receiving warfarin (WF), were analyzed in the present study. Baseline CMBs were observed in 19/81 patients (23.5%) and new CMBs in 18/81 patients (22.2%) on follow-up MRI (median interval, 34 months). Of the 31 new CMBs, 25 (80.6%) developed in the lobar location and 6 (19.4%) in the deep or infratentorial location. New CMBs occurred in 4 patients (10.0%) taking DOACs　alone, in 10 patients (35.7%) taking WF alone, in 3 patients (37.5%) taking WF plus antiplatelet agents and in 1 patient (20.0%) taking DOAC plus antiplatelet agent. Regarding location, the new CMBs were the lobar type in 7 of the 10 patients taking WF alone, as well as in 3 of the 4 patients taking DOACs alone. In multivariate analysis, the presence of CMBs at baseline and WF use (vs. DOAC use) were associated with new CMBs (CMB presence at baseline: OR 4.16, 95% CI 1.19-14.44; WF use: OR 3.38, 95% CI 1.02-11.42). The presence of ≥ 2 CMBs at baseline was related to a higher risk of subsequent stroke (OR 7.25, 95% CI 1.01-52.35, P = 0.048).. Our findings suggest that DOAC compared with WF use at discharge is associated with a lower incidence of new CMBs in cardioembolic stroke patients with atrial fibrillation. Further prospective studies in the clinical setting are needed to confirm our exploratory data.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Cerebral Small Vessel Diseases; Female; Humans; Incidence; Magnetic Resonance Imaging; Male; Middle Aged; Prospective Studies; Recurrence; Risk Factors; Stroke; Warfarin

Topics: Aged; Anticoagulants; Asian People; Atrial Fibrillation; Cerebral Hemorrhage; China; Female; Humans; Magnetic Resonance Imaging; Male; Prospective Studies; Risk Factors; Warfarin

Topics: Anticoagulants; Cerebral Hemorrhage; Humans; Warfarin

Cerebral microbleeds (CMBs), which predict future intracerebral haemorrhage (ICH), may guide anticoagulant decisions for atrial fibrillation (AF). We aimed to evaluate the risk of warfarin-associated ICH in Chinese patients with AF with CMBs.. In this prospective, observational, multicentre study, we recruited Chinese patients with AF who were on or intended to start anticoagulation with warfarin from six hospitals in Hong Kong. CMBs were evaluated with 3T MRI brain at baseline. Primary outcome was clinical ICH at 2-year follow-up. Secondary outcomes were ischaemic stroke, systemic embolism, mortality of all causes and modified Rankin Scale ≥3. Outcome events were compared between patients with and without CMBs.. A total of 290 patients were recruited; 53 patients were excluded by predefined criteria. Among the 237 patients included in the final analysis, CMBs were observed in 84 (35.4%) patients, and 11 had ≥5 CMBs. The mean follow-up period was 22.4±10.3 months. Compared with patients without CMBs, patients with CMBs had numerically higher rate of ICH (3.6% vs 0.7%, p=0.129). The rate of ICH was lower than ischaemic stroke for patients with 0 to 4 CMBs, but higher for those with ≥5 CMBs. CMB count (C-index 0.82) was more sensitive than HAS-BLED (C-index 0.55) and CHA2DS2-VASc (C-index 0.63) scores in predicting ICH.. In Chinese patients with AF on warfarin, presence of multiple CMBs may be associated with higher rate of ICH than ischaemic stroke. Larger studies through international collaboration are needed to determine the risk:benefit ratio of oral anticoagulants in patients with AF of different ethnic origins.

Topics: Aged; Aged, 80 and over; Anticoagulants; Asian People; Atrial Fibrillation; Cerebral Hemorrhage; Female; Hong Kong; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Risk Factors; Stroke; Warfarin

Non-valvular atrial fibrillation patients receiving non-vitamin K antagonist oral anticoagulants (NOACs) have half the incidence of intracerebral hemorrhage (ICH) compared to those receiving warfarin. However, the differences in outcomes of NOAC-associated ICH (NICH) and warfarin-associated ICH (WICH) remain controversial. In this study, we investigated the clinical outcome and radiologic findings of ICH in Asian patients receiving NOACs or warfarin. We retrospectively reviewed the medical records of 544 ICH patients admitted to our hospital from January 2013 through December 2017, and compared the baseline demographics, clinical characteristics, ICH-related radiologic findings, and clinical outcome between the WICH and NICH groups. WICH and NICH were diagnosed in 46 and 13 patients, respectively. Lesions were located more frequently in the supratentorial deep area (45.7% and 46.2%) than the lobar area (30.4% and 30.8%) or brainstem and cerebellum (23.9% and 23.1%) in the WICH and NICH groups, respectively. The hematoma expansion and concomitant intraventricular hemorrhage (IVH) rate was significantly higher in the WICH group than in the NICH group (58.7% versus 7.7%, P = 0.001 and 50.0% versus 15.4%, P = 0.030, respectively). Hematoma expansion (odds ratio [OR]: 50.546; 95% confidence interval [CI]: 2.763-924.748; P = 0.008) and concomitant IVH (OR: 9.240; 95% CI: 1.450-58.892; P = 0.019) were independently associated with mortality at three months, after adjustment for confounding variables. Our results indicate that the radiological findings and clinical outcome at three months in patients with ICH are more favorable in those receiving NOAC therapy than in those receiving warfarin treatment.

Topics: Administration, Oral; Aged; Anticoagulants; Asian People; Atrial Fibrillation; Cerebral Hemorrhage; Dabigatran; Female; Humans; Male; Middle Aged; Odds Ratio; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Warfarin; Young Adult

We investigated the precise clinical and radiologic characteristics of intracerebral hemorrhage associated with direct oral anticoagulant use.. Patients with acute spontaneous intracerebral hemorrhage admitted to our department from September 2014 to November 2017 were retrospectively analyzed. Clinical and neuroradiological characteristics of patients with direct oral anticoagulant-related intracerebral hemorrhage, and effects of prior treatment on the severity at admission and on outcome at discharge were assessed.. Of the 301 enrolled patients (103 women; median age 68 years), 261 received no oral anticoagulants (86.8%), 20 received warfarin (6.6%), and 20 received direct oral anticoagulants (DOACs) (6.6%). Median initial National Institutes of Health Stroke Scale scores differed significantly among the groups (P = .0283). Systolic blood pressure (P = .0031) and estimated glomerular filtration rate (P = .0019) were significantly lower in the oral anticoagulant-related intracerebral hemorrhage group than in other groups. Total small vessel disease scores were significantly higher in the oral anticoagulant-related intracerebral hemorrhage group than in the warfarin group (P = .0413). Multivariate analysis revealed that prior oral anticoagulant treatment (odds ratio: 0.21, 95% confidence interval: 0.05-0.96, P = .0445) was independently negatively associated with moderate-to-severe neurological severity (stroke scale score ≥10) after adjusting for intracerebral hemorrhage location and various risk factors. There were significant differences in hematoma volume in the basal ganglia (P = .0366).. DOAC-related intracerebral hemorrhage may occur particularly in patients with a high risk of bleeding; however, they had a milder initial neurological severity than those with warfarin-related intracerebral hemorrhage, possibly due to relatively smaller hematoma volume, especially in the basal ganglia.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Humans; Male; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Treatment Outcome; Warfarin

While warfarin use and the presence of the spot sign on computed tomography angiography are associated with a high frequency of hematoma enlargement and high mortality among patients with intracerebral hematomas (ICHs), the effects of various combinations of warfarin use and/or the spot sign have never been clarified. The combinations of both or either of warfarin use and/or the spot sign were used to investigate their relationships with hematoma enlargement and mortality before the introduction of prothrombin complex concentrate (PCC) treatment.. Consecutive patients with ICHs admitted within 6 h of onset from 2009 to 2017 were investigated.. Of 703 eligible patients, the combinations of warfarin use and spot sign-present and of warfarin use and spot sign-absent were seen in 23 (3.3%) and 35 patients (5.0%), respectively. The combination of warfarin use and spot sign-present was a predictor of hematoma enlargement (p < 0.05). In regard to mortality (13.5% for all patients), mortality with the combination of warfarin use and spot sign-present was 52.2%, which was significantly higher than in the 3 other groups. Multivariate analysis showed that the combination of warfarin use and spot sign-present was a significant predictor of mortality (p < 0.05).. Warfarin users with ICHs showing spot signs, who accounted for approximately 40% of ICH patients with warfarin use, showed a high frequency of hematoma enlargement and high mortality. This group was regarded as high-risk patients and should be considered candidates for prompt administration of PCC.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Angiography; Cerebral Hemorrhage; Computed Tomography Angiography; Disease Progression; Female; Humans; Male; Middle Aged; Tomography, X-Ray Computed; Treatment Outcome; Warfarin

Intracerebral hemorrhage (ICH) is a life-threatening complication of oral anticoagulant therapy that sometimes results in hematoma expansion after onset. Our facility did not have a standardized process for treating oral anticoagulant-associated ICH; this resulted in lag times from order to reversal agent administration.. The aim of this study was to examine the impact of a rapid anticoagulant reversal protocol, combined with warfarin and direct-acting oral anticoagulant therapy, in decreasing door to first intervention times.. This study used a retrospective quality assessment research approach in examining an oral anticoagulant reversal protocol to compare the control and intervention groups. Phytonadione was the first intervention treatment for most study participants diagnosed with warfarin-associated ICH with an international normalized ratio greater than 1.4. Factor IX was the first intervention treatment for all but one study participant with DOAC-associated ICH.. Findings were statistically significant (P < .05) for door to first intervention treatments. Door to phytonadione in minutes decreased from 232.7 (SD, 199.4) to posttest findings of 111.4 (SD, 64.6). Door to factor IX in minutes decreased from 183.9 (SD, 230.2) to posttest findings of 116.6 (SD, 69.1).. Study findings support the hypothesis that the new protocol was associated with lower door-to-treatment times for eligible patients.

Topics: Administration, Oral; Aged; Anticoagulants; Antifibrinolytic Agents; Cerebral Hemorrhage; Clinical Protocols; Factor IX; Female; Humans; Male; Retrospective Studies; Time Factors; Vitamin K 1; Warfarin

Background and Purpose- Recurrent bleeding associated with oral anticoagulants (OACs) causes a dilemma in patients with atrial fibrillation (AF) sustaining an intracerebral hemorrhage. Treatment recommendations guiding clinical practice on optimal OAC agent selection in this population are lacking. This study aimed to investigate the comparative effectiveness and safety of non-vitamin K antagonist OAC (NOAC) versus warfarin in patients with AF sustaining an intracerebral hemorrhage. Methods- We conducted a nationwide observational cohort study including patients with AF sustaining an intracerebral hemorrhage and who subsequently claimed an OAC prescription. Contrasts of 1-year risks for ischemic stroke and intracerebral hemorrhage risks were obtained and evaluated by inverse probability treatment weighted absolute risk reduction and risk ratios. Results- Among 622 AF patients with intracerebral hemorrhage, 274 claimed a warfarin prescription and 348 a NOAC prescription. Mean age was 76 years (39% females); 72% had an index nonsevere event and 28% moderate to severe index event according to the Scandinavian Stroke Severity scale. The 1-year ischemic stroke risk was 7.85% for warfarin and 4.01% for NOACs, with a weighted absolute risk reduction of 3.78% (95% CI, -0.15% to 7.71%); the weighted risk ratio was 0.52 (0.27-1.00). For recurrent intracerebral hemorrhage, the risk was 7.00% for warfarin and 5.07% for NOACs. The absolute risk reduction was 1.93% (-2.02% to 5.87%), with an a weighted risk ratio of 0.72 (0.38-1.38). Conclusions- NOACs were associated with a nonsignificant lower risk of ischemic stroke and recurrent intracerebral hemorrhage compared with warfarin. The results add to current recommendations of selecting a NOAC agent for stroke prophylaxis treatment in patients with AF, including those with sustaining an intracerebral hemorrhage.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Female; Humans; Incidence; Intracranial Hemorrhages; Male; Middle Aged; Risk; Severity of Illness Index; Stroke; Treatment Outcome; Warfarin

Background and Purpose- Mechanisms contributing to acute hematoma growth in intracerebral hemorrhage are not well understood. Neuropathological studies suggest that the initial hematoma may create mass effect that can tear vessels in the vicinity by shearing, causing further bleeding and hematoma growth. Methods- To test this in mice, we simulated initial intracerebral hemorrhage by intrastriatal injection of a liquid polymer that coagulates upon contact with tissue and measured the presence and volume of bleeding secondary to the mass effect using Hemoglobin ELISA 15 minutes after injection. Results- Secondary hemorrhage occurred in a volume-dependent (4, 7.5, or 15 μL of polymer) and rate-dependent (0.05, 0.5, or 5 μL/s) manner. Anticoagulation (warfarin or dabigatran) exacerbated the secondary hemorrhage volume. In a second model of hematoma expansion, we confirmed that intrastriatal whole blood injection (15 μL, 0.5 μL/s) also caused secondary bleeding, using acute Evans blue extravasation as a surrogate. Anticoagulation once again exacerbated secondary hemorrhage after intrastriatal whole blood injection. Secondary hemorrhage directly and significantly correlated with arterial blood pressures in both nonanticoagulated and anticoagulated mice, when modulated by phenylephrine or labetalol. Conclusions- Our study provides the first proof of concept for secondary vessel rupture and bleeding as a potential mechanism for intracerebral hematoma growth.

Topics: Acute Disease; Animals; Anticoagulants; Cerebral Hemorrhage; Dabigatran; Hemorrhage; Male; Mice; Random Allocation; Warfarin

Anticoagulant therapy presents iatrogenic effects such as intracerebral hemorrhage (ICH). The latest anticoagulants on the market, direct oral anticoagulants (DOACs) such as apixaban, dabigatran and rivaroxaban, are reported to cause less ICH than other anticoagulants. Next to the ICH area, the thrombin is accumulated and the blood-brain barrier (BBB) is opened. The effects of thrombin on the BBB are largely mediated by the protease activated receptor (PAR) family, especially the PAR-1 isoform. Our hypothesis is that DOACs may limit the effects of thrombin on endothelial cells (of the BBB) alteration by a mechanism probably involving PAR-1 activation. To test this hypothesis in vitro, we used HBEC-5i human brain endothelial cells as a human BBB model. The effects of thrombin under warfarin, heparin, rivaroxaban, apixaban, and dabigatran treatment on endothelial cells were then investigated by measuring of permeability and junction proteins: ZO-1 and VE-cadherin expressions and PAR-1 cleavage. Depending on the anticoagulant used, we observed three profiles of response of the endothelial cells after thrombin exposure: i) dabigatran treatment allowed maintaining the tightness of the endothelial monolayer; ii) other DOACs limited thrombin-induced alteration of the endothelial monolayer; and iii) pretreatment with warfarin and heparin did not protect from thrombin-induced BBB breakdown. Pretreatment with DOACs clearly limited the impact of thrombin on PAR-1 cleavage in our model, contrary to other anticoagulants, associated with ZO-1 and VE-cadherin expressions. In conclusion, DOACs seem to limit the alteration of the monolayer of endothelial cells of the BBB mediated by the thrombin/PAR-1 pathway.

Topics: Administration, Oral; Anticoagulants; Antigens, CD; Blood-Brain Barrier; Cadherins; Cell Line; Cerebral Hemorrhage; Endothelial Cells; Heparin; Humans; Protein Serine-Threonine Kinases; Pyrazoles; Pyridones; Receptor, PAR-1; Rivaroxaban; Thrombin; Warfarin; Zonula Occludens-1 Protein

Cerebral microbleeds (CMBs) may predict the occurrence of intracerebral hemorrhage (ICH). Warfarin use may cause ICH. It is still controversial whether warfarin increases CMBs in atrial fibrillation (AF) patients. The study aimed to investigate the prevalence of CMBs and risk factors in AF patient population.. This single retrospective center study included 113 patients with nonvalvular atrial fibrillation (NVAF) who were on outpatient treatment. CMBs were counted using 3D-enhanced T2*-weighted angiography (ESWAN) imaging. We compared clinical and radiological data between patients who used warfarin and not used warfarin with univariate analysis. The associations between clinical and radiological data and CMBs in NVAF population were analyzed with multivariate linear regression analyses.. Among 113 NVAF patients, CMBs were found in 33 (29.2%) patients; there were 53 patients who used warfarin for thromboembolism prevention and 60 patients with similar demographic features who did not use warfarin. CMBs on ESWAN MRI showed no significant difference between the 2 groups (p = 0.061). Patients with CMBs were older than patients without CMBs (p = 0.046), and the frequency of smokers (p = 0.028), hypertension (p = 0.029), previous ICH (p = 0.000), and leukoaraiosis (p = 0.020) in patients with CMBs were significantly higher than patients without CMBs. In multivariate linear regression analyses, previous ICH (β = 1.438, p = 0.000), age (β = 0.082, p = 0.000), hypertension (β = 0.956 p = 0.003), warfarin treatment (β = 0.849, p = 0.006), and smokers (β = 0.920, p = 0.016) were positive linear predictors of CMBs number levels in NVAF patients.. The present data demonstrated that CMBs were associated with age, hypertension, warfarin treatment, smoking, and a history of ICH. We also found neither CHA2DS2-VASc score nor HAS-BLED score was associated with CMBs in patients with NVAF.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cerebral Angiography; Cerebral Hemorrhage; Female; Humans; Male; Middle Aged; Prevalence; Retrospective Studies; Risk Factors; Warfarin

Rapid reversal of coagulopathy is recommended in warfarin-associated intracerebral hemorrhage (WAICH). However, rapid correction of the INR has not yet been proven to improve clinical outcomes, and the rate of correction with fresh-frozen plasma (FFP) can be variable. We sought to determine whether faster INR reversal with FFP is associated with decreased hematoma expansion and improved outcome. We performed a retrospective analysis of a prospectively collected cohort of consecutive patients with WAICH presenting to an urban tertiary care hospital from 2000 to 2013. Patients with baseline INR > 1.4 treated with FFP and vitamin K were included. The primary outcomes are occurrence of hematoma expansion, discharge modified Rankin Scale (mRS), and 30-day mortality. The association between timing of INR reversal, ICH expansion, and outcome was investigated with logistic regression analysis. 120 subjects met inclusion criteria (mean age 76.9, 57.5% males). Median presenting INR was 2.8 (IQR 2.3-3.4). Hematoma expansion is not associated with slower INR reversal [median time to INR reversal 9 (IQR 5-14) h vs. 10 (IQR 7-16) h, p = 0.61]. Patients with ultimately poor outcome received more rapid INR reversal than those with favorable outcome [9 (IQR 6-14) h vs. 12 (8-19) h, p = 0.064). We find no evidence of an association between faster INR reversal and either reduced hematoma expansion or better outcome.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Blood Component Transfusion; Cerebral Hemorrhage; Chi-Square Distribution; Cohort Studies; Female; Humans; International Normalized Ratio; Male; Massachusetts; Middle Aged; Plasma; Retrospective Studies; Statistics, Nonparametric; Tomography, X-Ray Computed; Treatment Outcome; Vitamin K; Warfarin

Although non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used to prevent thromboembolic disease, there are limited data on NOAC-related intracerebral hemorrhage (ICH).. To assess the association between preceding oral anticoagulant use (warfarin, NOACs, and no oral anticoagulants [OACs]) and in-hospital mortality among patients with ICH.. Retrospective cohort study of 141 311 patients with ICH admitted from October 2013 to December 2016 to 1662 Get With The Guidelines-Stroke hospitals.. Anticoagulation therapy before ICH, defined as any use of OACs within 7 days prior to hospital arrival.. In-hospital mortality.. Among 141 311 patients with ICH (mean [SD] age, 68.3 [15.3] years; 48.1% women), 15 036 (10.6%) were taking warfarin and 4918 (3.5%) were taking NOACs preceding ICH, and 39 585 (28.0%) and 5783 (4.1%) were taking concomitant single and dual antiplatelet agents, respectively. Patients with prior use of warfarin or NOACs were older and had higher prevalence of atrial fibrillation and prior stroke. Acute ICH stroke severity (measured by the National Institutes of Health Stroke Scale) was not significantly different across the 3 groups (median, 9 [interquartile range, 2-21] for warfarin, 8 [2-20] for NOACs, and 8 [2-19] for no OACs). The unadjusted in-hospital mortality rates were 32.6% for warfarin, 26.5% for NOACs, and 22.5% for no OACs. Compared with patients without prior use of OACs, the risk of in-hospital mortality was higher among patients with prior use of warfarin (adjusted risk difference [ARD], 9.0% [97.5% CI, 7.9% to 10.1%]; adjusted odds ratio [AOR], 1.62 [97.5% CI, 1.53 to 1.71]) and higher among patients with prior use of NOACs (ARD, 3.3% [97.5% CI, 1.7% to 4.8%]; AOR, 1.21 [97.5% CI, 1.11-1.32]). Compared with patients with prior use of warfarin, patients with prior use of NOACs had a lower risk of in-hospital mortality (ARD, -5.7% [97.5% CI, -7.3% to -4.2%]; AOR, 0.75 [97.5% CI, 0.69 to 0.81]). The difference in mortality between NOAC-treated patients and warfarin-treated patients was numerically greater among patients with prior use of dual antiplatelet agents (32.7% vs 47.1%; ARD, -15.0% [95.5% CI, -26.3% to -3.8%]; AOR, 0.50 [97.5% CI, 0.29 to 0.86]) than among those taking these agents without prior antiplatelet therapy (26.4% vs 31.7%; ARD, -5.0% [97.5% CI, -6.8% to -3.2%]; AOR, 0.77 [97.5% CI, 0.70 to 0.85]), although the interaction P value (.07) was not statistically significant.. Among patients with ICH, prior use of NOACs or warfarin was associated with higher in-hospital mortality compared with no OACs. Prior use of NOACs, compared with prior use of warfarin, was associated with lower risk of in-hospital mortality.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Confounding Factors, Epidemiologic; Female; Hospital Mortality; Humans; Male; Platelet Aggregation Inhibitors; Registries; Retrospective Studies; Risk; Vitamin K; Warfarin

Direct oral coagulants (DOAC) have been shown to decrease the frequency of intracerebral hemorrhage (ICH) compared with warfarin. However, the precise characteristics, such as the size and locations of the hemorrhage, and outcome and onset time of ICH in patient taking DOAC are not fully elucidated.. We retrospectively analyzed the characteristics of symptomatic patients with ICH taking either DOAC or warfarin between January 2012 and December 2015.. Out of 400 consecutive patients with ICH, 15 patients were DOAC-ICH and 24 patients were warfarin-ICH. DOAC-ICH was observed in 6 patients with 10 mg of rivaroxaban, 5 patients with 15 mg of rivaroxaban, and 1 patient with 10 mg of apixaban, 5 mg of apixaban, 30 mg of edoxaban, and 60 mg of edoxaban. Prothrombin time was well controlled in most of the warfarin-ICH patients (83.3%). The locations of ICH were similar in both groups; however, median ICH volume was significantly smaller in DOAC-ICH patients than in warfarin-ICH patients (P < .01) and ICH around basal ganglia seemed to show great difference between the groups. DOAC-ICH patients showed better neurological outcome at the time of discharge than warfarin patients (P < .01), and the ratio of good prognosis was significantly higher in the DOAC-ICH patients than in the warfarin-ICH patients (P < .01). The onset of warfarin-ICH was frequently observed in the morning and evening, whereas DOAC-ICH did not show any specific onset time.. Patients with DOAC-ICH showed smaller ICH volume and better clinical outcomes than patients with warfarin-ICH, and DOAC-ICH did not show any specific onset peak.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Circadian Rhythm; Female; Humans; Male; Middle Aged; Prothrombin Time; Pyrazoles; Pyridines; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Thiazoles; Time Factors; Treatment Outcome; Warfarin

Whether to resume antithrombotic treatment after oral anticoagulant-related intracerebral haemorrhage (OAC-ICH) is debatable. In this study, we aimed at investigating long-term outcome associated with OAC resumption after warfarin-related ICH, in comparison with secondary prevention strategies with platelet inhibitors or antithrombotic discontinuation. Participants were patients who sustained an incident ICH during warfarin treatment (2002-2014) included in the Multicenter Study on Cerebral Hemorrhage in Italy. Primary end-point was a composite of ischemic stroke/systemic embolism (SE) and all-cause mortality. Secondary end-points were ischemic stroke/SE, all-cause mortality and major recurrent bleeding. We computed individual propensity score (PS) as the probability that a patient resumes OACs or other agents given his pre-treatment variables, and performed Cox multivariable analysis using Inverse Probability of Treatment Weighting (IPTW) procedure. A total of 244 patients qualified for the analysis. Unlike antiplatelet agents, OAC resumption was associated with a lower rate of the primary end-point (weighted hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.09-0.45), as well as of overall mortality (weighted HR, 0.17; 95% CI, 0.06-0.45) and ischemic stroke/SE (weighted HR, 0.19; 95% CI, 0.06-0.60) with no significant increase of major bleeding in comparison with patients receiving no antithrombotics. In the subgroup of patients with atrial fibrillation, OACs resumption was also associated with a reduction of the primary end-point (weighted HR, 0.22; 95% CI, 0.09-0.54), and the secondary end-point ischemic stroke/SE (weighted HR, 0.09; 95% CI, 0.02-0.40). In conclusion, in patients who have an ICH while receiving warfarin, resuming anticoagulation results in a favorable trade-off between bleeding susceptibility and thromboembolic risk.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Blood Platelets; Cerebral Hemorrhage; Female; Follow-Up Studies; Humans; Italy; Male; Middle Aged; Mortality; Platelet Aggregation Inhibitors; Proportional Hazards Models; Prospective Studies; Risk Factors; Thrombosis; Treatment Outcome; Warfarin

To assess the association between anticoagulation, ischaemic stroke, gastrointestinal and cerebral haemorrhage, and all cause mortality in older people with atrial fibrillation and chronic kidney disease.. Propensity matched, population based, retrospective cohort analysis from January 2006 through December 2016.. The Royal College of General Practitioners Research and Surveillance Centre database population of almost 2.73 million patients from 110 general practices across England and Wales.. Patients aged 65 years and over with a new diagnosis of atrial fibrillation and estimated glomerular filtration rate (eGFR) of <50 mL/min/1.73m. Receipt of an anticoagulant prescription within 60 days of atrial fibrillation diagnosis.. Ischaemic stroke, cerebral or gastrointestinal haemorrhage, and all cause mortality.. 6977 patients with chronic kidney disease and newly diagnosed atrial fibrillation were identified, of whom 2434 were on anticoagulants within 60 days of diagnosis and 4543 were not. 2434 pairs were matched using propensity scores by exposure to anticoagulant or none and followed for a median of 506 days. The crude rates for ischaemic stroke and haemorrhage were 4.6 and 1.2 after taking anticoagulants and 1.5 and 0.4 in patients who were not taking anticoagulant per 100 person years, respectively. The hazard ratios for ischaemic stroke, haemorrhage, and all cause mortality for those on anticoagulants were 2.60 (95% confidence interval 2.00 to 3.38), 2.42 (1.44 to 4.05), and 0.82 (0.74 to 0.91) compared with those who received no anticoagulation.. Giving anticoagulants to older people with concomitant atrial fibrillation and chronic kidney disease was associated with an increased rate of ischaemic stroke and haemorrhage but a paradoxical lowered rate of all cause mortality. Careful consideration should be given before starting anticoagulants in older people with chronic kidney disease who develop atrial fibrillation. There remains an urgent need for adequately powered randomised trials in this population to explore these findings and to provide clarity on correct clinical management.

Topics: Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Brain Ischemia; Cerebral Hemorrhage; England; Female; Gastrointestinal Hemorrhage; Humans; Male; Renal Insufficiency, Chronic; Retrospective Studies; Stroke; Wales; Warfarin

This cross-sectional survey explored the characteristics and outcomes of direct oral anticoagulant (DOAC)-associated nontraumatic intracerebral hemorrhages (ICHs) by analyzing a large nationwide Japanese discharge database.. We analyzed data from 2,245 patients who experienced ICHs while taking anticoagulants (DOAC: 227; warfarin: 2,018) and were urgently hospitalized at 621 institutions in Japan between April 2010 and March 2015. We compared the DOAC- and warfarin-treated patients based on their backgrounds, ICH severities, antiplatelet therapies at admission, hematoma removal surgeries, reversal agents, mortality rates, and modified Rankin Scale scores at discharge.. DOAC-associated ICHs were less likely to cause moderately or severely impaired consciousness (DOAC-associated ICHs: 31.3%; warfarin-associated ICHs: 39.4%;. This nationwide study revealed that DOAC-treated patients had less severe ICHs and lower mortality rates than did warfarin-treated patients, probably due to milder hemorrhages at admission and lower hematoma expansion frequencies.

Topics: Administration, Oral; Aged; Anticoagulants; Cerebral Hemorrhage; Comorbidity; Cross-Sectional Studies; Female; Humans; Male; Platelet Aggregation Inhibitors; Propensity Score; Severity of Illness Index; Warfarin

Left ventricular assist devices (LVADs) have emerged as an effective treatment for patients with advanced heart failure refractory to medical therapy. Post-LVAD strokes are an important cause of morbidity and reduced quality of life. Data on risks that distinguish between ischemic and hemorrhagic post-LVAD strokes are limited. The aim of this study was to determine the incidence of post-LVAD ischemic and hemorrhagic strokes, their association with stroke risk factors, and their effect on mortality.. Data are collected prospectively on all patients with LVADs implanted at Brigham and Women's Hospital. We added retrospectively collected clinical data for these analyses.. From 2007 to 2016, 183 patients (median age, 57; 80% male) underwent implantation of HeartMate II LVAD as a bridge to transplant (52%), destination therapy (39%), or bridge to transplant candidacy (8%). A total of 48 strokes occurred in 39 patients (21%): 28 acute ischemic strokes in 24 patients (13%) and 20 intracerebral hemorrhages in 19 patients (10.3%). First events occurred at a median of 238 days from implantation (interquartile range, 93-515) among those who developed post-LVAD stroke. All but 9 patients (4.9%) were on warfarin (goal international normalized ratio, 2-3.5) and all received aspirin (81-325 mg). Patients with chronic obstructive pulmonary disease were more likely to have an ischemic stroke (odds ratio, 2.96; 95% confidence interval, 1.14-7.70). Dialysis-dependent patients showed a trend toward a higher risk of hemorrhagic stroke (odds ratio, 6.31; 95% confidence interval, 0.99-40.47). Hemorrhagic stroke was associated with higher mortality (odds ratio, 3.92; 95% confidence interval, 1.34-11.45) than ischemic stroke (odds ratio, 3.17; 95% confidence interval, 1.13-8.85).. Stroke is a major cause of morbidity and mortality in patients on LVAD support. Chronic obstructive pulmonary disease increases the risk of ischemic stroke, whereas dialysis may increase the risk of hemorrhagic stroke. Although any stroke increases mortality, post-LVAD hemorrhagic stroke was associated with higher mortality compared with ischemic stroke.

Topics: Aged; Anticoagulants; Aspirin; Brain Ischemia; Cerebral Hemorrhage; Female; Heart Failure; Heart-Assist Devices; Humans; Incidence; International Normalized Ratio; Intracranial Hemorrhages; Male; Middle Aged; Platelet Aggregation Inhibitors; Quality of Life; Retrospective Studies; Risk Factors; Stroke; Warfarin

Atrial fibrillation (AF) increases risk of ischemic stroke, and oral anticoagulation (OAC) increases risk of intracerebral hemorrhage (ICH). This study aimed to compare OAC-treated AF patients with an ischemic stroke/transient ischemic attack (TIA) or spontaneous ICH as their first lifetime cerebrovascular event, especially focusing on patients with therapeutic international normalized ratio (INR).. We assumed that in AF patients suffering ischemic stroke/TIA or ICH, patient characteristics could be different in patients with therapeutic INR than in patients with warfarin.. FibStroke is a multicenter, retrospective registry collating details of AF patients with ischemic stroke/TIA or intracranial hemorrhage in 2003-2012. This substudy included AF patients on OAC with first lifetime ischemic stroke/TIA or spontaneous ICH.. A total of 1457 patients with 1290 ischemic strokes/TIAs and 167 ICHs were identified. Of these, 553 (42.9%) strokes/TIAs and 96 (57.5%) ICHs occurred in patients with INR within therapeutic range. During OAC with therapeutic INR, congestive heart failure (odds ratio [OR]: 2.33, 95% confidence interval [CI]: 1.18-4.58) and hypercholesterolemia (OR: 2.52, 95% CI: 1.51-4.19) were more common in patients with ischemic stroke/TIA, whereas a history of bleeding (OR: 0.30, 95% CI: 0.11-0.82) was less common when compared with patients with ICH. In the whole cohort, renal impairment (OR: 1.86, 95% CI: 1.23-2.80) and mechanical valve prosthesis (OR: 4.41, 95% CI: 1.32-14.7) were overrepresented in patients with stroke/TIA, whereas aspirin use (OR: 0.52, 95% CI: 0.30-0.91) and high INR (OR: 0.40, 95% CI: 0.33-0.48) were overrepresented in patients with ICH.. In anticoagulated AF patients with therapeutic INR and first lifetime cerebrovascular event, congestive heart failure and hypercholesterolemia were associated with ischemic stroke/TIA and history of bleeding with ICH.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Brain Ischemia; Cerebral Hemorrhage; Chi-Square Distribution; Comorbidity; Drug Monitoring; Female; Finland; Heart Failure; Humans; Hypercholesterolemia; International Normalized Ratio; Ischemic Attack, Transient; Logistic Models; Male; Multivariate Analysis; Odds Ratio; Registries; Renal Insufficiency; Retrospective Studies; Risk Factors; Stroke; Treatment Outcome; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Cohort Studies; Humans; Intracranial Hemorrhages; Ischemic Attack, Transient; Stroke; Warfarin

The aim of this study was to obtain a better insight into the adverse effects profiles of the new direct-acting oral anticoagulants (DOACs).. A review was undertaken of all reports of adverse effects for warfarin, dabigatran, rivaroxaban and apixaban reported to the regional medicines information and pharmacovigilance centres (RELIS) in the period June 2013-May 2015.. Approximately 65 000 persons used direct-acting oral anticoagulants and 80 000 used warfarin in the period of the study. A total of 409 reports of adverse effects were included. Altogether 55 % of the reports applied to men. In 76 % of the reports for direct-acting oral anticoagulants and 85 % for warfarin, the patients were more than 70 years of age. The most common adverse effects were haemorrhages (48 % for direct-acting oral anticoagulants and 75 % for warfarin), most of which were cerebral haemorrhages (91 for direct-acting oral anticoagulants and 92 for warfarin). Blood clots (therapeutic failure), cognitive effects, headache and hair loss were some of the other adverse effects. The highest comorbidity was among the patients who died. The number of reported deaths was highest for rivaroxaban (1.1 deaths/1000 users) with a declining incidence for apixaban (0.9 ‰), dabigatran (0.7 ‰) and warfarin (0.6 ‰). There were different degrees of reporting for these medications, and the spontaneous reporting system cannot therefore be used to compare the incidence of adverse effects for the drugs.. Adverse effects, including serious effects, may occur when using all anticoagulants. Factors that may increase the risk of adverse effects are advanced age, high comorbidity, reduced renal function, and polypharmacy.

Topics: Age Distribution; Anticoagulants; Cerebral Hemorrhage; Comorbidity; Dabigatran; Databases, Factual; Drug Utilization; Drug-Related Side Effects and Adverse Reactions; Female; Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Registries; Risk Factors; Rivaroxaban; Sex Distribution; Time Factors; Warfarin

Background and Purpose- The aim of this study was to prospectively validate our prior findings of smaller hematoma volume and lesser neurological deficit in nonvitamin K oral anticoagulant (NOAC) compared with Vitamin K antagonist (VKA)-related intracerebral hemorrhage (ICH). Methods- Prospective 12-month observational study in 15 tertiary stroke centers in the United States, Europe, and Asia. Consecutive patients with premorbid modified Rankin Scale score of <2 with acute nontraumatic anticoagulant-related ICH divided into 2 groups according to the type of anticoagulant: NOAC versus VKA. We recorded baseline ICH volume, significant hematoma expansion (absolute [12.5 mL] or relative [>33%] increase), neurological severity measured by National Institutes of Health Stroke Scale score, 90-day mortality, and functional status (modified Rankin Scale score). Results- Our cohort comprised 196 patients, 62 NOAC related (mean age, 75.0±11.4 years; 54.8% men) and 134 VKA related (mean age, 72.3±10.5; 73.1% men). There were no differences in vascular comorbidities, antiplatelet, and statin use; NOAC-related ICH patients had lower median baseline hematoma volume (13.8 [2.5-37.6] versus 19.5 [6.6-52.0] mL; P=0.026) and were less likely to have severe neurological deficits (National Institutes of Health Stroke Scale score of >10 points) on admission (37% versus 55.3%, P=0.025). VKA-ICH were more likely to have significant hematoma expansion (37.4% versus 17%, P=0.008). NOAC pretreatment was independently associated with smaller baseline hematoma volume (standardized linear regression coefficient:-0.415 [95% CI, -0.780 to -0.051]) resulting in lower likelihood of severe neurological deficit (odds ratio, 0.44; 95% CI, 0.22-0.85) in multivariable-adjusted models. Conclusions- Patients with NOAC-related ICH have smaller baseline hematoma volumes and lower odds of severe neurological deficit compared with VKA-related ICH. These findings are important for practicing clinicians making anticoagulation choices.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Hematoma; Humans; Male; Middle Aged; Neuroimaging; Prospective Studies; Treatment Outcome; Vitamin K; Warfarin

Patients undergoing anticoagulation therapy often experience intracerebral hemorrhages (ICHs), and warfarin in particular is known to increase hematoma expansion in ICHs, which results in a poor outcome. Recent studies reported that, in comparison with warfarin, direct oral anticoagulants (DOACs) cause fewer ICHs with better functional outcome. However, since it is still unknown whether DOACs are associated with a smaller hematoma volume of ICHs, we aimed to compare the volume, hematoma expansion, and outcomes associated with ICHs treated with DOACs and warfarin.. We performed a prospective multicenter cross-sectional study. The subjects included patients with acute ICHs who received either DOACs or warfarin. We evaluated the clinical characteristics, and measured initial and follow-up ICH volumes. The volume of ICHs and hematoma expansion were compared between the DOAC and warfarin groups. Mortality and modified Rankin score at discharge were evaluated as outcomes.. There were 18 patients in the DOAC group and 71 in the warfarin group. The baseline characteristics were similar between the 2 groups. Initial median hematoma volume of ICHs in the DOAC group was significantly lower than that in the warfarin group (6.2 vs. 24.2 mL, respectively; p = 0.04). In cases involving follow-up computed tomography scanning, the median hematoma volume of ICHs at follow-up was lower in the DOAC group than in the warfarin group (initial: DOACs 4.4 vs. warfarin 13.5 mL; follow-up: 5.0 vs. 18.4 mL, respectively; p = 0.05). Further, the hematoma in ICHs associated with DOACs did not expand. Although the mortality of ICHs associated with DOACs (11%) was lower than that associated with warfarin (24%), this difference was not statistically significant. The univariate analysis showed that the anticoagulant type (DOACs vs. warfarin) and sex (male vs. female) were associated with ICH volume. The multivariable linear regression showed that the use of DOACs (compared to warfarin; β: -0.23, p = 0.03) and female sex (compared to male; β: -0.25, p = 0.02) were associated with a small hematoma volume.. Based on the results of the present study, in terms of the risks associated with ICHs, the use of DOACs appears to be safer than warfarin for anticoagulation therapy. Further studies are required to validate these findings.
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Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Blood Coagulation; Cerebral Hemorrhage; Chi-Square Distribution; Cross-Sectional Studies; Dabigatran; Disability Evaluation; Factor Xa Inhibitors; Female; Hematoma; Humans; Japan; Linear Models; Male; Middle Aged; Multivariate Analysis; Patient Discharge; Prospective Studies; Pyrazoles; Pyridones; Registries; Risk Factors; Rivaroxaban; Tomography, X-Ray Computed; Treatment Outcome; Warfarin

[Background and purpose] Prothrombin fragment 1+2 (PF1+2) is a sensitive marker for blood coagulation system. In order to evaluate anticoagulant activity in patients treated with warfarin or non-vitamin K antagonist oral anticoagulant (NOAC), we measured plasma levels of PF1+2 and evaluated anticoagulant activity by each anticoagulant agent. [Methods] Subjects were 28 patients, 17 men and 11 women, 77±6 year old, with oral anticoagulant therapy for secondary prevention of stroke. We measured plasma levels of PF1+2 in 70 times in 7 patients treated with warfarin, and 154 times in 27 patients treated with NOAC. PT-INR was simultaneously measured in patients treated with warfarin. [Results] In warfarin treatment groups, PT-INR values were median 1.96 (IQR 1.8-2.1) and PF1+2 levels were median 111 pmol/l (IQR 95-141). All PF1+2 levels were below the upper limit of normal range, but 12 values (17%) of them in 5 patients were below the lower limit of normal range. 8 of the 12 values were at PT-INR below 2.5, and 1 of whom developed intracerebral hemorrhage. Plasma levels of PF1+2 in patients treated with dabigatran 150mg BID, dabigatran 110mg BID, rivaroxaban 15mg QD, rivaroxaban 10mg QD, apixaban 5mg BID, apixaban 2.5mg BID, and edxaban 30mg QD were median 116 pmol/l (IQR 99-136), 132 pmol/l (IQR 99-162), 109 pmol/l (IQR 100-125), 133 pmol/l (IQR 100-177), 88 pmol/l (IQR 76-102), 148 pmol/l (IQR 93-167), 221 pmol/l (IQR 208-234). They were all above the lower limit of the normal range, 3 of which were above the upper limit of the normal range. Excessive suppression of thrombin production was more frequently seen in warfarin treatment than in NOAC treatment (p<0.05). [Conclusion] In warfarin treatment, thrombin production was suppressed excessively in 17%, although it was not in NOAC treatment. (Received September 21, 2016; Accepted December 26, 2016; Published May 1, 2017).

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Dabigatran; Female; Humans; Male; Peptide Fragments; Prothrombin; Rivaroxaban; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Humans; Stroke; Warfarin

Limited information is available on the incidence and progress of spontaneous intracerebral haemorrhages in Norway. The objective of this article is to describe the frequency of and the prognosis for such haemorrhages in a geographically well-defined population.. All patients admitted to Vestfold Hospital with a first-time spontaneous intracerebral haemorrhage during the period from 1 September 2010 to 31 May 2014 were included. Age, gender, risk factors, haemorrhaged volume, treatment and mortality were registered. For survivors, the use of nursing and rehabilitation resources was identified, as were neurological function and the ability to cope with daily activities after three months.. A total of 182 patients (102 men) were included. The incidence of first-time intracerebral haemorrhages amounted to 20.5/100 000/year. Altogether 25.8 % used anticoagulants prior to the haemorrhage, and 38.5 % used a platelet inhibitor. After two days 23.0 % had died, while the 30-day mortality amounted to 39.6 %. Warfarin use was associated with a significantly increased 90-day mortality when compared to no anticoagulation treatment (p = 0.002). Of those patients who were alive 90 days after their intracerebral haemorrhage, 50.0 % functioned very well according to their Barthel score, and 67.6 % had returned to their own homes.. First-time spontaneous intracerebral haemorrhage is a serious event with high mortality.

