phenprocoumon and Cerebral-Hemorrhage

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

In numerous situations stroke physicians face a lack of evidence during their daily practice. In this report the authors address some of the difficult treatment decisions encountered in acute therapy and secondary prevention. Examples include off-label thrombolysis and prevention in high-risk situations. The available data from trials and registries are discussed, and personal views and recommendations are expressed.

Topics: Age Factors; Aged; Aged, 80 and over; Antihypertensive Agents; Atrial Fibrillation; Blood Glucose; Cerebral Hemorrhage; Clinical Trials as Topic; Diagnosis, Differential; Endarterectomy, Carotid; Epilepsy; Evidence-Based Medicine; Humans; Hypertension; International Normalized Ratio; Off-Label Use; Phenprocoumon; Platelet Aggregation Inhibitors; Registries; Risk Factors; Secondary Prevention; Stroke; Survival Analysis; Thrombolytic Therapy; Treatment Outcome

Rapid reversal of the anticoagulatory effect of vitamin K antagonists represents the primary emergency treatment for oral anticoagulant-related intracerebral hemorrhage (OAC-ICH). Predicting the amount of prothrombin complex concentrate (PCC) needed to reverse OAC in individual patients is difficult, and repeated international normalized ratio (INR) measurements in central laboratories (CLs) are time-consuming. Accuracy and effectiveness of point-of-care INR coagulometers (POCs) for INR reversal in OAC-ICH have not been evaluated.. In phase 1, the agreement of emergency POC and CL INR measurements was determined. In phase 2, stepwise OAC reversal was performed with PCC using a predetermined dosing schedule. Concordance of POC and CL INR measurements during reversal and time gain due to POC were determined.. In phase 1 (n = 165), Bland-Altman analysis showed close agreement between POCs and CLs (mean INR deviation 0.04). In phase 2 (n = 26), POCs caused a median initial net time gain of 24 minutes for the start of treatment with PCC. Median time for POC-documented complete OAC reversal was 28 minutes, compared with 120 minutes for CLs. Bland-Altman analysis between POCs and CLs revealed a mean INR deviation of 0.13 during stepwise PCC administration. POCs tended to slightly overestimate the INR, especially at higher INR levels. Remarkably, POC-guided reversal led to a median reduction of 30.5% of PCC dose compared with the a priori dose calculation. Hematomas enlarged in 20% of patients.. POC INR monitoring is a fast, effective, and economic means of PCC dose-titration in OAC-ICH. Larger studies examining the clinical efficacy of this procedure are warranted.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Factors; Cerebral Hemorrhage; Female; Follow-Up Studies; Hematoma; Humans; International Normalized Ratio; Male; Phenprocoumon; Prospective Studies; Time Factors; Treatment Outcome

Death due to pulmonary embolism caused by thrombosis formation along a pacing wire has been reported in patients with antibradycardia pacemakers. The purpose of this prospective and randomized study was to evaluate the effects of prophylactically assigned aspirin (100 mg per day) or phenprocoumon (a coumarin derivative) on the incidence of right-sided thromboembolic complications associated with transvenous defibrillation leads. Multiplane transoesophageal echocardiography and pulmonary scintigraphy were performed in 62 consecutive patients immediately and 6 +/- 2 months after transvenous defibrillator implantation. Aspirin or phenprocoumon was administered to the patients in a randomized and parallel manner. By means of multiplane transoesophageal echocardiography and pulmonary scintigraphy no thromboembolic events were observed immediately after transvenous defibrillator implantation. After 6 +/- 2 months, however, multiplane transoesophageal echocardiography disclosed thrombi on the transvenous leads in 13 of 62 patients (21%) despite antithrombotic therapy. At the same time, pulmonary scintigraphy did not reveal any defects compatible with pulmonary embolism. Although thrombi occurred in only four patients treated with phenprocoumon, but in nine patients receiving aspirin, this difference was statistically insignificant. Other variables associated with the occurrence of thrombosis formation were not identified. One fatal intracranial haemorrhage occurred in the phenprocoumon group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aspirin; Blood Coagulation Tests; Cerebral Hemorrhage; Defibrillators, Implantable; Dose-Response Relationship, Drug; Drug Administration Schedule; Echocardiography; Electrodes, Implanted; Equipment Failure; Female; Follow-Up Studies; Humans; Male; Middle Aged; Phenprocoumon; Prospective Studies; Thromboembolism