Topics: Activities of Daily Living; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Child; Female; Humans; Incidence; Male; Middle Aged; Norway; Platelet Aggregation Inhibitors; Prognosis; Risk Factors; Warfarin; Young Adult

Non-vitamin K antagonist oral anticoagulant (NOAC) use has significantly reduced intracerebral hemorrhagic (ICH) risk compared with standard anticoagulant treatment. Hematoma expansion (HE) is a known predictor of mortality in warfarin-associated ICH. Little is known about HE in patients using NOACs.. We conducted a retrospective chart review of patients with ICH admitted to Cedars-Sinai Medical Center from October 2010 to June 2016. We identified patients with concomitant administration of an oral anticoagulant and collected data including evidence of HE on imaging and modified Rankin Scale (mRS) at discharge. We defined HE as relative (≥33% increase) or absolute expansion (≥12 mL). We compared outcomes of patients with and without HE.. Out of 814 patients with ICH who were admitted, we identified 9 patients with recent NOAC use and 18 intentionally matched controls on warfarin. We found no significant differences in National Institutes of Health Stroke Scale or ICH score on presentation (median [interquartile range] 15 [5,21] versus 7 [1.25,19.5] [P = .41] and 2 [1,4] versus 1 [1,3] [P = .33]) between patients on NOACs and those on warfarin. Four out of the 9 patients on NOAC and 5 of the 18 patients on warfarin demonstrated HE, with no significant difference (P = .42). There were no significant differences in mRS on discharge between groups (P = .52).. In our coagulopathic NOAC patient population, HE occurs within 6 hours in 44% of patients. This case series did not have sufficient statistical power to detect significant differences between the groups. To our knowledge, this is one of the largest case series reporting on HE with concomitant NOAC use.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Disability Evaluation; Female; Hematoma; Humans; Los Angeles; Magnetic Resonance Imaging; Male; Middle Aged; Retrospective Studies; Risk Factors; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Warfarin

Limited real-world data exist comparing each non-vitamin K antagonist oral anticoagulant (NOAC) to warfarin in patients with nonvalvular atrial fibrillation who have had a previous ischemic stroke or transient ischemic attack.. Using MarketScan claims from January 2012 to June 2015, we identified adults newly initiated on oral anticoagulation, with ≥2 diagnosis codes for nonvalvular atrial fibrillation, a history of previous ischemic stroke/transient ischemic attack, and ≥180 days of continuous medical and prescription benefits before anticoagulation initiation. Three analyses were performed comparing 1:1 propensity score-matched cohorts of apixaban versus warfarin (n=2514), dabigatran versus warfarin (n=1962), and rivaroxaban versus warfarin (n=5208). Patients were followed until occurrence of a combined end point of ischemic stroke and intracranial hemorrhage (ICH) or major bleed, switch/discontinuation of index oral anticoagulation, insurance disenrollment, or end of follow-up. Mean follow-up was 0.5 to 0.6 years for all matched cohorts.. Using Cox regression, neither apixaban nor dabigatran reduced the combined primary end point of ischemic stroke or ICH (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.33-1.48 and HR, 0.53; 95% CI, 0.26-1.07) and had nonsignificant effect on hazards of major bleeding (HR, 0.79; 95% CI, 0.38-1.64 and HR, 0.58; 95% CI, 0.26-1.27) versus warfarin. Rivaroxaban reduced the combined end point of ischemic stroke or ICH (HR, 0.45; 95% CI, 0.29-0.72) without an effect on major bleeding (HR, 1.07; 95% CI, 0.71-1.61). ICH occurred at rates of 0.16 to 0.61 events per 100 person-years in the 3 NOAC analyses, with no significant difference for any NOAC versus warfarin.. Results from our study of the 3 NOACs versus warfarin in nonvalvular atrial fibrillation patients with a previous history of stroke/transient ischemic attack are relatively consistent with their respective phase III trials and previous stroke/transient ischemic attack subgroup analyses. All NOACs seemed no worse than warfarin in respect to ischemic stroke, ICH, or major bleeding risk.

Topics: Adolescent; Adult; Aged; Anticoagulants; Antithrombins; Atrial Fibrillation; Cerebral Hemorrhage; Cohort Studies; Dabigatran; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Ischemic Attack, Transient; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Treatment Outcome; Warfarin; Young Adult

Topics: Aged; Anticoagulants; Blood Coagulation Disorders; Blood Coagulation Factors; Cerebral Hemorrhage; Humans; Male; Warfarin

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Dabigatran; Humans; Male; Off-Label Use; Stroke; Warfarin

New oral anticoagulants for the prevention of stroke and systemic embolism in patients with atrial fibrillation have recently been introduced. In this translational study, we explored the risk of long-term anticoagulation on intracerebral hemorrhage under sustained severe arterial hypertension. We initiated anticoagulation with warfarin or apixaban in spontaneously hypertensive rats prone to develop severe hypertension and subsequent intracerebral bleeding complications. A non-anticoagulated group served as control. During an 11-week-study period, blood pressure, anticoagulation parameters, and clinical status were determined regularly. The incidence of histopathologically proven intracerebral hemorrhage was defined as the primary endpoint. Both warfarin and apixaban anticoagulation was fairly stable during the study period, and all rats developed severe hypertension. Intracerebral hemorrhage was determined in 29% (4/14) of warfarin rats and in 10% (1/10) of apixaban rats. Controls did not show cerebral bleeding complications (chi-square not significant). Mortality rate at study termination was 33% (2/6) in controls, 43% (6/14) in the warfarin group, and 60% (6/10) in the apixaban group. Animals died from extracerebral complications in most cases. Our study describes an experimental intracerebral hemorrhage model in the context of sustained hypertension and long-term anticoagulation. Extracerebral bleeding complications occurred more often in warfarin-treated animals compared with apixaban and control rats.

Topics: Animals; Anticoagulants; Cerebral Hemorrhage; Hemorrhage; Hypertension; Pyrazoles; Pyridones; Rats; Time Factors; Warfarin

Intracerebral hemorrhage (ICH) during oral anticoagulation therapy with an oral vitamin K epoxidase reductase such as warfarin is a life-threatening complication. However, whether direct oral anticoagulants (DOACs) are associated with larger hematoma volume and higher mortality rates remains controversial. We evaluated the hematoma volume and pathophysiology of ICH during anticoagulation with warfarin or rivaroxaban, an orally active direct factor Xa inhibitor.. Mice were orally pretreated with rivaroxaban (10 or 30 mg/kg), warfarin (4 mg/kg), or vehicle. ICH was induced by intrastriatal collagenase-injection. Hematoma volume and neurological deficits 24 h after ICH induction were significantly decreased in the rivaroxaban-pretreated group in comparison with the warfarin-pretreated group. Rivaroxaban did not increase the hematoma volume relative to that observed for vehicle, and improved survival rate 7 days after ICH induction compared with warfarin.. We evaluated blood-brain barrier (BBB) permeability 6 h after ICH induction using Evans blue spectrophotometry. Evans blue extravasation was significantly reduced in the rivaroxaban group compared with the warfarin group. To investigate the mechanism underlying hematoma expansion and BBB permeability, we focused on thrombin, a clot-derived factor and one of the major contributors to ICH-induced brain injury. To investigate the effects of anticoagulant agents on thrombin-induced injuries, human brain endothelial cells were used in membrane permeability assays. Rivaroxaban, but not warfarin, significantly mitigated the thrombin-induced increase in membrane permeability.. These findings indicate that rivaroxaban decreases BBB disruption after ICH, and limits early hematoma expansion in these experimental models compared with warfarin. Our study suggests that rivaroxaban has advantages over warfarin with respect to ICH, an important complication during long-term anticoagulation therapy.

Topics: Animals; Anticoagulants; Blood-Brain Barrier; Cells, Cultured; Cerebral Hemorrhage; Disease Models, Animal; Electric Impedance; Endothelial Cells; Factor Xa Inhibitors; Hematoma; Isothiocyanates; Mice; Neurologic Examination; Permeability; Rivaroxaban; Treatment Outcome; Warfarin

This study aimed to assess the risk of intracerebral hemorrhage (ICH) after tissue-type plasminogen activator (tPA) treatment in rivaroxaban compared with warfarin-pretreated male Wistar rat brain after ischemia in relation to activation profiles of protease-activated receptor-1, -2, -3, and -4 (PAR-1, -2, -3, and -4). After pretreatment with warfarin (0.2 mg/kg/day), low-dose rivaroxaban (60 mg/kg/day), high-dose rivaroxaban (120 mg/kg/day), or vehicle for 14 days, transient middle cerebral artery occlusion was induced for 90 min, followed by reperfusion with tPA (10 mg/kg/10 ml). Infarct volume, hemorrhagic volume, immunoglobulin G leakage, and blood parameters were examined. Twenty-four hours after reperfusion, immunohistochemistry for PARs was performed in brain sections. ICH volume was increased in the warfarin-pretreated group compared with the rivaroxaban-treated group. PAR-1, -2, -3, and -4 were widely expressed in the normal brain, and their levels were increased in the ischemic brain, especially in the peri-ischemic lesion. Warfarin pretreatment enhanced the expression of PAR-1 and PAR-2 in the peri-ischemic lesion, whereas rivaroxaban pretreatment did not. The present study shows a lower risk of brain hemorrhage in rivaroxaban-pretreated compared with warfarin-pretreated rats following tPA administration to the ischemic brain. It is suggested that the relative downregulation of PAR-1 and PAR-2 by rivaroxaban compared with warfarin pretreatment might be partly involved in the mechanism of reduced hemorrhagic complications in patients receiving rivaroxaban in clinical trials. © 2016 Wiley Periodicals, Inc.

Topics: Animals; Anticoagulants; Cerebral Hemorrhage; Down-Regulation; Factor Xa Inhibitors; Fibrinolytic Agents; Male; Rats; Rats, Wistar; Receptor, PAR-1; Receptor, PAR-2; Rivaroxaban; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator; Warfarin

For stroke prevention, patients with atrial fibrillation typically receive oral anticoagulation. The commonly used anticoagulant warfarin increases the risk of hemorrhagic transformation (HT) when a stroke occurs; tissue-type plasminogen activator treatment is therefore restricted in these patients. This study was designed to test the hypothesis that 12/15-lipoxygenase (12/15-LOX) inhibition would reduce HT in warfarin-treated mice subjected to experimental stroke.. Warfarin was dosed orally in drinking water, and international normalized ratio values were determined using a Coaguchek device. C57BL6J mice or 12/15-LOX knockout mice were subjected to transient middle cerebral artery occlusion with 3 hours severe ischemia (model A) or 2 hours ischemia and tissue-type plasminogen activator infusion (model B), with or without the 12/15-LOX inhibitor ML351. Hemoglobin was determined in brain homogenates, and hemorrhage areas on the brain surface and in brain sections were measured. 12/15-LOX expression was detected by immunohistochemistry.. Warfarin treatment resulted in reproducible increased international normalized ratio values and significant HT in both models. 12/15-LOX knockout mice suffered less HT after severe ischemia, and ML351 reduced HT in wild-type mice. When normalized to infarct size, ML351 still independently reduced hemorrhage. HT after tissue-type plasminogen activator was similarly reduced by ML351.. In addition to its benefits in infarct size reduction, 12/15-LOX inhibition also may independently reduce HT in warfarin-treated mice. ML351 should be further evaluated as stroke treatment in anticoagulated patients suffering a stroke, either alone or in conjunction with tissue-type plasminogen activator.

Topics: Animals; Anticoagulants; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Cerebral Hemorrhage; Enzyme Inhibitors; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Stroke; Warfarin

Direct oral anticoagulants (DOACs) have shown noninferiority to warfarin for stroke prevention in nonvalvular atrial fibrillation (AF) and a more promising safety profile. Unanswered safety aspects remain to be addressed and available evidence on the risk associated with these drugs are conflicting. In order to contribute to the debate on their safety profile, we conducted a comparative analysis of the reports of suspected adverse drug reactions (ADRs) associated with DOACs in VigiBase.. Study based on reports of suspected ADRs held in VigiBase as at December 2014, in which a DOAC or warfarin were administered in patients with nonvalvular AF and listed as suspected/interacting drugs. Medical Dictionary for Regulatory Activities was used to classify ADRs. Reporting odds ratio (ROR) with 95% confidence interval were calculated. Results with P ≤ 0.05 were statistically significant.. We retrieved 32 972 reports. We identified 204 ADRs with a ROR >1 (P ≤ 0.05) and we focused on 105 reactions. Positive ROR emerged for DOACs and gastrointestinal haemorrhage compared with warfarin [(1.6 (1.47-1.75)], but no disproportionality with cerebral haemorrhage was found [0.31 (0.28-0.34)]. We identified other potential signals that have not been associated with DOACs previously.. As well as premarketing authorization clinical trial studies, we found a reduced risk of intracranial haemorrhage, but an increased risk of gastrointestinal haemorrhage in patients treated with DOACs compared to warfarin. We provide new data and we highlight several differences between the three novel oral anticoagulants, in the rate and type of ADRs occurred.

Topics: Administration, Oral; Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Child; Child, Preschool; Dabigatran; Databases, Factual; Female; Gastrointestinal Hemorrhage; Humans; Infant; Infant, Newborn; Male; Middle Aged; Pyrazoles; Pyridones; Risk Factors; Rivaroxaban; Stroke; Warfarin; World Health Organization; Young Adult

Bridging anticoagulation is commonly prescribed to patients with atrial fibrillation who are initiating warfarin or require interruption of anticoagulation. Current guidelines recommend bridging for patients at high risk of stroke. Among patients with atrial fibrillation and one or more risk factors for ischemic stroke, the recently published BRIDGE trial found forgoing bridging during interruption to be, on average, noninferior to bridging with respect to ischemic complications, with significantly fewer hemorrhagic complications.. We sought to examine the benefits and harms of bridging anticoagulation across the spectrum of ischemic and hemorrhagic stroke risk and thereby enable more nuanced, risk-stratified decision-making when bridging is considered during initiation or interruption of vitamin K antagonists.. A Monte Carlo simulation, using a combination of literature-derived estimates, registry data, and trial data.. Net clinical benefit, weighting for ischemic strokes, intracranial hemorrhages, and extracranial major hemorrhages.. The benefits and harms of bridging anticoagulation vary according to underlying patient risk profiles for both thromboembolic stroke and major intracranial bleeding. Patients at high risk of ischemic stroke and low risk of hemorrhage derive benefit from bridging during initiation or interruption of warfarin therapy. Patients at similarly high or low risk of both outcomes may receive benefit from bridging during initiation and bridging during interruption, but this was sensitive to underlying assumptions. The need for stratification along both axes of risk was robust to a wide range of parameters.. Bridging anticoagulation may provide benefit to patients at high risk of ischemic stroke and low risk of intracranial hemorrhage who are initiating or interrupting warfarin therapy, while patients at high or low risk of both complications may be harmed. The use of bridging anticoagulation in patients with non-valvular atrial fibrillation should be considered only after stratification by risk of ischemic and hemorrhagic complications.

Topics: Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Drug Administration Schedule; Drug Therapy, Combination; Hemorrhage; Humans; International Normalized Ratio; Monte Carlo Method; Risk Assessment; Stroke; Thromboembolism; Warfarin

The direct oral anticoagulants (DOACs) have been compared with parenteral anticoagulants and vitamin K antagonists (VKAs) for the treatment of venous thromboembolism (VTE) in several robust studies. DOACs have shown similar efficacy in preventing recurrent VTE and significant reductions in critical site (intracranial) bleeding, fatal bleeding, major and nonmajor bleeding. Warfarin and other VKAs are not dead as treatment modalities for VTE. A better way to describe the current situation is to use a boxing expression, "down but not out." VKAs and parenteral anticoagulants still have a role to play in the management of VTE in several clinical settings. In indications where DOACs can be used, VKAs should not, as the safety profile of VKAs is considerably worse than DOACs. Hence, guidelines are now recommending DOACs in preference to VKAs. In this article, we consider where DOACs are indicated, where there is growing evidence for use, where we have little evidence for use, and finally where there is no evidence for use and where they, thus, should not be used. We have included recommendations and examples of our own practice which may not be applicable to all settings.

Topics: Administration, Oral; Anticoagulants; Cerebral Hemorrhage; Humans; Secondary Prevention; Venous Thromboembolism; Warfarin

Coagulopathy-associated intracerebral haemorrhage has become increasingly common because of the rising demand in the ageing population for anticoagulation for atrial fibrillation. This study compared the clinical features and neurological outcomes of intracerebral haemorrhage in patients with atrial fibrillation who were prescribed warfarin with those who were not.. This was a retrospective matched case series of patients with intracerebral haemorrhage from three tertiary hospitals in Hong Kong from 1 January 2006 to 31 December 2011. Patients who developed intracerebral haemorrhage and who were prescribed warfarin for atrial fibrillation (ICH-W group) were compared with those with intracerebral haemorrhage and not prescribed warfarin (ICH-C group); they were matched for age and gender in 1:1 ratio. Clinical features and neurological outcomes were compared, and the impact of coagulopathy on haematoma size was also studied.. We identified 114 patients in the ICH-W group with a mean age of 75 years. Both ICH-W and ICH-C groups had a median intracerebral haemorrhage score of 2. There was a non-statistically significant trend of higher intracerebral haemorrhage volume in the ICH-W group (12.9 mL vs 10.5 mL). The median modified Rankin Scale and the proportion with good recovery (modified Rankin Scale score ≤3) at 6 months were comparable. Nonetheless, ICH-W patients had higher hospital mortality (51.8% vs 36.0%; P=0.02) and 6-month mortality (60.5% vs 43.0%; P=0.01) than ICH-C patients. Overall, 60% of ICH-W patients had their admission international normalised ratio within the therapeutic range during intracerebral haemorrhage, and 14% had a subtherapeutic admission international normalised ratio. International normalised ratio at admission was not associated with intracerebral haemorrhage volume or neurological outcome.. Warfarin-associated intracerebral haemorrhage in patients with atrial fibrillation carried a higher stroke mortality than the non-warfarinised patients.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Case-Control Studies; Cerebral Hemorrhage; Female; Hong Kong; Humans; Male; Middle Aged; Retrospective Studies; Severity of Illness Index; Tomography, X-Ray Computed; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Humans; Warfarin

This study aimed at identifying the determinants and prognostic significance of a sedimentation level (fluid-blood level) in the hematoma among patients with acute intracerebral hemorrhage (ICH) who participated in the main Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2).. Post-hoc analysis of the INTERACT2 dataset, a randomized controlled trial of patients with acute ICH with elevated systolic blood pressure (SBP), randomly assigned to intensive (target SBP <140 mm Hg) or guideline-based (<180 mm Hg) BP management. Patients with a sedimentation level at baseline assessment on CT, and modified Rankin Scale score at 90-day, were included in these analyses. Factors associated with a sedimentation level and its significance in relation to 90-day clinical outcomes were assessed in univariable and multivariable logistic regression models.. Of 2,065 participants, 19 (1%) had sedimentation level on baseline CT, which was independently associated with warfarin use (p = 0.006) and lobar ICH (p = 0.025). Sedimentation level was also associated with death or major disability at 90-day in both crude (84 vs. 53%; p = 0.014) and multivariable analyses adjusted for age, gender, Chinese region, warfarin use, baseline National Institutes of Health Stroke Scale score, onset to CT time, volume and location of ICH, intraventricular extension, and randomized intensive BP lowering (OR 3.94, 95% CI 1.01-15.37; p = 0.049).. The presence of hematoma sedimentation level on baseline CT is associated with warfarin use and lobar location of ICH, and predicts a worse outcome. Although uncommon, sedimentation level is an easily detectable prognostic factor in acute ICH.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antihypertensive Agents; Cerebral Hemorrhage; Disease Management; Female; Hematoma; Humans; Hypertension; Logistic Models; Male; Middle Aged; Multivariate Analysis; Prognosis; Risk Factors; Tomography, X-Ray Computed; Warfarin

To compare intracerebral hemorrhage (ICH) volume and clinical outcome of non-vitamin K oral anticoagulants (NOAC)-associated ICH to warfarin-associated ICH.. In this multicenter cross-sectional observational study of patients with anticoagulant-associated ICH, consecutive patients with NOAC-ICH were compared to those with warfarin-ICH selected from a population of 344 patients with anticoagulant-associated ICH. ICH volume was measured by an observer blinded to clinical details. Outcome measures were ICH volume and clinical outcome adjusted for confounding factors.. We compared 11 patients with NOAC-ICH to 52 patients with warfarin-ICH. The median ICH volume was 2.4 mL (interquartile range [IQR] 0.3-5.4 mL) for NOAC-ICH vs 8.9 mL (IQR 4.0-21.3 mL) for warfarin-ICH (p = 0.0028). In univariate linear regression, use of warfarin (difference in cube root volume 1.61; 95% confidence interval [CI] 0.69 to 2.53) and lobar ICH location (compared with nonlobar ICH; difference in cube root volume 1.52; 95% CI 2.20 to 0.85) were associated with larger ICH volumes. In multivariable linear regression adjusting for confounding factors (sex, hypertension, previous ischemic stroke, white matter disease burden, and premorbid modified Rankin Scale score [mRS]), warfarin use remained independently associated with larger ICH (cube root) volumes (coefficient 0.64; 95% CI 0.24 to 1.25; p = 0.042). Ordered logistic regression showed an increased odds of a worse clinical outcome (as measured by discharge mRS) in warfarin-ICH compared with NOAC-ICH: odds ratio 4.46 (95% CI 1.10 to 18.14; p = 0.037).. In this small prospective observational study, patients with NOAC-associated ICH had smaller ICH volumes and better clinical outcomes compared with warfarin-associated ICH.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Cross-Sectional Studies; Female; Humans; Male; Outcome Assessment, Health Care; Warfarin

Early or delayed onset of oral anticoagulant therapy in patients with acute ischemic stroke with atrial fibrillation is an unsolved issue. Retrospectively, 294 patient records at two hospitals were scrutinized according to a protocol consisting of 20 items regarding choice of therapy (warfarin or NOAC), time for onset of therapy, CT findings of bleeding, capacity to swallow, and occurrence of clinical deterioration during the acute phase. Out of 249 patients who survived the acute phase, 116 (47%) patients were given a new prescription of warfarin or NOAC at discharge, while 43 (17 %) continued with anticoagulant therapy already prescribed before the onset of stroke. The median value for new prescriptions in relation to stroke admission was 5 days. The pattern was similar for warfarin and NOAC. Patients in whom anticoagulant therapy was started early were characterized by good capacity to swallow and no signs of bleeding on initial CT. The question »early or delayed onset of oral anticoagulant therapy after acute ischemic stroke with atrial fibrillation« needs to be tested in a randomized clinical trial.

Topics: Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Dabigatran; Deglutition Disorders; Humans; Medical Records; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Rivaroxaban; Stroke; Time Factors; Time-to-Treatment; Treatment Outcome; Warfarin

Warfarin is used worldwide to prevent cardioembolic stroke (CES) in patients with atrial fibrillation even in the era of direct oral anticoagulant (DOAC). We evaluated clinical characteristics of the patients with CES and intracerebral hemorrhage (ICH) occurring during warfarin treatment, focusing on prothrombin time-international normalized ratio (PT-INR) at the occurrence. The consecutive 846 CES patients (78 ± 9 years) and 870 ICH patients (68 ± 13 years) admitted to the Hirosaki Stroke and Rehabilitation Center from April 2011 through March 2015 were studied. The antithrombotic agents administered in CES patients before the onset included antiplatelets in 146 patients (17%), warfarin in 205 (24%), DOAC in 37 (5%), and none in the other 458 (54%). Mean PT-INR within 24 hours after the onset in nonvalvular atrial fibrillation patients with warfarin was 1.34 ± 0.33 (n = 129), and 111 of them (86%) showed PT-INR value below the recommended therapeutic range in Japan. The antithrombotic agents administered in ICH patient included antiplatelets in 87 patients (10%), warfarin in 86 (10%), DOAC in 8 (1%), and none in the other 689 (79%). Mean PT-INR within 24 hours after the onset in patients with warfarin was 2.27 ± 0.62 (n = 65), and 56 of them (86%) showed PT-INR < 2.8. Thus, there is a large population with poor warfarin control complicating CES and that with good warfarin control complicating ICH, indicating limitation of warfarin treatment in the DOAC era.

Topics: Administration, Oral; Age Distribution; Age of Onset; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Female; Humans; International Normalized Ratio; Japan; Male; Middle Aged; Myocardial Infarction; Prothrombin Time; Sex Factors; Warfarin

The volume of intracerebral hemorrhage (ICH) measured at hospital admission is the strongest predictor of clinical outcomes in patients with ICH. Despite the high incidence rate of ICH in Asians, there is lack of data regarding predictors of ICH volume in this ethnic group. The purpose of this study was to determine predictors of deep ICH volume and examine their effect on short-term mortality in Asians.. Hematoma volume was measured using the ABC/2 method. ICH volume was transformed to the natural log scale to normalize distributions for all analyses. We estimated the coefficients of ICH volume based on relevant predictors using multivariable linear regression. We also determined the association between body mass index (BMI) and ICH volume using a regression line and a line determined by a locally weighted scatter plot smoothing.. A total of 1,039 patients from 2 twin hospitals in Korea who were admitted with primary spontaneous supratentorial deep ICH over a 12-year period were enrolled in this study. The median ICH volume was 19.7 ml. The average patient age was 59.2, and 62.4% of patients were men. The mean ICH volume showed a gradual, approximately 2% decrease per 1 BMI increase in the current study, after adjusting for all relevant variables (β = -0.024; SE 0.004; p < 0.001). In addition, patients with frequent alcohol consumption showed a 10% increase in mean ICH volume (β = 0.098; SE 0.041; p = 0.016), and patients undergoing warfarin treatment showed a 30% increase in mean ICH volume after full adjustment of all relevant variables (β = 0.296; SE 0.050; p < 0.001). Relative to overweight patients, there was a 47, 11, and 18% increase in admission mean ICH volume in underweight, normal weight and obese patients, respectively. Patients in the first quartile and underweight BMI groups had 1.45-fold (hazard ratio (HR) 1.45; 95% CI 1.03-2.03; p = 0.035) and 1.77-fold (HR 1.77; 95% CI 1.10-2.84; p = 0.019) higher increased risk of death during the first 3 months after ICH, retrospectively. In addition, patients in groups with frequent alcohol consumption and warfarin use both showed a significant association with mortality 90 days after ICH.. We demonstrated the association between various predictors and admission ICH volume with short-term mortality in Asians. Further studies are needed to account for these observations and determine their underlying mechanisms.

Topics: Aged; Alcohol Drinking; Angiography, Digital Subtraction; Anticoagulants; Asian People; Body Mass Index; Cerebral Angiography; Cerebral Hemorrhage; Computed Tomography Angiography; Female; Humans; Kaplan-Meier Estimate; Linear Models; Magnetic Resonance Angiography; Male; Middle Aged; Multivariate Analysis; Obesity; Patient Admission; Republic of Korea; Retrospective Studies; Risk Factors; Thinness; Time Factors; Warfarin

The neuroradiological findings and its outcomes of intracerebral hemorrhage (ICH) were compared between the non-vitamin K antagonist oral anticoagulant (NOAC) therapy and warfarin therapy. In the latest 3 years, 13 cases of nonvalvular atrial fibrillation on NOAC therapy were admitted for ICH. For comparison, 65 age- and gender-comparable patients with ICH on warfarin therapy were recruited. Three NOACs had been prescribed: dabigatran (n = 4), rivaroxaban (n = 2), and apixaban (n = 7). The average ages were 76 ± 9 and 78 ± 8 years in the warfarin (n = 65) and NOAC groups (n = 13), respectively. There was no difference in the clinical features, including the CHADS2 score or HAS-BLED score: 2.62 ± 1.31 versus 2.62 ± 1.33, or 1.09 ± 0.43 versus 1.00 ± 0.41, for the warfarin and NOAC groups, respectively. The volume of ICH <30 ml was found in 84.6% of the patients on NOACs, but it was found in 53.8% of the patients on warfarin (p = 0.0106). The expansion of hematoma was limited to 7 patients (10.8%) of the warfarin group. A lower hospital mortality and better modified Rankin Scale were observed in the NOAC group than in the warfarin group: 1 (7.7%) versus 27 (41.5%; p = 0.0105) and 3.2 ± 1.4 versus 4.5 ± 1.6 (p = 0.0057), respectively. In conclusion, ICH on NOAC therapy had smaller volume of hematoma with reduced rate of expansion and decreased mortality compared with its occurrence on warfarin.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Brain; Case-Control Studies; Cerebral Hemorrhage; Dabigatran; Factor Xa Inhibitors; Female; Hematoma; Hospital Mortality; Humans; Male; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Tomography, X-Ray Computed; Warfarin

In heart failure (HF), left ventricular ejection fraction (LVEF) is inversely associated with mortality and cardiovascular outcomes. Its relationship with stroke is controversial, as is the effect of antithrombotic treatment. We studied the relationship of LVEF with stroke and cardiovascular events in patients with HF and the effect of different antithrombotic treatments.. In the Warfarin Versus Aspirin in Reduced Ejection Fraction (WARCEF) trial, 2305 patients with systolic HF (LVEF≤35%) and sinus rhythm were randomized to warfarin or aspirin and followed for 3.5±1.8 years. Although no differences between treatments were observed on primary outcome (death, stroke, or intracerebral hemorrhage), warfarin decreased the stroke risk. The present report compares the incidence of stroke and cardiovascular events across different LVEF and treatment subgroups.. Baseline LVEF was inversely and linearly associated with primary outcome, mortality and its components (sudden and cardiovascular death), and HF hospitalization, but not myocardial infarction. A relationship with stroke was only observed for LVEF of <15% (incidence rates: 2.04 versus 0.95/100 patient-years; P=0.009), which more than doubled the adjusted stroke risk (adjusted hazard ratio, 2.125; 95% CI, 1.182-3.818; P=0.012). In warfarin-treated patients, each 5% LVEF decrement significantly increased the stroke risk (adjusted hazard ratio, 1.346; 95% CI, 1.044-1.737; P=0.022; P value for interaction=0.04).. In patients with systolic HF and sinus rhythm, LVEF is inversely associated with death and its components, whereas an association with stroke exists for very low LVEF values. An interaction with warfarin treatment on stroke risk may exist.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00041938.

Topics: Aged; Aspirin; Cardiovascular Diseases; Cerebral Hemorrhage; Female; Heart Failure; Humans; Incidence; Male; Middle Aged; Risk Factors; Stroke; Stroke Volume; Treatment Outcome; Ventricular Function, Left; Warfarin

Topics: Aged; Anticoagulants; Cerebral Hemorrhage; Female; Hematoma, Subdural; Humans; Medication Errors; Risk Assessment; Tomography, X-Ray Computed; Warfarin

Background and purpose Blood pressure reduction is a promising intervention for acute intracerebral hemorrhage, but clinical trials of this treatment often exclude those with anticoagulant-associated intracerebral hemorrhage, leaving it unclear whether this population might benefit. We examined whether persistently elevated blood pressure values (blood pressure burden) over the first 24 h are associated with hematoma expansion and mortality in anticoagulant-associated intracerebral hemorrhage. Methods We retrospectively identified consecutive patients with primary anticoagulant-associated intracerebral hemorrhage (warfarin anticoagulation) who presented within 6 h after symptom onset and a matched set of non-anticoagulant-associated intracerebral hemorrhage patients. Associations between 24 h blood pressure burden, hematoma expansion, and mortality were evaluated using univariable and multivariable logistic regression. Results Sixty-nine anticoagulant-associated intracerebral hemorrhage and 69 matched non-anticoagulant-associated intracerebral hemorrhage patients were included. Hematoma expansion occurred in 25 anticoagulant-associated intracerebral hemorrhage patients (36%) and 15 control patients (22 %; p = 0.091). Twenty-four-hour blood pressure burden was in fact lower in anticoagulant-associated intracerebral hemorrhage than in non-anticoagulant-associated intracerebral hemorrhage patients (p = 0.033). No association was found in anticoagulant-associated intracerebral hemorrhage and non-anticoagulant-associated intracerebral hemorrhage between BP burden, hematoma expansion, and 30-day mortality. Conclusion We found no evidence that higher 24 h blood pressure burden is associated with hematoma expansion or mortality in anticoagulant-associated intracerebral hemorrhage.

Topics: Aged; Anticoagulants; Blood Pressure; Cerebral Hemorrhage; Female; Humans; Logistic Models; Male; Multivariate Analysis; Retrospective Studies; Tomography, X-Ray Computed; Warfarin

The use of antithrombotic medication (ATM) frequently is reported in patients with intracranial hemorrhage (ICH) and is associated with increased mortality. Unfortunately, ATMs sometimes are prescribed and/or used inappropriately. We sought to determine the rate of ATM misprescription/misuse among patients with ICH in a single-center retrospective study.. All patients admitted with ATM-related ICH in 1998-2014 were included. Charts were reviewed and demographic, clinical, and radiologic variables were recorded. The type of ATM, dose, and duration of treatment were analyzed critically. The adequacy of ATM prescription/use was assessed in light of the recommendations and guidelines of the American Heart Association, American Stroke Association, and French National Authority for Health, in effect at the time of admission.. A total of 106 patients with mean age 68 years were identified. Aspirin (53.8%) was the most commonly used drug, followed by oral anticoagulants (31.1%) and clopidogrel (22.6%). In only 80 patients (75.5%), the use of ATM was in line with contemporary guidelines. In the remaining 26 (24.5%), the use of ATMs was inappropriate, including bad drug combination, wrong dose, poor indication, wrong drug class, and/or incorrect treatment duration.. In this Lebanese cohort of patients with ICH, the 24.5% rate of ATM misprescription and/or misuse is highly alarming and the origin of this problem is likely multifactorial. Immediate measures should be undertaken, and efforts should be focused on regaining tight control of ATM prescription and fulfillment, ensuring good patient education, and offering more vigilant oversight on physician licensure.

Topics: Acenocoumarol; Adult; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Atrial Fibrillation; Cerebral Hemorrhage; Clopidogrel; Coronary Artery Disease; Enoxaparin; Female; Fibrinolytic Agents; Humans; Inappropriate Prescribing; Intracranial Hemorrhages; Lebanon; Male; Middle Aged; Platelet Aggregation Inhibitors; Prescription Drug Misuse; Retrospective Studies; Risk Factors; Stroke; Ticlopidine; Warfarin; Young Adult

Patients with intracerebral hemorrhage during rivaroxaban treatment have small hematoma and favorable outcomes compared with those with warfarin. We investigated its possible mechanism, focusing on prothrombin fragment 1+2 (F1+2), a marker of thrombin generation.. In 65 patients with acute cardioembolic stroke (median 77years), rivaroxaban was initiated at 5days after the onset. Plasma F1+2 level (normal range, 69-229pmol/L), prothrombin time (PT), and rivaroxaban concentration evaluated by anti-Xa activity were serially measured.. Rivaroxaban retains a normal thrombin generation even at its peak level with prolonged PT, whereas warfarin at therapeutic levels inhibits thrombin generation. This may partly explain different outcomes in patients complicated with bleeding events.

Topics: Acute Disease; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Factor Xa Inhibitors; Female; Fibrin Fibrinogen Degradation Products; Hemorrhage; Humans; Male; Peptide Fragments; Prothrombin; Prothrombin Time; Rivaroxaban; Stroke; Warfarin

A 45-year-old man receiving warfarin treatment suffered from an intracerebral hemorrhage. Four-factor prothrombin complex concentrate (PCC) was administered to correct coagulopathy. However, bilateral renal infarcts and a cerebral infarct developed on day 5 and 7, respectively after PCC administration. Although the occurrence of PCC-related thromboembolism is low, health care practitioners should closely follow-up the symptoms and signs of thrombosis after PCC administration.

Topics: Anticoagulants; Cerebral Hemorrhage; Cerebral Infarction; Drug Combinations; Factor IX; Factor VII; Factor X; Humans; Infarction; Kidney; Male; Middle Aged; Prothrombin; Warfarin

Topics: Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Blood Coagulation; Case-Control Studies; Cerebral Hemorrhage; Dabigatran; Humans; Thromboplastin; Warfarin

Little is known about the pathophysiology of oral anticoagulation-associated intracerebral hemorrhage (OAC-ICH). We compared hematoma volume, number of terminal deoxynucleotidyl dUTP nick-end labeling (TUNEL)-positive cells (indicating cell death), MMP-9 levels, and perilesional edema formation between warfarin-treated mice and controls. Intracerebral hemorrhage was induced by an injection of collagenase into the right striatum. Twenty-four hours later, hematoma volume was measured using a photometric hemoglobin assay. Cell death was quantified using TUNEL staining. MMP-9 levels were determined by zymography, and edema formation was assessed via the wet-dry method. Warfarin increased hematoma volume by 2.6-fold. The absolute number of TUNEL-positive cells in the perihematomal zone was lower in warfarin-treated animals (300.5 ± 39.8 cells/mm2) than in controls (430.5 ± 38.9 cells/mm2; p = 0.034), despite the larger bleeding volume. MMP-9 levels were reduced in anticoagulated mice as compared to controls (p = 0.018). Perilesional edema formation was absent in warfarin mice and modestly present in controls. Our results suggest differences in the pathophysiology of OAC-ICH compared to intracerebral hemorrhage occurring under normal coagulation. A likely explanation is that thrombin, a strong inductor of apoptotic cell death and blood-brain barrier disruption, is produced to a lesser extent in OAC-ICH. In humans, however, we assume that the detrimental effects of a larger hematoma volume in OAC-ICH by far outweigh potential protective effects of thrombin deficiency.

Topics: Animals; Anticoagulants; Brain Edema; Cell Death; Cerebral Hemorrhage; Disease Models, Animal; Drug Administration Schedule; Hematoma; In Situ Nick-End Labeling; Male; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Mice; Neurologic Examination; Statistics, Nonparametric; Warfarin

Topics: Anticoagulants; Brain Ischemia; Cerebral Hemorrhage; Female; Humans; Male; Stroke; Warfarin

Topics: Anticoagulants; Cerebral Hemorrhage; Hemorrhage; Humans; International Normalized Ratio; Intracranial Hemorrhages; Warfarin

Topics: Anticoagulants; Cerebral Hemorrhage; Hemorrhage; Humans; International Normalized Ratio; Intracranial Hemorrhages; Warfarin

We investigated the clinical characteristics and prognosis of intracerebral hemorrhage(ICH)under antithrombotic therapy. We retrospectively reviewed the medical records of 463 patients admitted to our hospital due to ICH during 3-year periiod between January 2010 and December 2012. The ICH patients were classified into 4 groups: patients with anticoagulant therapy(AC, n=36), antiplatelet therapy(AP, n=65), anticoagulant and antiplatelet therapies(AC+AP, n=18), and no antiplatelet or anticoagulant therapy(NT, n=344). There were no significant differences between the groups in terms of gender, hematoma location, and initial hematoma size. Age and previous history of ischemic cerebral disease or ischemic coronary disease were significantly higher in the AC, AP, and AC+AP groups than in the NT group. The number of patients who had received previous treatment for hypertension was higher in the AC, AP, and AC+AP groups, and systolic blood pressure at admission was lower in the AC and AC+AP groups than in the NT group. Hematoma enlargement occurred more frequently in the AC and AC+AP groups. The AC, AP and AC+AP groups showed worse prognosis and higher mortality than the NT group. Anticoagulant therapy can be a risk factor for hematoma enlargement, and anticoagulant and/or antiplatelet therapy can be a risk factor of poor outcome.

Topics: Aged; Anticoagulants; Blood Pressure; Cerebral Hemorrhage; Female; Humans; Male; Retrospective Studies; Risk Factors; Treatment Outcome; Warfarin

Topics: Ambulances; Anticoagulants; Blood Coagulation Disorders; Cerebral Hemorrhage; Emergency Medical Services; Humans; Pilot Projects; Point-of-Care Systems; Stroke; Warfarin

Lack of specific antidotes is a major concern in intracerebral hemorrhage (ICH) related to direct anticoagulants including dabigatran (OAC-ICH). We examined the efficacy of idarucizumab, an antibody fragment binding to dabigatran, in a mouse model of OAC-ICH. Dabigatran etexilate (DE) dose-dependently prolonged diluted thrombin time and tail-vein bleeding time, which were reversed by idarucizumab. Pretreatment with DE increased intracerebral hematoma volume and cerebral hemoglobin content. Idarucizumab in equimolar dose prevented excess hematoma expansion for both DE doses. In more extensive ICH, idarucizumab significantly reduced mortality. Thus, idarucizumab prevents excess intracerebral hematoma formation in mice anticoagulated with dabigatran and reduces mortality.

Topics: Animals; Antibodies, Monoclonal, Humanized; Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Bleeding Time; Blood Coagulation; Brain; Cerebral Hemorrhage; Dabigatran; Disease Models, Animal; Hematoma; Mice; Thrombin Time; Warfarin

This is a case report of an 83-year-old man in warfarin treatment with stable international normalised ratio (INR) after aortic valve replacement and atrial fibrillation. Due to back pain he took paracetamol (acetaminophen) 4 g/day, morphine 30 mg/day and diclofenac as rescue medication for two weeks. After 14 days of treatment he was admitted to a hospital with acute neurological deficits, and a blood sample showed INR levels above 10. A CT-scan of the brain showed an intracerebral haemorrhage. The patient died eight days after admission. Mechanisms of the possible interaction between paracetamol and warfarin are discussed.

Topics: Acetaminophen; Aged, 80 and over; Analgesics, Non-Narcotic; Anticoagulants; Cerebral Hemorrhage; Drug Interactions; Fatal Outcome; Humans; Male; Tomography, X-Ray Computed; Warfarin

Four-factor prothrombin complex concentrates (4FPCCs) are emerging as the standard of care for emergent warfarin reversal due to their ability to rapidly and effectively achieve hemostasis. The ideal dose of this medication is not known. Recently, our hospital instituted a protocol where all doses of 4FPCC were a fixed dose of 1500 IU. This protocol provides 4FPCC rapidly and precludes delay waiting for international normalized ratio (INR) values. The purpose of this study was to evaluate our experience with this fixed dose protocol.. This is a retrospective review of patients who received 1500 IU of 4FPCC for emergent warfarin reversal between March 2014 and January 2015. Demographic and clinical data regarding administration, efficacy, and safety were collected and analyzed.. A total of 39 patients met inclusion criteria. The most common indication for treatment was intracranial hemorrhage (28, 71.8%). The median INR at presentation was 3.3, and the median INR after a single dose of 1500 IU was 1.4 (P < .001). A total of 36 patients (92.3%) achieved successful reversal with a target INR of less than 2.0, and 28 patients (71.8%) achieved successful reversal with a target INR of 1.5 or less. There were no thrombotic adverse events within 7 days.. Administration of a fixed dose of 1500 IU of 4FPCC leads to high rates of successful INR reversal and no related thrombotic adverse events within 7 days, and there was no need to wait for INR at presentation. These findings suggest good efficacy and safety when using 1500 IU of 4FPCC for emergent warfarin reversal.