Secondary intracerebral hemorrhage (sICH) is a potentially serious complication of ischemic stroke, in particular under concomitant oral anticoagulation. Previous studies in murine stroke models defined a novel vascular repair function of hematogenous monocytes/macrophages (MO/MP), which proved essential for the prevention of oral anticoagulation-associated sICH. Here, we addressed the question whether hyperglycemia as a clinically relevant prohemorrhagic risk factor and peroxisome proliferator-activated receptor gamma (PPARγ) activation affect MO/MP differentiation and the risk of sICH after ischemic stroke.. Oral anticoagulation-associated sICH was induced by phenprocoumon feeding to mice undergoing transient middle cerebral artery occlusion. Hyperglycemia was induced by streptozotocin treatment. The role of PPARγ-dependent MO/MP differentiation was addressed in mice with myeloid cell-specific PPARγ-knockout (LysM-PPARγ(KO)). Pharmacological PPARγ activation via pioglitazone was tested as a treatment option.. Hyperglycemic mice and normoglycemic LysM-PPARγ(KO) mice exhibited abnormal proinflammatory skewing of their hematogenous MO/MP response and abnormal vascular remodeling in the infarct border zone, leading to an increased rate of oral anticoagulation-associated sICH. Pharmacological PPARγ activation in hyperglycemic mice corrected the inflammatory response toward an anti-inflammatory profile, stabilized neovessels in the infarct border zone, and reduced the rate of sICH. This preventive effect was dependent on the presence of macrophages, but independent from effects on blood glucose levels.. Hyperglycemia and macrophage-specific PPARγ activation exert opposing effects on MO/MP polarization in ischemic stroke lesions and, thereby, critically determine the risk of hemorrhagic infarct transformation.

Topics: Animals; Anticoagulants; Cell Polarity; Cerebral Hemorrhage; Diabetes Mellitus, Experimental; Disease Models, Animal; Gene Expression Profiling; Hyperglycemia; Hypoglycemic Agents; Infarction, Middle Cerebral Artery; Inflammation; Inflammation Mediators; Macrophages; Mice; Mice, Knockout; Monocytes; Neovascularization, Physiologic; Phenprocoumon; Pioglitazone; PPAR gamma; Risk Factors; Thiazolidinediones; Vascular Remodeling

For patients who survive intracerebral haemorrhage (ICH) during treatment with oral anticoagulation (OAC), the balance between the benefits and risks of restarting OAC is unclear. The decision to restart OAC or to start antiplatelet therapy in these patients therefore poses a dilemma for all physicians involved. We assessed the long-term outcome of patients who did or did not restart antithrombotic therapy after OAC-associated ICH.. We conducted a retrospective follow-up study of all patients discharged from our institution after OAC-associated ICH over a 10-year period. Data on the use of OAC or platelet inhibitors and the occurrence of vascular events during follow-up were assessed through questionnaires and patient files. The primary outcome was recurrent fatal or non-fatal stroke. Secondary outcomes were the occurrence of other haemorrhagic, thrombotic or thromboembolic events. With patients without antithrombotic treatment as reference, we calculated incidence ratios with corresponding 95% confidence intervals (CI) for treatment with OAC and for treatment with antiplatelet therapy.. We included 38 patients, of whom 21 (55%) died during a mean follow-up of 3.5 years. The medication regime changed frequently during follow-up, illustrated by the fact that two thirds of the patients who had resumed OAC within 2 months of ICH terminated this at later points in time. Two recurrent strokes occurred during 35.4 patient-years without antithrombotic medication, 7 during 63.8 patient-years on antiplatelet medication (incidence ratio 1.9; 95% CI, 0.4-9.4), and 3 during 19.5 patient-years on OAC (incidence ratio 2.7; 95% CI, 0.5-16.3). There was only 1 recurrent ICH, which occurred during treatment with OAC.. In this observational study, no significant difference in the primary outcome measure was found between the treatment groups, but there was a tendency towards a higher long-term risk of any stroke in patients who resumed OAC or started antiplatelet therapy. However, based on these results it is difficult to draw any concrete conclusions or make any strong recommendations. A randomized trial to assess the optimal long-term strategy after OAC-related ICH is warranted. Based on the point estimates of our study, such a trial should involve at least 300 patient-years of follow-up.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Fibrinolytic Agents; Follow-Up Studies; Hemorrhage; Humans; Male; Middle Aged; Phenprocoumon; Platelet Aggregation Inhibitors; Recurrence; Retrospective Studies; Risk Factors; Stroke; Surveys and Questionnaires; Survival Analysis; Thromboembolism; Treatment Outcome