Topics: Age Factors; Aged; Anticoagulants; Blood Coagulation Factors; Body Weight; Cerebral Hemorrhage; Clinical Protocols; Hemorrhage; Humans; International Normalized Ratio; Middle Aged; Retrospective Studies; Treatment Failure; Treatment Outcome; Warfarin

Dabigatran is approved for stroke risk reduction in patients with nonvalvular atrial fibrillation (NVAF). Data from diverse clinical practice settings will help establish whether the risk:benefit ratio seen in clinical trials is comparable with routine clinical care. This study aimed to compare the safety and effectiveness of dabigatran and warfarin in clinical practice. We undertook a propensity score-matched (PSM) cohort study (N=12,793 per group; mean age 74) comparing treatment with dabigatran or warfarin in the US Department of Defense claims database, October 2009 to July 2013. Treatment-naïve patients with first prescription claim for dabigatran (either FDA-approved dose) or warfarin between October 2010 and July 2012 (index) and a diagnosis of NVAF during the 12 months before index date were included. Primary outcomes were stroke and major bleeding. Secondary outcomes included ischaemic and haemorrhagic stroke, major gastrointestinal (GI), urogenital or other bleeding, myocardial infarction (MI) and death. Time-to-event was investigated using Kaplan-Meier survival analyses. Outcomes comparisons were made utilising Cox-proportional hazards models of PSM groups. Dabigatran users experienced fewer strokes (adjusted hazard ratio [95 % confidence intervals] 0.73 [0.55-0.97]), major intracranial (0.49 [0.30-0.79]), urogenital (0.36 [0.18-0.74]) and other (0.38 [0.22-0.66]) bleeding, MI (0.65 [0.45-0.95]) and deaths (0.64 [0.55-0.74]) than the warfarin group. Major bleeding (0.87 [0.74-1.03]) and major GI bleeding (1.13 [0.94-1.37]) was similar between groups and major lower GI bleeding events were more frequent (1.30 [1.04-1.62]) with dabigatran. In conclusion, compared with warfarin, dabigatran treatment was associated with a lower risk of stroke and most outcomes measured, but increased incidence of major lower GI bleeding.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cerebral Hemorrhage; Comorbidity; Dabigatran; Databases, Factual; Disease-Free Survival; Drug Evaluation; Factor Xa Inhibitors; Female; Follow-Up Studies; Hemorrhage; Humans; Insurance Coverage; Kaplan-Meier Estimate; Male; Middle Aged; Military Personnel; Mortality; Myocardial Infarction; Propensity Score; Proportional Hazards Models; Retrospective Studies; Stroke; Thrombophilia; Treatment Outcome; Warfarin; Young Adult

The RE-LY study demonstrated the safety and efficacy of dabigatran relative to warfarin for stroke prevention in non-valvular atrial fibrillation. It is important to further evaluate safety and effectiveness of drugs in routine care. This study used a sequential cohort design with propensity score matching to compare dabigatran with warfarin among patients in two commercial health insurance databases. New users of these anticoagulants were followed from initiation until discontinuation, the end of the study, or the occurrence of a study outcome (primary study outcomes were stroke and major bleeding). Proportional hazards regression was conducted separately within each data source and results were pooled. Among 19,189 matched dabigatran and warfarin initiators (mean age: 68 years, 36 % female), as-treated follow-up (average of 5 months for dabigatran, 4 months for warfarin) identified 62 and 69 strokes, respectively (pooled HR = 0.77; 95 % CI = 0.54 to 1.09), and 354 and 395 major haemorrhages, respectively (HR = 0.75; 0.65 to 0.87). No meaningful heterogeneity was identified across subgroups, but numeric trends suggest more pronounced stroke prevention by dabigatran relative to warfarin among patients age 75+ (HR = 0.57; 0.33 to 0.97) or with < 6 months of use (HR = 0.51; 0.19 to 1.42). Major bleeds were reduced more by dabigatran among patients aged < 55 (HR = 0.51; 0.30 to 0.87) and with CHADS2 < 2 (HR = 0.58; 0.44 to 0.77). In conclusion, in routine care of patients with non-valvular atrial fibrillation, dabigatran treatment resulted in improved health outcomes compared with warfarin.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cerebral Hemorrhage; Comorbidity; Dabigatran; Databases, Factual; Drug Evaluation; Embolism; Factor Xa Inhibitors; Female; Follow-Up Studies; Hemorrhage; Hospitalization; Humans; Insurance Coverage; Male; Middle Aged; Myocardial Infarction; Polypharmacy; Propensity Score; Retrospective Studies; Stroke; Thrombophilia; Treatment Outcome; Warfarin; Young Adult

Warfarin-associated intracerebral haemorrhage carries poor outcome due to rapid haemorrhage growth. Reversal of warfarin anticoagulation with prothrombin complex concentrate has been implemented as an acute treatment option for these subjects.. We investigated whether survival of subjects with warfarin-associated intracerebral haemorrhage had improved after implementation of reversal of warfarin anticoagulation with prothrombin complex concentrate.. We identified all subjects with warfarin-associated intracerebral haemorrhage during 1993-2008 among the population of Northern Ostrobothnia, Finland. From 2004 onwards, prothrombin complex concentrate was used in Oulu University Hospital, the only hospital treating intracerebral haemorrhage subjects in the region, to counteract the effect of warfarin in subjects with warfarin-associated intracerebral haemorrhage. We compared the outcomes of subjects admitted during 1993-2003 and 2004-2008 and those treated and not treated with prothrombin complex concentrate. We also explored the predictors for one-year survival of the warfarin-associated intracerebral haemorrhage subjects.. We identified altogether 181 subjects who had intracerebral haemorrhage while on warfarin. One-year survival was significantly (P = 0·031) higher for the 60 subjects admitted during 2004-2008 (43·3%) than for the 121 admitted before 2004 (30·6%). In multivariable analysis, prothrombin complex concentrate treatment reduced one-year case fatality (hazard ratio 0·52, 95% confidence interval 0·29-0·93). Thromboembolic complications did not occur more frequently among those treated with prothrombin complex concentrate.. The survival of warfarin-associated intracerebral haemorrhage subjects among the population of Northern Ostrobothnia has improved likely because of introduction of prothrombin complex concentrate.

Topics: Aged; Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Coagulants; Female; Finland; Humans; Longitudinal Studies; Male; Retrospective Studies; Survival Analysis; Treatment Outcome; Warfarin

Despite extensive studies of supratentorial intracerebral hemorrhage (ICH), limited data are available on determinants of hematoma volume in infratentorial ICH. We therefore aimed to identify predictors of infratentorial ICH volume and to evaluate whether location specificity exists when comparing cerebellar to brainstem ICH.. We undertook a retrospective analysis of 139 consecutive infratentorial ICH cases (95 cerebellar and 44 brainstem ICH) prospectively enrolled in a single-center study of ICH. ICH volume was measured on the CT scan obtained upon presentation to the Emergency Department using an established computer-assisted method. We used linear regression to identify determinants of log-transformed ICH volume and logistic regression to evaluate their role in surgical evacuation.. Median ICH volumes for all infratentorial, cerebellar, and brainstem ICH were nine [interquartile range (IQR), 3-23], ten (IQR, 3-25), and eight (IQR, 3-19) milliliters, respectively. Thirty-six patients were on warfarin treatment, 31 underwent surgical evacuation, and 65 died within 90 days. Warfarin was associated with an increase in ICH volume of 86 % [β = 0.86, standard error (SE) = 0.29, p = 0.003] and statin treatment with a decrease of 69 % (β = -69, SE = 0.26, p = 0.008). Among cerebellar ICH subjects, those on warfarin were five times more likely to undergo surgical evacuation (OR = 4.80, 95 % confidence interval 1.63-14.16, p = 0.005).. Warfarin exposure increases ICH volume in infratentorial ICH. Further studies will be necessary to confirm the inverse relation observed between statins and ICH volume.

Topics: Aged; Anticoagulants; Brain Stem Hemorrhage, Traumatic; Cerebellar Diseases; Cerebral Hemorrhage; Female; Hematoma; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Radiography; Retrospective Studies; Treatment Outcome; Warfarin

Percutaneous left atrial appendage suture ligation with the LARIAT® device (Sentre HEART, Redwood City, CA) was successfully performed on an 84-year-old woman with non-valvular atrial fibrillation who developed intracranial hemorrhage on warfarin. However, a large gap developed at follow-up precluding warfarin cessation. To the best of our knowledge, this case report represents the first description of the use of a Gore® Helex® Septal Occluder (W. L. Gore and Associates, Newark, Delaware) as a novel approach to close a gap following percutaneous LAA suture ligation.

Topics: Aged, 80 and over; Anticoagulants; Atrial Appendage; Atrial Fibrillation; Cardiac Surgical Procedures; Cerebral Hemorrhage; Echocardiography, Transesophageal; Female; Hemorrhage; Humans; Ligation; Suture Techniques; Treatment Outcome; Warfarin

Warfarin-associated intracerebral hemorrhage (WICH) is a serious neurological condition associated with significant mortality and morbidity. We aimed to study the clinical features and factors that predict clinical outcome of Chinese patients with WICH.. Medical records of patients with spontaneous intracerebral hemorrhage (ICH) admitted to our hospital between July 2001 and June 2010 were reviewed and those with WICH were studied in detail retrospectively.. Fifty-one patients with WICH were studied. The mean age was 74.3 ± 10.5 years and 52.9% of the patients were female. The mean international normalized ratio (INR) on presentation was 2.9 ± 1.0. The median ICH volume was 23·3 (10·4-59·3) ml. The mortality rate at 3-6 months for WICH was 62·0%. Multivariate logistic analysis revealed that an initial ICH volume of > 20 ml (OR 34·4, P  =  0·037) and presence of intraventricular hemorrhage (OR 22.9, P  =  0·046) were independently associated with poor outcome. Supratherapeutic INR (INR > 3.0) on admission (P  =  0.724) and complete correction of INR within 24 hours after admission (P  =  0·486) were not independent predictors of poor outcome. The median ICH volumes did not differ between INR groups (18·2 (9·4-61·1) ml for INR ≤ 3 vs 27.3 (13.7-58.5) ml for INR > 3, P  =  0·718). Neurological deterioration (ND) was documented in 19 (63·3%) of the 30 patients included in a smaller sub-cohort, and was associated with poor neurological outcome (OR 20·7, P  =  0·027). Warfarin was resumed in 7 of the 20 survivors. There were two episodes of recurrent WICH and one episode of ischemic stroke during a mean follow-up duration of 5·4 years. In survivors who were not resumed on warfarin, there were two episodes of recurrent ICH and 12 episodes of ischemic vascular events (nine ischemic strokes) during a mean follow-up duration of 2·6 years.. Warfarin-associated intracerebral hemorrhage is a very serious complication of warfarin therapy with high mortality and morbidity. Initial ICH volume, presence of intraventricular hemorrhage, and ND are independent predictors of clinical outcome.

Topics: Aged; Anticoagulants; Asian People; Blood Pressure; Brain; Cerebral Hemorrhage; Female; Follow-Up Studies; Hong Kong; Humans; Logistic Models; Male; Multivariate Analysis; Odds Ratio; Prognosis; Retrospective Studies; Severity of Illness Index; Warfarin

Topics: Anticoagulants; Cerebral Hemorrhage; Female; Humans; Male; Warfarin

Topics: Anticoagulants; Cerebral Hemorrhage; Female; Humans; Male; Warfarin

Anticoagulation therapy is essential in atrial fibrillation (AF), and in Japan, less intense control is popular.. To assess the efficacy and safety with a special reference to low intensity warfarin therapy.. In 488 out of 508 patients with non-valvular AF, prothrombin time-international normalized ratio (PT-INR) was kept at 1.6-2.59, and they were followed for 49.5 months: 2098 person-years. The mean age was 73.7±9.9 years and 62% were male. The patients were divided by age: ≥70 years and <70 years, and by the intensity of warfarin therapy: PT-INR at 1.6-1.99 and at 2.0-2.59, respectively. The clinical data and event rates, ischemic stroke and major bleeding, were compared among the subgroups.. Heart failure, previous stroke, and higher CHADS2 score were more often reported in patients ≥70 years while males were involved more often as younger patients. A total of 166 of 339 patients ≥70 years and 69 of 149 patients <70 years belonged to the low intensity group. Ischemic stroke and major bleeding occurred in 1.47%/year and 1.27%/year, respectively but there was no difference between the two age groups and between the two intensities of warfarin therapy. Time in therapeutic range was a predictor for ischemic stroke. A fall of PT-INR to <1.6 was found in 41.9% with ischemic stroke and a rise >2.61 in 40.0% with major bleeding at the time of the events. Blunt trauma and concomitant use of antiplatelets were risks for intracranial hemorrhage in the patients ≥70 years.. The event rates were similar between the low- (1.6-1.99) and high- (2.0-2.59) intensity warfarin therapy groups in aged patients: <70 years and ≥70 years. Time in therapeutic range and a transient fall or rise in PT-INR were risks for clinical events. Blunt head trauma and concomitant use of antiplatelets were risks for intracranial hemorrhage.

Topics: Age Factors; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Drug Therapy, Combination; Embolism; Female; Follow-Up Studies; Head Injuries, Closed; Humans; International Normalized Ratio; Male; Middle Aged; Platelet Aggregation Inhibitors; Prothrombin Time; Retrospective Studies; Risk; Sex Factors; Stroke; Time Factors; Warfarin

Intracerebral hemorrhage (ICH) is the most feared complication of oral anticoagulation (OAC). Our aim was to investigate the impact of the international normalized ratio (INR) level on mortality in OAC-associated ICH compared with non-OAC-associated ICH.. A retrospective chart review of consecutive ICH patients treated at the Helsinki University Central Hospital from January 2005 to March 2010 (n = 1013) was performed. An ICH was considered to be OAC-associated if the patient was on warfarin at ICH onset. The association of INR with 3-month mortality was adjusted in a multivariable logistic regression model for factors influencing the crude odds ratios (ORs) in bivariable logistic regression by more than 5%.. One in eight ICHs was OAC-associated (n = 132). Of these, 50% had therapeutic INR (2.0-3.0), 7% had INR <2.0 and 43% had high INR (>3.0) on admission. Patients on OAC were older (median 76 vs. 66 years; P < 0.001) with more severe symptoms (median National Institutes of Health Stroke Scale 14 vs. 10; P < 0.001) and larger hematomas (median 11.4 vs. 9.7 ml; P < 0.001) on admission than patients not on OAC. After adjustment for confounders, 3-month mortality in the whole cohort was associated with higher baseline INR (OR 1.06; CI 1.03-1.09 per 0.1 increment). Mortality was higher with both therapeutic (51% at 3 months; OR 3.59; CI 1.50-8.60) and high (61%; OR 5.26; CI 1.94-14.27) INR values compared with non-OAC-associated ICH (29%).. Patients with OAC-associated ICH had more severe strokes and higher mortality compared with patients with ICH not related to OAC. Higher baseline INR was associated with increased 3-month mortality.

Topics: Aged; Aged, 80 and over; Anticoagulants; Catchment Area, Health; Cerebral Hemorrhage; Female; Finland; Humans; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Outcome Assessment, Health Care; Reference Values; Retrospective Studies; Warfarin

Patients receiving oral anticoagulants run a higher risk of cerebral hemorrhage with a poor outcome. Serotonin-modulating antidepressants (selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs]) are frequently used in combination with warfarin, but it is unclear whether this combination of drugs influences outcome after primary intracerebral hemorrhage (PICH). The authors investigated case fatality in PICH among patients from a defined population who were receiving warfarin alone, with aspirin, or with serotonin-modulating antidepressants.. Nine hundred eighty-two subjects with PICH were derived from the population of Northern Ostrobothnia, Finland, for the years 1993-2008, and those with warfarin-associated PICH were eligible for analysis. Their hospital records were reviewed, and medication data were obtained from the national register of prescribed medicines. Kaplan-Meier survival curves were drawn to illustrate cumulative case fatality, and a Cox proportional-hazards analysis was performed to demonstrate predictors of death.. Of the 176 patients eligible for analysis, 17 had been taking aspirin and 19 had been taking SSRI/SNRI together with warfarin. The 30-day case fatality rates were 50.7%, 58.8%, and 78.9%, respectively, for those taking warfarin alone, with aspirin, or with SSRI/SNRI (p = 0.033, warfarin plus SSRI/SNRI compared with warfarin alone). Warfarin combined with SSRI/SNRI was a significant independent predictor of case fatality (adjusted HR 2.10, 95% CI 1.13-3.92, p = 0.019).. Concurrent use of warfarin and a serotonin-modulating antidepressant, relative to warfarin alone, seemed to increase the case fatality rate for PICH. This finding should be taken into account if hematoma evacuation is planned.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antidepressive Agents; Cerebral Hemorrhage; Depression; Drug Therapy, Combination; Female; Finland; Humans; Kaplan-Meier Estimate; Male; Retrospective Studies; Risk Factors; Selective Serotonin Reuptake Inhibitors; Stroke; Survival Rate; Treatment Outcome; Warfarin

To date, only limited data are available on the effects of pretreatment with novel oral anticoagulants in the event of traumatic brain injury (TBI). We determined intracerebral hemorrhage volume and functional outcome in a standardized TBI model in mice treated with warfarin or dabigatran. Additionally, we investigated whether excess concentrations of dabigatran could increase bleeding and whether this was preventable by using prothrombin complex concentrate (PCC). C57 mice were treated orally with warfarin or dabigatran; sham-treated mice served as controls. Effective anticoagulation was verified by measurement of international normalized ratio and diluted thrombin time, and TBI was induced by controlled cortical impact (CCI). Twenty-four hours after CCI, intracerebral hemorrhage volume was larger in warfarin-pretreated mice than in controls (10.1 ± 4.9 vs 4.1 ± 1.7 μL; analysis of variance post hoc P=0.001), but no difference was found between controls and dabigatran-pretreated mice (5.3 ± 1.5 μL). PCC applied 30 minutes after CCI did not reliably reduce intracerebral hemorrhage induced by excess dabigatran concentration compared with saline (10.4 ± 11.2 vs 8.7 ± 7.1 μL). Our data suggest pathophysiological differences in TBI occurring during warfarin and dabigatran anticoagulation. The reduced hemorrhage formation under dabigatran therapy could present a safety advantage compared with warfarin. An excess dabigatran concentration, however, can increase hemorrhage.

Topics: Animals; Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation; Blood Coagulation Factors; Brain; Brain Injuries; Cerebral Hemorrhage; Dabigatran; Hemorrhage; Mice; Mice, Inbred C57BL; Warfarin

There have been neither appropriate guidelines nor clinical studies about the use of antithrombotics after hemorrhagic transformation (HT). We sought to find whether the use of antithrombotics after hemorrhagic infarction might be associated with aggravation of HT and neurological deterioration.. This retrospective study included prospectively registered consecutive patients with acute ischemic stroke and HT in our tertiary stroke center. We focused on the hemorrhagic infarction. Aggravation of HT was defined as either enlargement of the original HT or newly developed HT within the infarcted area by visual analysis. We analyzed relationships between antithrombotics and HT, and neurological deterioration after HT in patients with hemorrhagic infarction. In addition, we assessed composite outcomes including neurological deterioration, vascular events, and death at 1 month after HT. We analyzed relationships between antithrombotics after discharge and composite outcomes within 1 month after HT.. 222 patients were finally analyzed. Of the 150 patients with hemorrhagic infarction, 75 (50.0%) were type 1. The use of warfarin after detection of hemorrhagic infarction more frequently increased aggravation of HT than did the use of antiplatelets (4 of 24 vs 3 of 69; p = 0.094), but neither warfarin nor antiplatelets caused more HT than no medication. In addition, the use of antithrombotics after hemorrhagic infarction was not significantly associated with neurological deterioration after HT. The frequency of composite events at 1 months was significantly lower in patients treated with antithrombotics than those treated without (p = 0.041).. In conclusion, the results of this study suggest that antithrombotics can safely be used after hemorrhagic infarction and may not be associated with neurological deterioration and aggravation of HT. Further studies are needed to confirm our results.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Humans; Male; Middle Aged; Stroke; Warfarin

The aim was to investigate the risk of intracerebral hemorrhage (ICH) in patients with ischemic stroke taking warfarin and whether this risk changed over time.. Between 2001 and 2008, the Swedish Stroke Register registered 12,790 patients with ischemic stroke discharged on warfarin. The patients was studied in two 4-year periods (inclusion 2001-2004: follow-up until 2005 and inclusion 2005-2008: follow-up until 2009) for which rates of subsequent ICH were calculated. Adjusted hazard ratios, comparing the second period with the first period, were estimated in Cox regression models.. Of 6039 patients, 58 patients (1.0%) in the first period and 69 of 6751 patients (1.0%) in the second period had subsequent ICH. Annual rates of ICH ranged from 0.37% in the first period to 0.39% in the second period (adjusted hazard ratio, 1.04; 95% confidence interval, 0.73-1.48).. In this nationwide study, the risk of warfarin-associated ICH among ischemic stroke patients was low and did not change during the 2000s.

Topics: Aged; Aged, 80 and over; Anticoagulants; Brain Ischemia; Cerebral Hemorrhage; Female; Follow-Up Studies; Humans; Male; Middle Aged; Registries; Risk; Stroke; Sweden; Time Factors; Treatment Outcome; Warfarin

Stachybotrys microspora triprenyl phenol-7 (SMTP-7) is a new thrombolytic agent that exhibits anti-inflammatory effects. We previously demonstrated that the hemorrhagic transformation was fewer with SMTP-7 than with recombinant tissue plasminogen activator (rt-PA) following ischemia-reperfusion in animal models. We hypothesized that SMTP-7 may decrease hemorrhagic transformation after ischemia-reperfusion under the warfarin-treated condition. Transient middle cerebral artery occlusion (MCAO) was induced for 3h using an intraluminal suture in warfarin-treated mice to produce hemorrhagic transformation. Warfarin was administered orally for a 24-h feeding period before MCAO through bottled drinking water (5mg in 375 ml tap water), resulting in a mean INR of 5.6±0.2. Mice were treated with vehicle, rt-PA, or SMTP-7 5h before reperfusion. Twenty percent of vehicle-treated and 50.0% of rt-PA-treated mice died 24h after reperfusion, while all SMTP-7-treated mice survived. Hemorrhagic severity in SMTP-7-treated mice was significantly lower than that in rt-PA-treated mice. Neurological deficit was significantly lower in SMTP-7-treated mice than vehicle- and rt-PA-treated mice. These results indicate that SMTP-7 decreases mortality, hemorrhagic transformation, and neurological deficits, and can be a safe thrombolytic agent following MCAO under the warfarin-treated condition.

Topics: Animals; Anticoagulants; Benzopyrans; Blood-Brain Barrier; Cerebral Hemorrhage; Fibrinolytic Agents; Infarction, Middle Cerebral Artery; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Pyrrolidinones; Warfarin

Neuroradiological characteristics and functional outcomes of patients with intracerebral hemorrhage (ICH) during novel oral anticoagulant treatment were not well defined. We examined these in comparison with those during warfarin treatment.. The consecutive 585 patients with ICH admitted from April 2011 through October 2013 were retrospectively studied. Of all, 5 patients (1%) had ICH during rivaroxaban treatment, 56 (10%) during warfarin, and the other 524 (89%) during no anticoagulants. We focused on ICH during rivaroxaban and warfarin treatments and compared the clinical characteristics, neuroradiological findings, and functional outcomes.. Patients in the rivaroxaban group were all at high risk for major bleeding with hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly (HAS-BLED) score of 3 and higher rate of past history of ICH. Moreover, multiple cerebral microbleeds (≥4) were detected more frequently in rivaroxaban group than in warfarin (80% versus 29%; P=0.04). Hematoma volume in rivaroxaban group was markedly smaller than that in warfarin (median: 4 versus 11 mL; P=0.03). No patient in the rivaroxaban group had expansion of hematoma and surgical treatment. Rivaroxaban group showed lower modified Rankin Scale at discharge relative to warfarin, and the difference between modified Rankin Scale before admission and at discharge was smaller in rivaroxaban than in warfarin (median: 1 versus 3; P=0.047). No patient in the rivaroxaban group died during hospitalization, whereas 10 (18%) warfarin patients died.. Rivaroxaban-associated ICH occurs in patients at high risk for major bleeding. However, they had a relatively small hematoma, no expansion of hematoma, and favorable functional and vital outcomes compared with warfarin-associated ICH.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Female; Hemorrhage; Humans; Male; Middle Aged; Morpholines; Retrospective Studies; Risk; Rivaroxaban; Stroke; Thiophenes; Treatment Outcome; Warfarin

We aimed to assess the effect of APOE ε variants on warfarin-related intracerebral hemorrhage (wICH), evaluated their predictive power, and tested for interaction with warfarin in causing wICH.. This was a prospective, 2-stage (discovery and replication), case-control study. wICH was classified as lobar or nonlobar based on the location of the hematoma. Controls were sampled from ambulatory clinics (discovery) and random digit dialing (replication). APOE ε variants were directly genotyped. A case-control design and logistic regression analysis were utilized to test for association between APOE ε and wICH. A case-only design and logistic regression analysis were utilized to test for interaction between APOE ε and warfarin. Receiver operating characteristic curves were implemented to evaluate predictive power.. The discovery stage included 319 wICHs (44% lobar) and 355 controls. APOE ε2 was associated with lobar (odds ratio [OR] 2.46; p < 0.001) and nonlobar wICH (OR 1.67; p = 0.04), whereas ε4 was associated with lobar (OR 2.09; p < 0.001) but not nonlobar wICH (p = 0.35). The replication stage (63 wICHs and 1,030 controls) confirmed the association with ε2 (p = 0.03) and ε4 (p = 0.003) for lobar but not for nonlobar wICH (p > 0.20). Genotyping information on APOE ε variants significantly improved case/control discrimination of lobar wICH (C statistic 0.80). No statistical interaction between warfarin and APOE was found (p > 0.20).. APOE ε variants constitute strong risk factors for lobar wICH. APOE exerts its effect independently of warfarin, although power limitations render this absence of interaction preliminary. Evaluation of the predictive ability of APOE in cohort studies is warranted.

Topics: Apolipoprotein E2; Case-Control Studies; Cerebral Hemorrhage; Genetic Predisposition to Disease; Genotype; Humans; Prospective Studies; Risk; Warfarin

Warfarin-related intracerebral haemorrhage is associated with significant morbidity but long term treatment costs are unknown. Our study aimed to assess the cost of warfarin-related intracerebral haemorrhage.. We included all patients with intracerebral haemorrhage between July 2006 and December 2011 at a single centre. We collected data on anticoagulant use, baseline clinical variables, discharge destinations, modified Rankin Scale at discharge and in-hospital costings. First year costings were extracted from previous studies. Multiple linear regression for treatment cost was performed with stratified analysis to assess for effect modification.. There were 694 intracerebral haemorrhage patients, with 108 (15.6%) previously on warfarin. Mean age (SD) of participants was 70.3 (13.6) and 58.5% were male. Patients on warfarin compared to those not on warfarin had significantly lower rates of discharge home (12.0% versus 18.9%, p=0.013). Overall total costs between groups were similar, $AUD 25,767 for warfarin-related intracerebral haemorrhage and $AUD 27,388 for non-warfarin intracerebral haemorrhage (p=0.353). Stratified analysis showed survivors of warfarin-related intracerebral haemorrhage had higher costs compared to those without warfarin ($AUD 33,419 versus $AUD 30,193, p<0.001) as well as increased length of stay (12 days versus 8 days, p<0.001). Inpatient mortality of patients on warfarin was associated with a shorter length of stay (p=0.001) and lower costs.. Survival of initial haemorrhage on warfarin was associated with increased treatment cost and length of stay but this was discounted by higher rates and earlier nature of mortality in warfarinised patients.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Hospital Costs; Hospital Mortality; Hospitalization; Humans; Male; Middle Aged; Warfarin

To compare the outcomes of patients with warfarin-associated intracerebral haemorrhage given different treatments to reverse the effect of anticoagulation.. Historical cohort study.. A regional hospital in Hong Kong.. Patients on warfarin who developed intracerebral haemorrhage.. Prothrombin complex concentrate versus fresh frozen plasma treatment.. The primary outcome measures included the international normalised ratio before and after prothrombin complex concentrate treatment and the neurological deterioration in patients with Glasgow Coma Scale score of more than 8/not intubated/not planned for immediate surgery (target group). Secondary outcome measures were haematoma expansion, 7-day and 30-day mortality rates, and 3-month functional outcome. Safety outcome was the occurrence of a thrombotic event after prothrombin complex concentrate treatment within the index admission.. Among 33 patients with clearly documented time of infusion of prothrombin complex concentrate, and whose international normalised ratio was checked before and after prothrombin complex concentrate treatment, the mean international normalised ratio was reduced from 2.81 to 1.21 within 24 hours. Within the target group of patients, there was a significantly lower rate of neurological deterioration in the prothrombin complex concentrate group (17.4% of 23 patients) versus fresh frozen plasma group (45.5% of 33 patients) [P=0.027]. In terms of the 7-day mortality, 30-day mortality, and 3-month functional outcome, prothrombin complex concentrate-treated group showed a favourable trend although the difference did not reach a statistical significance. No patient developed thrombotic complications after prothrombin complex concentrate treatment.. Prothrombin complex concentrates can reverse the warfarin effect of prolonged international normalised ratio in a timely manner. It might better improve the outcome of warfarin-associated intracerebral haemorrhage compared with fresh frozen plasma treatment by reduction in neurological deterioration.

Topics: Aged; Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Emergency Service, Hospital; Female; Glasgow Coma Scale; Hong Kong; Hospitals; Humans; Male; Plasma; Retrospective Studies; Treatment Outcome; Warfarin

Topics: Aged; Anticoagulants; Cerebral Hemorrhage; Female; Frontal Lobe; Heparin, Low-Molecular-Weight; Humans; Intracranial Embolism; Pons; Warfarin; White Matter

Dabigatran etexilate (DE) has recently been introduced for stroke prevention in atrial fibrillation, but management of acute ischaemic stroke during therapy with DE is a challenge. Thrombolysis is contraindicated because of a presumed increased risk of intracerebral haemorrhagic complications. We studied in different ischaemia models whether DE increases secondary haemorrhage after thrombolysis. C57BL/6 mice were anticoagulated with high-dose DE or warfarin. After 2 hour (h) or 3 h transient filament MCAO, rt-PA was injected. At 24 h after MCAO, secondary haemorrhage was quantified using a macroscopic haemorrhage score and haemoglobin spectrophotometry. Post-ischaemic blood-brain-barrier (BBB) damage was assessed using Evans blue. To increase the validity of findings, the duration of anticoagulation was prolonged in mice (5 x DE over 2 days), and the effect of DE after thrombolysis was also examined in thromboembolic MCAO in rats.Pretreatment with warfarin resulted in significantly more secondary haemorrhage (mean haemorrhage score 2.6 ± 0.2) compared to non-anticoagulated animals (1.7 ± 0.3) and DE (9 mg/kg, 1.6 ± 0.3) in 2 h ischaemia. Also after a 3 h period of ischaemia, haemorrhage was more severe in animals anticoagulated with warfarin compared to 9 mg/kg DE and non-anticoagulated control. Prolonged or enteral dabigatran pretreatment led to identical results. Also, thrombolysis after thromboembolic MCAO in rats did not induce more severe bleeding in DE-treated animals. Mice pretreated with warfarin had higher BBB permeability and increased activation of matrix-metalloproteinase 9. In conclusion, DE does not increase the risk of secondary haemorrhage after thrombolysis in various rodent models of ischaemia and reperfusion. The implications of this finding for stroke patients have to be determined in the clinical setting.

Topics: Animals; Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Blood-Brain Barrier; Cerebral Arteries; Cerebral Hemorrhage; Dabigatran; Disease Models, Animal; Humans; Ischemia; Mice; Mice, Inbred C57BL; Rats; Stroke; Thrombolytic Therapy; Warfarin

Cerebral microbleeds (CMBs) are known to be indicative of bleeding-prone microangiopathy. Little is known about the significance of CMBs in anticoagulated patients. We determined the frequency of new CMBs in ischemic stroke patients who had been receiving warfarin treatment for 2 years.. A total of 204 ischemic stroke patients on warfarin therapy for 2 years underwent a repeat MRI. We compared demographic features, vascular risk factors, and radiological findings of patients with and without new CMBs.. New CMBs on gradient-echo MRI were found in 29 of 204 patients (10%). Of 35 patients who had CMBs in the original study, 9 developed new CMBs after 2 years (26%), compared with 20 of the 169 patients (12%) who did not have CMBs at baseline (p=0.03). Patients with new CMBs were older than patients without CMBs (p=0.04), and the frequency of leukoaraiosis was significantly higher (p=0.02). The mean duration of warfarin treatment was not significantly different between the patients with and without new CMBs (p=0.28).. This longitudinal study suggested that the presence of CMBs at baseline increased the frequency of new CMBs in patients on warfarin therapy.

Topics: Aged; Anticoagulants; Brain Ischemia; Cerebral Hemorrhage; Female; Follow-Up Studies; Humans; Hypertension; International Normalized Ratio; Leukoaraiosis; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Risk Factors; Stroke; Warfarin

Intracerebral hemorrhage (ICH) is the most devastating complication of oral anticoagulation (OAC). As the number of patients on long-term OAC is expected to rise, the proportion of intracerebral hemorrhage related to OAC (OAC-ICH) in relation to spontaneous ICH (spont-ICH) is expected to increase as well. We determined the proportion of OAC-ICH in consecutive stroke patients and explored differences between OAC-ICH and spont-ICH regarding initial volume, hematoma expansion and outcome. Our prospective study consecutively enrolled patients with supra- and infratentorial ICH. The National Institute of Health Stroke Scale Score and the modified Rankin Scale (mRS) score at baseline and after 3 months, medical history and demographic variables were recorded. All admission and follow-up CTs/MRIs were analysed regarding ICH volume using the ABC/2-method. Intraventricular hemorrhage (IVH) was quantified using the Graeb score. Within 19 months, 2,282 patients were admitted to our ER. 206 ICH patients were included. Overall, 24.8 % of all ICH were related to OAC. Compared to patients with spont-ICH, OAC-ICH patients were older (p = 0.001), more frequently had initial extension of ICH into the ventricles (p = 0.05) or isolated primary IVH (p = 0.03) and a higher Graeb score upon admission (p = 0.01). In contrast, initial ICH volume (p = 0.16) and ICH expansion (p = 0.9) in those receiving follow-up imaging (n = 152) did not differ between the two groups. After correction for age, there was a trend towards poorer outcome in OAC-ICH (p = 0.08). One-fourth of all ICH are related to OAC. Initial extension of ICH into the ventricles and primary IVH are more frequent in OAC-ICH. The rate of hematoma expansion in OAC-ICH patients is similar to non-anticoagulated ICH patients.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Cohort Studies; Data Interpretation, Statistical; Disease Progression; Female; Follow-Up Studies; Humans; Logistic Models; Male; Middle Aged; Neurologic Examination; Prospective Studies; Stroke; Treatment Outcome; Vitamin K; Warfarin

Controversy surrounds the safety of intravenous (IV) tissue plasminogen activator (tPA) in ischemic stroke patients treated with warfarin. The European tPA license precludes its use in anticoagulated patients altogether. American guidelines accept IV tPA use with an international normalized ratio (INR) ≤ 1.7. The influence of warfarin on symptomatic intracerebral hemorrhage (SICH), arterial recanalization, and long-term functional outcome in stroke thrombolysis remains unclear.. We analyzed data from 45,074 patients treated with IV tPA enrolled in the Safe Implementation of Thrombolysis in Stroke (SITS) International Stroke Thrombolysis Register. A total of 768 patients had baseline warfarin treatment with INR ≤ 1.7. Outcome measures were SICH, arterial recanalization, mortality, and functional independence at 3 months.. Patients on warfarin with INR ≤ 1.7 were older, had more comorbidities, and had more severe strokes compared to patients without warfarin. There were no significant differences between patients with and without warfarin in SICH rates (adjusted odds ratio [aOR] = 1.23, 95% confidence interval [CI] = 0.72-2.11 per SITS-MOST; aOR = 1.26, 95% CI = 0.82-1.70 per European Cooperative Acute Stroke Study II) after adjustment for age, stroke severity, and comorbidities. Neither did warfarin independently influence mortality (aOR = 1.05, 95% CI = 0.83-1.35) or functional independence at 3 months (aOR = 1.01, 95% CI = 0.81-1.24). Arterial recanalization by computed tomography/magnetic resonance angiography trended higher in warfarin patients (62% [37 of 59] vs 55% [776/1,475], p = 0.066). Recanalization approximated by disappearance at 22 to 36 hours of a baseline hyperdense middle cerebral artery sign was increased (63% [124 of 196] vs 55% [3,901 of 7,099], p = 0.022).. Warfarin treatment with INR ≤ 1.7 did not increase the risk for SICH or death, and had no impact on long-term functional outcome in patients treated with IV tPA for acute ischemic stroke.

Topics: Aged; Aged, 80 and over; Anticoagulants; Brain Ischemia; Cerebral Hemorrhage; Female; Fibrinolytic Agents; Humans; Infusions, Intravenous; Male; Middle Aged; Outcome Assessment, Health Care; Radiography; Registries; Risk Factors; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome; Warfarin

Life-long oral anticoagulant therapy is recommended to all patients with mechanical heart valves to reduce the incidence of thromboembolic events. However, intracerebral haemorrhage is the fatal complication associated with anticoagulation, with an estimated 6-month mortality of 67%. (1) The incidence of cerebral bleeding while on anticoagulation is 0.3-0.7%/year, with as many as 85% of survivors left with permanent neurological deficits. (2) Difficulties in management arise when anticoagulation is temporarily discontinued as mechanical valves, particularly mitral, are exposed to significant thromboembolic and valve dysfunction risk. The decision on when to appropriately restart anticoagulation needs to be balanced with the risk of precipitating further cerebral haemorrhage. There are currently no guidelines on the optimal time to start anticoagulation. We describe a case of the management approach implemented in a patient with a mechanical valve presenting to the emergency department with an acute intracerebral haemorrhage.

Topics: Aged; Anticoagulants; Cerebral Hemorrhage; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Humans; Male; Mitral Valve Prolapse; Thromboembolism; Warfarin

Although long-term treatment with the oral anticoagulant warfarin is widely used to prevent cardioembolic ischemic stroke, it has been reported that warfarin can exacerbate hemorrhagic transformation (HT) after cerebral ischemia. We investigated whether cilostazol, a phosphodiesterase-III inhibitor, suppressed the warfarin-induced HT after cerebral ischemia in mice.. Male ddY mice were treated with oral warfarin before 3-hour middle cerebral artery occlusion followed by 21-hour reperfusion to induce HT. The duration of warfarin pretreatment was determined by measurement of prothrombin time-international normalized ratio value. Cilostazol or vehicle was administered by intraperitoneal injection immediately after reperfusion. The infarct volume, brain swelling, and brain hemoglobin content were evaluated at 24 hours after middle cerebral artery occlusion. We also evaluated the survival rate of each treated group for 7 days after surgery. To investigate the mechanism underlying cilostazol's effects, the proteins involved in vascular endothelial integrity were investigated using Western blotting.. HT volume was exacerbated by warfarin treatment, and cilostazol (3 mg/kg, i.p.) suppressed this exacerbation (sham, mean±SD, 29.2±13.4 mg/dL; vehicle, 33.3±11.9 mg/dL; warfarin, 379.4±428.9 mg/dL; warfarin+cilostazol 1 mg/kg, 167.5±114.2 mg/dL; warfarin+cilostazol 3 mg/kg, 116.9±152.3 mg/dL). Furthermore, cilostazol improved survival rate and upregulated the expression of tight junction proteins and vascular endothelial cadherin.. Cilostazol reduced the warfarin-related risk of HT after ischemia by protecting the vascular endothelial cells. This result suggested that cilostazol administration in patients with acute ischemic stroke might reduce HT.

Topics: Animals; Anticoagulants; Brain Ischemia; Cerebral Hemorrhage; Cilostazol; Endothelium, Vascular; Male; Mice; Phosphodiesterase 3 Inhibitors; Tetrazoles; Tight Junctions; Time Factors; Warfarin

Warfarin use increases mortality in patients with intracerebral hemorrhage (ICH). Larger hematoma volume and infratentorial location are both major determinants of poor outcome in ICH. Although warfarin-associated intracerebral hemorrhages have greater volumes, there is uncertainty about the effects of location. We aimed to investigate the influence of warfarin on hematoma volume and location.. We conducted a retrospective study of all patients hospitalized for ICH at a large stroke center from October 2007 to January 2012. Initial CT scans were used to quantify hematoma volumes using the computer-assisted planimetric analysis. Univariate and multivariable analyses determined the influence of warfarin on hemorrhage location. Median regression analysis was performed to estimate the effects of INR on hematoma volumes.. We included 404 consecutive patients with ICH of whom 69 were on warfarin. Patients on warfarin had larger hematoma volumes (median 23.9mL vs. 14.2mL; P=0.046). In patients excessively anticoagulated with warfarin (defined as INR>3.0), compared with those in the therapeutic range, brainstem ICH was more frequent (24.0% vs. 6.1%; P=0.005). Patients with INR>3.0 had increased odds of infratentorial hemorrhage (OR 3.63; 95% CI 1.52-8.64; P=0.004) when compared to non-warfarin ICH patients. After adjustment for hematoma location, there was no significant association between INR and hematoma volume.. Patients with warfarin-associated ICH have a predilection for brainstem ICH. After adjustment for ICH location, no relationship between admission INR and hematoma volume was found.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Hematoma; Humans; Male; Middle Aged; Retrospective Studies; Tomography, X-Ray Computed; Warfarin

Contrast medium extravasation (CE) in intracerebral hemorrhage (ICH) is a marker of ongoing bleeding and a predictor of hematoma expansion. The aims of the study were to establish an ICH model in which CE can be quantified, characterized in ICH during warfarin and dabigatran anticoagulation, and to evaluate effects of prothrombin complex concentrates on CE in warfarin-associated ICH.. CD1-mice were pretreated orally with warfarin, dabigatran, or vehicle. Prothrombin complex concentrates were administered in a subgroup of warfarin-treated mice. ICH was induced by stereotactic injection of collagenase VIIs into the right striatum. Contrast agent (350 μL Isovue 370 mg/mL) was injected intravenously after ICH induction (2-3.5 hours). Thirty minutes later, mice were euthanized, and CE was measured by quantifying the iodine content in the hematoma using dual-energy computed tomography.. The optimal time point for contrast injection was found to be 3 hours after ICH induction, allowing detection of both an increase and a decrease of CE using dual-energy computed tomography. CE was higher in the warfarin group compared with the controls (P=0.002). There was no significant difference in CE between dabigatran-treated mice and controls. CE was higher in the sham-treated warfarin group than in the prothrombin complex concentrates-treated warfarin group (P<0.001).. Dual-energy computed tomography allows quantifying CE, as a marker of ongoing bleeding, in a model of anticoagulation-associated ICH. Dabigatran induces less CE in ICH than warfarin and consequently reduces risks of hematoma expansion. This constitutes a potential safety advantage of dabigatran over warfarin. Nevertheless, in case of warfarin anticoagulation, prothrombin complex concentrates reduce this side effect.

Topics: Animals; Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Blood Coagulation Factors; Cerebral Hemorrhage; Contrast Media; Dabigatran; Iopamidol; Male; Mice; Radiography, Dual-Energy Scanned Projection; Time Factors; Warfarin

The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial found no difference between warfarin and aspirin in patients with low ejection fraction in sinus rhythm for the primary outcome: first to occur of 84 incident ischemic strokes (IIS), 7 intracerebral hemorrhages or 531 deaths. Prespecified secondary analysis showed a 48% hazard ratio reduction (p = 0.005) for warfarin in IIS. Cardioembolism is likely the main pathogenesis of stroke in heart failure. We examined the IIS benefit for warfarin in more detail in post hoc secondary analyses.. We subtyped IIS into definite, possible and noncardioembolic using the Stroke Prevention in Atrial Fibrillation method. Statistical tests, stratified by prior ischemic stroke or transient ischemic attack, were the conditional binomial for independent Poisson variables for rates, the Cochran-Mantel-Haenszel test for stroke subtype and the van Elteren test for modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS) distributions, and an exact test for proportions.. Twenty-nine of 1,142 warfarin and 55 of 1,163 aspirin patients had IIS. The warfarin IIS rate (0.727/100 patient-years, PY) was lower than for aspirin (1.36/100 PY, p = 0.003). Definite cardioembolic IIS was less frequent on warfarin than aspirin (0.22 vs. 0.55/100 PY, p = 0.012). Possible cardioembolic IIS tended to be less frequent on warfarin than aspirin (0.37 vs. 0.67/100 PY, p = 0.063) but noncardioembolic IIS showed no difference: 5 (0.12/100 PY) versus 6 (0.15/100 PY, p = 0.768). Among patients experiencing IIS, there were no differences by treatment arm in fatal IIS, baseline mRS, mRS 90 days after IIS, and change from baseline to post-IIS mRS. The warfarin arm showed a trend to a lower proportion of severe nonfatal IIS [mRS 3-5; 3/23 (13.0%) vs. 16/48 (33.3%), p = 0.086]. There was no difference in NIHSS at the time of stroke (p = 0.825) or in post-IIS mRS (p = 0.948) between cardioembolic, possible cardioembolic and noncardioembolic stroke including both warfarin and aspirin groups.. The observed benefits in the reduction of IIS for warfarin compared to aspirin are most significant for cardioembolic IIS among patients with low ejection fraction in sinus rhythm. This is supported by trends to lower frequencies of severe IIS and possible cardioembolic IIS in patients on warfarin compared to aspirin.

Topics: Anticoagulants; Aspirin; Brain Damage, Chronic; Brain Ischemia; Cerebral Hemorrhage; Heart Failure; Humans; Intracranial Embolism; Multicenter Studies as Topic; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Recurrence; Severity of Illness Index; Stroke; Stroke Volume; Warfarin

Warfarin-associated intracerebral hemorrhage (WAICH) is a devastating disease with increasing incidence. In this setting, treatment with prothrombin complex concentrates (PCC) is essential to correct coagulopathy. Yet despite the availability of coagulopathy correction strategies, significant treatment delays can occur in emergency departments (EDs), which may be overcome using stroke prenotification strategies. To explore this, we compared arrival-to-treatment times with PCC for WAICH between two different stroke response systems that used the same international normalized ratio (INR) correction protocol.. We established a registry of consecutive patients presenting with WAICH and treated with PCC presenting to two Canadian tertiary-care academic stroke centers: one with a stroke prenotification system, and one with a traditional ED assessment, treatment and referral system. In this comparative cohort design, we defined the WAICH diagnosis time as the earliest time point where both INR and CT were available. We compared median times from arrival to treatment, as well as arrival to diagnosis, and diagnosis to treatment.. Between 2008 and 2010, we collected data from 123 consecutive patients with intracranial hemorrhage who received PCC for INR correction (79 from ED referral, and 44 prenotification). Onset-to-arrival times, demographics, Glasgow Coma Scale scores, and baseline INR were similar between the two systems. Arrival-to-treatment times were significantly shorter in the prenotification system as compared to the traditional ED referral system (135 vs. 267 min; p = 0.001), which was driven by both decreased arrival-to-diagnosis time (49 vs. 117 min; p = 0.006), as well as decreased diagnosis-to-treatment time (56 vs. 112 min; p < 0.001). Arrival-to-scan times and arrival-to-INR times were similarly shorter in the prenotification system (68 vs. 118 min and 20.5 vs. 47 min, respectively).. Stroke prenotification was associated with shorter arrival-to-treatment times for emergent INR correction in patients with WAICH, which was driven by both faster diagnosis and treatment. Our results are consistent with those seen in ischemic stroke, suggesting that prenotification systems present an opportunity to optimize acute intracerebral hemorrhage therapy.

Topics: Aged; Aged, 80 and over; Anticoagulants; Brain Ischemia; Canada; Cerebral Hemorrhage; Female; Humans; International Normalized Ratio; Male; Middle Aged; Stroke; Thrombolytic Therapy; Time Factors; Warfarin

Warfarin has unmet medical needs such as blood coagulation monitoring, limitation of vitamin K intake, and interaction with other drugs, while novel oral anticoagulants (NOACs) do not have such kind of unmet medical needs. Therefore, NOACs are recommended to busy patients or patients far from hospitals, or who do not want to limit vitamin K or use many other drugs concomitantly. NOACs are also recommended to patients with low time in therapeutic range (TTR). NOACs are also recommended to warfarin-naïve patients. Warfarin is recommended to patients with economical difficulty because it is much cheaper than NOACs. If needed, warfarin should be selected in patients with renal insufficiency or under hemodialysis because NOACs are contraindicated. New guidelines by the European Society of Cardiology recommend NOACs to low risk patients with CHA2DS2-VASc score 1, and also as the first line to those with CHA2DS2-VASc 2 or more. Finally, drug should be determined by patients' preference. Doctors should give adequate information helpful for patients' selection.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Humans; International Normalized Ratio; Morpholines; Practice Guidelines as Topic; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Warfarin

To prevent major hemorrhage during anticoagulation, it is quite important to manage controllable risk factors such as hypertension, diabetes mellitus, smoking habit, and too much alcohol intake. It is also important to avoid dual antithrombotic therapy as long as possible, which increases severe bleeding events. For patients with major bleeding during anticoagulation, we should stop oral medication, stop bleeding by mechanical compression or surgical interventions, and maintain circulation blood volume and blood pressure by appropriate intravenous drip infusion. When intracranial hemorrhage happens, adequate treatment to suppress blood pressure should be provided. Administration of prothrombin complex concentrate (PCC) and vitamin K is effective for urgent reversal of anticoagulation by warfarin. The PCC may be also useful for that by novel oral anticoagulants.

Topics: Administration, Oral; Alcohol Drinking; Anticoagulants; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Dabigatran; Diabetes Mellitus; Drug Therapy, Combination; Factor IX; Fibrinolytic Agents; Hemorrhage; Humans; Hypertension; Risk Assessment; Risk Factors; Smoking; Vitamin K; Warfarin

In October 2005 in Japan, the recombinant tissue plasminogen activator (tPA) alteplase was approved for patients with acute ischemic stroke within 3 hours of onset at a dose of 0.6 mg/kg. The present study was undertaken to assess the safety and efficacy of alteplase in Japan. Between October 2005 and December 2009, a total of 114 consecutive patients admitted to 4 hospitals received intravenous tPA within 3 hours of stroke onset. Clinical backgrounds and outcomes were investigated. The patients were divided into 2 chronological groups: an early group, comprising 45 patients treated between October 2005 and December 2007, and a later group, comprising 69 patients treated between January 2008 and December 2009. The mean time from arrival at the hospital to the initiation of treatment was significantly reduced in the later group, from 82.6 minutes to 70.9 minutes. Intracerebral hemorrhage (ICH) occurred in 26 patients (22.8%); compared with patients without ICH, these patients had a significantly higher prevalence of cardiogenic embolism (88.5% vs 58.0%); greater warfarin use (26.8% vs 6.8%); higher mean National Institutes of Health Stroke Scale (NIHSS) scores on admission (16 vs 10), at 3 days after admission (14 vs 5), and at 7 days after admission (13.5 vs 3); and a lower Diffusion-Weighted Imaging-Alberta Stroke Program Early CT Score (7.8 vs 9.1). Patients who received edaravone had a higher prevalence of cardiogenic embolism (70.9% vs 36.4%), a higher recanalization rate (77.7% vs 36.4%), and lower NIHSS scores on admission and at 3 and 7 days after admission compared with those who did not receive edaravone. Our data suggest that administration of intravenous alteplase 0.6 mg/kg within 3 hours of stroke onset is safe and effective, that the NIHSS and Diffusion-Weighted Imaging-Alberta Stroke Program Early CT Score are useful predictors of ICH after tPA administration, and that warfarin-treated patients are more likely to develop symptomatic ICH despite an International Normalized Ratio <1.7.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anticoagulants; Brain Ischemia; Cerebral Hemorrhage; Chi-Square Distribution; Diffusion Magnetic Resonance Imaging; Disability Evaluation; Female; Fibrinolytic Agents; Hospitals; Humans; Incidence; International Normalized Ratio; Japan; Logistic Models; Male; Middle Aged; Odds Ratio; Predictive Value of Tests; Recombinant Proteins; Retrospective Studies; Risk Assessment; Risk Factors; Stroke; Thrombolytic Therapy; Time Factors; Time-to-Treatment; Tissue Plasminogen Activator; Treatment Outcome; Warfarin

Topics: Anticoagulants; Cerebral Hemorrhage; Female; Humans; Male; Platelet Aggregation Inhibitors; Warfarin

Anticoagulant and antiplatelets for prevention of ischaemic stroke and cardiovascular diseases may increase the risk of intracerebral hemorrhage (ICH). This study aimed to investigate the influence of pre-ICH use of anticoagulant and antiplatelets on ICH patients.. Consecutive patients with acute spontaneous ICH registered in a single-center stroke registry during 2001 to 2010 were analyzed and categorized according to their pre-ICH use of warfarin (Group I), antiplatelets (Group II), or neither (Group III). Survival analysis and the Cox proportional hazard model were used to compare between the three groups and the predictors.. Of 2021 ICH patients (male, 63.3%; mean age, 62.6 ± 14.4 years) included, there were 94 (4.7%) in Group I, 232 (11.4%) in Group II, and 1695 (83.9%) in Group III. Warfarin users had larger hematoma volume, more intraventricular extension, higher frequencies of lobar ICH, and higher case fatality than non-warfarin users (Groups II and III). The Cox proportional hazard model showed increased 6-month case fatality in pre-ICH warfarin users (adjusted hazard ratio 2.75, 95% confidence interval 2.04-3.72, P < 0.001), but not in pre-ICH antiplatelet users (adjusted hazard ratio 0.95, 95% confidence interval 0.72-1.26).. Intracerebral hemorrhage patients with prior warfarin use, but not antiplatelet use, had significantly higher case fatality at 6 months.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Area Under Curve; Cerebral Hemorrhage; Female; Glasgow Coma Scale; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Proportional Hazards Models; Registries; ROC Curve; Stroke; Survival Analysis; Taiwan; Warfarin

It has been suggested that antiplatelet or anticoagulant drugs elevate the rate of intracerebral hemorrhage (ICH) in patients with cerebral microbleeds (MBs). To investigate the mechanism by which antiplatelet drugs or warfarin may contribute to deep ICH occurrences in patients with deep MBs, we prospectively analyzed deep ICH occurrences in 807 consecutive patients (351 females and 456 males; mean age ± standard deviation 69.8 ± 12.0 years) who were admitted to our hospital with strokes.. Occurrence-free rate curves were generated using the Kaplan-Meier method; deep ICH occurrence-free rates were compared using the log-rank test. The follow-up period was 0.5 to 71 months (mean ± standard deviation 31.6 ± 22.2 months).. In patients with deep MBs, the rates (1.0%/year; 6 ICHs in 180 patients) of deep ICH occurrence associated with antiplatelet drugs were not significantly greater than that without the drugs (1.0%/year; 6 ICHs in 167 patients; P = .977). The incidence of deep ICHs associated with warfarin use was not significantly greater than that without warfarin use.. Multivariate analysis revealed that the use of antiplatelet drugs or warfarin did not significantly influence the occurrence of deep ICH in patients with deep MBs. Antiplatelet drugs or warfarin did not significantly elevate the rate of deep ICHs in stroke patients with pre-existing deep MBs.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Chi-Square Distribution; Disease-Free Survival; Female; Fibrinolytic Agents; Hospitalization; Humans; Incidence; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Platelet Aggregation Inhibitors; Proportional Hazards Models; Prospective Studies; Recurrence; Risk Factors; Stroke; Time Factors; Treatment Outcome; Warfarin

The goal of this study was to determine the risk of using antithrombotic agents in patients with established intracerebral cavernous malformations (ICMs).. From a previously described cohort of 292 patients with radiographically defined ICMs, 40 required an antithrombotic after the ICM was diagnosed. Patients underwent follow-up to determine the incidence of hemorrhage.. The mean age of these 40 patients was 62.4 years; there were 21 male and 19 female patients. Five (12.5%) of the 40 patients initially presented with hemorrhage and 4 (10%) had multiple ICMs. Of these patients, 32 were placed on an antiplatelet agent alone, 6 on an anticoagulant alone, and 2 were placed on both. In patients necessitating any antithrombotic agent, 1 patient developed a prospective hemorrhage over the 258 person-years of follow-up (prospective hemorrhage rate 0.41% per person-year).. Antithrombotics likely do not precipitate hemorrhage in patients with known ICMs. However, caution should be exercised in the use of antithrombotics in patients with ICMs at high risk for hemorrhage. The risks and benefits of antithrombotics in each situation should be carefully weighed against the natural history of ICM.

Topics: Aged; Aspirin; Cerebral Hemorrhage; Dipyridamole; Female; Fibrinolytic Agents; Follow-Up Studies; Hemangioma, Cavernous, Central Nervous System; Humans; Male; Middle Aged; Risk Factors; Warfarin

Warfarin-associated intracerebral hemorrhage (WAICH) is expected to increase in prevalence as the population ages. We sought to evaluate national trends, characteristics, and in-hospital outcomes among intracerebral hemorrhage (ICH) patients taking warfarin at baseline.. We reviewed the Nationwide Inpatient Sample to identify all admissions with primary diagnosis of ICH by International Classification of Diseases, Ninth Revision code (431) from 2005 to 2008. We identified premorbid warfarin use by the V code (V58.93) and calculated the proportion of WAICH among all ICH patients in each year. We employed univariate statistics and generalized estimating equation regression models to assess whether warfarin use independently increased the risk of in-hospital mortality after adjusting for relevant covariates. P value less than .05 was considered significant.. There were 52,993 patients (mean age 68.8 years; 49.7% male) coded for ICH between 2005 and 2008. The proportion with WAICH increased each year (2005, 5.8%; 2006, 6.5%; 2007, 6.9%; 2008, 7.3%; P < .001). While in-hospital mortality declined each year for non-WAICH (29.0%-25.4%, P < .001), it remained unchanged for WAICH (42.1%-40.0%, P = .346). In multivariable analysis, warfarin use (adjusted odds ratio 1.35; 95% confidence interval 1.24-1.47) remained an independent predictor of in-hospital mortality.. WAICH is increasing in prevalence in the United States and is associated with a 35% higher mortality than non-WAICH. While mortality has declined over time for non-WAICH, mortality after WAICH is unchanged. Specific strategies to decrease the mortality of WAICH such as rapid reversal of anticoagulation are warranted.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Hospital Mortality; Humans; Male; Middle Aged; Prevalence; Risk Factors; Treatment Outcome; United States; Warfarin

The role of surgery after primary intracerebral hemorrhage (ICH) is controversial. To explore whether hematoma evacuation after ICH had improved short-term survival or functional outcome we conducted a retrospective observational population-based study.. We identified all subjects with primary ICH between 1993 and 2008 among the population of Northern Ostrobothnia, Finland. Hematoma evacuation was carried out by using standard craniotomy or through a burr hole. We compared mortality rates and functional outcomes of patients with hematoma evacuation with those treated conservatively.. Of 982 patients with verified ICH during the study period, 127 (13%) underwent hematoma evacuation. Surgically treated patients were significantly younger (mean±SD, 63±11 vs. 70±12 years; p<0.001), had larger hematomas (66±36 vs. 28±40 ml; p<0.001), lower Glasgow Coma Scale scores (median, 11 vs. 14; p<0.001) and more frequently subcortical hematomas (68% vs. 24%; p<0.001) than those treated conservatively. In multivariable analysis, hematoma evacuation independently lowered 3-month mortality (adjusted hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.43-0.88; p<0.03), particularly among patients aged≤70 years with ≥30 ml supratentorial hematomas (adjusted HR, 0.26; 95% CI, 0.14-0.49; p<0.001). However, poor outcome was not improved by surgery (adjusted odds ratio 0.71; 95% CI 0.29-1.70).. Improved 3-month survival was observed in patients who had undergone hematoma evacuation relative to patients not undergoing evacuation particularly in the subgroup of patients aged≤70 years with ≥30 ml supratentorial hematomas. Surgery might improve outcome if cases could be selected more precisely and if performed before deterioration.

Topics: Adult; Age Factors; Aged; Anticoagulants; Cerebral Hemorrhage; Cerebral Ventricles; Craniotomy; Female; Glasgow Coma Scale; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neurosurgical Procedures; Odds Ratio; Population; Retrospective Studies; Survival Analysis; Tomography, X-Ray Computed; Treatment Outcome; Trephining; Warfarin

A nationwide survey was conducted regarding anticoagulant therapy in patients with acute intracerebral hemorrhage (ICH) on warfarin with nonvalvular atrial fibrillation (NVAF).. A questionnaire on standard therapeutic strategy for warfarin-related ICH in patients with NVAF was mailed to 416 institutes.. A total of 329 physicians (79%) responded with a completed questionnaire. On admission, all respondents stopped warfarin medication and 94% normalized the international normalized ratio (INR) mainly by Vitamin K (63%), followed by fresh frozen plasma (20%), and prothrombin complex concentrate (10%). Afterwards, 91% of the respondents restarted anticoagulation and 3% used antiplatelet for prevention of thromboembolism, but the remaining 6% disagreed with restarting antithrombotic therapy. As contraindications for resuming anticoagulation, recurrent ICH (59%) and poor functional condition (59%) were often chosen. Of those who restarted anticoagulation, the timing was within 4 days in 7%, 5 to 7 days in 21%, 8 to 14 days in 25%, 15 to 28 days in 28% and 29 days or later in 18%. The major key finding on follow-up CT to restart anticoagulation was the absorption tendency of hematomas (47%). When restarting anticoagulation, 76% of the respondents used warfarin alone and 20% used either unfractionated heparin plus warfarin or heparin alone.. A large majority of respondents responsible for ICH management stopped oral warfarin medication and normalized INR on admission, and restarted anticoagulation after acute ICH in patients with NVAF. However, the strategies to normalize INR and to restart anticoagulant therapy varied greatly and depended on each individual physician's decision.

Topics: Acute Disease; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Health Care Surveys; Humans; Japan; Neurology; Warfarin

Hypertension is the most important modifiable risk factor for intracerebral hemorrhage (ICH), but blood pressure (BP) management during the acute phase of ICH is still controversial. Approximately one-fourth of ICHs occur during treatment with warfarin or aspirin.. This study was designed to determine the effect of admission BP on the early prognosis of ICH patients by dividing them into three groups (warfarin, aspirin, and no drugs).. Three hundred and sixty-nine patients with supratentorial ICH were divided into three groups according to medication. Each group was evaluated in terms of prognosis and the risk for mortality based on the modified Rankin Scale (mRS) score at discharge (good prognosis: mRS ≤ 3; poor prognosis: mRS > 3). The effect of admission BP on prognosis was evaluated for each group.. The in-hospital mortality rate was 72% for ICH patients treated with warfarin, 41.6% for ICH patients treated with aspirin, and 35% for ICH patients treated with no drugs. Admission mean arterial blood pressure (MABP) values were higher in patients with poor prognosis compared with patients with good prognosis for the aspirin (P = .002) and no-drug (P = .001) groups, but not in the warfarin (P = .067) group.. A high MABP at admission was found to be an independent predictor of poor prognosis for ICH patients treated with aspirin or with no drugs, but not for ICH patients treated with warfarin.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antihypertensive Agents; Aspirin; Blood Pressure; Cerebral Hemorrhage; Female; Fibrinolytic Agents; Humans; Hypertension; International Normalized Ratio; Male; Middle Aged; Prognosis; Risk Factors; Warfarin

Based on an experimental model of warfarin-associated intracerebral hemorrhage, we investigated whether the rapid reversal of anticoagulation using prothrombin complex concentrates (PCC) or recombinant activated coagulation factor VII (rFVIIa) reduces hematoma volume.. Mice were orally pretreated with warfarin (2 mg/kg). Intracerebral hemorrhage was induced by collagenase injection into the right striatum. Forty-five minutes later, PCC (100 IE/kg), rFVIIa (1 mg/kg), or an equal volume of saline was administered intravenously. Hematoma volume after 24 hours was quantified using a photometric hemoglobin assay.. International normalized ratio was 4.3±0.4 in saline-treated mice, 0.9±0.1 in rFVIIa mice, and 1.4±0.2 in PCC mice. Intracerebral hemorrhage volume was 29.0±19.7 μL in the saline group (n=7), 8.6±4.3 μL in the rFVIIa group (n=6), and 6.1±1.8 μL in the PCC group (n=7; analysis of variance between-group differences P=0.004; post hoc rFVIIa versus saline P=0.021; PCC versus saline P=0.007). No significant difference was found between PCC- and rFVIIa-treated animals.. Our results suggest that PCC and rFVIIa are equally effective in restoring coagulation and preventing excessive hematoma growth in acute warfarin-associated intracerebral hemorrhage.

Topics: Animals; Blood Coagulation Factors; Brain; Cerebral Hemorrhage; Collagenases; Factor VII; Hematoma; Hemostasis; Male; Mice; Treatment Outcome; Warfarin

Topics: Brain Ischemia; Cerebral Hemorrhage; Contraindications; Emergency Service, Hospital; Female; Fibrinolytic Agents; Humans; Middle Aged; Tissue Plasminogen Activator; Warfarin

Intracerebral hemorrhage (ICH) is the most serious bleeding complication of vitamin K antagonist (VKA) therapy, carrying a high mortality. Rapid reversal of VKA in ICH is critical. Plasma therapy, the standard of care in the US, is not optimal. The ideal prothrombin complex concentrate (PCC) containing all vitamin K-dependent factors (VKDFs) is not available in the US. Therefore, the authors developed a Trauma Coumadin Protocol (TCP) consisting of a 3-factor PCC available in the US (which contains insufficient factor VII [FVII]) with a low-dose recombinant FVIIa to rapidly reverse VKA.. Forty-six patients treated with the TCP were retrospectively analyzed. Fourteen patients had pre- and post-TCP plasma samples collected to assess their VKDF increment. Eleven patients had measurable intraparenchymal hematomas, which were evaluated for expansion.. The mean pre- and post-TCP international normalized ratios (INRs) were 3.4 (median 2.9) and 1.0 (median 0.9), respectively. Once corrected, INR was maintained at < 1.3 during a patient's hospital stay. The pre-TCP median values of FII, FVII, FIX, and FX were 28%, 21%, 45%, and 20%, respectively; post-TCP median values increased to 144%, 417%, 102%, and 143%, respectively. Four of the 11 patients with measurable intraparenchymal hemorrhage had expansion at 24 hours after TCP. One patient probably (8 hours post-TCP) and 1 patient possibly (3 days post-TCP) had thrombotic complications.. The TCP was very effective in rapidly reversing VKA-associated coagulopathy; however, this protocol should be used cautiously in patients at high risk for thrombosis.

Topics: Adult; Aged; Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Clinical Protocols; Drug Combinations; Factor VIIa; Female; Hematoma; Humans; International Normalized Ratio; Male; Middle Aged; Recombinant Proteins; Retrospective Studies; Vitamin K; Warfarin

“Blood/fluid level” represents interface between the plasma and sedimented blood and is defined radiologically as presence of area of low computed tomography (CT) attenuation above and high CT attenuation below a discrete line of separation in an area of intraparenchymal hemorrhage. It is a rare finding seen in association with large clot volume of intraparenchymal hemorrhage. We present a case of warfarin-related intraparenchymal hemorrhage presenting with a classic sign of “blood/fluid level” on CT head with small clot volume.

Topics: Aged, 80 and over; Anticoagulants; Brain; Cerebral Hemorrhage; Emergency Service, Hospital; Female; Humans; Neuroimaging; Tomography, X-Ray Computed; Warfarin

Atrial fibrillation is an important risk factor for stroke. New drugs for oral anticoagulation that do not exhibit the limitations of vitamin K antagonists like warfarin are under investigation. These include direct factor Xa inhibitors and direct thrombin-inhibitors. Recent studies provide promising results for apixaban, dabigatran, and rivaroxaban, including higher efficacy and significantly lower incidences of intracranial bleeds compared with warfarin. The new oral anticoagulants substances show similar results in secondary as in primary stroke prevention in patients with AF and will on the long run replace warfarin.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Brain Ischemia; Cerebral Hemorrhage; Dabigatran; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Randomized Controlled Trials as Topic; Risk; Risk Factors; Stroke; Thrombin; Warfarin

Anticoagulation with dabigatran etexilate (DE) has a favorable risk-to-benefit profile for the prevention of ischemic events in patients with atrial fibrillation compared to warfarin. Whereas warfarin constitutes a strong contraindication for thrombolysis, it is unclear whether patients anticoagulated with DE can be thrombolysed. We compared the risk of thrombolysis-associated hemorrhagic transformation (HT) after pretreatment with DE or warfarin in a mouse model of ischemic stroke.. Thirty-nine C57BL/6 mice were pretreated orally with 75 mg/kg DE, 112.5mg/kg DE, 2mg/kg warfarin, or saline. We performed right middle cerebral artery occlusion for 3 hours, administered recombinant tissue plasminogen activator (rt-PA) directly before reperfusion, and assessed neurological deficit and HT blood volume after 24 hours.. Warfarin anticoagulation increased HT secondary to rt-PA treatment as compared to nonanticoagulated controls (6.9 ± 5.5 μl vs 0.8 ± 0.6 μl, p < 0.05). In contrast, the rate of HT after pretreatment with 75 mg/kg DE, which led to plasma levels comparable to the highest plasma levels observed in participants of the RE-LY trial, did not differ significantly from controls (1.6 ± 0.8; p > 0.05 vs control). However, a high-dose group receiving 112.5mg/kg DE showed a considerable extent of HT (9.2 ± 5.6 μl, p < 0.01).. Our experimental data suggest that the risk of thrombolysis-associated HT may not be increased under DE pretreatment with standard doses leading to plasma levels of up to 400 ng/ml, a concentration that was not exceeded in the majority of DE trial patients. At higher DE plasma levels, however, the risk of severe HT rises considerably, emphasizing the need for a readily available assay of DE anticoagulant activity.

Topics: Animals; Anticoagulants; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Dabigatran; Disease Models, Animal; Drug Interactions; Fibrinolytic Agents; Mice; Mice, Inbred C57BL; Stroke; Tissue Plasminogen Activator; Warfarin

Known risk factors for bleeding during anticoagulant treatment are largely the same as those predicting thromboembolic events in patients with atrial fibrillation (AF). Our objective was to investigate how to maximize the likelihood of avoiding both stroke and bleeding.. All 182 678 subjects with atrial fibrillation in the Swedish Hospital Discharge Register were studied for an average of 1.5 years (260 000 patient-years at risk). Patients were stratified according to risk scores with the use of historic International Classification of Disease diagnostic codes in the register. Information about medication was obtained from the Swedish Drug Registry. Our primary end point was net benefit defined as number of avoided ischemic strokes with anticoagulation minus the number of excess intracranial bleedings with a weight of 1.5 to compensate for the generally more severe outcome with intracranial bleedings. The adjusted net clinical benefit favored anticoagulation for almost all atrial fibrillation patients. The exceptions were patients at very low risk of ischemic stroke with a CHA(2)DS(2)-VASc score of 0 and moderately elevated bleeding risk (-1.7%/y). The results were broadly similar with CHADS(2), except for patients with very low embolic risk; the CHA(2)DS(2)-VASc was able to identify those patients (n=6205, 3.9% of all patients) who had no net clinical benefit or even some disadvantage from anticoagulant treatment.. In almost all patients with atrial fibrillation, the risk of ischemic stroke without anticoagulant treatment is higher than the risk of intracranial bleeding with anticoagulant treatment. Analysis of the net benefit indicates that more patients may benefit from anticoagulant treatment.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Cohort Studies; Female; Follow-Up Studies; Humans; Incidence; Intracranial Embolism; Male; Middle Aged; Registries; Risk Factors; Stroke; Sweden; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Female; Humans; Male; Stroke; Warfarin

The decision to prescribe oral anticoagulant therapy in patients with atrial fibrillation is based on an assessment of the competing risks of ischemic stroke and major bleeding, of which intracerebral hemorrhage (ICH) is the most important type. We sought to determine the comparative importance of risk factors for ischemic stroke and ICH in patients with acute stroke and atrial fibrillation with particular emphasis on risk factors common to both stroke types.. Consecutive patients with acute ischemic stroke or ICH and atrial fibrillation included in the Registry of the Canadian Stroke Network constituted the cohort. Multivariable logistic regression analysis was used to determine the association between baseline risk factors and presentation with ICH versus ischemic stroke. Risk factors included: (1) those previously reported to be risk factors for both ischemic stroke and major bleeding (particularly ICH) ("shared" risk factors, including age, alcohol, hypertension, diabetes mellitus, renal impairment, prior stroke/transient ischemic attack and preadmission dementia); and (2) other risk factors associated with either stroke subtype alone.. A total of 3197 patients presented with atrial fibrillation and acute stroke, of which 12.2% presented with ICH. Of the "shared" risk factors, age (OR, 1.19; 95% CI, 1.06-1.34 per decade) and prior stroke/transient ischemic attack (OR, 1.45; 95% CI, 1.12-1.87) were more associated with ischemic stroke than ICH, whereas a history of hypertension (OR, 0.89; 95% CI, 0.68-1.17), diabetes mellitus (OR 1.23; 95% CI, 0.92-1.64), renal impairment (OR, 1.28; 95% CI, 0.95-1.71), and alcohol intake were not more strongly associated with either stroke subtype.. Of the risk factors known to be associated with both ischemic stroke and ICH in patients with atrial fibrillation, we found that none had a stronger association with ICH. Older age was more strongly associated with ischemic stroke than ICH.

Topics: Age Factors; Aged; Alcohol Drinking; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Canada; Cerebral Hemorrhage; Data Interpretation, Statistical; Dementia; Diabetes Mellitus; Female; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Recurrence; Registries; Risk Assessment; Risk Factors; Stroke; Warfarin

The CT angiography (CTA) spot sign predicts hematoma expansion and poor outcome in patients with primary intracerebral hemorrhage (ICH). The biological underpinnings of the spot sign remain poorly understood; it may be that the underlying vasculopathy influences its presence. Therefore, we conducted a study to identify genetic predictors of the spot sign.. In an ongoing prospective cohort study, we analyzed 371 patients with CTA and genetic data available. CTAs were reviewed for the spot sign by 2 experienced readers, blinded to clinical data, according to validated criteria. Analyses were stratified by ICH location.. In multivariate analysis, patients on warfarin were more likely to have a spot sign regardless of ICH location (OR, 3.85; 95% CI, 1.33-11.13 in deep ICH and OR, 2.86; 95% CI, 1.33-6.13 in lobar ICH). Apolipoprotein E ε2, but not ε4, was associated with the presence of a spot sign in lobar ICH (OR, 2.09; 95% CI, 1.05-4.19). There was no effect for ε2 or ε4 in deep ICH.. Patients with ICH on warfarin are more likely to present with a spot sign regardless of ICH location. Among patients with lobar ICH, those who possess the apolipoprotein E ε2 allele are more likely to have a spot sign. Given the established relationship between apolipoprotein E ε2 and vasculopathic changes in cerebral amyloid angiopathy, our findings suggest that both hemostatic factors and vessel pathology influence spot sign presence.

Topics: Acute Disease; Aged; Anticoagulants; Apolipoprotein E2; Apolipoprotein E4; Apolipoproteins E; Cerebral Angiography; Cerebral Hemorrhage; Cohort Studies; Data Interpretation, Statistical; DNA; Female; Follow-Up Studies; Genotype; Glasgow Coma Scale; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Prospective Studies; Retrospective Studies; Tomography, X-Ray Computed; Warfarin

The purpose of this study was to investigate time delays, adherence to guidelines, and their impact on outcomes in patients with warfarin-associated intracerebral hemorrhage transferred from community emergency departments to a comprehensive stroke center.. We collected demographic, clinical, transfer time, treatment, and outcome data for patients transferred to our institution with warfarin-associated intracerebral hemorrhage from community emergency departments.. Among 928 patients with intracerebral hemorrhage, 56 (6%) with warfarin-associated intracerebral hemorrhage (median international normalized ratio, 2.55) were transferred to the comprehensive stroke center. Twenty patients received no acute reversal therapy before transfer, only 4 of whom had international normalized ratios ≤1.4 in the community emergency department. Median time of emergency department stay was 3.66 hours and median time to initiation of acute reversal therapy was 4.48 hours. Those who received ≥3 U of fresh-frozen plasma or recombinant activated Factor VIIa (11 patients) before transfer had lower repeat international normalized ratios and better discharge dispositions than those treated less aggressively.. Treatment of warfarin-associated intracerebral hemorrhage in community emergency departments is often suboptimal and does not adhere to published guidelines. Treating coagulopathy aggressively before interhospital transfer may improve outcomes and warrants further investigation.

Topics: Aged; Anticoagulants; Cerebral Hemorrhage; Community Health Centers; Emergency Medical Services; Emergency Service, Hospital; Factor VIIa; Female; Hospital Mortality; Humans; International Normalized Ratio; Male; Plasma; Registries; Time Factors; Warfarin

The effectiveness of prothrombin complex concentrate (PCC) products available in the United States that contain low levels of factor VII (3-factor PCC) has not been tested. The purpose of this study was to review our experience with 3-factor PCC (Profilnine) in the setting of warfarin-associated intracranial hemorrhage (wICH).. In November 2007, we implemented a protocol for reversal of anticoagulation in wICH using Profilnine. Additional treatment with fresh-frozen plasma was at the discretion of the treating physician. Medical records of all patients receiving PCC for wICH between November 1, 2007, and December 7, 2011 were reviewed. Correction of the international normalized rate (INR) was defined as an INR <1.4.. Seventy wICH patients were treated with Profilnine, including 46 (66%) with intraparenchymal hemorrhage, 22 (31%) with subdural hemorrhage, and 2 (3%) with subarachnoid hemorrhage. Mean INR was reduced from 3.36 to 1.96, and in 44 (62.9%) patients the INR corrected to <1.4. Baseline INR ≥3.0 decreased the likelihood of INR correction. Concomitant administration of fresh-frozen plasma (mean, 2.6 U) did not increase the likelihood of INR correction. Seven (10%) patients had serious adverse events during their hospital course, including 2 sudden deaths from suspected pulmonary embolism.. Reversal of coagulopathy in wICH with Profilnine was incomplete and associated with serious adverse events. In the absence of available 4-factor PCC, options for urgent reversal of anticoagulation in wICH remain limited.

Topics: Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Humans; International Normalized Ratio; Kaplan-Meier Estimate; Survival Analysis; Tomography, X-Ray Computed; Warfarin

Topics: Acute Lung Injury; Aged; Anticoagulants; Cerebral Hemorrhage; Factor VII; Female; Heart Valve Prosthesis; Hemostatic Techniques; Hemostatics; Humans; International Normalized Ratio; Plasma; Prothrombin; Transfusion Reaction; Warfarin

Topics: Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Evidence-Based Medicine; Guidelines as Topic; Hemostasis; Hemostatics; International Normalized Ratio; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Female; Humans; Male; Stroke; Warfarin

Cerebral cavernous malformations (CCMs) are one of the most frequently diagnosed vascular malformations of the brain and constitute a potential source of intracranial hemorrhage. In CCM patients suffering ischemic stroke or heart disease, the use of anticoagulants or antiplatelet therapy is generally avoided by fear of hemorrhagic complications, but no systematic studies exist to support this hypothesis.. We prospectively followed-up consecutive patients with a diagnosis of one or more CCMs in a prospective database since 2008. Retrospective data collection was used for patients with a diagnostic event or imaging studies done before first assessment. Symptomatic hemorrhage and other focal neurological events during prospective follow-up were defined according to the current guidelines of the Angioma Alliance Scientific Advisory board.. A total of 87 patients were prospectively enrolled in our cohort [50 women (57%), mean age 44.8 years (SD±17.6), mean follow-up 3.9 years], harboring a total of 738 CCMs. Fifty-five patients (63%) had a single CCM, and 32 patients (37%) had multiple CCMs. Longitudinal follow-up included 16 (18%) patients receiving long-term antithrombotic therapy by antiplatelet treatment (n=11) or oral anticoagulants (n=5). During 5536 lesion-years of observation, none of the patients under antithrombotic therapy experienced CCM hemorrhage on follow-up.. Our observational data suggest that long-term antithrombotic treatment by antiplatelet drugs or warfarin does not increase the frequency of CCM-related hemorrhage. Patients harboring single or multiple CCMs suffering ischemic stroke or heart disease should not be withheld antithrombotic therapy.

Topics: Adult; Anticoagulants; Cerebral Hemorrhage; Databases, Factual; Female; Fibrinolytic Agents; Follow-Up Studies; Hemangioma, Cavernous, Central Nervous System; Humans; Longitudinal Studies; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Retrospective Studies; Risk Factors; Warfarin

Novel anticoagulants including dabigatran and rivaroxaban have lower incidence of intracranial hemorrhage compared to warfarin. Therefore, in patients with high risks for intracranial hemorrhage, such as past history of brain infarction, brain hemorrhage, microbleeds on MRI, or concomitant use of antiplatelet, novel anticoagulant may be appropriate. Irrespective of any anticoagulants, it is essential to manage controllable risk factors, such as hypertension, diabetes mellitus, smoking habit, and excessive alcohol drinking. Combination therapy of other antithrombotic agents had better be avoided as long as possible. In emergency of hemorrhage complications, discontinuation of anticoagulants, procedure to stop bleeding, and appropriate intravenous infusion is quite important and lowering blood pressure is also important when intracranial hemorrhage happens. There is no antidote to novel anticoagulants. However, oral activated charcoal may be effective if early after taking medicine. The dabigatran can be dialysed. Some experimental evidences support the role of prothrombin complex concentrate to stop bleeding. However, their usefulness in clinical setting has not been established. Collecting and analyzing data regarding immediate reversal of novel anticoagulants is required in near future.

Topics: Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Cerebral Hemorrhage; Dabigatran; Humans; Intracranial Embolism; Morpholines; Rivaroxaban; Thiophenes; Warfarin

intracerebral hemorrhage associated with oral anticoagulants has a poor prognosis. Current treatment guidelines are based on case series and plausibility only, and a common consensus on effective hemostatic therapy is missing. We compared the effectiveness of diverse hemostatic approaches in a mouse model of warfarin-associated intracerebral hemorrhage.. male C57BL/6 mice received anticoagulant treatment with warfarin (0.4 mg/kg for 3 days). Intracerebral hemorrhage was induced by striatal injection of collagenase, and 30 minutes later, mice received an intravenous injection of saline (200 μL n=15), prothrombin complex concentrate (100 U/kg, n=10), fresh-frozen plasma (200 μL, n=13), recombinant human Factor VII activated (3.5 mg/kg, n=8 and 10 mg/kg, n=8), or tranhexamic acid (400 mg/kg, n=12). Intracerebral hemorrhage volume was quantified on T2-weighted images after 24 hours.. mean hematoma volumes were 7.4 ± 1.8 mm(3) in the nonwarfarin controls and 21.9 ± 5.0 mm(3) in the warfarin group receiving saline. Prothrombin complex concentrate (7.5 ± 2.3 mm(3)) and fresh-frozen plasma (8.7 ± 2.1) treatment resulted in significantly smaller hematoma volume compared with saline. Recombinant human Factor VII activated (10 mg/kg: 14.7 ± 3.4; 3.5 mg/kg: 15.0 ± 6.8 mm(3)) and tranexamic acid (16.2 ± 4.1 mm(3)) were less effective. Water content in the hemorrhagic hemisphere was similar in all groups except for tranexamic acid in which it was significantly increased.. prothrombin complex concentrate and fresh-frozen plasma effectively prevent hematoma growth in murine warfarin-associated intracerebral hemorrhage, whereas Factor VIIa was less effective. Tranexamic acid exacerbates perihematoma edema in this mouse warfarin-associated intracerebral hemorrhage model.