The uncertain risk of secondary intracerebral hemorrhage (sICH) frequently keeps clinicians from initiating oral anticoagulation (OAC) early after ischemic cardioembolic stroke. The goal of this experimental study was to determine the risk of sICH depending on the timing of OAC initiation relative to stroke onset and to address the role of hematogenous macrophages for repair processes preventing OAC-associated sICH.. C57BL/6 mice were subjected to transient middle cerebral artery occlusion. Subgroups were treated with either the vitamin K antagonist (VKA) phenprocoumon or the direct thrombin inhibitor dabigatran etexilate. Hematogenous macrophages were depleted using intraperitoneal injections of clodronate-filled liposomes.. Time to therapeutic OAC was 48 hours with VKA and 0.5 hours with dabigatran etexilate treatment. In VKA-treated mice, the risk of sICH was high if effective OAC was already present at stroke onset or achieved within 48 hours after ischemia. With more delayed OAC, the risk of sICH rapidly decreased. Compared with VKA treatment, effective anticoagulation with dabigatran etexilate was associated with a significantly reduced extent of sICH, either if present at stroke onset or if achieved 48 hours later. Partial depletion of macrophages greatly increased the extent of OAC-associated sICH in the subacute stage of 3 to 4 days after ischemia.. Our findings suggest that repair mechanisms involving hematogenous macrophages rapidly decrease the risk of OAC-associated sICH in the first days after ischemic stroke. The lower risk of sICH under dabigatran etexilate compared with VKA treatment may facilitate early initiation of OAC after cardioembolic stroke.

Topics: Administration, Oral; Animals; Anticoagulants; Benzimidazoles; Blood Coagulation; Brain Ischemia; Cerebral Hemorrhage; Dabigatran; Disease Models, Animal; Intracranial Embolism; Macrophages; Male; Mice; Mice, Inbred C57BL; Phenprocoumon; Pyridines; Risk Factors; Stroke; Time Factors

Intracerebral hemorrhage (ICH) is the most serious complication of oral anticoagulation. This study investigated the risk of ICH for phenprocoumon which is the most widely used oral anticoagulant in Germany.. We conducted a nested case-control study in a cohort of 13.4 million insurants of 4 German statutory health insurances (SHIs) who were continuously enrolled for 6 months prior to cohort entry. Cases were patients hospitalized for ICH. Ten controls were matched to each case by SHI, birth year, and sex using incidence density sampling. Rate ratios (RR) of ICH for current phenprocoumon use as compared to non-use were estimated from odds ratios calculated by conditional logistic regression analyses considering multiple risk factors.. Analysis of the full cohort revealed a strong increase in incidence of ICH with increasing age. In the nested case-control study including 8138 cases of ICH and 81,373 matched controls, we observed an increased risk of ICH for current phenprocoumon exposure that varied with age. The phenprocoumon-associated risk of ICH was lower in older age groups with RRs from 4.20 (95% confidence interval (CI) 2.44-7.21) for phenprocoumon users less than 55 years of age to 2.43 (95%CI, 1.81-3.27) for those older than 85 years. Our study confirmed known risk factors of ICH.. Phenprocoumon exposure was associated with an increased risk of ICH. The interaction of risk for phenprocoumon with age was unexpected and needs further study.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Case-Control Studies; Cerebral Hemorrhage; Databases, Factual; Female; Follow-Up Studies; Germany; Hospitalization; Humans; Logistic Models; Male; Middle Aged; Phenprocoumon; Risk Factors; Young Adult

A 67-year-old lady was admitted with a myocardial infarction. Coronarography revealed thrombotic material within coronary arteries. The underlying disease was paroxysmal nocturnal hemoglobinuria (PNH), a stem cell defect characterized by episodes of complement-induced hemolysis and thromboembolic events. Anticoagulation and antiaggregation were initiated. Subsequently, massive cerebral bleeding developed, to which the patient finally succumbed despite neurosurgical craniectomy. This tragic case illustrates that an antithrombotic treatment is always a balancing act with an unsecure outcome.