Topics: Animals; Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Collagenases; Disease Models, Animal; Factor VIIa; Hematoma; Hemostasis; Humans; Male; Mice; Plasma; Recombinant Proteins; Tranexamic Acid; Warfarin

The present study was carried out to determine the effect of prothrombin complex concentrate (PCC) on hematoma enlargement (HE) and the early clinical outcome of intracerebral hemorrhage (ICH) patients on long-term warfarin treatment.. The medical records and computed tomography (CT) images of 50 consecutive ICH patients on long-term warfarin treatment (35 men, 15 women; 69 ± 12 years old) were reviewed. International normalized ratio (INR) values, frequency of HE and clinical outcome were compared between patients treated with and without PCC.. INR values on admission were above 2.0 in 37 patients, of whom 19 were given PCC (PCC group) and 18 were not given PCC (control group). In these 37 patients, the frequency of HE (p = 0.017), the number of patients with a poor clinical outcome (modified Rankin Scale score ≥3 at 30 days or at discharge; p = 0.045) and in-hospital mortality (p = 0.042) were significantly higher in the control than in the PCC group. On multivariate logistic regression analysis with adjustment, PCC administration was independently associated (odds ratio 0.03, 95% confidence interval 0.00-0.63; p = 0.023) with a reduction in poor clinical outcome in ICH patients whose INR values were >2.0 on admission.. Immediate INR reversal with PCC may prevent HE and subsequent poor outcome.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Case-Control Studies; Cerebral Hemorrhage; Chi-Square Distribution; Coagulants; Female; Hematoma; Hospital Mortality; Humans; International Normalized Ratio; Japan; Logistic Models; Male; Middle Aged; Odds Ratio; Risk Assessment; Risk Factors; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Warfarin; Young Adult

Topics: Cerebral Hemorrhage; Humans; Injections, Intravenous; Risk Factors; Thrombolytic Therapy; Tissue Plasminogen Activator; Warfarin

The prevalence of long-term oral anticoagulant therapy is rising. Treatment options for patients who have an ischemic stroke under oral anticoagulant therapy are limited, and clinical data on the risk of hemorrhagic transformation (HT) in this condition are scarce. We therefore aimed to establish a mouse model of ischemic stroke occurring during oral anticoagulant therapy to assess the frequency and characteristics of HT.. C57BL/6 mice (n=59) were pretreated with warfarin. Untreated mice (n=32) served as controls. We performed a 3-hour transient filament occlusion of the right middle cerebral artery. In a first set of animals, ischemic lesion size and HT were evaluated macroscopically at 24 hours after middle cerebral artery occlusion. In a second set of mice, quantitative analysis of HT was performed at different time points after middle cerebral artery occlusion and in animals with different international normalized ratio levels using a photometric hemoglobin assay.. Oral anticoagulant therapy at the onset of ischemia led to HT in all anticoagulated mice, whereas only 14% of the control mice showed HT. Mean HT blood volume 24 hours after middle cerebral artery occlusion was 0.3±0.4 μL in controls, 4.2±1.7 μL in mice anticoagulated to a mean international normalized ratio of 1.9±0.5 (P<0.05 versus controls), and 5.2±2.7 μL in mice with an international normalized ratio of 2.9±0.9 (P<0.001 versus controls). Anticoagulated mice euthanized at the time point of reperfusion had less HT than mice euthanized after 21 hours of reperfusion (1.6±0.5 μL versus 5.9±3.6 μL, P<0.05).. We present a mouse model of ischemic stroke occurring during oral anticoagulant therapy. Warfarin pretreatment dramatically increases the risk of HT 24 hours after middle cerebral artery occlusion. Reperfusion injury seems to be a critical component in this condition.

Topics: Animals; Anticoagulants; Brain Ischemia; Cerebral Hemorrhage; Cerebrovascular Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Reperfusion Injury; Risk Factors; Stroke; Warfarin

Although oral antithrombotic therapy (OAT) is a risk factor of intracerebral hemorrhage (ICH), the clinical course of supratentorial ICH with prior OAT is unclear. We therefore assessed the characteristics of supratentorial ICH with OAT to determine whether OAT is independently associated with early death in supratentorial ICH.. We retrospectively enrolled consecutive patients with supratentorial ICH admitted to the Stroke Center of Kawasaki Medical School Hospital within 24 hours of onset, from April 2004 to March 2009. The group with OAT therapy (OA group) was compared with the group without (non-OA group).. A total of 389 patients with supratentorial ICH (median age 68 years, 61% males) were enrolled in the present study. OAT was used in 24% of patients. The OA group was older than the non-OA group (median 74 vs. 66 years, p<0.001). In the OA group, Glasgow Coma Scale was less (10 vs. 13, p<0.001), and hematomas were larger (22 mL vs. 14 mL, p<0.001). Early death was more frequently observed in the OA group than in the non-OA group (28% vs. 8.1%, p<0.001). Unadjusted HR of OAT for death within 14 days was 3.62 (95% CI: 2.06-6.33, p<0.001), the age- and sex-adjusted HR was 3.84 (95% CI: 2.12-6.96, p<0.001), and HR adjusted for age, sex, GCS, and hematoma volume was 2.01 (95% CI: 1.11-3.65, p=0.022). HR adjusted for age, sex, GCS, and hematoma volume at day 1 was 2.63 (p=0.34), day 3: 2.35 (p=0.03), day 7: 2.01 (p=0.04), and day 14: 1.90 (p=0.04).. The OA group patients were older, their GCS was lower, they had larger hematoma volume, and more frequent occurrence of early death. Prior oral antithrombotic therapy is associated with early death in patients with supratentorial ICH.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Fibrinolytic Agents; Humans; Japan; Kaplan-Meier Estimate; Male; Middle Aged; Platelet Aggregation Inhibitors; Proportional Hazards Models; Retrospective Studies; Risk Factors; Warfarin

The prevalent use of anticoagulation in a growing elderly population has led to an increasing incidence of intracerebral hemorrhage. Furthermore, the understanding of the interactions and adverse effects of oral anticoagulants when used with non-FDA approved drugs is limited. Diosmin is one such non-FDA approved drug which is a semisynthetic, phlebotropic supplement with multiple microcirculatory effects. We report a case of a patient on oral anticoagulation and diosmin, who presented with spontaneous intraventricular hemorrhage, and discuss the possible etiology behind this rare event.. A retrospective chart review and a comprehensive search of the literature using the PubMed database were performed.. A 77-year old female with a 6 week history of warfarin therapy and a several year history of diosmin use presented with severe bitemporal headache. Computed tomography scan revealed an acute hemorrhage within the right ventricle without associated intraparenchymal hemorrhage. International normalized ratio measured 1.8 and was corrected using fresh frozen plasma and vitamin K. She was discharged without neurological deficits.. Diosmin inhibits platelet aggregation and prolongs the effect of norepinephrine on venous tone, leading to increased venoconstriction. The combined effect of chronic microcirculatory hypertension and inhibition of platelet aggregation due to diosmin may have predisposed to spontaneous hemorrhage in this anticoagulated patient. Individual cases such as this serve as a reminder that over-the-counter dietary supplements may be associated with serious adverse events. The practicing clinician should be aware of this possible adverse event when evaluating patients on oral anticoagulation and chronic diosmin treatment.

Topics: Aged; Anticoagulants; Cerebral Angiography; Cerebral Hemorrhage; Cerebral Ventricles; Dietary Supplements; Diosmin; Drug Interactions; Female; Flavonoids; Humans; Long-Term Care; Magnetic Resonance Angiography; Self Medication; Tomography, X-Ray Computed; Warfarin

Topics: Angiotensin II Type 1 Receptor Blockers; Anticoagulants; Aspirin; Atrial Fibrillation; Biphenyl Compounds; Cerebral Hemorrhage; Clopidogrel; Evidence-Based Medicine; Follow-Up Studies; Humans; Hypertension; Irbesartan; Platelet Aggregation Inhibitors; Stroke; Tetrazoles; Ticlopidine; Treatment Outcome; Warfarin

There is uncertainty whether warfarin-treated patients (despite international normalized ratio < 1.7) have increased risks of symptomatic intracerebral hemorrhage after intravenous thrombolysis.. Vascular risk factors, stroke subtype, and outcome measures were compared between warfarin- and nonwarfarin-treated patients undergoing acute thrombolysis within 3 hours of symptom onset.. From 212 patients (mean age, 74 ± 14 years; 50% men) studied, 14 (6.5%) had prior warfarin use. After adjusting for age, baseline National Institutes of Health Stroke Scale, and stroke subtype, warfarin-treated patients had significantly increased risks of developing symptomatic intracerebral hemorrhage (adjusted OR, 14.7; 95% CI, 1.3 to 54.3). A trend for poorer stroke recovery and increased mortality was observed in warfarin-treated patients on univariate, but not on multivariable, analyses.. Warfarin-treated patients with stroke have increased risks of symptomatic intracerebral hemorrhage after thrombolytic treatment. These data raise safety concerns of thrombolytic treatment in warfarin-treated patients with subtherapeutic international normalized ratio.

Topics: Aged; Aged, 80 and over; Brain Ischemia; Cerebral Hemorrhage; Female; Fibrinolytic Agents; Humans; Infusions, Intravenous; International Normalized Ratio; Male; Middle Aged; Risk; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome; Warfarin

Topics: Anticoagulants; Cerebral Hemorrhage; Female; Humans; Male; Warfarin

The direct thrombin inhibitor dabigatran etexilate (DE) may constitute a future replacement of vitamin K antagonists for long-term anticoagulation. Whereas warfarin pretreatment is associated with greater hematoma expansion after intracerebral hemorrhage (ICH), it remains unclear what effect direct thrombin inhibitors would have. Using different experimental models of ICH, this study compared hematoma volume among DE-treated mice, warfarin-treated mice, and controls.. CD-1 mice were fed with DE or warfarin. Sham-treated mice served as controls. At the time point of ICH induction, DE mice revealed an increased activated partial thromboplastin time compared with controls (mean±SD 46.1 ± 5.0 versus 18.0 ± 1.5 seconds; P=0.022), whereas warfarin pretreatment resulted in a prothrombin time prolongation (51.4 ± 17.9 versus 10.4 ± 0.3 seconds; P<0.001). Twenty-four hours after collagenase-induced ICH formation, hematoma volume was 3.8 ± 2.9 μL in controls, 4.8 ± 2.7 μL in DE mice, and 14.5 ± 11.8 μL in warfarin mice (n=16; Welch ANOVA between-group differences P=0.007; posthoc analysis with the Dunnett method: DE versus controls, P=0.899; warfarin versus controls, P<0.001; DE versus warfarin, P=0.001). In addition, a model of laser-induced cerebral microhemorrhage was applied, and the distances that red blood cells and blood plasma were pushed into the brain were quantified. Warfarin mice showed enlarged red blood cell and blood plasma diameters compared to controls, but no difference was found between DE mice and controls.. In contrast with warfarin, pretreatment with DE did not increase hematoma volume in 2 different experimental models of ICH. In terms of safety, this observation may represent a potential advantage of anticoagulation with DE over warfarin.

Topics: Administration, Oral; Animals; Anticoagulants; Antithrombin Proteins; Benzimidazoles; Cerebral Hemorrhage; Collagenases; Dabigatran; Hematoma; Injections; Male; Mice; Mice, Inbred Strains; Microscopy, Fluorescence; Partial Thromboplastin Time; Pyridines; Time Factors; Warfarin

Oral anticoagulation therapy (OAT) with warfarin increases mortality and disability after intracerebral hemorrhage (ICH), the result of increased ICH volume and risk of hematoma expansion. We investigated whether OAT also influences risk of development of intraventricular hemorrhage (IVH), the volume of IVH and IVH expansion, and whether IVH is a substantive mediator of the overall effect of OAT on ICH outcome.. We performed a retrospective analysis of a prospectively collected single-center cohort of 1,879 consecutive ICH cases (796 lobar, 865 deep, 153 cerebellar, 15 multiple location, 50 primary IVH) from 1999 to 2009. ICH and IVH volumes at presentation, as well as hematoma expansion (>33% or >6 mL increase) and IVH expansion (>2 mL increase), were determined using established semiautomated methods. Outcome was assessed at 90 days using either the modified Rankin Scale or Glasgow Outcome Scale.. Warfarin use was associated with IVH risk, IVH volume at presentation, and IVH expansion in both lobar and deep ICH (all p < 0.05) in a dose-response relationship with international normalized ratio. Warfarin was associated with poor outcome in both lobar and deep ICH (p < 0.01), and >95% of this effect was accounted for by baseline ICH and IVH volumes, as well as ICH and IVH expansion.. Warfarin increases IVH volume and risk of IVH expansion in lobar and deep ICH. These findings (along with effects on ICH volume and expansion) likely represent the mechanisms by which anticoagulation worsens ICH functional outcome.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Cerebral Ventricles; Female; Humans; Male; Middle Aged; Prospective Studies; Retrospective Studies; Tomography, X-Ray Computed; Warfarin

Topics: Anticoagulants; Brain Ischemia; Cerebral Hemorrhage; Drug Administration Schedule; Humans; Stroke; Warfarin

Topics: Anticoagulants; Brain Ischemia; Cerebral Hemorrhage; Humans; Stroke; Warfarin

To determine the incidence, and any change in incidence, of spontaneous intracerebral haemorrhage (ICH) detected in the hospitals of the Waikato region of New Zealand (NZ) between 1999 and 2008. To analyse clinical and patient parameters, and to correlate these with outcome.. A retrospective analysis was performed on patients presenting to Waikato and Thames Hospitals with ICH during the study period. Radiology reports, blood tests and the electronic clinical record were reviewed for each patient.. 653 episodes of ICH were identified. The average annual incidence per 100,000 per year was 17.4 (16.1-18.7, 95% confidence interval). This increased from an average of 14.4 (13.7-15.1) between 1999-2001 to 21.4 (20.6-22.2) between 2006-2008 (rate ratio 1.49, p<0.0001). 249 (38.1%) patients died within 30 days of their sentinel bleed. The presence of intraventricular extension of bleed on neuroimaging (Odds Ratio (OR) 6.18, p<0.001), warfarin use (OR 1.11, p=0.76), warfarin use and intraventricular extension of bleed (OR 23.8, p=0.014), lobar location of bleed (OR 1.88, p=0.001) and age (OR 1.16 for every 10-year increase in age, p=0.02) increased the likelihood of death within 30 days.. Observed ICH has increased in incidence in our hospitals over the past 10 years. Increasing availability of neuroimaging, increasing numbers of elderly, and increasing warfarin associated ICH were likely contributors to this observed increase. Radiological evidence of extension of intraventricular bleed, warfarin use, lobar location of bleed, and increasing age correlated with poorer survival. This data will be available for comparison with future studies to assess trends in incidence, patient characteristics and outcome in ICH.

Topics: Age Factors; Aged; Anticoagulants; Cerebral Hemorrhage; Diagnostic Imaging; Female; Hospital Mortality; Humans; Incidence; Logistic Models; Male; Middle Aged; New Zealand; Prevalence; Recurrence; Retrospective Studies; Risk Factors; Survival Analysis; Warfarin

Knowledge about stroke risk in paroxysmal atrial fibrillation (PxAF) is limited. Although current guideline recommendations advocate the same treatment as in permanent atrial fibrillation (PermAF), most patients with PxAF do not receive prophylactic anticoagulation. The aim of this study is to investigate whether there are differences in stroke risk between PxAF and PermAF.. All patients with PxAF (n = 855) and PermAF (n = 1126) treated for atrial fibrillation (AF) during 2002 at one of Scandinavia's largest hospitals were followed-up for 3.6 years regarding incidence of stroke. Information about type of AF, comorbidity, medication, and clinical events during follow-up was acquired from medical records and the National Register of Hospital Discharges. The incidence of ischaemic stroke was similar in PxAF and PermAF (26 vs. 29 events/1000 patient years). The multivariable-adjusted hazard ratio (HR) for ischaemic stroke in PxAF compared with PermAF was 1.07 (95% CI 0.71-1.61) in subjects without prior stroke. The corresponding HR for any stroke, ischaemic or haemorrhagic, was 0.89 (95% CI 0.61-1.30). Compared with the general population, ischaemic stroke was twice as common as expected in PxAF after standardization for age and sex (standardized incidence ratio 2.12, 95% CI 1.52-2.71). PxAF patients who took warfarin had approximately half as many ischaemic strokes as those who did not take warfarin (HR 0.44, 95% CI 0.30-0.65).. Ischaemic stroke is about as common in PxAF as in PermAF, and about twice as common as in the general population. Yet, PxAF patients do not receive protective anticoagulant treatment as often as patients with PermAF do. It is therefore important to increase the use of anticoagulants among PxAF patients in accordance with current guideline recommendations.

Topics: Adult; Aged; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Female; Humans; Male; Middle Aged; Recurrence; Risk Factors; Stroke; Warfarin

Hematoma volume is a major determinant of outcome in patients with intracerebral hemorrhage (ICH). Accurate volume measurements are critical for predicting outcome and are thought to be more difficult in patients with oral anticoagulation-related ICH (OAT-ICH) due to a higher frequency of irregular shape. We examined hematoma shape and methods of volume assessment in patients with OAT-ICH.. We performed a case-control analysis of a prospectively identified cohort of consecutive patients with ICH. We retrospectively reviewed 50 consecutive patients with OAT-ICH and 50 location-matched non-OAT-ICH controls. Two independent readers analyzed CT scans for hematoma shape and volume using both ABC/2 and ABC/3 methods. Readers were blinded to all clinical variables including warfarin status. Gold-standard ICH volumes were determined using validated computer-assisted planimetry.. Within this cohort, median INR in patients with OAT-ICH was 3.2. Initial ICH volume was not significantly different between non-OAT-ICH and OAT-ICH (35 +/- 38 cc vs. 53 +/- 56 cc, P = 0.4). ICH shape did not differ by anticoagulation status (round shape in 10% of OAT-ICH vs. 16% of non-OAT-ICH, P = 0.5). The ABC/3 calculation underestimated median volume by 9 (3-28) cc, while the ABC/2 calculation did so by 4 (0.8-12) cc.. Hematoma shape was not statistically significantly different in patients with OAT-ICH. Among bedside approaches, the standard ABC/2 method offers reasonable approximation of hematoma volume in OAT-ICH and non-OAT-ICH.

Topics: Aged; Aged, 80 and over; Anticoagulants; Case-Control Studies; Cerebral Hemorrhage; Cohort Studies; Female; Hematoma; Humans; Image Processing, Computer-Assisted; International Normalized Ratio; Male; Point-of-Care Systems; Prognosis; Retrospective Studies; Software; Tomography, X-Ray Computed; Warfarin

The burden of intracerebral hemorrhage associated with oral anticoagulants (OAC-ICH) is growing. However, little is known about the pathophysiology of W-ICH. Herein, we refine a mouse model of OAC-ICH using repetitive T2* MRI to describe kinetics of hematoma enlargement, and establish a benchside point of care INR assay (PoC) for assessment of anticoagulation.. C57/BL6 mice drank warfarin (0.4mg/kg/24h) in their water. ICH was induced by stereotactic injection of collagenase type VII (0.045U) into the left striatum. Hemorrhagic blood volume was quantified by MRI T2* images and on cryosections 48h after ICH induction. Kinetics of hematoma expansion were compared in strongly, moderately, and non-anticoagulated mice using repeated MRI T2* imaging. The PoC INR technique was validated against standard laboratory INR, and tail vein bleeding time (TVBT).. PoC INR correlated with central laboratory measurements (r=0.989; p<0.0001) and with TVBT (r=0.982; p<0.0001). Hematoma volume was 21.2+/-6.7mm(3) in heavily (PoC INR 4-5), 12.3+/-4.8 in moderately (INR 2-3), and 8.6+/-3.3 in non-anticoagulated mice (INR<1.2). Hematoma volume determined from cryosections and T2* MRI correlated well (r=0.922). Strength of anticoagulation was associated with neurologic outcome. Hematoma enlargement occurred mainly during the first 3h in anticoagulated mice.. PoC allows repeated benchside INR measurements in individual mice which reflect the level of anticoagulation. Stronger anticoagulation results in larger hematoma volumes. As hematoma enlargement occurs mainly during the first hours, potential hemostatic therapies should be tested early in this OAC-ICH model.

Topics: Animals; Bleeding Time; Brain; Calibration; Cerebral Hemorrhage; Collagenases; Disease Models, Animal; Disease Progression; International Normalized Ratio; Kinetics; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Severity of Illness Index; Tail; Veins; Warfarin

The relationship between warfarin administration and the frequent development of enlarged hematomas in patients with acute intracerebral hemorrhage (ICH) is controversial. The present study was carried out to examine this issue.. This study reviewed 41 patients with nontraumatic ICH within 24 h after stroke onset from 1999 to 2003 who received long-term warfarin treatment (29 men and 12 women, 70 +/- 12 years old) and 323 patients who had not been on warfarin (177 men and 146 women, 66 +/- 13 years old). The hematoma volume (HV) on admission, final HV, frequency of hematoma enlargement (HE) and other background characteristics were investigated.. Both the HV on admission (p = 0.031) and final HV (p = 0.001) were larger in patients on warfarin than in those not receiving warfarin. HE occurred more frequently (p < 0.001), and mortality at 30 days or at discharge was higher (p = 0.003) in the warfarin group than in the control group. A multivariate adjusted logistic regression analysis showed that warfarin treatment (OR = 5.75, 95% CI = 2.41-13.8, p < 0.001), liver disease (OR = 2.59, 95% CI = 1.12-5.99, p = 0.026), and the National Institutes of Health Stroke Scale score (OR = 1.10, 95% CI = 1.04-1.15, p < 0.001, per 1-score increase) on admission were independently related to HE.. Acute ICH in patients on long-term warfarin treatment appears to be associated with HE.

Topics: Aged; Aged, 80 and over; Anticoagulants; Case-Control Studies; Cerebral Hemorrhage; Dose-Response Relationship, Drug; Female; Hematoma; Humans; Logistic Models; Longitudinal Studies; Male; Middle Aged; Retrospective Studies; Stroke; Tomography, X-Ray Computed; Warfarin

To determine whether warfarin-treated patients with an international normalized ratio less than 1.7 who receive intravenous tissue plasminogen activator for acute ischemic stroke are at increased risk for symptomatic intracerebral hemorrhage.. Retrospective study.. Academic hospital.. Consecutive patients with acute ischemic stroke who are treated with intravenous tissue plasminogen activator.. Symptomatic intracerebral hemorrhage.. One hundred seven patients were included (mean age, 69.2 years; 43.9% men; median National Institutes of Health Stroke Scale score, 14; median onset-to-treatment time, 140 minutes; baseline warfarin use, 12.1%). The median international normalized ratio was 1.04 (range, 0.82-1.61). The overall rate of symptomatic intracerebral hemorrhage was 6.5%, but it was nearly 10-fold higher among patients taking warfarin compared with those not taking warfarin at baseline (30.8% vs 3.2%, respectively; P = .004). Baseline warfarin use remained strongly associated with symptomatic intracerebral hemorrhage (P = .004) after adjusting for relevant covariates, including age, atrial fibrillation, National Institutes of Health Stroke Scale score, and international normalized ratio.. Despite an international normalized ratio less than 1.7, warfarin-treated patients are more likely than those not taking warfarin to experience symptomatic intracerebral hemorrhage following treatment with intravenous tissue plasminogen activator. Larger studies in this subgroup are warranted.

Topics: Acute Disease; Anticoagulants; Brain Ischemia; Cerebral Arteries; Cerebral Hemorrhage; Drug Synergism; Drug Therapy, Combination; Fibrinolytic Agents; Humans; Iatrogenic Disease; Retrospective Studies; Risk Factors; Stroke; Tissue Plasminogen Activator; Warfarin

Chronic hypertension and anticoagulation are important risk factors for the development of intracerebral hemorrhage (ICH). Spontaneous ICH occurring in the Emergency Department (ED) following a normal unenhanced computed tomography (CT) scan of the brain and an acute blood pressure (BP) surge is exceedingly rare and has, to our knowledge, never been reported in the literature.. Single case observation in a suburban tertiary care medical center.. A neurologically intact 72-year-old man whose BP and neurologic status were monitored during an ED evaluation suddenly became unresponsive following an acute BP surge. A CT of the brain shortly before the episode was normal; following the episode, a repeat CT demonstrated a large right ganglionic ICH.. We present a rare case of an elderly man on warfarin who developed a spontaneous ICH during an ED evaluation following an acute BP surge. We propose that the ICH occurred as a result of the BP surge and was contributed to by warfarin anticoagulation.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Blood Pressure; Brain; Cerebral Hemorrhage; Emergency Service, Hospital; Humans; Hypertension; Male; Tomography, X-Ray Computed; Warfarin

We report our initial experience using Profilnine SD, a 3-Factor prothrombin complex concentrate (PCC) in combination with fresh frozen plasma and vitamin K in seven patients admitted to our neurointensive care unit with oral anticoagulation therapy-related intracranial haemorrhage over a six-month period, to achieve rapid normalisation of the international normalised ratio (INR) and allow surgical evacuation when indicated. Four patients presented with subdural haematomas while three had intracerebral haematomas. Six of seven patients had admission INR in the appropriate therapeutic range for oral anticoagulation therapy. The median dose of PCC administered was 28.5 IU/kg body weight (interquartile range 21.3 to 38.5 IU/kg). All four patients with subdural haematoma underwent surgical evacuation once INR was less than 1.5. Median time from computed tomography diagnosis to surgery was 275 minutes (range 102 to 420 minutes). The median time to INR normalisation post-PCC administration was shorter, at 85 minutes (range 50 to 420 minutes) for the four patients who survived, versus 10 hours (range 9 to 44 hours) in the three patients who died. Two of the three patients who died had haematoma increase, worsening midline shift and subfalcine herniation, leading to withdrawal of therapy. Prothrombin complex concentrates should be considered for use in the urgent reversal of INR in oral anticoagulation therapy-related intracranial haemorrhage, potentially halting haematoma expansion and expediting urgent neurosurgical intervention, although data from randomised controlled trials is still lacking. The literature supporting the use of PCC is reviewed and a protocolised emergent treatment algorithm is proposed, which may help achieve earlier consistent normalisation of the INR.

Topics: Aged; Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Female; Humans; International Normalized Ratio; Male; Middle Aged; Warfarin

Recombinant Factor VIIa decreases hematoma growth after spontaneous intracerebral hemorrhage (ICH) and rapidly decreases international normalized ratios in patients on warfarin but is also associated with an increased risk for thromboembolic complications. In this study, we assessed the risk of thromboembolic events in patients receiving recombinant Factor VIIa after ICH associated with warfarin treatment.. We reviewed the medical charts, laboratory data, and radiological findings of consecutive patients with anticoagulation-related hemorrhages of the central nervous system who received recombinant Factor VIIa at Mayo Clinic Rochester and Mayo Clinic Florida between 2002 and 2009. The primary end point was the frequency of new thromboembolic events, including myocardial infarction, deep vein thrombosis, ischemic stroke, and pulmonary embolism.. We identified 101 patients; 54% had ICH and 30% subdural hematomas. The most common indications for anticoagulation were atrial fibrillation, deep vein thrombosis, and prosthetic valve. Thirteen patients (12.8%) had new thromboembolic events (10 deep vein thromboses and 3 ischemic strokes) within 90 days after recombinant Factor VIIa administration. Eight of these adverse events occurred within 2 weeks of treatment. In patients with ICH, the rate of thromboembolic complications was 5% and all events were venous.. The risk of thromboembolic events in patients who received recombinant Factor VIIa for anticoagulation-associated ICH was not higher than that seen in patients treated for spontaneous ICH in the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial. Spontaneous deep vein thrombosis was the most common complication in our series.

Topics: Adult; Aged; Aged, 80 and over; Central Nervous System Diseases; Cerebral Hemorrhage; Factor VIIa; Female; Hematoma, Epidural, Spinal; Humans; Male; Middle Aged; Recombinant Proteins; Warfarin

A 71-year-old man was stable on warfarin (2.25 mg daily) therapy with an international normalized ratio (INR) of 1.8-2.2 after a heart valve replacement surgery. Recently, he consumed the liquid-like herbal product called shengmai-yin (10 mL daily) against medical advice. Seven days after the daily consumption of shengmai-yin, he was admitted to the intensive care unit because of consciousness disturbance [Glasgow Coma Scale (GCS) score 7] with an INR of 5.08. Head computed topography revealed intracerebral hematoma in the left temporoparietal region. Both warfarin therapy and the herbal product were withdrawn. At the same time, therapy with intravenous vitamin K1 40 mg was started. On the second day of admission, craniectomy was performed to remove the intacerebral hematoma under general anesthesia. He remained confused and restless for 2 days, but then showed progressive recovery in the consciousness level as well as motor and verbal functions. Shengmai-yin contains herbal ingredients that can interact with warfarin. The Drug Interaction Probability Scale (DIPS) indicated that warfarin and shengmai-yin were highly probable causes of intracerebral hematoma. Patients on warfarin therapy should be discouraged from taking herbal medicines, especially preparations that are already known to have antiplatelet and antithrombotic effects.

Topics: Aged; Anticoagulants; Cerebral Hemorrhage; Drug Interactions; Drugs, Chinese Herbal; Hematoma; Humans; Male; Treatment Outcome; Vitamin K 1; Warfarin

To identify and compare clinical and neuroimaging predictors of primary lobar intracerebral hemorrhage (ICH) recurrence, assessing their relative contributions to recurrent ICH.. Subjects were consecutive survivors of primary ICH drawn from a single-center prospective cohort study. Baseline clinical, imaging, and laboratory data were collected. Survivors were followed prospectively for recurrent ICH and intercurrent aspirin and warfarin use, including duration of exposure. Cox proportional hazards models were used to identify predictors of recurrence stratified by ICH location, with aspirin and warfarin exposures as time-dependent variables adjusting for potential confounders.. A total of 104 primary lobar ICH survivors were enrolled. Recurrence of lobar ICH was associated with previous ICH before index event (hazard ratio [HR] 7.7, 95% confidence interval [CI] 1.4-15.7), number of lobar microbleeds (HR 2.93 with 2-4 microbleeds present, 95% CI 1.3-4.0; HR = 4.12 when >or=5 microbleeds present, 95% CI 1.6-9.3), and presence of CT-defined white matter hypodensity in the posterior region (HR 4.11, 95% CI 1.01-12.2). Although aspirin after ICH was not associated with lobar ICH recurrence in univariate analyses, in multivariate analyses adjusting for baseline clinical predictors, it independently increased the risk of ICH recurrence (HR 3.95, 95% CI 1.6-8.3, p = 0.021).. Recurrence of lobar ICH is associated with previous microbleeds or macrobleeds and posterior CT white matter hypodensity, which may be markers of severity for underlying cerebral amyloid angiopathy. Use of an antiplatelet agent following lobar ICH may also increase recurrence risk.

Topics: Aged; Aged, 80 and over; Anticoagulants; Aspirin; Cerebral Amyloid Angiopathy; Cerebral Hemorrhage; Cohort Studies; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Secondary Prevention; Warfarin

Hemorrhage is a major complication of thrombolytic treatment. Concerns have been raised about the risk of hemorrhage in patients having received warfarin. Therefore, different indications for thrombolytic treatment are in use for stroke patients on warfarin. However, it remains uncertain whether the prior warfarin use actually increases their risk of bleeding in patients treated with thrombolysis.. This study included 179 consecutive patients who had high-risk cardioembolic sources and received thrombolytic treatment. Patients were treated with intravenous thrombolytic agents, or underwent intraarterial thrombolysis if their international normalized ratio (INR) was ≤1.7. We compared the frequency of bleeding complications between patients with prior warfarin use and those without. We also investigated whether there were differences in functional outcome and recanalization rates between them.. A prior warfarin use was present in 28 patients (15.6%). Although INR levels were higher in the prior warfarin group, the frequency of bleeding complications was not different between patients who received prior warfarin and those who did not. No differences were observed in patients with or without prior warfarin use, for successful recanalization rate (Thrombolysis in Myocardial Infarction grade 2 or 3), mortality, or modified Rankin score (≤2) at 3months.. Thrombolytic therapy for patients who previously received warfarin and had an INR≤1.7 did not affect bleeding risk, clinical outcome, or recanalization rate. Our data suggest that patients with a history of prior warfarin use may be safely treated with thrombolytic agents when their INR levels are low.

Topics: Adult; Aged; Aged, 80 and over; Aging; Anticoagulants; Brain Ischemia; Carotid Artery Thrombosis; Cerebral Angiography; Cerebral Hemorrhage; Embolism; Female; Fibrinolytic Agents; Heart; Humans; International Normalized Ratio; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Male; Middle Aged; Prognosis; Risk Factors; Sex Characteristics; Stroke; Tomography, X-Ray Computed; Treatment Outcome; Warfarin

During the period 1991-2007, autopsy was undertaken in 13 fetuses with warfarin embryopathy. Pregnancy data and radiographic babygrams were available in each instance. Gestational age ranged from 17 to 37 weeks. Eleven of the fetuses had the characteristic nasal hypoplasia, but only three had radiological epiphyseal stippling. Cerebral hemorrhage was a major feature of autopsy in 8 of the fetuses, and it is evident that bleeding is a significant factor in the pathogenesis of warfarin embryopathy. A wide variety of additional visceral manifestations which were observed at autopsy have been tabulated. There was no obvious correlation between maternal or gestational age and the presence and severity of any specific embryopathic feature. No information was available concerning the dose and timing of warfarin administration in this series.

Topics: Abnormalities, Drug-Induced; Adolescent; Adult; Anticoagulants; Autopsy; Cerebral Hemorrhage; Chondrodysplasia Punctata; Female; Fetal Development; Heart Valve Diseases; Humans; Hyperplasia; Nose; Pregnancy; Retrospective Studies; Warfarin; Young Adult

The optimum timing of resumption of anticoagulation after warfarin-related intracranial hemorrhage in patients with indication for continued anticoagulation is uncertain. We performed a large retrospective cohort study to obtain more precise risk estimates.. We reviewed charts of 2869 consecutive patients with objectively verified intracranial hemorrhage over 6 years at 3 tertiary centers. We calculated the daily risk of intracranial hemorrhage or ischemic stroke with and without resumption of warfarin; we focused on patients who survived the first week and had cardiac indication for anticoagulation or previous stroke. Using a Cox model, we estimated rates for these 2 adverse events in relation to different time points of resumed anticoagulation. The combined risk of either a new intracranial hemorrhage or an ischemic stroke was calculated for a range of warfarin resumption times.. We identified warfarin-associated intracranial hemorrhage in 234 patients (8.2%), of whom 177 patients (76%) survived the first week and had follow-up information available; the median follow-up time was 69 weeks (interquartile range [IQR] 19-144). Fifty-nine patients resumed warfarin after a median of 5.6 weeks (IQR 2.6-17). The hazard ratio for recurrent intracranial hemorrhage with resumption of warfarin was 5.6 (95% CI, 1.8-17.2), and for ischemic stroke it was 0.11 (95% CI, 0.014-0.89). The combined risk of recurrent intracranial hemorrhage or ischemic stroke reached a nadir if warfarin was resumed after approximately 10 to 30 weeks.. The optimal timing for resumption of warfarin therapy appears to be between 10 and 30 weeks after warfarin-related intracranial hemorrhage.

Topics: Aged; Aged, 80 and over; Anticoagulants; Brain Ischemia; Cerebral Hemorrhage; Cohort Studies; Female; Fibrinolytic Agents; Humans; International Normalized Ratio; Male; Middle Aged; Proportional Hazards Models; Recurrence; Retrospective Studies; Risk Assessment; Stroke; Time Factors; Warfarin

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Diagnosis, Differential; Humans; Magnetic Resonance Imaging; Male; Pituitary Apoplexy; Tomography, X-Ray Computed; Warfarin

Topics: Cerebral Hemorrhage; Hemorrhage; Humans; Stroke; Thrombolytic Therapy; Warfarin

Topics: Age Factors; Aged; Aging; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Clinical Trials as Topic; Humans; Intracranial Embolism; Meta-Analysis as Topic; Risk Assessment; Stroke; Warfarin

Intracerebral hemorrhage (ICH) is the most feared complication of oral anticoagulant therapy (OAT). While anticoagulated patients have increased severity of bleeding following ICH, they may also be at increased risk for thromboembolic events (TEs) given that they had been prescribed OAT prior to their ICH. We hypothesized that TEs are relatively common following ICH, and that anticoagulated patients are at higher risk for these complications.. Consecutive patients with primary ICH presenting to a tertiary care hospital from 1994 to 2006 were prospectively characterized and followed. Hospital records were retrospectively reviewed for clinically relevant in-hospital TEs and patients were prospectively followed for 90 day mortality.. For 988 patients of whom 218 (22%) were on OAT at presentation, median hospital length of stay was 7 (IQR 4-13) days and 90-day mortality was 36%. TEs were diagnosed in 71 patients (7.2%) including pulmonary embolism (1.8%), deep venous thrombosis (1.1%), myocardial ischemia (1.6%), and cerebrovascular ischemia (3.0%). Mean time to event was 8.4 +/- 7.0 days. Rates of TE were 5% among those with OAT-related ICH and 8% among those with non-OAT ICH (P = 0.2). After multivariable Cox regression, the only independent risk factor for developing a TE was external ventricular drain placement (HR 2.1, 95% CI 1.1-4.1, P = 0.03). TEs had no effect on 90-day mortality (HR 0.7, 95% CI 0.5-1.1, P = 0.1).. The incidence of TEs in an unselected ICH population was 7.2%. Patients with OAT-related ICH were not at increased risk of TEs.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Cohort Studies; Female; Humans; Length of Stay; Male; Middle Aged; Retrospective Studies; Risk Factors; Survival Analysis; Thromboembolism; Treatment Outcome; Warfarin

To determine whether the use of oral antithrombotic agents before the onset of intracerebral hemorrhage (ICH) affects hematoma features and early patient outcome.. A retrospective, multicenter study involving 1,006 consecutive Japanese patients (607 men, 67 +/- 12 years of age) hospitalized within 24 h after the onset of nontraumatic ICH was conducted.. One hundred and eighty patients were taking oral antiplatelet agents (17.9%, AP group), 67 were taking warfarin (6.7%, W group), and 21 were taking both (2.1%, W + AP group). After adjustment for age, sex, and known confounders, the taking of each kind of antithrombotic therapy was independently related to cerebellar hemorrhage; the odds ratios (OR) and 95% CI, with patients taking no antithrombotic agents as the reference group, were 2.31 (1.23-4.32) for the AP group, 2.90 (1.26-6.63) for the W group, and 3.43 (1.02-11.59) for the W + AP group. Similarly, the taking of each kind of antithrombotic therapy was independently related to hematoma enlargement within the initial 24 h (OR and 95% CI: AP group, 1.92, 1.10-3.34; W group, 4.80, 2.12-10.87; W + AP group, 4.94, 1.31-18.61) and mortality at 3 weeks post-ICH (OR and 95% CI: AP group, 2.70, 1.56-4.68; W group, 2.50, 1.05-5.96; W + AP group, 9.41, 2.78-31.88).. Prior medication with antiplatelet agents, warfarin, or both was predictive of cerebellar hemorrhage, hematoma enlargement, and early death in Japanese ICH patients.

Topics: Administration, Oral; Aged; Cerebral Hemorrhage; Drug Therapy, Combination; Female; Fibrinolytic Agents; Hematoma; Humans; Japan; Male; Middle Aged; Multivariate Analysis; Platelet Aggregation Inhibitors; Retrospective Studies; Risk Factors; Treatment Outcome; Warfarin

Cerebral microbleeds are known to be indicative of bleeding-prone microangiopathy and may predict incident intracerebral hemorrhage (ICH). In this study, we investigated whether microbleeds are associated with the incidence of warfarin-related ICH.. Twenty-four patients with ICH while on outpatient treatment with warfarin were selected from a consecutive cohort. Control, warfarin-using subjects with no history of ICH were randomly selected during the same time period (n = 48). We compared demographic factors, vascular risk factors, laboratory findings, and radiologic findings including microbleeds between the groups.. There were more cases of patients with microbleeds in the ICH than control group (79.2% vs 22.9%: p < 0.001), and the number of microbleeds was much higher for the ICH group (9.0 +/- 26.8 vs 0.5 +/- 1.03: p < 0.001). Moreover, the number of microbleeds was significantly correlated with the presence of warfarin-related ICH (r = 0.299; p < 0.001). Conditional logistic regression analysis showed that increased prothrombin time and the presence of microbleeds were independently related to the incidence of warfarin-related ICH (microbleeds: adjusted OR, 83.12).. This study suggests that underlying microbleeds are independently associated with an incidence of warfarin-related intracerebral hemorrhage. Future research should focus on elucidating the risks and benefits of warfarin medication in patients with microbleeds.

Topics: Aged; Anticoagulants; Arterioles; Brain; Cerebral Arteries; Cerebral Hemorrhage; Female; Humans; Incidence; Intracranial Thrombosis; Male; Microcirculation; Middle Aged; Prothrombin Time; Risk Factors; Warfarin

To derive expressions for the standard errors (SEs) and coefficients of variation (CV) of the threshold number needed to treat (NNT(t)) and the minimum target event risk for treatment (MERT).. NNT(t) reflects the point at which the risks and costs of a clinical intervention balance the benefit. MERT defines the minimum target event risk at which the intervention is justified. Uncertainty in these measures has not previously been investigated.. SEs for NNT(t) and MERT were derived. The corresponding CVs are particularly useful, because they decompose the variability of NNT(t) and MERT into the uncertainty in their components (the values of target and adverse events, and the adverse event risk [AER]). The precision required for these components to formulate treatment recommendations is, thereby, highlighted. These ideas were illustrated with data concerning warfarin treatment for atrial fibrillation.. Our expressions for uncertainty in NNT(t) and MERT inform the confidence one has in initiating a clinical intervention. In our example, a recommendation for treatment could be made for groups of patients whose risk exceeded the range of uncertainty in MERT. However, for lower-risk patients, a recommendation for or against treatment could not be made, mainly because of the limited data on AERs. Our methods can also be used to estimate how much additional data would be required to provide a firmer recommendation for such patient groups.

Topics: Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Data Interpretation, Statistical; Decision Making; Evidence-Based Medicine; Humans; Risk Assessment; Stroke; Treatment Outcome; Uncertainty; Warfarin

Warfarin-associated intracerebral hemorrhage (WICH) became more frequent in the past 2 decades. Interest in potential WICH treatment trials has grown, but the practicality of such trials has received less attention. We determined the number of patients that would be eligible for enrollment in hypothetical treatment trials for WICH using a population-based study.. We identified all patients aged 18 years or older from the Greater Cincinnati/Northern Kentucky region with nontraumatic intracerebral hemorrhage in 2005. Three hypothetical WICH treatment trial criteria sets were used to determine eligibility for enrollment, varying from relatively strict to broadly inclusive. For the hypothetical trials, we assumed the comparison of a standard therapy to an alternative therapy. Sample size calculations assumed different rates of poor outcome depending on the criteria set, various effect sizes, a 2-sided alpha of 0.05, and 80% power. Given 5 years of trial enrollment, the population base needed to enroll the required subjects was then calculated.. Warfarin-associated intracerebral hemorrhage accounted for 54 of 286 (19%) cases of intracerebral hemorrhage within the Greater Cincinnati/Northern Kentucky region in 2005. Eligibility rates ranged from 2 of 54 WICH patients (4% of cases, strictest set) to 11 of 54 WICH patients (20% of cases, most inclusive set). Given these rates, a population base of at least 67 million persons would be required to conduct a 5-year trial for WICH with a 10% effect size using a moderately strict criteria set.. Any planned treatment trial for WICH should anticipate significant challenges in successfully enrolling adequate numbers of patients.

Topics: Adolescent; Adult; Aged; Anticoagulants; Cerebral Hemorrhage; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Research Design; Sample Size; Treatment Outcome; Warfarin; Young Adult

Warfarin-associated intracerebral hemorrhage (W-ICH) is a severe type of stroke. There is no consensus on the optimal treatment for W-ICH. Using a mouse model, we tested whether the rapid reversal of anticoagulation using human prothrombin complex concentrate (PCC) can reduce hemorrhagic blood volume. Male CD-1 mice were treated with warfarin (2 mg/kg over 24 h), resulting in a mean (+/-s.d.) International Normalized Ratio of 3.5+/-0.9. First, we showed that an intravenous administration of human PCC rapidly reversed anticoagulation in mice. Second, a stereotactic injection of collagenase was administered to induce hemorrhage in the right striatum. Forty-five minutes later, the animals were randomly treated with PCC (100 U/kg) or saline i.v. (n=12 per group). Twenty-four hours after hemorrhage induction, hemorrhagic blood volume was quantified using a photometric hemoglobin assay. The mean hemorrhagic blood volume was reduced in PCC-treated animals (6.5+/-3.1 microL) compared with saline controls (15.3+/-11.2 microL, P=0.015). In the saline group, 45% of the mice developed large hematomas (i.e., >15 microL). In contrast, such extensive lesions were never found in the PCC group. We provide experimental data suggesting PCC to be an effective acute treatment for W-ICH in terms of reducing hemorrhagic blood volume. Future studies are needed to assess the therapeutic potential emerging from our finding for human W-ICH.

Topics: Animals; Blood Coagulation; Blood Coagulation Factors; Cerebral Hemorrhage; Coagulants; Disease Models, Animal; Drug Administration Schedule; Humans; Injections, Intravenous; Male; Mice; Mice, Inbred Strains; Time Factors; Treatment Outcome; Warfarin

We present a retrospective, case-controlled study of the degree of over-warfarinisation and the frequency of International Normalized Ratio (INR) monitoring in patients with spontaneous intracranial haemorrhage (ICH) compared with a control group without ICH. A higher proportion of patients with ICH were taking warfarin than patients in the control group (33/221 [15%] versus 16/201 [8%], p<0.05). There was no significant difference between the ICH group and the controls in the mean INR of warfarinised patients on presentation, the mean INR when last measured prior to presentation, or in the number of days since the INR was last tested. There was no correlation between the time since the INR was last measured and the INR on presentation. Only 2 (6%) of patients were excessively anticoagulated at the time of ICH. Thus, in this study, warfarin use was associated with an increased risk of ICH despite appropriate community INR monitoring and therapeutic anticoagulation.

Topics: Aged; Aged, 80 and over; Anticoagulants; Case-Control Studies; Cerebral Hemorrhage; Chi-Square Distribution; Drug Monitoring; Female; Hematoma, Subdural; Humans; International Normalized Ratio; Male; Middle Aged; Retrospective Studies; Time Factors; Warfarin

Anti-platelet medication and reduced platelet activity are associated with an increased risk of death after intracerebral hemorrhage (ICH). The optimal assay for assessing platelet activity is not defined. We hypothesized that reduced platelet activity would be common after ICH.. We prospectively enrolled 72 consecutive patients with ICH and routinely measured platelet activity with both the PFA-100 (Siemens AG, Germany) and the VerifyNow-ASA (Accumetrics, CA, USA) systems on admission. We prospectively recorded anti-platelet medication use prior to ICH.. VerifyNow-ASA measurements were associated with aspirin (P = 0.001) and clopidogrel (P = 0.01) use prior to ICH. Combined clopidogrel and aspirin therapy was more potent than either alone. Of 33 patients with reduced platelet activity on the VerifyNow-ASA assay, 14 (42%) were not known to take anti-platelet agents. Of 27 patients with reduced platelet activity on the PFA-100, a related but different 14 (52%) were not known to take anti-platelet agents. There was a poor agreement between the assays (κ = 0.26, P = 0.07) on which patients had reduced platelet activity among the patients not known to take aspirin.. A medication history does not reliably identify patients with reduced platelet activity after ICH, and this may explain studies that found no association between known aspirin use and outcomes. Future studies should screen for unknown use of anti-platelet medications after ICH. Neither assay perfectly identified patients who reportedly used anti-platelet medication before ICH.

Topics: Aged; Aspirin; Blood Platelets; Cerebral Hemorrhage; Clopidogrel; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prospective Studies; Risk Factors; Ticlopidine; Warfarin

Cerebral microbleeds (CMBs) are known to be indicative of bleeding prone microangiopathy. Little is known about its significance in anticoagulated patients. We aimed to determine the frequency of CMBs in ischemic stroke patients on warfarin treatment.. A total of 141 ischemic stroke patients on warfarin therapy were enrolled in this study. One hundred five patients with similar demographic features who do not use warfarin were chosen as controls. We compared vascular risk factors and radiological findings including CMBs and leukoaraiosis between the groups.. CMBs on gradient-echo MRI (GE-MRI) were found in 31 patients (22%) and 17 controls (16%) and there was not a significant difference between 2 groups (P=0.25). Study patients with CMBs were older than patients without CMBs (P=0.04) and frequency of leukoaraiosis was significantly higher (P=0.008). Mean duration of warfarin treatment was not different between the patients with and without CMBs (P=0.83).. Although patients with CMBs were older and had more leukoaraiosis the impact of warfarin treatment on CMBs is still controversial.

Topics: Aged; Brain Ischemia; Cerebral Hemorrhage; Female; Follow-Up Studies; Humans; Male; Microcirculation; Middle Aged; Risk Factors; Stroke; Warfarin

To determine the direct healthcare costs associated with the onset of chronic nonvalvular atrial fibrillation (CNVAF), warfarin utilization and the occurrence of cerebrovascular events in a commercially-insured population.. This retrospective, observational cohort study utilized medical and pharmacy claims from a large, geographically diverse managed-care organization (N = 18.5 million) to identify continuously benefit-eligible CNVAF patients > or =45 years of age without prior valvular disease or warfarin use between January 1, 2001 and June 1, 2002. All patients were followed at least 6 months, until plan termination or the end of study follow-up. Stroke risk was assessed using the CHADS(2) (stroke-risk) index; warfarin use was defined as having filled at least one pharmacy claim. Inpatient and outpatient cost benchmarks were utilized to estimate total direct healthcare costs (pre- and post-AF index claim). For patients with transient ischemic attacks (TIA), ischemic stroke (IS) and major bleed (MB) total direct healthcare costs were also assessed. The limitations of this study included a descriptive retrospective study design without a comparison group or adjustment for baseline disease severity and drug exposure, as well as, the reliance upon administrative claims data and use of a standardized reference costing methodology.. The pre- and post-AF onset total direct healthcare costs (pmpm) for 3891 incidence CNVAF patients were $412 and $1235, respectively, a 200% increase. Of the 448 (12%) patients with a cerebrovascular event, pmpm costs post-AF ranged from $2235 to $3135 correlating with CHADS(2) stroke-risk status and exposure to warfarin. Total cohort pmpm costs pre and post event increased 24% from $3446.91 to $4262.12. Approximately 20% of all events occurred <2 days and 46% within 1 month after the index AF claim. Any warfarin exposure, regardless of CHADS(2) risk had an 18% to 29 % decrease in pmpm costs.. Post-AF total direct healthcare costs were 3 times greater than pre-AF costs. For those with a TIA, IS or MB, post-AF total direct healthcare costs increased 4.5 times from pre-AF costs; overall post-event costs in this cohort increased approximately 25% over pre-event costs. Nearly half of the events occurred within 1 month of a claim associated with an AF diagnosis. Warfarin exposure appeared to be associated with lower pmpm costs in this population.

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Cerebral Hemorrhage; Chronic Disease; Female; Health Care Costs; Humans; Incidence; Ischemic Attack, Transient; Male; Middle Aged; Retrospective Studies; Stroke; Warfarin

The level of anticoagulation at the time of stroke onset may influence the size, composition, and dissolution rate of the occlusive clot. We explored the relation between admission international normalized ratio (INR) and acute infarct volume in patients with ischemic stroke.. We studied 93 consecutive patients with preadmission warfarin use who had INR measurement and diffusion-weighted imaging performed within 24 hours of stroke onset. Ninety-three etiologic stroke subtype-matched patients without prior warfarin use served as control patients. Linear regression analysis was used to test for independence of INR as a predictor of infarct volume.. In patients with preadmission warfarin use, admission INR was inversely correlated with lesion volume on diffusion-weighted imaging (r = -0.38). This relation was retained after adjustment for potential covariates (p = 0.014). INR less than 2.0 was associated with 3.5-fold (95% confidence interval, 2.9-4.2) greater lesion volume on diffusion-weighted imaging as compared with INR of 2.0 or more. Patients who were on therapeutic INR (>or=2.0) had smaller infarcts compared with patients without preadmission warfarin use (p = 0.001). Admission INR was inversely correlated with acute perfusion defect (r = -0.33), chronic infarct volume (r = -0.42), National Institutes of Health Stroke Scale score at admission (r = -0.27), and modified Rankin score at discharge (r = -0.28).. These results suggest that preadmission warfarin use associated with therapeutic level of anticoagulation can offer a benefit in limiting the extent of ischemic injury in an event of acute stroke.

Topics: Aged; Aged, 80 and over; Anticoagulants; Brain; Brain Infarction; Brain Ischemia; Cerebral Arteries; Cerebral Hemorrhage; Diffusion Magnetic Resonance Imaging; Female; Humans; International Normalized Ratio; Intracranial Embolism; Male; Middle Aged; Patient Admission; Regression Analysis; Retrospective Studies; Risk Assessment; Treatment Outcome; Warfarin

To determine whether there are modifiable risk factors for spontaneous intracerebral hemorrhage in patients receiving oral anticoagulation (OAC) therapy.. Retrospective chart review between January 2002 and December 2004.. A total of 315 consecutive patients presenting with spontaneous intracerebral hemorrhage.. Overall mortality rates and surgical mortality rates, and discharge home compared with discharge to a long-term care facility.. Of the 315 patients reviewed, 65 (20.6%) were receiving OAC therapy. Age, Glasgow Coma Scale score, and size of hematoma at presentation were similar in the 65 patients taking OAC and the 250 patients not taking it. Mean arterial pressure at presentation was significantly higher in the OAC group than in the control group (132 mm Hg vs 107 mm Hg, P = .01) as was the number of hematomas that progressed (52% vs 14%, P = .01). Overall mortality rates were higher in the OAC group than in the control group (52% vs 41%, P = .03) as were surgical mortality rates (62% vs 41%, P = .04). There were no significant differences in morbidity between the 2 groups.. Mortality rates were higher among patients taking OAC therapy despite their having similarly sized hematomas at presentation. The higher initial mean arterial pressure among such patients has not been described previously in this setting. This higher mean arterial pressure correlates with the propensity of these patients' hematomas to expand after initial imaging and might partially mediate the mortality effect. In patients taking OAC, hypertension appears to be a modifiable risk factor for morbidity and mortality from intracerebral hemorrhage.

Topics: Administration, Oral; Adult; Age Distribution; Aged; Aged, 80 and over; Anticoagulants; Case-Control Studies; Cerebral Hemorrhage; Female; Follow-Up Studies; Glasgow Coma Scale; Hematoma; Humans; Logistic Models; Magnetic Resonance Imaging; Male; Middle Aged; Multivariate Analysis; Reference Values; Retrospective Studies; Risk Factors; Severity of Illness Index; Sex Distribution; Survival Analysis; Treatment Outcome; Warfarin

Warfarin is a well established oral anticoagulant for the treatment of thromboembolic disorders. Warfarin therapy is complicated by a narrow therapeutic index and marked inter-individual dose variability with therapeutic doses ranging from 1 mg to 10 mg/day. Recently genetic variation and resultant drug metabolizing polymorphisms have been found to contribute to warfarin dose variability with resultant hemorrhagic or thromboembolic complications. Cytochrome P4502C9 alters the rate of warfarin metabolism and clearance. A second enzyme, Vitamin K Epoxide Reductase Complex (VKORC) binds and reduces Vitamin K which is necessary for activation of clotting Factors II, VII, IX and X. The VKORC1 gene encodes for Vitamin K Epoxide Reductase Complex subunit 1, a key component of VKORC. The combination of physiologic factors (30%), CYP2C9 variations (20%) and VKORC1 variants (25%) accounts for approximately 75% of warfarin dose variability. This illustrative case report demonstrates the clinical importance of this new information. Clinicians need to incorporate these new genomic findings into appropriate management of warfarin dose anticoagulation.

Topics: Adult; Anticoagulants; Cerebral Hemorrhage; Female; Genomics; Genotype; Humans; Polymorphism, Genetic; Risk Factors; Thrombophlebitis; Warfarin

Future demographic changes predict an increase in the number of patients with atrial fibrillation. As long-term anticoagulation for the prevention of ischemic strokes becomes more prevalent, the burden of warfarin-associated intracerebral hemorrhage (W-ICH) is likely to grow. However, little is known about the clinical aspects and pathophysiologic mechanisms of W-ICH. This study describes the development of a mouse model of W-ICH in which hematoma growth and outcomes can be correlated with anticoagulation parameters.. CD-1 mice were treated with warfarin (2 mg/kg per 24 hours) added to drinking water. ICH was induced by stereotactic injection of collagenase type VII (0.075 U) into the right striatum. Hemorrhagic blood volume was quantified by means of a photometric hemoglobin assay 2 and 24 hours after hemorrhage induction. Neurologic outcomes were assessed on a 5-point scale.. The international normalized ratio in nonanticoagulated mice was 0.8+/-0.1. After 24 (W-24) and 30 (W-30) hours of warfarin pretreatment, international normalized ratio values increased to 3.5+/-0.9 and 7.2+/-3.4, respectively. Compared with nonanticoagulated mice, mean hemorrhagic blood volume determined 24 hours after hemorrhage induction was found to be 2.5-fold larger in W-24 mice (P=0.019) and 3.1-fold larger in W-30 mice (P<0.001, n=10 per group). Mortality at 24 hours after hemorrhage induction was 0% in nonanticoagulated mice, 10% in W-24 mice, and 30% in W-30 mice. Hematoma enlargement between 2 and 24 hours after hemorrhage induction was -1.4% for nonanticoagulated mice, 22.9% for W-24 mice, and 62.2% for W-30 mice.. This study characterizes the first experimental model of W-ICH. It may be helpful in gaining further insights into the pathophysiology of W-ICH and may be used for testing the efficacy of treatment strategies, such as hemostatic therapy, in this severe subtype of stroke.

Topics: Administration, Oral; Animals; Anticoagulants; Brain Damage, Chronic; Cerebral Hemorrhage; Collagenases; Corpus Striatum; Disease Models, Animal; Disease Progression; Hematoma; Injections; International Normalized Ratio; Male; Mice; Microbial Collagenase; Movement Disorders; Warfarin

Among patients with intracerebral hemorrhage (ICH), warfarin use before onset leads to greater mortality. In a retrospective study, we sought to determine whether warfarin use is associated with larger initial hematoma volume, one determinant of mortality after ICH.. We identified all patients hospitalized with ICH in the Greater Cincinnati region from January through December 2005. ICH volumes were measured on the first available brain scan by using the abc/2 method. Univariable analyses and a multivariable generalized linear model were used to determine whether international normalized ratio (INR) influenced initial ICH volume after adjusting for other factors, including age, race, sex, antiplatelet use, hemorrhage location, and time from stroke onset to scan.. There were 258 patients with ICH, including 51 patients taking warfarin. In univariable comparison, when INR was stratified, there was a trend toward a difference in hematoma volume by INR category (INR <1.2, 13.4 mL; INR 1.2-2.0, 9.3 mL; INR 2.1-3.0, 14.0 mL; INR >3.0, 33.2 mL; p = 0.10). In the model, compared with patients with INR <1.2, there was no difference in hematoma size for patients with INR 1.2-2.0 (p = 0.25) or INR 2.1-3.0 (p = 0.36), but patients with INR >3.0 had greater hematoma volume (p = 0.02). Other predictors of larger hematoma size were ICH location (lobar compared with deep cerebral, p = 0.02) and shorter time from stroke onset to scan (p < 0.001).. Warfarin use was associated with larger initial intracerebral hemorrhage (ICH) volume, but this effect was only observed for INR values >3.0. Larger ICH volume among warfarin users likely accounts for part of the excess mortality in this group.

Topics: Age of Onset; Aged; Anticoagulants; Brain; Causality; Cerebral Arteries; Cerebral Hemorrhage; Disease Progression; Humans; International Normalized Ratio; Magnetic Resonance Imaging; Multivariate Analysis; Platelet Aggregation Inhibitors; Proportional Hazards Models; Retrospective Studies; Risk Factors; Severity of Illness Index; Tomography, X-Ray Computed; Warfarin

Intracerebral hemorrhage (ICH) accounts for a majority of long-term morbidity and mortality associated with bleeding while on warfarin. Both ICH and warfarin-related ICH appear to have a genetic component. Furthermore, advanced neuroimaging using MRI can now identify individuals at increased risk of ICH. We explore whether screening strategies that include genetic profiling and neuroimaging might improve the safety of chronic anticoagulation for atrial fibrillation by identifying individuals from whom warfarin should be withheld.. We used a Markov state transition decision model. Effectiveness was measured in quality-adjusted life-years. Data sources included the English language literature using MEDLINE searches and bibliographies from selected articles along with empirical data from our institutions. The base case was a 69-year-old man with newly diagnosed nonvalvular atrial fibrillation.. For patients at average risk for thromboembolic events and known to possess a hypothetical genetic profile increasing risk for warfarin ICH, anticoagulation remains the preferred strategy until the relative hazard of ICH exceeds 23.8. Genetic profiling would be favored for patients at low risk of thromboembolism (1.5% per year) if the hypothetical gene variant(s) conferred a relative risk of ICH >4.1. Screening strategies in which patients underwent genotyping and MRI before anticoagulation did not improve aggregate patient outcomes unless the predictive power of MRI exceeded current best guess estimates and patients were at low to moderate risk of thromboembolism.. Currently identified genetic markers of bleeding risk do not confer a risk of ICH sufficiently high to warrant routine genetic testing for patients at average risk of thromboembolism. Even if patients undergo screening with MRI as well as genotyping, currently available data on the role of MRI on risk of ICH and warfarin ICH do not support use of these tests for withholding anticoagulation in patients with atrial fibrillation.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Decision Support Techniques; Genetic Markers; Genetic Testing; Genetic Variation; Humans; Intracranial Embolism; Magnetic Resonance Imaging; Male; Markov Chains; Risk; Thromboembolism; Thrombophilia; Warfarin

Intracerebral hemorrhage (ICH) associated with warfarin sodium therapy is becoming more common as the use of this medication increases in the aging population.. To delineate factors associated with early mortality, determine variables responsible for poor functional outcome, and evaluate possible reasons for expansion of hemorrhage and associated parenchymal edema.. Retrospective study of clinical and radiologic information for 88 patients with warfarin-associated ICH.. A single hospital. Patients Eighty-eight consecutive patients with warfarin-associated ICH.. Patients were included if the international normalized ratio (INR) at presentation with ICH was 1.5 or greater. Computed tomographic scans were reviewed for volumetric analysis of hematoma and perihematomal edema volume. Outcome variables included 7-day mortality, hematoma enlargement, and functional outcome based on the modified Rankin Scale score.. Seven-day mortality (39.8%) was associated with a lower Glasgow Coma Scale sum score and larger ICH volume at presentation. Univariate analysis revealed that a lower Glasgow Coma Score sum score, larger initial ICH volume, higher initial and 48-hour maximum glucose concentrations, and higher percentage of ICH expansion were significantly associated with poor functional outcome at hospital discharge. At multivariate analysis, only Glasgow Coma Score and ICH volume remained significantly associated with functional outcome measured at hospital discharge and at the last follow-up visit. Conversely, INR at presentation, time to INR correction, initial blood pressure, and enlargement of edema were not associated with functional outcome either at hospital discharge or at the last follow-up. Neither serum glucose concentration at admission nor highest level during the first 48 hours had any correlation with ICH or parenchymal edema enlargement. In addition, neither initial INR nor time to INR correction correlated with expansion of ICH or parenchymal edema.. Lower level of consciousness at presentation and larger initial ICH volume predict poor prognosis in patients with warfarin-associated ICH. In our study population, INR at presentation was not associated with functional outcome.

Topics: Aged; Aged, 80 and over; Anticoagulants; Brain Edema; Cerebral Hemorrhage; Female; Glasgow Coma Scale; Humans; Longevity; Male; Middle Aged; Predictive Value of Tests; Prognosis; Retrospective Studies; Risk Assessment; Treatment Outcome; Venous Thromboembolism; Warfarin

Reinitiating warfarin sodium therapy in a patient with a recent warfarin-related intracerebral hemorrhage (WAICH) is a difficult clinical decision. Therefore, it is important to assess the outcome of resumption or discontinuation of warfarin therapy after WAICH.. To compare patients who survived an episode of WAICH and restarted warfarin therapy with a group of WAICH patients who did not resume warfarin therapy. Design, Setting, and Patients We conducted a follow-up study from November 1, 2001, through December 31, 2005, in a cohort from a single center. Long-term outcome was assessed at last clinical follow-up or via questionnaire.. Recurrent WAICH and thromboembolic events.. Fifty-two patients were discharged from the hospital after a diagnosis of WAICH. Four patients were lost to follow-up. Mean follow-up among all patients was 43 (range, 1-108) months. Of the 23 patients who restarted warfarin therapy, 1 had a recurrent nontraumatic WAICH, 2 had traumatic intracerebral hemorrhages, and 2 had major extracranial hemorrhages. Of the 25 patients who did not restart warfarin therapy, 3 had a thromboembolic stroke, 1 had a pulmonary embolus, and 1 had a distal arterial embolus.. Restarting warfarin therapy in patients with a recent WAICH is associated with a low risk of recurrence, but patients are subjected to known, substantial risks of warfarin use. Withholding warfarin therapy is associated with a risk of thromboembolization.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Brain; Cerebral Hemorrhage; Clinical Protocols; Cohort Studies; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mortality; Pulmonary Embolism; Retrospective Studies; Risk Assessment; Stroke; Time; Venous Thromboembolism; Warfarin

The objective of this study is to show the effectiveness of Factor IX complex concentrate (FIXCC) for rapid reversal of an elevated International Normalized Ratio (INR) in patients with anticoagulation-associated intracerebral hemorrhage (AAICH).. We, retrospectively, analyzed the clinical data of 19 patients with the diagnosis of AAICH from January 2005 to May 2006. A comparison was made among patients treated with FFP and Vit.K [FFP-group (n = 9)] and patients treated with FIXCC in addition to FFP and Vit.K [FIXCC-group (n = 10)]. INR of 1.4 or less was taken as target.. Mean INR on admission for FFP and FIXCC group was 1.84 +/- 0.31 and 2.44 +/- 1.48, respectively (P = 0.315). After administration of therapy, the INR was reduced from 1.84 +/- 0.31 to 1.34 +/- 0.08 (P < 0.05) in FFP group and 2.44 +/- 1.48 to 1.34 +/- 0.07 (P < 0.005) in FIXCC group. Three patients in FFP group (33%) and 8 patients in FIXCC group (80%) reached their target INR in 3-4 h after initiation of therapy (P = 0.012). Mean time taken by both FFP and FIXCC groups to reach the target INR was 8.52 +/- 5.60 h and 4.25 +/- 2.12 h, respectively (P < 0.05). The mean rate of INR correction was 0.06 +/- 0.03 and 0.27 +/- 0.25 per hour for the FFP and FIXCC group, respectively (P < 0.005). There was one death in FIX group and two in FFP group and no thrombotic complications.. Our data suggests that FIXCC in combination with FFP and Vit.K may result in decreased time required when compared to FFP and Vit.K alone for correction of warfarin associated coagulopathy in neurosurgical emergencies.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Disorders; Cerebral Hemorrhage; Drug Interactions; Drug Therapy, Combination; Factor IX; Female; Humans; International Normalized Ratio; Male; Middle Aged; Plasma; Retrospective Studies; Treatment Outcome; Vitamin K; Vitamins; Warfarin

To determine whether taking aspirin or warfarin at the time of an intracerebral haemorrhage (ICH) has an independent effect on early survival.. All people with ICH presenting in Christchurch, New Zealand over a three-year period were identified. Independent predictors of mortality at 7, 14 and 28 days were calculated using binary logistic regression.. Two hundred and fifty three cases were identified. Unadjusted 28-day mortality was 43% overall, but 53 % for warfarin associated ICH and 43% for patients taking aspirin. Haemorrhage volume, haemorrhage location, intraventricular spread and the use of warfarin were all independently and significantly associated with mortality at all three time intervals (7, 14 and 28 days). The effect of warfarin was apparent despite similar volumes of bleed in each group. Aspirin was not associated with increased early mortality. Increasing age was also an independent predictor associated with death at 28 days.. Use of warfarin (but not aspirin) immediately prior to ICH was independently associated with increased mortality, after controlling for comorbidities. Thus therapeutic efforts to rapidly reverse the warfarin induced coagulopathy may be justified to lower mortality.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Brain; Cerebral Hemorrhage; Female; Humans; Logistic Models; Male; Middle Aged; Neurosurgical Procedures; Platelet Aggregation Inhibitors; Prognosis; Survival; Time Factors; Warfarin

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Blood Coagulation Factors; Brain Ischemia; Cerebral Hemorrhage; Clinical Protocols; Clinical Trials as Topic; Comorbidity; Humans; Patient Selection; Platelet Aggregation Inhibitors; Predictive Value of Tests; Risk Assessment; Risk Factors; Stroke; Warfarin

We sought to determine the incidence and severity of bleeding events in patients with stroke and cardiovascular diseases who were taking oral antithrombotic agents in Japan, where the incidence of hemorrhagic stroke is higher than in Western countries.. A prospective, multicenter, observational study was conducted; 4009 patients who were taking oral antithrombotic agents for stroke and cardiovascular diseases were enrolled. The patients were classified into 4 groups according to their antithrombotic treatment: the single antiplatelet agent group (47.2%); the dual antiplatelet agent group (8.7%); the warfarin group (32.4%); and the warfarin plus antiplatelet agent group (11.7%). The primary end point was life-threatening or major bleeding according to the MATCH trial definition.. During a median follow-up of 19 months, there were 57 life-threatening and 51 major bleeding events, including 31 intracranial hemorrhages. The annual incidence of the primary end point was 1.21% in the single antiplatelet agent group, 2.00% in the dual antiplatelet agent group, 2.06% in the warfarin group, and 3.56% in the warfarin plus antiplatelet agent group (P<0.001). After adjustment for baseline characteristics, adding an antiplatelet agent to warfarin increased the risk of the primary end point (relative risk=1.76; 95% CI, 1.05 to 2.95), and adding another antiplatelet agent to single antiplatelet agent therapy increased the secondary end point of any bleeding, including minor events (relative risk=1.37; 95% CI, 1.07 to 1.76).. The incidence of bleeding events during antithrombotic therapy in Japan was similar to that reported for Western countries, although the trials used different study designs. Dual antithrombotic therapy was independently related to an increased risk of bleeding events.

Topics: Aged; Anticoagulants; Cardiovascular Diseases; Causality; Cerebral Hemorrhage; Clinical Protocols; Comorbidity; Drug Combinations; Drug Therapy, Combination; Female; Fibrinolytic Agents; Humans; Incidence; Japan; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Risk Factors; Stroke; Warfarin

It has been >25 years since the interaction between warfarin and metronidazole was last reported in the literature. The current case report represents the first documentation of this interaction associated with intracerebral hemorrhage.. We present a case of a 78-year-old white woman started on metronidazole (250 mg every 8 hours for 5 days) and levofloxacin (500 mg QD for 6 days) for an upper respiratory tract infection after visiting a walk-in clinic. The patient did not notify any of the health care professionals involved that she was on concomitant warfarin therapy, which had been stable over the last 3 months. Her warfarin dose was 7 mg daily, and her most recent international normalized ratio (INR) reading was 2.5. Nine days after her clinic visit, the patient was admitted to the hospital for a profuse nosebleed with an INR of 8.0 and was found to have an intraparenchymal hemorrhage of the left occipital lobe. The Naranjo adverse drug reaction probability scale indicated that the association with metronidazole was probable and the association with levofloxacin was possible (scores of 7 and 4, respectively). After a 1-week hospital stay, she was discharged.. This adverse event is highly suggestive of a drug interaction caused primarily by metronidazole, which produces an increase in S-warfarin concentrations. Treatment provided by health care providers who were not familiar with the patient and the use of a different pharmacy (where the pharmacist was unaware of her current medications) likely contributed to the event.

Topics: Aged; Anti-Infective Agents; Anticoagulants; Cerebral Hemorrhage; Drug Interactions; Female; Humans; International Normalized Ratio; Metronidazole; Warfarin

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been associated with improved outcome after ischemic stroke and subarachnoid hemorrhage but an increased risk of incident intracerebral hemorrhage (ICH). We investigated (1) whether statin use before ICH was associated with functional independence at 90 days, and (2) whether survivors exposed to statins after ICH had an increased risk of recurrence.. We analyzed 629 consecutive ICH patients with 90-day outcome data enrolled in a prospective cohort study between 1998 to 2005. Statin use was determined by patient interview at the time of ICH and supplemented by medical record review. Independent status was defined as Glasgow Outcome Scale 4 or 5. ICH survivors were followed by telephone interview every 6 months.. Statins were used by 149/629 (24%) before ICH. There was no effect of pre-ICH statin use on the rates of functional independence (28% versus 29%, P=0.84) or mortality (46% versus 45%, P=0.93). Medical comorbidities and warfarin use were more common in statin users. Hematoma volumes were similar (median 28 cm(3) in pre-ICH statin users compared to 22 cm(3) in nonusers, P=0.18). The multivariable-adjusted odds ratio for independent status in pre-ICH statin users was 1.16 (95% CI 0.65 to 2.10, P=0.62). ICH survivors treated with statins after discharge did not have a higher risk of recurrence (adjusted HR 0.82, 95% CI 0.34 to 1.99, P=0.66).. Pre-ICH statin use is not associated with improved ICH functional outcome or mortality. Post-ICH statin use is not associated with an increased risk of ICH recurrence.

Topics: Aged; Cerebral Hemorrhage; Cohort Studies; Comorbidity; Female; Glasgow Outcome Scale; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Recurrence; Retrospective Studies; Risk; Treatment Outcome; Warfarin

To evaluate the frequency, severity and preventability of warfarin-induced cerebral haemorrhages due to warfarin and warfarin-drug interactions in patients living in the county of Ostergötland, Sweden.. All patients with a diagnosed cerebral haemorrhage at three hospitals during the period 2000-2002 were identified. Medical records were studied retrospectively to evaluate whether warfarin and warfarin-drug interactions could have caused the cerebral haemorrhage. The proportion of possibly avoidable cases due to drug interactions was estimated.. Among 593 patients with cerebral haemorrhage, 59 (10%) were assessed as related to warfarin treatment. This imply an incidence of 1.7/100,000 treatment years. Of the 59 cases, 26 (44%) had a fatal outcome, compared to 136 (25%) among the non-warfarin patients (p < 0.01). A warfarin-drug interaction could have contributed to the haemorrhage in 24 (41%) of the warfarin patients and in 7 of these (12%) the bleeding complication was considered being possible to avoid.. Warfarin-induced cerebral haemorrhages are a major clinical problem with a high fatality rate. Almost half of the cases was related to a warfarin-drug interaction. A significant proportion of warfarin-related cerebral haemorrhages might have been prevented if greater caution had been taken when prescribing drugs known to interact with warfarin.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Child; Drug Interactions; Female; Humans; Incidence; Male; Middle Aged; Practice Patterns, Physicians'; Retrospective Studies; Sweden; Warfarin

To define temporal trends in the incidence of anticoagulant-associated intracerebral hemorrhage (AAICH) during the 1990s and relate them to rates of cardioembolic ischemic stroke.. We identified all patients hospitalized with first-ever intracerebral hemorrhage (ICH) in greater Cincinnati during 1988, from July 1993 through June 1994, and during 1999. AAICH was defined as ICH in patients receiving warfarin or heparin. Patients from the same region hospitalized with first-ever ischemic stroke of cardioembolic mechanism were identified during 1993/1994 and 1999. Incidence rates were calculated and adjusted to the 2000 US population. Estimates of warfarin distribution in the United States were obtained for the years 1988 through 2004.. AAICH occurred in 9 of 184 ICH cases (5%) in 1988, 23 of 267 cases (9%) in 1993/1994, and 54 of 311 cases (17%) in 1999 (p < 0.001). The annual incidence of AAICH per 100,000 persons was 0.8 (95% CI 0.3 to 1.3) in 1988, 1.9 (1.1 to 2.7) in 1993/1994, and 4.4 (3.2 to 5.5) in 1999 (p < 0.001 for trend). Among persons aged > or =80, the AAICH rate increased from 2.5 (0 to 7.4) in 1988 to 45.9 (25.6 to 66.2) in 1999 (p < 0.001 for trend). Incidence rates of cardioembolic ischemic stroke were similar in 1993/1994 and 1999 (31.1 vs 30.4, p = 0.65). Warfarin distribution in the United States quadrupled on a per-capita basis between 1988 and 1999.. The incidence of anticoagulant-associated intracerebral hemorrhage quintupled in our population during the 1990s. The majority of this change can be explained by increasing warfarin use. Anticoagulant-associated intracerebral hemorrhage now occurs at a frequency comparable to subarachnoid hemorrhage.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Brain Ischemia; Cerebral Hemorrhage; Comorbidity; Female; Humans; Incidence; Kentucky; Male; Middle Aged; Ohio; Retrospective Studies; Risk Assessment; Risk Factors; Stroke; United States; Warfarin

Long-term anticoagulation is often considered a contraindication to shunt surgery for elderly patients with normal pressure hydrocephalus (NPH). However, no studies have investigated this question.. We evaluated 25 patients who were taking warfarin for NPH between 2001 and 2004 with a protocol of cerebrospinal fluid (CSF) pressure monitoring and controlled CSF drainage via spinal catheter. Warfarin was stopped 5 to 7 days before lumbar puncture or shunt surgery and restarted 3 to 5 days after operation or at the time of discharge from the hospital. Programmable shunts with antisiphon devices set at the high-pressure range were preferentially used and adjusted in small increments.. After CSF drainage, 16 patients showed improvement and 15 underwent shunt surgery. Thirteen (87%) out of these 15 patients showed significant improvement in at least one symptom during a mean follow-up period of 8.2 months (range, 1-70 mo) after shunt surgery. There were two bleeding complications. One patient (6.7%) with cirrhosis who developed a subdural hematoma 13 days after operation had the shunt removed; another patient who developed an abdominal subcutaneous hematoma 5 days after operation required surgical evacuation and shunt revision surgery. Otherwise, 14 (93.3%) out of the 15 patients had no subdural hematoma during the follow-up period and there were no thromboembolic complications while the patients were not taking warfarin.. Elderly patients on long-term warfarin anticoagulation can be safely evaluated and treated for NPH using a protocol of continuous CSF drainage via spinal catheter for diagnosis, cautious periprocedural management of anticoagulation, and use of programmable shunts with antisiphon devices. The risk of subdural hematoma is not higher than reported series. Long-term anticoagulation with warfarin is not a contraindication per se for shunt surgery in NPH.

Topics: Aged; Anticoagulants; Cerebral Hemorrhage; Cerebrospinal Fluid Shunts; Female; Humans; Hydrocephalus, Normal Pressure; Risk Assessment; Treatment Outcome; Warfarin

Topics: Anticoagulants; Cerebral Hemorrhage; Factor VII; Factor VIIa; Factor VIII; Fibrinogen; Humans; Myocardial Infarction; Plasma; Recombinant Proteins; Research Design; Retrospective Studies; Risk; Selection Bias; Troponin; Warfarin

In atrial fibrillation (AF) patients, age >or=75 years is one of the major risk factors for stroke. However, it is not clear if an upper limit for the indication to OAT exists.. For this reason, we performed a prospective study on 290 AF patients on OAT aged >or=75 years (median age 82 years, total follow-up period 814 pt/years) followed by our Anticoagulation Clinic. Seventeen major bleeding events were recorded (rate 2.1 x 100 pt/years), 11 of which cerebral (1.35 x 100 pt/years). The occurrence of major bleedings was associated with history of previous TIA or stroke [OR 3.4 (1.1-12.5), p=0.01] and with diabetes [OR 4.4 (1.3-14.7) p=0.01]. We found a trend to a progressive increase in the rate of bleeding risk with the increase of the CHADS2 score: patients with score 4-6 showed a rate of 3.4 x 100 pt/years with respect to 1.5 x 100 pt/years of patients with lower score. Number Needed to Harm (NNH) was calculated in relation to different classes of age (75-89, 80-84, >or=85 years) and to CHADS2 score. For patients in CHADS2 score 1-3 NNH remained stable across the different age classes. Instead for patients in CHADS2 score 4-6, NNH varied among the 3 groups of ages, reaching a value of 10 in patients >or=85 years.. Our data suggest that: 1) in AF patients older than 75 years with CHADS2 score 1-3 the risk of bleeding is low, 2) in AF patients >85 years with CHADS2 4-6 the risk of bleeding is high so that the use of OAT should be highly individualised.

Topics: Aged; Aged, 80 and over; Aging; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Female; Hemorrhage; Humans; Ischemic Attack, Transient; Male; Prospective Studies; Risk Factors; Stroke; Warfarin

To ascertain current British practice regarding the emergency medical management of patients who sustain a spontaneous intracerebral haemorrhage (ICH) whilst receiving warfarin therapy and to compare this with established national and international guidelines.. Standardised, telephone based, questionnaire survey.. All 32 adult British neuroscience intensive care units (ICUs). Duty consultant of each neuroscience ICU.. Response rate was 100%. The international normalised ratio (INR) would be reversed by over 90% of ICU consultants treating patients on warfarin with an ICH, except patients with mechanical heart valves (MHV), when only 59.4% would reverse. Prothrombin complex concentrate (PCC) was used by 15 ICUs (46.9%); however, only six units (18.8%) apply reversal strategies with PCC and intravenous vitamin K in accordance with national guidelines. Fresh frozen plasma (FFP) continues to be used by 71.9% of the ICUs. A protocol for warfarin reversal in ICH was present in five ICUs, of which four followed national guidelines. None of the units that use FFP had a protocol. Following ICH, two-thirds of the ICUs (65.6%) would commence bridging heparinisation in the first 4 days for MHV patients and 25% would recommence warfarin before, and 64.5% after, 7 days.. There is considerable variation in practice amongst clinicians who regularly manage these patients and, in most cases (81.2%), practice is not in keeping with national or international guidelines. This study has demonstrated the need amongst senior ICU clinicians for a heightened awareness of current treatment recommendations and the availability of effective haemostatic therapies.

Topics: Cerebral Hemorrhage; Critical Care; Humans; Neurosurgery; Practice Patterns, Physicians'; Surveys and Questionnaires; United Kingdom; Warfarin

The pathophysiology and clinical significance of perihematomal edema (PHE), a cause of secondary neuronal injury after intracerebral hemorrhage (ICH), is poorly understood. A leading theory proposes that early PHE results from activation of the clotting cascade. We sought to test this theory by examining the relationship between early PHE and warfarin use in ICH patients.. ICH and PHE volumes were measured in consecutive patients with warfarin-related ICH and compared to those of controls with non-coagulopathic ICH. Subjects were identified from a prospective database of ICH patients. Clinical and radiological predictors of PHE volume and relative PHE (PHE volume/ICH volume) were identified. The relationship between PHE volume and 90-day mortality was determined.. For the 49 consecutive warfarin-related ICH patients and 49 matched controls: median INRs (interquartile ranges) were 3.2 (2.3, 4.1) and 1.1 (1.08, 1.2); median hematoma volumes were 37.8 cm(3) (6.7, 102.9) and 18.1 cm(3) (9, 51) (P = 0.18); median PHE volumes were 12 cm(3) (3.7, 36.7), and 11 cm(3) (4.1, 24) (P = 0.87); and median relative PHE was 0.38 (0.28, 0.52) and 2 (1.37, 3.06), respectively. In multivariable analysis, ICH volume and warfarin use independently predicted PHE volume. There was an association between higher PHE volume and decreased 90-day mortality.. Warfarin-related ICH is associated with less early relative edema than non-coagulopathic ICH. This is consistent with the theory that coagulation contributes to early edema. Early edema may be associated with improved functional outcome.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation; Brain Edema; Cerebral Hemorrhage; Humans; Middle Aged; Radiography; Retrospective Studies; Severity of Illness Index; Time Factors; Warfarin

Little is known about the outcomes of patients who have hemorrhagic complications while receiving warfarin therapy. We examined the rates of death and disability resulting from warfarin-associated intracranial and extracranial hemorrhages in a large cohort of patients with atrial fibrillation.. We assembled a cohort of 13,559 adults with nonvalvular atrial fibrillation and identified patients hospitalized for warfarin-associated intracranial and major extracranial hemorrhage. Data on functional disability at discharge and 30-day mortality were obtained from a review of medical charts and state death certificates. The relative odds of 30-day mortality by hemorrhage type were calculated using multivariable logistic regression.. We identified 72 intracranial and 98 major extracranial hemorrhages occurring in more than 15,300 person-years of warfarin exposure. At hospital discharge, 76% of patients with intracranial hemorrhage had severe disability or died, compared with only 3% of those with major extracranial hemorrhage. Of the 40 deaths from warfarin-associated hemorrhage that occurred within 30 days, 35 (88%) were from intracranial hemorrhage. Compared with extracranial hemorrhages, intracranial events were strongly associated with 30-day mortality (odds ratio 20.8 [95% confidence interval, 6.0-72]) even after adjusting for age, sex, anticoagulation intensity on admission, and other coexisting illnesses.. Among anticoagulated patients with atrial fibrillation, intracranial hemorrhages caused approximately 90% of the deaths from warfarin-associated hemorrhage and the majority of disability among survivors. When considering anticoagulation, patients and clinicians need to weigh the risk of intracranial hemorrhage far more than the risk of all major hemorrhages.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; California; Cerebral Hemorrhage; Cohort Studies; Female; Hemorrhage; Hospital Mortality; Humans; Logistic Models; Male; Risk Assessment; Stroke; Warfarin

Goals of hemorrhage management involve promoting coagulation and reducing fibrinolysis to enhance clot formation and stability, and minimizing hemorrhagic expansion to reduce the likelihood of adverse outcomes. The optimal hemostatic regimen to obtain these goals will differ according to the clinical scenario. Two hypothetical cases of patients with hemorrhage are presented that are typical of those encountered by clinical pharmacists who practice in centers that treat trauma or surgical patients or patients in need of emergency or critical care because of serious bleeding. To maximize therapy, the clinician must be aware of how best to clinically apply hemostatic agents, their comparative benefits and disadvantages, and the optimal methods for monitoring their effectiveness and toxicities.