Topics: Aged; Anticoagulants; Aspirin; Cerebral Hemorrhage; Clopidogrel; Coronary Thrombosis; Drug Therapy, Combination; Fatal Outcome; Female; Hemoglobinuria, Paroxysmal; Heparin; Heparin, Low-Molecular-Weight; Humans; Phenprocoumon; Platelet Aggregation Inhibitors; Ticlopidine; Tomography, X-Ray Computed

According to their code of professional conduct, German physicians are obliged to report suspected cases of adverse drug reactions (ADRs) to the Drug Commission of the German Medical Association (AkdA). On the basis of an agreement between the German Medical Association and the Federal Institute for Drugs and Medical Devices (BfArM) a common pharmacovigilance database within the German spontaneous reporting system was created. A user-friendly application program developed in-house enables the user to conduct searches about reported ADRs covering a wide variety of questions within a short period of time. ADRs caused by anticoagulants and by antiplatelet drugs still belong to the most reported adverse events. The most frequently reported suspected drugs are heparins, followed by ticlopidine, phenprocoumon, acetylsalicylic acid, and clopidogrel. Bleeding complications are the most often described ADR symptoms of any anticoagulation therapy, especially of phenprocoumon and acetylsalicylic acid. Another serious ADR is heparin-induced thrombocytopenia or changes in blood counts (CBC) due to ticlopidine and clopidogrel. During the past few years a reduction in severe reactions, such as cerebral hemorrhage, especially with fatal outcome was detectable because of better clinical management of oral anticoagulant therapy and of adverse events concerning heparin.

Topics: Administration, Oral; Adverse Drug Reaction Reporting Systems; Anticoagulants; Aspirin; Association; Blood Cell Count; Cerebral Hemorrhage; Clopidogrel; Databases, Factual; Drug Information Services; Germany; Hemorrhage; Heparin; Humans; Phenprocoumon; Platelet Aggregation Inhibitors; Product Surveillance, Postmarketing; Thrombocytopenia; Ticlopidine; Time Factors; Treatment Outcome; Vitamin K

Topics: Aged; Aged, 80 and over; Anticoagulants; Cerebral Hemorrhage; Female; Heparin, Low-Molecular-Weight; Humans; Phenprocoumon; Time Factors

Topics: Administration, Oral; Age Factors; Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Cerebral Hemorrhage; Cerebral Infarction; Clinical Trials as Topic; Contraindications; Fibrinolytic Agents; Humans; Male; Middle Aged; Phenprocoumon; Recurrence; Risk Factors

Physicians face a therapeutic dilemma in patients with acute hemorrhagic stroke requiring long-term, high-intensity anticoagulants because this treatment increases the risk of intracranial hemorrhage (ICH) 8- to 11-fold. We retrospectively studied 15 patients with ICH which occurred under anticoagulation with phenprocoumon, with an international norrmalized ratio (INR) of 2.5-6.5 on admission. Hemispheric, thalamic, cerebellar, intraventricular, or subarachnoid hemorrhage without aneurysm occurred. Absolute indications for anticoagulation were double, mitral, or aortic valve replacement, combined mitral valve failure with atrial fibrillation and atrial enlargement, internal carotid artery-jugular vein graft, frequently recurring deep vein thrombosis with risk of pulmonary embolism, and severe nontreatable ischemic heart disease. As soon as the diagnosis of ICH was established, INR normalization was attempted in all patients by administration of prothrombin complex, fresh frozen plasma, or vitamin K. After giving phenprocoumon antagonists (and neurosurgical therapy in four patients) heparin administration was started. Nine patients received full-dose intravenous and six low-dose subcutaneous heparin. The following observations were made: (a) All patients with effective, full-dose heparin treatment with a 1.5- to 2-fold elevation in partial thromboplastin time after normalization of the INR were discharged without complication. (b) Three of four of the patients with only incomplete correction of the INR (> 1.35) experienced relevant rebleeding within 3 days (all patients with an INR higher than 1.5), two of whom were on full-dose heparin. (c) Three of seven of the patients with normalized INR and without significant PTT elevation developed severe cerebral embolism. Although our data are based on a retrospective analysis, they support treatment with intravenous heparin (partial thromboplastin time 1.5-2 times baseline value) after normalization of the INR in patients with an ICH and an urgent need for anticoagulation.