Topics: Anticoagulants; Antifibrinolytic Agents; Blood Coagulation; Blood Coagulation Factors; Cerebral Hemorrhage; Critical Care; Emergency Service, Hospital; Evidence-Based Medicine; Factor VII; Factor VIIa; Female; Fibrinolysis; Hemorrhage; Hemostasis; Hemostatics; Humans; Intraoperative Complications; Male; Middle Aged; Pharmacists; Plasma; Recombinant Proteins; Vitamin K; Warfarin

Selective serotonin reuptake inhibitors (SSRI) are widely prescribed. Several reports have observed an increased bleeding risk associated with SSRI use, which is hypothesized to be secondary to their antiplatelet effect.. We tested the hypothesis that SSRIs increase the risk for or potentiate the risk of hemorrhagic stroke associated with antiplatelets and anticoagulants.. In multivariate analysis, we found no increased risk associated with SSRI use for intracerebral hemorrhage (odds ratio=1.1, 95% CI: 0.7 to 1.8; P=0.63) or subarachnoid hemorrhage (odds ratio=0.6, 95% CI: 0.4 to 1.0; P=0.054). In addition, potentiation of risk with warfarin or antiplatelets was not observed.. Further studies with larger populations would be needed to exclude a small increase in intracranial hemorrhage risk with SSRI use.

Topics: Aged; Blood Coagulation; Blood Platelets; Case-Control Studies; Cerebral Hemorrhage; Depressive Disorder; Drug Synergism; Female; Humans; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Platelet Aggregation Inhibitors; Risk Factors; Selective Serotonin Reuptake Inhibitors; Serotonin; Stroke; Treatment Outcome; Warfarin

Venous angiomas were found to be the most common cerebral vascular malformations, composing 63% of such lesions in two autopsy series. Annual bleeding risk associated with venous angiomas is about 0.22 % per year. Venous angiomas are generally silent lesions because of their dynamic features, and are low flow and low pressure vascular structures draining normal brain tissue. An angioma rarely causes symptoms such as bleeding, seizure, hemifacial spasm, trigeminal neuralgia, aqueduct compression, nonhemorrhagic infarction and thrombosis of the draining vein. Even if it should bleed, the lesion can be managed conservatively in asymptomatic or mildly symptomatic patients. In this paper we report two venous angioma cases. The first patient bled twice in a short period of time and the angioma was located at the posterior fossa next to the left lateral recess. The second patient recently suffered a cerebral stroke that was located in the vicinity of the right caudate nucleus and not associated with the venous angioma that was located next to the left caudate nucleus. This patient had been under warfarin sodium treatment for 14 years due to his previous coronary artery bypass surgery, but unknowingly there was a venous angioma located next to the caudate nucleus.

Topics: Aged; Anticoagulants; Central Nervous System Venous Angioma; Cerebral Hemorrhage; Female; Humans; Male; Middle Aged; Severity of Illness Index; Stroke; Tomography, X-Ray Computed; Warfarin

Cerebral hemorrhage occurs rarely in endocarditis caused by Actinobacillus actinomycetemcomitans. A 51-year-old man with a prosthetic mitral valve, who had been prophylactically treated (7 years) with warfarin, presented with intermittent fever. On admission, a Levine grade II/VI systolic cardiac murmur was detected. A transthoracic echocardiogram was negative for valve vegetation. Cefepime (1 g every 8 hours) was administered intravenously. On day 4, culturing of Gram-negative bacilli from blood and a transesophageal echocardiogram revealed a small oscillating filament attached to lateral mitral prosthetic ring on the atrial side. Ceftriaxone (2 g once daily) was started. Gait instability and left-side weakness developed abruptly 2 weeks later; brain magnetic resonance imaging revealed a hematoma over the right parietal-occipital lobe. Ceftriaxone was adjusted to 2 g every 12 hours. Actinobacillus actinomycetemcomitans was identified 3 weeks later. Recovery was achieved, with significant interval improvement and resolution of the cerebral lesions evident on CT.

Topics: Actinobacillus Infections; Aggregatibacter actinomycetemcomitans; Anti-Bacterial Agents; Anticoagulants; Ceftriaxone; Cerebral Hemorrhage; Endocarditis; Humans; Male; Middle Aged; Warfarin

In this study, we have reviewed our experience with anticoagulation-associated intraventricular hemorrhage (IVH). Our goal was to determine if IVH is also an independent prognosticator of fatal outcome in patients with anticoagulation-associated intracerebral hemorrhage (ICH).. This study is a retrospective analysis of medical records and computed tomographic imaging. Eighty-eight patients with warfarin-associated ICH were analysed, including eight patients with predominant IVH.. There was a very low rate of hemorrhage extension in patients with predominant IVH. Despite that, those patients had 50% 30 day mortality. Overall patients with ICH had 45% 30 day mortality. Ventricular extension raised mortality in ICH patients to 75%, while the absence of ventricular extension carried only 23% 30 day mortality. IVH was significantly associated with 30 day mortality (p<0.001). Panventricular extension was uniformly fatal in patients with ICH and carried 75% 30 day mortality in patients with predominant IVH. On a multivariate logistic regression model including age, ICH volume and IVH, ICH volume (p<0.001) and IVH (p = 0.003) remained independently associated with early mortality.. Extension of anticoagulation-associated ICH into ventricular system caused a high mortality, especially in patients with panventricular involvement. IVH is an independent predictor of early death in these patients. In our experience, the majority of IVH do not expand over time and poor outcome appears to be related to the magnitude of the initial insult.

Topics: Aged; Aged, 80 and over; Anticoagulants; Brain; Cerebral Arteries; Cerebral Hemorrhage; Choroid Plexus; Female; Hospital Mortality; Humans; Lateral Ventricles; Male; Predictive Value of Tests; Prognosis; Retrospective Studies; Risk Factors; Tomography, X-Ray Computed; Warfarin

Topics: Anticoagulants; Blood Transfusion; Cerebral Hemorrhage; Clinical Trials as Topic; Hematoma; Humans; International Normalized Ratio; Plasma; Random Allocation; Stroke; Warfarin

Anticoagulation-related intracerebral hemorrhage (ICH) is often fatal, and rapid reversal of anticoagulation is the most appealing strategy currently available for treatment. We sought to determine whether particular emergency department (ED) interventions are effective in reversing coagulopathy and improving outcome.. Consecutive patients with warfarin-related ICH presenting to an urban tertiary care hospital from 1998 to 2004 were prospectively captured in a database. ED records were retrospectively reviewed for dose and timing of fresh-frozen plasma (FFP) and vitamin K, as well as serial coagulation measures. After excluding patients with incomplete ED records, do-not-resuscitate orders established in the ED, initial international normalized ratio (INR) < or =1.4, and for whom no repeat INR was performed, 69 patients were available for analysis. The primary outcome was a documented INR < or =1.4 within 24 hours of ED presentation.. Patients whose INR was successfully reversed within 24 hours had a shorter median time from diagnosis to first dose of FFP (90 minutes versus 210 minutes; P=0.02). In multivariable analysis, shorter time to vitamin K, as well as FFP, predicted INR correction. Every 30 minutes of delay in the first dose of FFP was associated with a 20% decreased odds of INR reversal within 24 hours (odds ratio, 0.8; 95% CI, 0.63 to 0.99). Dosing of FFP and vitamin K had no effect. No ED intervention was associated with improved clinical outcome.. Time to treatment is the most important determinant of 24-hour anticoagulation reversal. Although additional study is required to determine the clinical benefit of rapid reversal of anticoagulation, minimizing delays in FFP administration is a prudent first step in emergency management of warfarin-related ICH.

Topics: Aged; Anticoagulants; Blood Transfusion; Cerebral Hemorrhage; Emergency Medicine; Female; Hospitals; Humans; International Normalized Ratio; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Plasma; Prospective Studies; Retrospective Studies; Time Factors; Treatment Outcome; Vitamin K; Warfarin

Hematoma volume and impaired level of consciousness are the most potent predictors of outcome after spontaneous intracerebral hemorrhage (ICH). The effect of preceding aspirin-use on outcome after ICH is poorly investigated. We investigated short-term mortality and hematoma enlargement in subjects with ICH to find the predictors for these outcomes.. This population-based study included all subjects with ICH during a period of 33 months in the population of Northern Ostrobothnia, Finland. The subjects were identified, and their clinical characteristics and outcomes were checked from hospital records or death records.. Three-month mortality of the 208 identified subjects with ICH was 33%. The independent risk factors for death were regular aspirin-use at the onset of ICH (relative risks [RR], 2.5; 95% CI, 1.3 to 4.6; P=0.004), warfarin-use at the onset of ICH (RR, 3.2; 95% CI, 1.6 to 6.1; P=0.001), and ICH score higher than 2 on admission (RR, 13.8; 95% CI, 6.0 to 31.4; P<0.001). Regular aspirin-use preceding the onset of ICH associated significantly with hematoma enlargement during the first week after ICH (P=0.006).. We observed poor short-term outcomes and increased mortality, probably attributable to rapid enlargement of hematomas, in the subjects with ICH who had been taking regularly moderate doses of aspirin (median 250 mg) immediately before the onset of the stroke.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Aspirin; Cerebral Hemorrhage; Cohort Studies; Female; Hematoma; Hemorrhage; Humans; Iatrogenic Disease; Male; Middle Aged; Models, Statistical; Platelet Aggregation Inhibitors; Platelet Transfusion; Risk; Risk Factors; Time Factors; Treatment Outcome; Warfarin

The ABC/2 formula is a reliable estimation technique of intracerebral hematoma volume. However, oral anticoagulant therapy (OAT)-related intracerebral hemorrhage (ICH) compared with primary ICH is based on a different pathophysiological mechanism, and various shapes of hematomas are more likely to occur. Our objective was to validate the ABC/2 technique based on analyses of the hematoma shapes in OAT-related ICH.. We reviewed the computed tomography scans of 83 patients with OAT-associated intraparenchymal ICH. Location was divided into deep, lobar, cerebellar, and brain stem hemorrhage. Shape of the ICH was divided into (A) round-to-ellipsoid, (B) irregular with frayed margins, and (C) multinodular to separated. The ABC/2 technique was compared with computer-assisted planimetric analyses with regard to hematoma site and shape.. The mean hematoma volume was 40.83+/-3.9 cm3 (ABC/2) versus 36.6+/-3.5 cm3 (planimetric analysis). Bland-Altman plots suggested equivalence of both estimation techniques, especially for smaller ICH volumes. The most frequent location was a deep hemorrhage (54%), followed by lobar (21%), cerebellar (14%) and brain stem hemorrhage (11%). The most common shape was round-to-ellipsoid (44%), followed by irregular ICH (31%) and separated and multinodular shapes (25%). In the latter, ABC/2 formula significantly overestimated volume by +32.1% (round shapes by +6.7%; irregular shapes by +14.9%; P ANOVA <0.01). Variation of the denominator toward ABC/3 in cases of irregularly and separately shaped hematomas revealed more a precise volume estimation with a deviation of -10.3% in irregular and +5.6% in separately shaped hematomas.. In patients with OAT-related ICH, >50% of bleedings are irregularly shaped. In these cases, hematoma volume is significantly overestimated by the ABC/2 formula. Modification of the denominator to 3 (ie, ABC/3) measured ICH volume more accurately in these patients potentially facilitating treatment decisions.

Topics: Algorithms; Brain; Cerebral Hemorrhage; Hematoma, Subdural; Humans; Image Processing, Computer-Assisted; Models, Statistical; Prognosis; Prospective Studies; Software; Stroke; Thrombolytic Therapy; Tomography, X-Ray Computed; Warfarin

Clinical trials have illustrated warfarin's protective effect on stroke risk in patients with atrial fibrillation (AF). The current study investigated temporal trends in AF prevalence, warfarin use, and its relation to stroke risk in Medicare patients with AF from 1992 to 2002.. The Medicare 5% sample for 1992 to 2002 was used to create 1-year cohorts of patients with Medicare as primary payer throughout the year. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify AF, ischemic and hemorrhagic stroke, and comorbid conditions. A previously validated surrogate measure, prothrombin/international normalized ratio claims, was used to identify warfarin use. Cox proportional hazards regression was used to examine time to stroke with warfarin use as a time-dependent variable.. Among Medicare patients aged > or = 65 years, AF prevalence increased from 3.2% in 1992 to 6.0% in 2002 with higher prevalence in older subsets of the study population. Among patients with AF, warfarin use increased significantly (P< or = 0.001) for each year examined, from 24.5% in 1992 to 56.3% in 2002. Stroke rates per 1000 patient-years declined from 46.7 in 1992 to 19.5 in 2002 for ischemic stroke but remained fairly steady for hemorrhagic stroke (range, 1.6 to 2.9). Time-to-event modeling confirmed a protective association of warfarin against ischemic stroke among Medicare patients with AF.. This analysis represents an observational validation of stroke prevention in AF trials. The significant increase in warfarin use among patients with AF illustrates diffusion of trial evidence into clinical practice.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cerebral Hemorrhage; Cohort Studies; Female; Humans; Incidence; Male; Medicare; Prevalence; Proportional Hazards Models; Risk Assessment; Stroke; Time Factors; Warfarin

The objective of this study was to study the clinical course and outcome of warfarinised patients who were hospitalised because of head trauma.. 13 patients (ten males and three females; median age 69 years) who presented to the Royal Perth Hospital, Australia and who had suffered a head injury between July 1994 and June 2000 while concurrently taking warfarin, were studied.. Confusion was the commonest presenting symptom (four patients). Five patients presented after more than 24 hours of the injury. Eight patients were anticoagulated for thromboembolic disease and five for atrial fibrillation. The patients had a median injury severity score of 25 (range 1-43). The median international normalised ratio was 2.4 (range 1.8-10) on admission and 1.8 (range 1.0-10) on discharge. 11 of the 13 patients had computed tomography of the head. Intracerebral bleeding was the commonest injury (nine patients). The median length of hospital stay was six days (range 3-30). Five patients died (38.5%).. Warfarinised patients who sustain minor head trauma should be hospitalised for close neurological observation and should have a low threshold for performing computed tomography.

Topics: Accidental Falls; Accidents, Traffic; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Confusion; Craniocerebral Trauma; Female; Glasgow Coma Scale; Humans; Male; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors; Warfarin

To identify hematoma progression in patients with warfarin-associated intracerebral hemorrhage (ICH) despite international normalized ratio (INR) normalization with fresh-frozen plasma (FFP), we reviewed 45 patients with warfarin-associated ICH given FFP. The median time for door to INR normalization was 30 hours (14 to 49.5), with 4 patients' hematomas enlarging after INR normalization. FFP is associated with substantial time delay to actual administration and pulmonary edema and may not prevent progression of ICH despite INR normalization.

Topics: Aged; Anticoagulants; Blood Transfusion; Cerebral Hemorrhage; Disease Progression; Female; Humans; International Normalized Ratio; Male; Plasma; Pulmonary Edema; Retrospective Studies; Treatment Outcome; Warfarin

The characteristics of patients with anticoagulant-associated intracerebral hemorrhage (AAICH) have not been well characterized in a population-based setting.. We attempted to ascertain all patients with ICH in Greater Cincinnati from May 1998 to July 2001 and August 2002 to April 2003 via retrospective review of ICD-9 codes 430-438.9 at all area hospitals and prospective surveillance at tertiary centers. Cases of ICH without coagulopathy and AAICH were compared with multivariate logistic modeling and survival analysis.. AAICH occurred in 190 of 1041 ICH cases (18%). In multivariate analysis, predictors of AAICH were cerebellar location of hemorrhage (p = 0.01) and a history of coronary artery disease (p < 0.001), ischemic stroke (p < 0.001), atrial fibrillation (p < 0.001) and DVT or PE (p < 0.001). Relative to other ICH locations, only cerebellar ICH showed an excess risk of anticoagulant-associated hemorrhage (OR 2.2, 95% CI 1.2 to 4.0). In multivariate modeling the only predictor of cerebellar location of ICH was anticoagulation (p < 0.001). Patients with AAICH were more likely to die than other ICH patients. The difference in morality occurred by day one (mortality 33.2% vs 16.3%, p < 0.001) and remained stable through one year (mortality 66.3% vs 50.3%, p < 0.001).. AAICH preferentially affects the cerebellum. Despite its association with amyloid angiopathy, lobar ICH was no more likely to be anticoagulant-associated than deep cerebral ICH. The excess mortality among AAICH patients accrues within one day of hemorrhage. Patients with AAICH have a high burden of vascular risk factors. New treatments for AAICH with prothrombotic potential should be evaluated in randomized controlled trials before routine use.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebellar Diseases; Cerebral Hemorrhage; Cerebral Infarction; Coronary Disease; Female; Hospital Mortality; Humans; Male; Middle Aged; Multivariate Analysis; Population Surveillance; Prospective Studies; Retrospective Studies; Risk Factors; Survival Rate; Warfarin

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Biopsy; Cerebral Hemorrhage; Cerebral Infarction; Colitis, Ulcerative; Colon; Colonoscopy; Humans; Magnetic Resonance Imaging; Male; Sagittal Sinus Thrombosis; Sulfasalazine; Warfarin

Head CT is frequently ordered for trauma patients who are receiving anticoagulation. However, whether patients with a Glasgow Coma Scale (GCS) score of 15 and normal findings on neurologic examination require CT is still debated. The purpose of our study was to assess the use of cranial CT in patients receiving anticoagulants after head trauma and to establish clinical criteria to identify those in this group who do not need emergency CT.. We retrospectively reviewed patients receiving heparin or coumadin who had head trauma and who subsequently underwent cranial CT at a level I trauma center within a 4-year period. Patients were evaluated for mechanism of injury, clinical signs and symptoms of head injury, and type and reason for anticoagulation. Prothrombin time, international normalized ratio, partial thromboplastin time, GCS score, age, and head CT results were recorded for each patient.. A total of 89 patients fulfilled the enrollment criteria. Among them, 82 had no evidence of intracranial injury on CT. Seven patients had evidence of intracranial hemorrhage. Patients without hemorrhage had no significant focal neurologic deficits and presented with an average GCS score of 14.8. Patients with intracranial hemorrhage tended to have focal neurologic deficits and presented with an average GCS score of 12.0.. Patients with head injury, normal GCS scores, and no focal neurologic deficits and who are receiving the anticoagulants heparin or coumadin may not necessarily require emergency CT.

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Craniocerebral Trauma; Female; Glasgow Coma Scale; Heparin; Humans; Male; Nervous System Diseases; Retrospective Studies; Tomography, X-Ray Computed; Warfarin

Topics: Anticoagulants; Cerebral Hemorrhage; Cerebral Hemorrhage, Traumatic; Humans; Tomography, X-Ray Computed; Warfarin

A 51-year-old woman on warfarin thromboprophylaxis for transient ischemic attacks developed sudden onset nausea, vomiting, and decreased mental status, rapidly becoming comatose. Head computed tomography (CT) showed intracerebral hemorrhage, extending into all ventricular chambers, and acute obstructive hematocephalus requiring urgent ventricular drainage. CT angiogram showed no evidence of an aneurysm or vascular malformation.. The pretreatment international normalized ratio (INR) of 4.9 was rapidly corrected with recombinant activated factor VII and an external ventricular drain was placed. Despite accurate positioning, the ventriculostomy thrombosed and became nonfunctional. Recombinant tissue plasminogen activator was given intraventricularly and resulted in partial ventricular decompression within 24 hours, with dramatic improvement in the patient's level of consciousness.. Repeated intraventricular fibrinolysis resulted in further reduction of the intraventricular hematoma within a few days and a good patient outcome. The patient did not require permanent ventricular shunt.. To our knowledge, this is the first reported case of combined systemic enhancement of hemostasis and local fibrinolysis as a life-saving measure in intracranial hemorrhage.

Topics: Anticoagulants; Cerebral Hemorrhage; Factor VIIa; Female; Fibrinolytic Agents; Hematoma; Hemostatic Techniques; Humans; Intracranial Thrombosis; Middle Aged; Recombinant Proteins; Thalamus; Tissue Plasminogen Activator; Tomography, X-Ray Computed; Treatment Outcome; Warfarin

Warfarin sodium is highly effective for prevention of embolic stroke, particularly in nonvalvular atrial fibrillation, but its expected benefit can be offset by risk of intracerebral hemorrhage (ICH). We studied the determinants of ICH outcome to quantify the independent effect of warfarin.. Consecutive patients with supratentorial ICH treated in a tertiary care hospital with a neurointensive care unit were prospectively identified during a 7-year period, and data on hemorrhage location, clinical characteristics, and warfarin use were collected. Independent predictors of 3-month mortality were determined using multiple logistic regression analysis.. Of 435 consecutive patients aged 55 years or older, 102 (23.4%) were taking warfarin at the time of ICH. Three-month mortality was 25.8% for those not taking warfarin and 52.0% for those taking warfarin. Independent predictors of death were warfarin use (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.3-3.8), age 70 years or older (OR, 2.4; 95% CI, 1.4-4.0), and presence of diabetes mellitus (OR, 1.8; 95% CI, 1.0-3.3). Although 68.0% of all warfarin-related hemorrhages occurred at an international normalized ratio (INR) of 3.0 or less, increasing degrees of anticoagulation were strongly associated with increasing risk of death compared with no warfarin use.. Patients taking warfarin had a doubling in the rate of intracerebral hemorrhage mortality in a dose-dependent manner. The data suggest that careful control of the INR, already known to limit the risk of warfarin-related ICH, may also limit its severity.

Topics: Aged; Anticoagulants; Cerebral Hemorrhage; Dose-Response Relationship, Drug; Female; Humans; International Normalized Ratio; Logistic Models; Male; Middle Aged; Multivariate Analysis; Warfarin

Stroke is a devastating complication in patients with prosthetic valves, but characterization of its late occurrence from a large cohort is lacking.. Three thousand one hundred eighty-nine adult patients who underwent a total of 3,576 operations for left-heart valve replacement were managed with contemporary anticoagulation guidelines and prospectively followed in a dedicated clinic. Total follow-up was 20,096 patient years. Bootstrapped survival analysis was used to determine the impact of patient and valve related factors on the incidence of stroke.. Most strokes were embolic. Linearized embolic stroke rates were 1.3% +/- 0.2% per year for aortic bioprostheses, 1.4% +/- 0.2% per year for aortic mechanical valves, 1.3% +/- 0.3% per year for mitral bioprostheses, and 2.3% +/- 0.4% per year for mitral mechanical valves (p = 0.002, vs other implant types). Age more than 75 years, female gender, and smoking were independent risk factors after aortic and mitral valve replacement. Atrial fibrillation, coronary disease, and tilting-disc mechanical prostheses were independent predictors of embolic stroke after aortic valve replacement. Preoperative left ventricular (LV) dysfunction was an independent risk factor in patients with mitral prostheses. Primary operative indication, diabetes, redo status, or the presence of two prosthetic valves were not associated with an increased hazard. The addition of acetyl salicylic or dipyridamole to warfarin anticoagulation did not significantly lower embolic stroke risk in patients with mechanical prostheses.. Approximately 20% of patients with valve prostheses have an embolic stroke by 15 years after valve replacement. Some risk factors such as the avoidance of smoking, mitral mechanical prostheses, aortic tilting-disc valves, and proceeding to mitral surgery before LV dysfunction occurs are potentially modifiable.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Aortic Valve; Aspirin; Atrial Fibrillation; Cerebral Hemorrhage; Comorbidity; Coronary Disease; Dipyridamole; Drug Therapy, Combination; Female; Follow-Up Studies; Heart Valve Prosthesis Implantation; Humans; Incidence; International Normalized Ratio; Intracranial Embolism; Life Tables; Male; Middle Aged; Mitral Valve; Postoperative Complications; Proportional Hazards Models; Prospective Studies; Risk Factors; Smoking; Stroke; Ventricular Dysfunction, Left; Warfarin

To examine older patients' preferences regarding the use of warfarin to prevent atrial fibrillation related strokes when faced with cumulative probabilities of treatment risk and benefit.. A semi-qualitative researcher administered questionnaire and interview.. 81 patients attending a general elderly medicine outpatient clinic.. Up to 50% of participants would decline warfarin treatment when shown both cumulative benefits of stroke risk reduction and risk of intracerebral haemorrhage. Principal themes highlighted concepts of gambling and trade offs relating to risk and benefit. Attitudes about stroke and negative perceptions of intracerebral haemorrhage were major contributory themes in the decision to refuse warfarin treatment.. Older people use very individualistic health beliefs in judging how to trade risks to preserve quality of life. Carefully explaining risk information and listening to elders' views and reasoning is likely to result in a more informed choice regarding the use of anticoagulation in stroke prevention.

Topics: Aged; Aged, 80 and over; Anticoagulants; Attitude to Health; Cerebral Hemorrhage; Female; Humans; Interviews as Topic; Male; Stroke; Surveys and Questionnaires; Warfarin

Warfarin increases mortality of intracerebral hemorrhage (ICH). The authors investigated whether this effect reflects increased baseline ICH volume at presentation or increased ICH expansion.. Subjects were drawn from an ongoing prospective cohort study of ICH outcome. The effect of warfarin on baseline ICH volume was studied in 183 consecutive cases of supratentorial ICH age > or = 18 years admitted to the emergency department over a 5-year period. Baseline ICH volume was determined using computerized volumetric analysis. The effect of warfarin on ICH expansion (increase in volume > or = 33% of baseline) was analyzed in 70 consecutive cases in whom ICH volumes were measured on all subsequent CT scans up to 7 days after admission. Multivariable analysis was used to determine warfarin's influence on baseline ICH, ICH expansion, and whether warfarin's effect on ICH mortality was dependent on baseline volume or subsequent expansion.. There was no effect of warfarin on initial volume. Predictors of larger baseline volume were hyperglycemia (p < 0.0001) and lobar hemorrhage (p < 0.0001). Warfarin patients were at increased risk of death, even when controlling for ICH volume at presentation. Warfarin was the sole predictor of expansion (OR 6.2, 95% CI 1.7 to 22.9) and expansion in warfarin patients was detected later in the hospital course compared with non-warfarin patients (p < 0.001). ICH expansion showed a trend toward increased mortality (OR 3.5, 95% CI 0.7 to 8.9, p = 0.14) and reduced the marginal effect of warfarin on ICH mortality.. Warfarin did not increase ICH volume at presentation but did raise the risk of in-hospital hematoma expansion. This expansion appears to mediate part of warfarin's effect on ICH mortality.

Topics: Adult; Aged; Anticoagulants; Apolipoproteins E; Cerebral Hemorrhage; Cohort Studies; Disease Progression; Female; Genotype; Hematoma; Hospital Mortality; Humans; Hyperglycemia; Hypertension; Life Tables; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Radiography; Risk; Treatment Outcome; Warfarin

The quality control of oral anticoagulant therapy (OAT) during the initiation and maintenance treatment is generally poor. Physicians' ordering of OAT (especially fluindione and warfarin) can be improved by dose adjustment algorithms, taking into account the results of International Normalized Ratio (INR). Reminders at the point of care, computerized or not, have been demonstrated to be effective in changing physicians prescription behavior.However, few studies have addressed the benefit of personalized reminders versus non personalized reminders, whereas the personalized reminders require more development to access patient record data and integrate with the computerized physician order entry system. The Hospital Information System of George Pompidou European Hospital integrates an electronic medical record, lab test and drugs order entry system. This system allows to evaluate such reminders and to consider their implementation for routine use as well as the continuous evaluation of their impact on medical practice quality indicators. The objective of this study is to evaluate the impact of two types of reminders on overtreatment by oral anticoagulant: a simple reminder of text formatted dose adjustment table and a personalized recommendation for oral anticoagulant dose and next date of INR control, adapted to patient data. Both types of reminders appear to the physician at the moment of drug ordering.

Topics: Administration, Oral; Anticoagulants; Cerebral Hemorrhage; Chemoprevention; Clinical Pharmacy Information Systems; Decision Support Systems, Clinical; Drug Utilization Review; France; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Medical Staff, Hospital; Medication Errors; Nomograms; Phenindione; Quality Control; Reminder Systems; Systems Integration; Time; Treatment Outcome; Venous Thrombosis; Warfarin

The importation of medications is strongly discouraged in the United States. However, with the cost of prescription medications on the rise, an increasing number of patients are seeking alternative ways of obtaining drugs. Although medication errors involving imported drugs have been described in the literature, there is little available information on the prevalence of such problems.. A 74-year-old woman who had been taking warfarin therapy for >2 years presented to the emergency department with new-onset headache. She was found to have a small subdural hematoma on computed tomography and a prothrombin time >120 seconds. Warfarin was stopped and anticoagulation was corrected with fresh frozen plasma. At follow-up testing, the international normalized ratio (INR) continued to be >2 despite vitamin K therapy and the patient's insistence that she had discontinued warfarin. Further evaluation by a hematologist detected warfarin in the blood. Subsequent inspection of her medications revealed unmarked white tablets labeled "phenytoin" that had been dispensed by a pharmacy in another country. The INR normalized after these tablets were discarded and a new prescription for phenytoin was started.. Application of the Naranjo scale to this case suggested a high likelihood of an adverse drug reaction (ADR). Potential causes of the ADR included the placement of warfarin in a bottle mislabeled "phenytoin" and contamination of phenytoin with warfarin.. Obtaining medications from pharmacies in or by mail order from other countries means that patients miss the opportunity to ask questions and receive counseling from a pharmacist. Physicians and pharmacists should inspect patients' medications to ensure product legitimacy and confirm that the indications, dispensing, and labeling are accurate.

Topics: Aged; Anticoagulants; Anticonvulsants; Cerebral Hemorrhage; Drug Contamination; Drug Labeling; Female; Humans; International Normalized Ratio; Medication Errors; Phenytoin; Tablets; Warfarin

Topics: Cerebral Hemorrhage; Emergency Service, Hospital; Fatal Outcome; Female; Humans; Middle Aged; New York City; Stroke; Warfarin

Warfarin increases both the likelihood and the mortality of intracerebral hemorrhage (ICH), particularly in patients with a history of prior ICH. In light of this consideration, should a patient with both a history of ICH and a clear indication for anticoagulation such as nonvalvular atrial fibrillation be anticoagulated? In the absence of data from a clinical trial, we used a decision-analysis model to compare the expected values of 2 treatment strategies-warfarin and no anticoagulation-for such patients.. We used a Markov state transition decision model stratified by location of hemorrhage (lobar or deep hemispheric). Effectiveness was measured in quality-adjusted life years (QALYs). Data sources included English language literature identified through MEDLINE searches and bibliographies from selected articles, along with empirical data from our own institution. The base case focused on a 69-year-old man with a history of ICH and newly diagnosed nonvalvular atrial fibrillation.. For patients with prior lobar ICH, withholding anticoagulation therapy was strongly preferred, improving quality-adjusted life expectancy by 1.9 QALYs. For patients with prior deep hemispheric ICH, withholding anticoagulation resulted in a smaller gain of 0.3 QALYs. In sensitivity analyses for patients with deep ICH, anticoagulation could be preferred if the risk of thromboembolic stroke is particularly high.. Survivors of lobar ICH with atrial fibrillation should not be offered long-term anticoagulation. Similarly, most patients with deep hemispheric ICH and atrial fibrillation should not receive anticoagulant therapy. However, patients with deep hemispheric ICH at particularly high risk for thromboembolic stroke or low risk of ICH recurrence might benefit from long-term anticoagulation.

Topics: Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Cerebral Hemorrhage; Cohort Studies; Decision Support Techniques; Fibrinolytic Agents; Humans; Intracranial Thrombosis; Male; Markov Chains; Quality-Adjusted Life Years; Risk; Risk Assessment; Sensitivity and Specificity; Warfarin

Warfarin is involved in the majority of fatal adverse drug events in Norway. The aim of this study is to identify risk factors behind the haemorrhagic complications.. We analysed all adverse event reports involving bleeding related to warfarin that were received by the Norwegian Medicines Agency from 1990 to 2000.. 713 reports were included; 71% of the patients were above 70 years of age. The most frequent diagnosis was atrial fibrillation (39%). Cerebral bleedings were reported in 57% of the cases, 73% of which were fatal, as were 39 % of gastrointestinal bleedings and 14% of other bleedings. International normalised ratio values (INR values) at the time of bleeding were reported in 83% of the cases; mean INR value was 4.4 (range 1.2 - > 8.0). INR values above recommended limits at the time of bleeding were found in 74% of the patients. In 63%, bleedings occurred during the first month; in 30% during the first five days. Median duration of treatment was shorter in fatal (16 days) than in non-fatal cases (24 days).. Our results show that haemorrhagic complications are associated with high INR values and initiation of treatment. Simple strategies for reducing bleedings include better monitoring of patients, careful dose adjustment, and INR values in the lower end of the recommended ranges.

Topics: Adult; Adverse Drug Reaction Reporting Systems; Aged; Anticoagulants; Cerebral Hemorrhage; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Risk Factors; Warfarin

Major bleeding is a frequent and hazardous complication associated with thromboprophylaxis using vitamin-K antagonists (VKA). Suggested regimens for control of highly elevated International Normalized Ratio (INR) and hemorrhagic events during VKA treatment include administration of vitamin K, infusion of fresh frozen plasma (FFP) or a prothrombin complex concentrate (PCC). In contrast, this communication present the first report on the efficacious use of recombinant factor VIIa (rFVIIa) as additional therapy in seven patients presenting with central nervous system (CNS) bleeding emergencies. Pre-treatment INRs ranged from 1.7 to 6.6, and 10 min after a single dose of rFVIIa (10-40 microg/kg) all INRs were

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation; Cerebral Hemorrhage; Computer Systems; Drug Evaluation; Factor VII; Factor VIIa; Female; Hematoma; Hemostatics; Humans; International Normalized Ratio; Male; Middle Aged; Recombinant Proteins; Thrombelastography; Thromboembolism; Treatment Outcome; Vitamin K; Warfarin

The primary objective of this study was to evaluate the incidence of warfarin use in 156 consecutive patients presenting to a single tertiary referral centre with spontaneous intracerebral haemorrhage. Our study found that 11% of patients (16/159) presenting with spontaneous intracerebral haemorrhage were on warfarin for prophylactic anticoagulation at time of presentation. Comparison was made to other published Australian data with regard to the incidence of warfarin use in patients presenting with spontaneous intracerebral haemorrhage. Patient outcomes were also examined.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Australia; Cerebral Hemorrhage; Female; Humans; International Normalized Ratio; Male; Retrospective Studies; Risk Factors; Software; Tomography, X-Ray Computed; Warfarin

Prior ischemic stroke is a risk factor for intracerebral hemorrhage (ICH) in patients taking warfarin, but the mechanism is not known. This study investigates radiographic and clinical characteristics of patients with warfarin-related ICH following ischemic stroke.. In this case-control study, the authors selected all patients with warfarin-related ICH and previous symptomatic ischemic stroke from a prospective cohort of consecutive patients with ICH. Control subjects were similarly aged patients with history of symptomatic stroke randomly chosen from an anticoagulant therapy unit. The 26 eligible ICH cases and 56 controls were compared for vascular risk factors, stroke characteristics, and extent of leukoaraiosis (graded in anterior and posterior brain regions on a validated scale of 0 to 4).. The presence and severity of leukoaraiosis on CT scan correlated strongly with the occurrence of ICH. Leukoaraiosis was seen in 24 of 26 cases (92%) compared with 27 of 56 controls (48%), yielding an odds ratio of 12.9 (95% CI 2.8 to 59.8). Other clinical factors associated with ICH included an international normalized ratio >3.0, history of multiple previous strokes, and the presence of carotid artery stenosis. The relationship between leukoaraiosis and ICH persisted in multivariable analyses controlling for these risk factors as well as hypertension and diabetes mellitus.. Leukoaraiosis is an independent risk factor for warfarin-related ICH in survivors of ischemic stroke, including those in the commonly employed range of anticoagulation.

Topics: Aged; Aged, 80 and over; Anticoagulants; Brain; Brain Ischemia; Case-Control Studies; Cerebral Hemorrhage; Female; Humans; International Normalized Ratio; Male; Middle Aged; Risk Factors; Severity of Illness Index; Warfarin

Topics: Anticoagulants; Apolipoproteins E; Biomarkers; Brain; Brain Ischemia; Case-Control Studies; Cerebral Hemorrhage; Genotype; Humans; International Normalized Ratio; Risk Factors; Tomography, X-Ray Computed; Vitamin K; Warfarin

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Decision Making; Ethics, Clinical; Heart Failure; Hemorrhage; Humans; Judgment; Risk Factors; Stroke; Warfarin; Withholding Treatment

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Contraindications; Decision Making; Fatal Outcome; Female; Humans; Male; Practice Guidelines as Topic; Primary Prevention; Warfarin

We investigated the effect of prothrombin complex concentrate (PCC, median 500 IU) and vitamin K (10-20 mg) or either on blood coagulation and clinical findings in 17 patients with major hemorrhagic complication during warfarin treatment. Their international normalized ratio (INR) at admission was median 2.7 (2.0-above 10.0). In 11 patients treated with PCC and vitamin K, INR decreased to median 1.13 (0.91-1.36) 10 min after the administration with elevation of plasma levels of coagulant factors II, VII, IX, X and protein C.INR decreased abruptly after the administration of PCC without vitamin K in two patients but it increased again 12-24 h after, with decrease of coagulant factors levels. In one of them, a hematoma of the brain enlarged with INR re-increase 12-24 h after the administration. In four patients treated with vitamin K alone, INR decreased slowly from 2.69 (1.03-3.35) to 1.28 (1.25-1.44) 12-24 h after the administration in parallel with gradual increase of the coagulant factors.PCC administration with or without vitamin K seems to be more effective in rapidly correcting increased INR levels than vitamin K treatment without PCC. PCC without vitamin K may result in re-increase of INR and clinical deterioration.

Topics: Aged; Aged, 80 and over; Blood Coagulation Factors; Brain; Cerebral Hemorrhage; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Tomography, X-Ray Computed; Vitamin K; Warfarin

The characteristics, management and outcomes of patients who suffer intracerebral hemorrhage (ICH) while taking oral anticoagulants (OAC) are relatively unreported.. Retrospective cohort study of consecutive cases with ICH associated with OAC.. A university-affiliated tertiary care hospital in Ontario, Canada.. 368 charts of individuals with a discharge diagnosis of ICH (ICD-9 code 431) between January 1993 and May 1998 were reviewed.. 20 (5.4%, 95% confidence interval (CI): 3.1-7.7%) of the 368 ICHs occurred in people taking OAC. The median age of patients on OAC was 74 years (S.D.+/-9.8), and 70% (95% CI: 49-91%) were female. The median INR at presentation was 3.4 (intraquartile (IQR) range 2.2-4.4). Nine of 20 (45%) patients had INR values which exceeded the target range. The case fatality rate was 45% (95% CI: 23-67%). Approximately 2.8 years after the initial ICH, 9 of the 11 patients who survived the initial ICH were still alive, and 6 had restarted OAC.. ICH is a serious complication in patients taking OAC, and the case-fatality rate is high. Given the increasing use of OAC in patients with cardiovascular disease, the relative benefits and risks of this therapy must be weighed carefully.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Cohort Studies; Female; Humans; International Normalized Ratio; Male; Middle Aged; Prognosis; Retrospective Studies; Risk Factors; Treatment Outcome; Warfarin

Topics: Age Factors; Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Cerebral Hemorrhage; Drug Therapy, Combination; Fibrinolytic Agents; Humans; Platelet Aggregation Inhibitors; Risk Factors; Stroke; Warfarin

A 27-year-old Laotian woman with a St Jude mechanical mitral valve became pregnant, requiring a change in her anticoagulant after the first trimester when her warfarin sodium (coumadin) was replaced with enoxaparin sodium (lovenox). Her prosthetic valve clotted and became dysfunctional. She was 16 weeks pregnant and was taken to the operating room for emergency surgery for replacement of the valve. The fetus had not been viable for 1-2 weeks, but still remained in utero. The clotted valve was replaced with another St Jude valve of a slightly smaller diameter (27 mm). The patient could not be weaned from bypass so a right ventricular assist device (RVAD) was inserted. The patient was weaned from the RVAD after 2 days of support. Two days following removal of the RVAD the fetus spontaneously aborted. The patient had a long, complicated hospital course and was discharged 3 months later. She subsequently died 4 months after discharge of a cerebral hemorrhage from excessive anticoagulation.

Topics: Adult; Anticoagulants; Blood Coagulation; Cardiac Surgical Procedures; Cerebral Hemorrhage; Enoxaparin; Equipment Failure; Fatal Outcome; Female; Fetal Death; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Heart-Assist Devices; Humans; Mitral Valve; Pregnancy; Warfarin

Topics: Anticoagulants; Cerebral Hemorrhage; Heart Valve Prosthesis; Humans; Risk Factors; Thromboembolism; Warfarin

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Aspirin; Cerebral Hemorrhage; Humans; Risk Factors; Vitamin E; Warfarin

A 53-year-old woman suffered intracranial hemorrhage from a cerebellar tumor several days after aortic valve replacement. Surgical intervention was not performed because the patient refused blood infusion for religious reasons (Jehovah's Witness). Instead, the anticoagulation therapy was interrupted for a week, and the patient was conservatively treated with administration of mannitol and steroid. The anticoagulation therapy was restarted 7 days after the hemorrhage. The intratumoral hemorrhage did not recur, and no systemic embolism occurred. The tumor was treated with gamma knife radiosurgery 6 weeks after the hemorrhage, under the radiological diagnosis of meningioma. Anticoagulation therapy is routinely used for patients following cardiac surgery to decrease the risk of thromboembolic complications, but also increases the risk of hemorrhagic events which often involve the central nervous system. Temporary discontinuation of anticoagulation therapy is an option for intratumoral hemorrhage in patients with replacement heart valves, and patients with known brain tumors should be informed about the risk of intracranial hemorrhage before cardiac surgery.

Topics: Adrenal Cortex Hormones; Anticoagulants; Aortic Valve; Aortic Valve Insufficiency; Cerebellar Neoplasms; Cerebral Hemorrhage; Cranial Fossa, Posterior; Female; Heart Valve Prosthesis Implantation; Heparin; Humans; Magnetic Resonance Imaging; Mannitol; Meningeal Neoplasms; Meningioma; Middle Aged; Postoperative Complications; Radiosurgery; Thromboembolism; Warfarin

Mechanical heart valves are associated with a risk of thromboembolism and anticoagulation is generally recommended. However, this is inevitably associated with a risk of intracranial bleeding. The case of a patient who sustained an intracranial bleed while taking warfarin for a prosthetic aortic valve and a further two intracranial bleeds while on heparin as an inpatient is discussed and the literature on the management of intracranial haemorrhage in patients on warfarin with prosthetic valves is reviewed.