Topics: Aged; Anticoagulants; Cardiovascular Diseases; Cerebral Hemorrhage; Female; Heparin; Humans; Male; Middle Aged; Partial Thromboplastin Time; Phenprocoumon; Retrospective Studies; Stroke; Venous Thrombosis

A 9-year series of 45 intracranial and spinal hematomas in patients under oral anticoagulant treatment with phenprocoumon was analyzed and compared to data from the literature. In 42% of the patients, International Normalized Ratio (INR) values >4.5 were found on admission, 36% were older than 70 years and most patients (38%) were under long-term treatment after cardiac valve replacement. Patients who recovered did not report to have given informed consent at the start of anticoagulant therapy. Because an average of five serious hemorrhages are reported/year from German neurosurgical departments, it can be estimated that about 650 intracerebral or intraspinal hematomas, including about 250 fatalities/year occur in Germany under oral anticoagulant treatment. These complications reach the same incidence than spontaneous hematomas either from aneurysms or angiomas. Standards for indications, clinical control, quality INR testing and INR targets not exceeding 4.0, and collecting more data on incidences and causative factors of complications may be an important contribution to reduce these fatalities.

Topics: Anticoagulants; Cerebral Hemorrhage; Drug Evaluation; Germany; Humans; International Normalized Ratio; Phenprocoumon; Radiography; Thrombosis

Topics: Accidental Falls; Accidents, Traffic; Alcohol Drinking; Alcoholism; Anticoagulants; Atrial Fibrillation; Carotid Stenosis; Cerebral Hemorrhage; Contraindications; Craniocerebral Trauma; Heart Defects, Congenital; Humans; Phenprocoumon

Topics: Anticoagulants; Blood Coagulation Tests; Cerebral Hemorrhage; Heart Valve Prosthesis; Humans; Phenprocoumon; Postoperative Complications; Practice Guidelines as Topic; Thrombosis; Treatment Outcome

A 32-year-old patient died of a cerebellar haemorrhage and the blood coagulation analysis before death suggested defective synthesis of vitamin K-dependent clotting factors due to vitamin K deficiency. The post-mortem toxicological examination of different tissues revealed phenprocoumon poisoning as the cause of death. The differential diagnosis of vitamin K deficiency and the toxicology of hydroxycoumarins are discussed.

Topics: Adult; Blood Coagulation Tests; Brain; Brain Death; Cerebellar Diseases; Cerebral Hemorrhage; Dose-Response Relationship, Drug; Drug Overdose; Humans; Male; Phenprocoumon; Vitamin K Deficiency

A woman aged 60 years receiving anticoagulation treatment on account of artificial mitral and aortic valve prostheses developed severe thrombocytopenia three weeks after the commencement of quinidine treatment. The results of investigations suggested severe thrombocytopenia precipitated by quinidine. The severe thrombocytopenia persisted despite intensive treatment and the condition ended fatally on account of cerebral haemorrhage. The combination of quinidine and oral anticoagulation treatment is not unusual and it is important to bear in mind that both of these preparations may cause increased haemorrhagic tendencies.

Topics: Cerebral Hemorrhage; Female; Humans; Middle Aged; Phenprocoumon; Quinidine; Thrombocytopenia

From 1978-1986, 63 patients (48-79 years) under coumarin derivatives had to be hospitalized neurosurgically because of intracranial or intraspinal bleedings. This corresponds to a twelvefold increased risk compared to the untreated people. The male/female ratio was 1.5. At the time of the bleeding there was no true indication for anticoagulation in at least 60% of the patients. 80% with coma on admission died. Only for 2/7 with an intraspinal hemorrhage the outcome was better than paraplegic. Women proved to have a better chance of survival. There is a need for more concise indications for chronic anticoagulation.

Topics: Acenocoumarol; Aged; Cerebral Hemorrhage; Coma; Coumarins; Female; Follow-Up Studies; Hematoma, Subdural; Hemorrhage; Humans; Male; Middle Aged; Paraplegia; Phenprocoumon; Risk Factors; Spinal Cord Diseases