Topics: Aged; Anticoagulants; Cerebral Hemorrhage; Heart Valve Prosthesis; Humans; Male; Thromboembolism; Warfarin

Topics: Brain Ischemia; Cerebral Hemorrhage; Humans; Stroke; Warfarin

Intracerebral hemorrhage (ICH) is the most feared complication of warfarin therapy. The pathogenesis of this often-fatal complication remains obscure. Cerebral amyloid angiopathy (CAA) is a major cause of spontaneous lobar hemorrhage in the elderly and is associated with specific alleles of the APOE gene.. To assess the role of CAA in warfarin-associated ICH.. Clinical characteristics and APOE genotype were compared between 41 patients with warfarin-related ICH (from a cohort of 59 consecutive patients aged > or = 65 years with supratentorial ICH on warfarin) and 66 randomly selected individuals aged > or = 65 years without ICH taking warfarin. In addition, all neuropathologic specimens from ICH patients were reviewed for the presence and severity of CAA.. Hemorrhages tended to be in the lobar regions of the brain, and most (76%) occurred with an international normalized ratio of < or = 3.0. The APOE epsilon2 allele was overrepresented among patients with warfarin-associated lobar hemorrhage (allele frequency 0.13 versus 0.04 in control subjects; p = 0.031). After controlling for other variables associated with ICH, carriers of the epsilon2 allele had an OR of 3.8 (95% CI, 1.0 to 14.6) for lobar ICH. CAA was pathologically diagnosed as the cause of lobar hemorrhage in 7 of 11 patients with available tissue samples.. CAA is an important cause of warfarin-associated lobar ICH in the elderly. Although diagnosis of CAA before hemorrhage is not yet possible, these data offer hope that future patients at high risk for hemorrhage may be identified before initiation of warfarin therapy.

Topics: Aged; Aged, 80 and over; Alleles; Apolipoproteins E; Cerebral Amyloid Angiopathy; Cerebral Hemorrhage; Female; Genotype; Humans; Male; Prospective Studies; Warfarin

The incidence of spontaneous intracranial haemorrhage has increased markedly in line with the increased use of oral anticoagulant agents. Recent guidelines for reversal of this acquired coagulation defect in an emergency have been established, but they are not adhered to in all centres. Our unit is referred between 20 and 60 patients per year (1994-1999) who are anticoagulated and require urgent neurosurgical intervention. In order to investigate this, we performed a prospective study using prothrombin complex concentrate (PCC). PCC was given to the first six patients with intracranial haemorrhage admitted to the neurosurgical unit requiring urgent correction of anticoagulation (Group 1) and compared with patients receiving standard treatment with fresh frozen plasma and vitamin K (Group 2). Mean International Normalised Ratios of Group 1 were 4.86 pretreatment and 1.32 posttreatment, and of Group 2 were 5.32 and 2.30, respectively. Results for complete reversal and reversal time were significant for PCC with p < 0.001. We recommend PCC for rapid and effective reversal of warfarin in life-threatening neurosurgical emergencies.

Topics: Adult; Aged; Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Emergencies; Female; Hematoma, Subdural; Humans; International Normalized Ratio; Male; Middle Aged; Pilot Projects; Preoperative Care; Prospective Studies; Subarachnoid Hemorrhage; Vitamin K; Warfarin

Complication rates of medical therapy for secondary stroke prevention derived from clinical trials may or may not be applicable to patients with cerebrovascular disease in the general population.. To determine complication rates for aspirin, warfarin, and intravenous heparin administered for secondary stroke prevention after first episodes of ischemic stroke, transient ischemic attack, or amaurosis fugax in a community.. Population-based historical cohort study.. Rochester, Minnesota.. All residents of Rochester who, between 1985 and 1989, received aspirin (n = 339) or warfarin (n = 145) within 2 years after first ischemic stroke, transient ischemic attack, or amaurosis fugax or received intravenous heparin (n = 201) within 2 weeks after first ischemic stroke, transient ischemic attack, or amaurosis fugax.. Occurrence of major complications caused by therapy.. Twenty aspirin-associated complications (1 fatal) occurred during an average 1.7 years of treatment, 8 warfarin-associated complications occurred during an average 0.7 years of treatment, and 3 heparin-associated complications (1 fatal) occurred during an average 5.1 days of treatment. Complication rates were 3.5 per 100 person-years (95% CI, 2.1 to 5.4) for aspirin, 7.9 per 100 person-years (CI, 3.4 to 15.6) for warfarin, and 0.30 (CI, 0.06 to 0.86) per 100 person-days for heparin. Rates of fatal complications were 0.2 per 100 person-years (CI, 0 to 1.0) for aspirin, 0 per 100 person-years (CI, 0 to 3.6) for warfarin, and 0.10 per 100 person-days (0 to 0.55) for heparin.. Complication rates for warfarin and intravenous heparin given as therapy for secondary stroke prevention in Rochester, Minnesota, were lower than rates reported from earlier trials and observational studies. However, complication rates for warfarin were higher than in more recent referral-based studies and multicenter randomized trials. After adjustment for duration of therapy, complication rates for heparin were higher than those for aspirin or warfarin. These rates can be used to judge the applicability of complication rates derived from ongoing clinical trials.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Aspirin; Cerebral Hemorrhage; Cerebrovascular Disorders; Cohort Studies; Drug Therapy, Combination; Female; Gastrointestinal Hemorrhage; Heparin; Humans; Infusions, Intravenous; Male; Warfarin

Topics: Animals; Aspirin; Brain Damage, Chronic; Brain Ischemia; Calcium Channel Blockers; Cerebral Hemorrhage; Cerebrovascular Circulation; Clinical Trials as Topic; Fibrinolytic Agents; Heparin; Heparin, Low-Molecular-Weight; Humans; N-Methylaspartate; Neuroprotective Agents; Platelet Aggregation Inhibitors; Reperfusion Injury; Rodentia; Thrombolytic Therapy; Warfarin

Most studies of oral anticoagulant-related bleeding have analyzed the incidence of adverse outcomes among patients with a variety of different conditions and without any comparison with a control group. We determined the incidence, time course, and risk factors associated with major bleeding after hospital discharge among patients with deep-vein thrombosis, and estimated the excess risk of bleeding associated with oral anticoagulant therapy.. A total of 22,000 adults were hospitalized in California for 3 or more days with a diagnosis of deep-venous thrombosis between January 1, 1992, and September 30, 1994. We determined the risk factors associated with readmission for bleeding. We compared the incidence of readmission for bleeding with comparison cohorts of patients with pneumonia or cellulitis who were matched for age, gender, race, and length of hospital stay.. Of 21,250 patients with deep-venous thrombosis who were discharged without bleeding, 1.4% were readmitted for bleeding within 91 days; the rate was 2.7 times greater in the first 30 days than in the next 61 days. Risk factors for bleeding included hospitalization with gastrointestinal bleeding during the previous 18 months (relative hazard [RH] = 2.6, 95% confidence interval [CI]: 1.6 to 4.1), hospitalization with an alcohol-related diagnosis during the previous 18 months (RH = 2.6, 95% CI: 1.4 to 4.8), chronic renal disease (RH = 2.4, 95% CI: 1.4 to 4.2), female gender (RH = 1.7, 95% CI: 1.3 to 2.2), presence of a malignancy (RH = 1.6, 95% CI: 1.2 to 2.2), nonwhite race (RH = 1.6, 95% CI: 1.2 to 2.1), and age over 65 years (RH = 1.3, 95% CI: 1.0 to 1.7). Significantly more women (n = 40) had intracranial bleeding than men (n = 18, P = 0.02). In the comparison cohorts, the incidence of readmission for bleeding within 3 months of discharge was 0.7%, and the relative risk (RR) of readmission was greater in those with deep-venous thrombosis than in those with cellulitis (RR = 2.0, 95% CI: 1.6 to 2.5) or pneumonia (RR = 2.0, 95% CI: 1.7 to 2.5).. The incidence of rehospitalization for bleeding was greatest in the first 30 days after discharge, and was approximately twice that seen in patients hospitalized for cellulitis or pneumonia. Further studies are needed to determine why women and nonwhite patients are at increased risk for anticoagulant-related bleeding.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; California; Cerebral Hemorrhage; Female; Hemorrhage; Hospitalization; Humans; Incidence; Male; Middle Aged; Multivariate Analysis; Patient Readmission; Proportional Hazards Models; Pulmonary Embolism; Risk; Venous Thrombosis; Warfarin

A 26-year-old woman suffered concomitant inferior vena cava, iliac, and femoral vein thrombosis and cerebral venous thrombosis. Ten days before symptom onset she had started using an oral contraceptive that contained low-dose ethynilestradiol and gestodene. Both protein C deficiency and protein C activated resistance were detected. To our knowledge, the association of cerebral, caval, and ilio-femoral-popliteal venous thrombosis has not been described previously. The severity of the clinical features could be a consequence of the two combined thrombophilic mechanisms and of the continuation of the oral contraceptive. A thrombophilic disorder should be considered in young patients with thromboembolic disease. Because of the high prevalence of the genetic deficiency causing protein C activated resistance, it is probably worthwhile to perform general screening before prescription of oral contraceptives.

Topics: Adult; Anticoagulants; Cerebral Hemorrhage; Cerebral Veins; Contraceptives, Oral, Hormonal; Contraceptives, Oral, Synthetic; Drug Resistance; Estradiol Congeners; Ethinyl Estradiol; Female; Femoral Vein; Follow-Up Studies; Humans; Iliac Vein; Intracranial Embolism and Thrombosis; Norpregnenes; Popliteal Vein; Prevalence; Progesterone Congeners; Protein C; Protein C Deficiency; Thrombosis; Vena Cava, Inferior; Warfarin

The risk factors affecting intracranial haemorrhage in warfarinised patients are described and an attempt made to calculate the risk of haemorrhage in warfarinised patients with minor head injuries. Using the data from studies of patients with spontaneous haemorrhage while taking warfarin, guidelines for treatment and given and the likely outcome predicted.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Craniocerebral Trauma; Emergency Service, Hospital; Female; Humans; Injury Severity Score; Male; Middle Aged; Prevalence; Prognosis; Risk Assessment; Survival Rate; Thromboembolism; Tomography, X-Ray Computed; United Kingdom; Warfarin

We report the first case in which a fluid-blood interface was identified at autopsy in a patient with acute intracerebral hematoma on anticoagulant therapy. Anticoagulation may be one of the major factors contributing to the production of an intracerebral blood sedimentation level.

Topics: Aged; Anticoagulants; Blood Sedimentation; Blood-Brain Barrier; Brain; Cerebral Hemorrhage; Fibrin; Heart Valve Prosthesis Implantation; Hematoma; Humans; Male; Mitral Valve Stenosis; Postoperative Complications; Warfarin

A number of clinical trials have shown the value of anticoagulating patients with nonrheumatic atrial fibrillation to prevent ischemic stroke. The purpose of this study was to assess the cost-effectiveness of anticoagulation in nonrheumatic atrial fibrillation with particular reference to the very elderly (aged >75 years) who have a higher incidence of bleeding events while undergoing anticoagulation.. We calculated the incremental costs per life-year gained for 4 base cases using efficacy data from the Boston Area Anticoagulation Trial for Atrial Fibrillation, the meta-analysis of the 5 nonrheumatic atrial fibrillation trials, cost data from a district general hospital, and review of the literature.. The cost per life-year gained free from stroke over 10 years ranged from -pound sterling 400.45 (ie, a resource saving achieved for each life-year gained free from stroke) to pound sterling 13,221.29. The results were most sensitive to alteration in the frequency of anticoagulation monitoring.. For medical and economic reasons, anticoagulation treatment in the prevention of ischemic stroke is justified. Although older patients are more at risk of adverse events, anticoagulation is more cost-effective in this group.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Brain Ischemia; Cerebral Hemorrhage; Cerebrovascular Disorders; Cost-Benefit Analysis; Humans; Longevity; Risk Assessment; Sensitivity and Specificity; Thrombosis; Warfarin

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Humans; Middle Aged; Warfarin

Topics: Age Factors; Aged; Body Mass Index; Cerebral Hemorrhage; Humans; Nutrition Disorders; Predictive Value of Tests; Risk Factors; Warfarin

Topics: Anticoagulants; Atrial Fibrillation; Cerebral Hemorrhage; Cerebrovascular Disorders; Humans; Malpractice; Office Visits; Warfarin

Topics: Anticoagulants; Cerebral Hemorrhage; Drug Therapy; Fatal Outcome; Humans; Medical History Taking; Medication Errors; Warfarin

Topics: Age Factors; Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Cerebral Hemorrhage; Cerebrovascular Disorders; Humans; Intracranial Embolism and Thrombosis; Myocardial Infarction; Platelet Aggregation Inhibitors; Warfarin

Topics: Adult; Anticoagulants; Caudate Nucleus; Cerebral Hemorrhage; Female; Humans; Rupture, Spontaneous; Sneddon Syndrome; Warfarin

Topics: Aged; Cerebral Amyloid Angiopathy; Cerebral Hemorrhage; Diagnosis, Differential; Fatal Outcome; Female; Humans; Radiography; Warfarin

Two cases of patients on warfarin who developed intracranial haematoma after an apparently minor head injury are described. There is a 10-fold increase in the likelihood of developing an intracranial haematoma in these patients. Recommendations are made regarding the management of this type of patient seen in the accident and emergency department.

Topics: Aged; Anticoagulants; Cerebral Hemorrhage; Craniocerebral Trauma; Emergency Service, Hospital; Female; Heart Diseases; Humans; Male; Risk Factors; Warfarin

A 30-year-old female whose mitral valve had been replaced with a mechanical prosthetic valve 23 years ago gave birth to a healthy baby by cesarian section under controlled anticoagulant therapy. Warfarin was replaced with intravenous heparin just one week before cesarian section and heparin administration was stopped several hours prior to the operation which was successfully carried out without excessive blood loss. Although warfarin carries a risk of teratogenecity, fortunately, the baby had not any somatic malformation. We believe that pregnancy is not contraindicated in patients with mechanical prosthetic heart valves, however, a strict observation of the cardiac function during middle and late trimesters of gestation by echocardiography and planned anticoagulant therapy are necessary in order to prevent maternal congestive heart failure and thromboembolism and protect a neonate against intracranial hemorrhage.

Topics: Adult; Biomarkers; Blood Coagulation Factors; Cerebral Hemorrhage; Cesarean Section; Echocardiography; Female; Fibrinolytic Agents; Heart Failure; Heart Valve Prosthesis; Heparin; Humans; Infant, Newborn; Mitral Valve Insufficiency; Monitoring, Physiologic; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Complications, Hematologic; Pregnancy Outcome; Thromboembolism; Thrombolytic Therapy; Warfarin

Common indices for the quantal assessment of treatment efficacy are reviewed. The absolute risk reduction is a practical index for public health considerations. Its reciprocal has been termed the 'Number Needed to Treat' (NNT), representing the health effort that must on average be expended to accomplish one tangible treatment target. We extend the NNT to evaluate outcome combinations of treatment benefits versus treatment harms.. We describe the mathematical context of the NNT, and extend it to evaluate outcome combinations (treatment success/failure with/without treatment-induced adverse effects) in a treated population. These extensions are carried out assuming either independence or positive association between treatment benefit and treatment harm. A method is provided for calculating the standard errors of these extended NNT values. Applications to cost-effectiveness analysis are discussed.. We calculate NNT in three recent therapeutic studies. The results of a trial of the prevention of strokes with warfarin in patients with non-valvular atrial fibrillation are analysed to evaluate treatment success (stroke prevention) against treatment-induced bleeds. An NNT-related cost-benefit analysis is also carried out. We also analyse the results of a study of two modalities of chemotherapeutic treatment in small-cell lung cancer, and of two modalities of surgical intervention in the treatment of cholelithiasis.. The NNT are useful in direct evaluation of outcome-specific treatment benefits versus treatment-induced harms. They may also be used in cost-effectiveness analyses and are helpful in guiding public health programmes towards the identification of optimal treatment strategies.

Topics: Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Carcinoma, Small Cell; Cerebral Hemorrhage; Cerebrovascular Disorders; Cholecystectomy; Clinical Protocols; Cost-Benefit Analysis; Decision Support Techniques; Evaluation Studies as Topic; Health Care Costs; Humans; Models, Theoretical; Postoperative Complications; Quality-Adjusted Life Years; Sweden; Therapeutics; Treatment Failure; Treatment Outcome; Warfarin

Four patients with prosthetic heart valves suffered intracranial hemorrhage (cerebral hemorrhage in one patient, cerebellar hemorrhage in one, and chronic subdural hematoma in two) during long-term oral anticoagulant drug therapy (warfarin). In all patients, warfarin was discontinued and its effect neutralized by vitamin K, then surgery was performed after the thrombotest value exceeded 50%. No uncontrollable bleeding occurred at surgery. Warfarin was discontinued until 3-7 days postoperatively. Intravenous heparin administration was used to prevent embolic complications and the dose was modified based on the activated clotting time measured at the bedside. One patient, who could not receive heparin administration because of massive bleeding, developed myocardial infarction due to coronary artery thromboembolism 2 days after operation and died 4 days later. The other patients received heparin administration and were alive and well at the most recent follow-up examinations. Heparin administration monitored by activated clotting time is a useful method to prevent embolic and bleeding complications in the surgical treatment of intracranial hemorrhage in patients with prosthetic heart valves receiving long-term anticoagulant therapy.

Topics: Cerebral Hemorrhage; Child; Chronic Disease; Heart Valve Prosthesis; Hematoma, Subdural; Humans; Male; Middle Aged; Time Factors; Warfarin

An increased referral of patients with anticoagulation related haemorrhages necessitated an analysis of causes and outcome of these complications in a patient group that reflected Swedish therapeutic traditions of anticoagulation treatment. Prospectively, all patients from Stockholm evaluated for warfarin related intracranial haemorrhage occurring during 1987 were analysed and their 6 month outcome recorded. Sixty-eight patients were included. The results of intracranial haemorrhagic complications were catastrophic with a 77% mortality rate. Their incidence was much higher than expected. Forty-one patients had non-traumatic intracerebral haematomas, 1 had a non-traumatic subarachnoid haemorrhage and 26 had traumatic injuries. In the 42 patients with non-traumatic haemorrhages, the indications for anticoagulation were cerebral ischaemic events in a majority (27/42). The remaining 15 patients had different indications for anticoagulation. They also had an increased frequency of hypertension (p < 0.05). In the 26 patients with traumatic haematomas, only 6/26 patients had previous cerebral ischaemic injuries (p < 0.01). Valvular heart prosthesis was their most common indication (11/26) for anticoagulation. Caution in instituting anticoagulation therapy in patients with hypertension or cerebrovascular disease, which is an important indication for anticoagulation in Sweden, is mandatory. Adherence to strict treatment regimens and their continuous reevaluation may help to avoid complications. The finding of more patients than expected with haemorrhagic complications is not compatible with the risk evaluations used to justify anticoagulation therapy in the patient groups studied. Clinical practice must have changed with time, showing that risk evaluations from controlled trials or retrospectively collected clinical data from selected patients are not necessarily applicable for long-term clinical practice.

Topics: Adult; Aged; Brain; Cerebral Hemorrhage; Female; Heart Diseases; Heart Valve Prosthesis; Humans; Male; Prospective Studies; Survival Rate; Sweden; Warfarin

Intracranial hemorrhage may be a particularly devastating complication of anticoagulant therapy. Very few accounts have reported data on the duration of anticoagulant discontinuation following intracranial hemorrhage or the intensity of anticoagulation during treatment for it, although we must adequately manage such a complication.. We analyzed the management of warfarin-related intracranial hemorrhages in 27 patients with cardiac diseases. We evaluated the degree of anticoagulation using the thrombotest. Anticoagulants were stopped as soon as the diagnosis of intracranial hemorrhage was established by computed tomographic scan.. Mechanical valve prosthesis patients, who required intensive long-term anticoagulant therapy, constituted the majority of our series (74.1%). Intraoperative hemostasis was brought under control despite low thrombotest values (13%-68%) at the time of surgery except for the acute subdural hematoma (SDH) patients with cerebral contusion. Early resumption of anticoagulant therapy (within 3 days) did not cause intracranial rebleeding in any operative patient. All the chronic SDH patients and some of the subcortical hematoma patients had a good outcome. All three patients with acute SDH and contusion, however, had a fatal outcome because of intracranial rebleeding within a short period of time or ineffective intraoperative hemostasis.. The patients with anticoagulant-related intracranial hemorrhage may undergo surgery with thrombotest values approximately between 20% and 60%, and anticoagulants can be resumed after an interval of 3 days. Aggressive surgery should particularly be performed in patients with anticoagulation-related chronic SDH or subcortical hemorrhage, as in the cases of anticoagulant-unrelated intracranial hemorrhage.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Cerebral Hemorrhage; Child; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Retrospective Studies; Ticlopidine; Tomography, X-Ray Computed; Warfarin

Topics: Aged; Aspirin; Atrial Fibrillation; Cerebral Hemorrhage; Cerebrovascular Disorders; Humans; Warfarin

Topics: Aged; Atrial Fibrillation; Cerebral Hemorrhage; Cerebrovascular Disorders; Humans; Incidence; Warfarin

To explore the rational use of anticoagulants, especially among the elderly, balancing antithrombotic efficacy and risk for hemorrhage. Previous prospective studies have not provided powerful assessments of risk factors for intracranial hemorrhage, the dominant complication in reversing the anticoagulant decision.. Case-control analysis.. A large general hospital and its anticoagulant therapy unit.. 121 consecutive adult patients taking warfarin who were hospitalized with intracranial hemorrhage were each matched to three contemporaneous controls randomly selected from among outpatients managed by our hospital anticoagulant therapy unit.. 77 patients had intracerebral hemorrhage (46% fatal) and 44 had subdural hemorrhage (20% fatal). The prothrombin time ratio (PTR) was the dominant risk factor for intracranial hemorrhage. For each 0.5 increase in PTR over the entire range, the risk for intracerebral hemorrhage doubled (odds ratio, 2.1; 95% CI, 1.4 to 2.9). For subdural hemorrhage, the risk was unchanged over the PTR range from 1.0 to 2.0 but rose dramatically above a PTR of 2.0 (approximate international normalized ratio, 4.0). Age was the only other significant independent risk factor for subdural hemorrhage (odds ratio, 2.0 per decade; CI, 1.3 to 3.1). For intracerebral hemorrhage, age was of borderline significance (odds ratio, 1.3 per decade; CI, 1.0 to 1.6) after controlling for PTR and the two other independent risk factors: history of cerebrovascular disease (odds ratio, 3.1; CI, 1.7 to 5.6) and presence of a prosthetic heart valve (odds ratio, 2.8; CI, 1.3 to 5.8).. The results emphasize the importance of maintaining the prothrombin time ratios under 2.0 and the need for especially careful use of warfarin in the elderly.

Topics: Aged; Aged, 80 and over; Ambulatory Care; Case-Control Studies; Cerebral Hemorrhage; Female; Hematoma, Subdural; Humans; Male; Middle Aged; Prothrombin Time; Risk Factors; Statistics as Topic; Warfarin

A case of intercerebral hematoma due to warfarin-induced coagulopathy is presented. The 39-year-old woman had spread a warfarin-type rat poison around her house weekly using her bare hands, with no washing post application. Percutaneous absorption of warfarin causing coagulopathy, reported three times in the past, is a significant risk if protective measures, such as gloves, are not used. An adverse drug interaction with piroxicam, which she took occasionally, may have exacerbated the coagulopathy.

Topics: Administration, Cutaneous; Adult; Cerebral Hemorrhage; Drug Interactions; Female; Humans; Piroxicam; Poisoning; Rodenticides; Warfarin

Topics: Cerebral Hemorrhage; Cerebral Ventricles; Female; Fetal Diseases; Humans; Pregnancy; Pregnancy Complications, Cardiovascular; Ultrasonography, Prenatal; Warfarin

We have described two cases of spontaneous intracerebral hematoma, characterized by sedimentation level seen on unenhanced cerebral CT, in patients receiving anticoagulation therapy. Anticoagulation or coagulopathy may be important in producing sedimentation levels. The "sedimentation level" is a more accurate term than the commonly used "blood-fluid level" or "hematocrit effect."

Topics: Aged; Body Fluids; Cerebral Hemorrhage; Fatal Outcome; Hematocrit; Hematoma; Hemoglobins; Humans; Male; Middle Aged; Rheumatic Heart Disease; Thrombophlebitis; Tomography, X-Ray Computed; Warfarin

Cerebral hemorrhagic infarction visualized on CT, secondary to embolic stroke in an anticoagulated individual, is usually associated with clinically stable or improving neurologic signs; fear of transforming the hemorrhagic infarction into a hematoma, however, usually prompts cessation of anticoagulation until the blood has cleared on CT, despite the recognized risk of recurrent embolism during this non-anticoagulated period. We now report our experience with 12 patients with hemorrhagic infarction who remained anticoagulated. Eleven men and one woman, ages 33 to 77, developed hemorrhagic infarction while on heparin, warfarin, or both, for prevention of recurrent embolism. Patients were either continued on uninterrupted anticoagulation from stroke onset (n = 6), or anticoagulation was withheld for several days and then resumed (n = 4), or it was withheld for 5 and 14 days (n = 2) after stroke onset and then continued uninterrupted despite the CT appearance of hemorrhagic infarction. Eleven patients had a definite cardioembolic source for stroke (atrial fibrillation, seven; ventricular thrombus, two; and ventricular dyskinesia, two). One patient had carotid occlusion with local intra-arterial embolism. Hemorrhagic infarcts varied in size and were located in the middle cerebral artery territory in 11 patients and posterior cerebral artery territory in one. All patients remained clinically stable or improved on anticoagulation. Serial CTs showed fading hemorrhagic areas. When the risk of recurrent embolism is high, anticoagulation may be safely used in some patients with hemorrhagic infarction.

Topics: Adult; Aged; Brain; Cerebral Hemorrhage; Cerebral Infarction; Female; Heparin; Humans; Male; Middle Aged; Tomography, X-Ray Computed; Warfarin

Two cases of intracerebral hemorrhage in patients with prosthetic heart valves receiving anticoagulant therapy without preceding embolic cerebral infarction are reported. Phytonadione and fresh frozen plasma were immediately given, and the intracerebral hematoma evacuated successfully. In one case, intractable bleeding occurred perioperatively until the thrombotest value reached 40% or more. This patient later developed fatal massive multiple intracerebral hemorrhages.

Topics: Adolescent; Cerebral Hemorrhage; Heart Valve Prosthesis; Hematoma; Humans; Incidence; Male; Middle Aged; Postoperative Complications; Prothrombin Time; Risk Factors; Warfarin

Cerebral dural sinus thrombosis is an unusual syndrome in which a patient presents with a severe headache that may be associated with diverse neurologic and physical findings. The case of a 31-year-old woman with headache, vomiting, generalized tonic-clonic seizure, and subsequent dense hemiplegia is presented. The patient was diagnosed as having a cerebral dural sinus thrombosis, but only after the diagnosis was missed initially. The syndrome may be difficult to detect because it can mimic several other entities. There are several known or suspected predisposing factors. The syndrome, diagnostic modalities, and therapeutic options are reviewed.

Topics: Adult; Cerebral Hemorrhage; Contraceptives, Oral; Diagnosis, Differential; Female; Headache; Hemiplegia; Heparin; Humans; Magnetic Resonance Imaging; Mannitol; Phenytoin; Seizures; Sinus Thrombosis, Intracranial; Tomography, X-Ray Computed; Warfarin

We examined a series of 200 consecutive patients with spontaneous intracerebral hematoma clinically and by computed tomography, excluding patients with trauma, aneurysm, or tumor. Hematoma volume varied from 1 to 230 (average 35) ml, and overall mortality was 30% (60 patients). Of the 200 patients, 14% (28) were receiving anticoagulants; among these 28 patients hematoma volume averaged 72 ml and mortality 57% (16 patients). The 140 survivors were followed for 2-24 months. Our findings indicate that anticoagulation therapy after previous cerebral infarction or embolism of cardiogenic origin did not predispose to intracerebral hemorrhage. Prognosis was poor when the initial level of consciousness was low and the hematoma volume exceeded 50 ml in combination with dilatation of the contralateral ventricle. An intracerebral hematoma of greater than 80 ml volume was always fatal, regardless of therapy. With volumes of 40-80 ml, early surgical evacuation of the lobar hematoma may improve outcome.

Topics: Adult; Aged; Aged, 80 and over; Cerebral Hemorrhage; Female; Hematoma; Humans; Male; Middle Aged; Prognosis; Tomography, X-Ray Computed; Warfarin

Cerebral haemorrhage in anticoagulated patients with mechanical valvular prosthesis poses an uncommon but difficult management problem. Four such patients are presented: one patient had delayed haemorrhagic transformation of a preexisting cerebral infarct, one probably had de novo haemorrhage complicating hypertension and in two patients cerebral haemorrhage was associated with excessive anticoagulation. Conservative management including the use of fresh frozen plasma, delayed heparinisation and warfarinisation was used. Both patients with anticoagulant overdose died as a result of extensive haemorrhage despite the drainage of cerebellar haematoma in one patient. The remaining two patients survived with minimal neurological deficits. Diagnosis of the underlying cause of cerebral haemorrhage, and the timing of heparinisation and anticoagulation are discussed.

Topics: Adult; Aged; Cerebral Hemorrhage; Cerebral Infarction; Echocardiography, Doppler; Female; Heart Valve Prosthesis; Humans; Male; Middle Aged; Mitral Valve; Rheumatic Heart Disease; Tomography, X-Ray Computed; Warfarin

Hemorrhagic cerebral embolism should not be considered an absolute contraindication to immediate low-dose systemic anticoagulation. Low levels of anticoagulation may give some protection from recurrent embolism while minimizing the risks of intracranial bleeding. Until further studies are available, these decisions must be made on a case-by-case basis, supported by limited scientific information.

Topics: Anticoagulants; Cerebral Hemorrhage; Contraindications; Heparin; Humans; Intracranial Embolism and Thrombosis; Male; Middle Aged; Tomography, X-Ray Computed; Warfarin

We investigated incidence, age distribution in relation to etiology, and localization of spontaneous intracerebral hematoma in 100 consecutive cases. Incidence in the total population of the Giessen area was estimated to be greater than 11/100,000 inhabitants/yr and increased with age. There was a trend toward higher incidence in males. Overall mortality was 27%, 22% of 58 patients aged less than 70 years and 33% of 42 patients aged greater than or equal to 70 years. Hypertensive putaminal hematoma showed the highest mortality rate (42%, 10 of 24 cases). Chronic alcoholism and anticoagulant medication influenced the mortality rate unfavourably. We found the following localizations and etiologies to have a specific relation with age: 1) lobar hematomas from vascular malformations, group aged less than 40 years; 2) hypertensive putaminal hematomas and hypertensive thalamic hematomas, group aged 40-69 years; and 3) lobar hematomas, group aged greater than or equal to 70 years. Alcoholism was an additional factor in 38% of the 13 middle-aged men with hypertensive putaminal hematomas. Fourteen cases of spontaneous intracerebral hematoma were possibly due to cerebral amyloid angiopathy. Six of these 14 patients had recurrent lobar hematomas, but only three of the six could be histologically investigated. In these three cases, cerebral amyloid angiopathy was proven.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Alcoholism; Cerebral Hemorrhage; Female; Germany; Hematoma; Humans; Hypertension; Incidence; Male; Middle Aged; Sex Characteristics; Warfarin

Pregnant Sprague-Dawley rats were given daily oral doses of sodium warfarin (100 mg/kg) and concurrent intramuscular injections of vitamin K1 (10 mg/kg). This dosing regimen did not have any apparent deleterious effect on the dams and did not affect the fetuses when administered from day 1 to day 12 of pregnancy. However, similar treatment from day 9 to 20 caused hemorrhage in the fetuses examined on day 21 of gestation. There were no hemorrhages in the control fetuses from dams receiving vitamin K1 only. The lowest effective dose of warfarin, in conjunction with daily doses of vitamin K1, was 3 mg/kg. This dose caused hemorrhage in 28% of fetuses; the incidence of affected fetuses was not further increased by doses of warfarin up to 100 mg/kg. Hemorrhages affected the fetal brain, face, eyes, and ear and occasionally the limbs. Brain hemorrhages were frequently intraventricular and caused various degrees of hydrocephaly. Bony defects were not a feature of prenatal exposure to warfarin. These results show that prenatal exposure of the rat to warfarin and vitamin K duplicates the hemorrhagic abnormalities and pathology associated with prenatal exposure to warfarin in the human. It did not induce bony or facial defects probably because the vitamin K-dependent components of bone development occur postnatally in the rat. This model should allow detailed determination of the role of vitamin K-dependent proteins in development.

Topics: Animals; Bone and Bones; Cerebral Hemorrhage; Female; Fetal Diseases; Maternal-Fetal Exchange; Pregnancy; Rats; Rats, Inbred Strains; Teratogens; Vitamin K 1; Warfarin

To determine the incidence of major bleeding in outpatients treated with warfarin and to identify predictive factors known at the start of therapy.. The records of 565 patients starting outpatient therapy with warfarin upon discharge from a university hospital were reviewed. Follow-up information was obtained for 562 patients (99.5%). Bleeding was classified as major or minor using explicit criteria. The cumulative incidence of bleeding was estimated by means of survival analysis. Independent risk factors for major bleeding were identified using Cox regression analysis in 375 randomly chosen patients; they were tested in the remaining 187 patients.. Major bleeding occurred in 65 patients (12%) and was fatal in 10 patients (2%). The cumulative incidences of major bleeding at one, 12, and 48 months were 3%, 11%, and 22%, respectively. The monthly risk of major bleeding decreased over time, from 3% during the first month of outpatient therapy to 0.3% per month after the first year of therapy. Five independent risk factors for major bleeding--age 65 years or greater, history of stroke, history of gastrointestinal bleeding, a serious comorbid condition (recent myocardial infarction, renal insufficiency, or severe anemia), atrial fibrillation--predicted major bleeding in the testing group; the cumulative incidence of major bleeding at 48 months was 2% in 57 low-risk patients, 17% in 110 middle-risk patients, and 63% in 20 high-risk patients.. These findings provide a quantitative basis for evaluating the risk of major bleeding in individual patients at the start of outpatient therapy with warfarin. Whether the risk of bleeding can be reduced in high-risk patients without reducing the benefit of therapy remains to be determined.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ambulatory Care; Cerebral Hemorrhage; Cohort Studies; Follow-Up Studies; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Middle Aged; Risk Factors; Warfarin

The primary risk of anticoagulant therapy in cardiac embolic stroke is hemorrhage--particularly cerebral hemorrhage in the elderly. Improving the benefit/risk ratio for indicated anticoagulation involves consideration of the following: hemostatic competence, blood pressure, drug interactions, falls, interval surgery, diet, aspirin and last but not least, the intensity of anticoagulant prophylaxis. For the present it would be prudent to limit heparin administration to a low-dose regimen not exceeding 20,000 units/24 hours and warfarin maintenance to a low-dose prothrombin time ratio of 1.5.

Topics: Accidental Falls; Aged; Anticoagulants; Cerebral Hemorrhage; Diet; Drug Interactions; Hemodynamics; Heparin; Humans; Risk; Surgical Procedures, Operative; Warfarin

We reviewed the experience with infective endocarditis at some major US Army Medical Centers. One hundred patients were studied, comparing 82 patients who had native valve endocarditis (NVE) with 18 patients who had prosthetic valve endocarditis (PVE). Among patients with PVE, four had porcine valves and 14 had synthetic. None of the patients with NVE had received anticoagulants; 14 of 18 patients with PVE had received anticoagulants. The major causes of death were central nervous system hemorrhage, congestive heart failure, uncontrolled infection, and embolic phenomena. The principal cause of death in patients with PVE was CNS hemorrhage. Of the patients with PVE, 36% had symptomatic cerebral hemorrhage while receiving anticoagulants and 80% of them died.

Topics: Anti-Bacterial Agents; Anticoagulants; Aortic Valve; Cerebral Hemorrhage; Drug Evaluation; Endocarditis, Bacterial; Heart Failure; Heart Valve Prosthesis; Humans; Mitral Valve; Postoperative Complications; Premedication; Prothrombin Time; Retrospective Studies; Thromboembolism; Warfarin

The purpose of this investigation was to analyze the thromboembolic and/or major bleeding complications of 124 consecutive but nonrandomized patients who had only mitral valve replacement with the Hancock porcine xenograft between September, 1974 and June, 1979. These patients were treated either with or without anticoagulants. Four basic study groups were created: Group 1, warfarin; Group 2, aspirin; Group 3, no anticoagulants; and Group 4, warfarin and aspirin. Group 5 combined Groups 1 and 4 (warfarin and warfarin plus aspirin) and Group 6 combined Groups 2 and 3 (aspirin and no anticoagulants). The cardiac rhythm, history of embolism, and intraoperative findings of a thrombus in the left atrium were examined as risk factors for later thromboembolism . Follow-up time was 3.03 years (range 2.0 to 4.2 years). The embolic rate was not significantly different in any group (n = NS). In Groups 5 and 6 the embolic rate was 2.97 and 3.25 embolisms per 100 patient-years, respectively. Warfarin therapy resulted in significant major bleeding episodes, including two deaths (p less than 0.05). The number of patients with a history of a previous embolism, the finding of an intraoperative left atrial thrombus, or abnormal cardiac rhythm was insufficient to test embolic risk in the four treatment groups. We conclude that long-term warfarin therapy increases the risk of bleeding complications but may not significantly influence the incidence of thromboembolism arising from the Hancock porcine xenograft mitral valve. Other and larger studies are needed to confirm this last point.

Topics: Adult; Aged; Aspirin; Bioprosthesis; Cerebral Hemorrhage; Female; Gastrointestinal Hemorrhage; Heart Valve Prosthesis; Humans; Male; Middle Aged; Mitral Valve; Postoperative Complications; Risk; Thromboembolism; Warfarin

Among 54 consecutive patients with acute nonseptic embolic brain infarction, there was CT evidence of hemorrhagic infarction in 1 patient (2%). None had clinical or CT evidence of massive brain hemorrhage even when anticoagulation therapy was used immediately. Seven patients (13%) had recurrent brain emboli, all within 7 days of the initial stroke. None of these patients was adequately anticoagulated at the time of recurrence. Immediate anticoagulation therapy should be employed after nonseptic embolic brain infarction if CT does not show hemorrhage and there is a persistent cardiac source of emboli.

Topics: Cerebral Hemorrhage; Cerebral Infarction; Female; Heart Diseases; Heparin; Humans; Intracranial Embolism and Thrombosis; Male; Middle Aged; Recurrence; Tomography, X-Ray Computed; Warfarin

Topics: Aged; Cerebral Hemorrhage; Drug Synergism; Female; Humans; Phenylbutazone; Warfarin

Topics: Adult; Aged; Brain; Brain Neoplasms; Cerebral Hemorrhage; Female; Glioma; Humans; Infarction; Intracranial Aneurysm; Intracranial Arteriovenous Malformations; Male; Middle Aged; Tomography, X-Ray Computed; Warfarin

Two mothers with heart valve prosthesis were treated with warfarin during pregnancy. In the first case a caesarean section was done one week after replacement of warfarin with heparin. The baby died of cerebral and pulmonary hemorrhage. The second mother had a male infant by caesarean section. The baby showed warfarin-induced embryopathy with nasal hypoplasia and stippled epiphyses (chondrodysplasia punctata). Nasal hypoplasia with or without stippled epiphyses has now been reported in 11 infants born to mothers treated with warfarin during the first trimester, and a causal association is probable. In view of the risks to both mother and fetus in women with prosthetic cardiac valves it is recommended that therapeutic abortion be advised as the first alternative.

Topics: Abnormalities, Drug-Induced; Adult; Cerebral Hemorrhage; Cesarean Section; Chondrodysplasia Punctata; Female; Fetus; Heart Valve Prosthesis; Hemorrhage; Heparin; Humans; Infant, Newborn; Infant, Newborn, Diseases; Lung Diseases; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications, Cardiovascular; Warfarin

Topics: Adult; Aged; Angiography; Brain Edema; Cerebral Hemorrhage; Cerebral Ventriculography; Corpus Striatum; Diagnosis, Computer-Assisted; Female; Hematoma; Humans; Hypertension; Infant, Newborn; Infant, Newborn, Diseases; Intracranial Arteriovenous Malformations; Male; Phlebitis; Thalamus; Tomography, X-Ray; Warfarin

Topics: Adolescent; Adult; Aortic Valve Insufficiency; Atrial Fibrillation; Cerebral Hemorrhage; Child; Death, Sudden; Endocarditis, Bacterial; Female; Follow-Up Studies; Heart Valve Diseases; Heart Valve Prosthesis; Humans; Male; Middle Aged; Mitral Valve Insufficiency; Mitral Valve Stenosis; Myocardial Infarction; Postoperative Complications; Thromboembolism; Tricuspid Valve Insufficiency; Warfarin

Topics: Anticoagulants; Aortic Valve; Aspirin; Cerebral Hemorrhage; Heart Valve Diseases; Heart Valve Prosthesis; Hemorrhage; Humans; Mitral Valve; Prosthesis Design; Thromboembolism; Tricuspid Valve; Warfarin

Topics: Cerebral Angiography; Cerebral Hemorrhage; Humans; Intracranial Aneurysm; Male; Middle Aged; Rupture; Vitamin K 1; Warfarin

Topics: Aged; Blood Pressure Determination; Brain Abscess; Brain Neoplasms; Cerebral Hemorrhage; Dicumarol; Female; Follow-Up Studies; Hematoma, Subdural; Humans; Intracranial Embolism and Thrombosis; Male; Prothrombin Time; Warfarin

Topics: Cerebral Angiography; Cerebral Hemorrhage; Hematoma; Hematoma, Subdural; Humans; Intracranial Hemorrhages; Neurosurgery; Neurosurgical Procedures; Toxicology; Warfarin

Topics: Angiography; Anticoagulants; Blood Coagulation Disorders; Cerebral Hemorrhage; Deoxyribonuclease I; Drug Therapy; Fibrinogen; Heparin; Intracranial Embolism; Intracranial Embolism and Thrombosis; Streptodornase and Streptokinase; Streptokinase; Stroke; Thrombosis; Toxicology; Warfarin

Topics: Abortion, Induced; Angiography; Anticoagulants; Cerebral Hemorrhage; Drug Therapy; Female; Femoral Vein; Heparin; Humans; Iliac Vein; Infant, Newborn; Infant, Premature, Diseases; Pregnancy; Pregnancy Complications; Pregnancy Complications, Cardiovascular; Pulmonary Embolism; Thrombectomy; Thrombophlebitis; Vascular Surgical Procedures; Venous Thrombosis; Warfarin