sanorg-34006 and Atrial-Fibrillation

This study was designed to compare efficacy and safety among novel oral anticoagulants (NOACs), which have not been directly compared in randomized control trials to date.. We performed network meta-analyses of randomized control trials in preventing thromboembolic events and major bleeding in patients with atrial fibrillation. PubMed, Embase, and the Cochrane Database of Systematic Reviews for published studies and various registries of clinical trials for unpublished studies were searched for 2002-2013. All phase III randomized controlled trials (RCTs) of NOACs (apixaban, edoxaban, dabigatran, rivaroxaban), idraparinux, and ximelagatran were reviewed.. A systematic literature search identified nine phase III RCTs for primary analyses. The efficacy of each NOAC was similar with respect to our primary composite endpoint following adjustment for open label designs [odds ratios (ORs) versus vitamin K antagonists: apixaban 0.79; dabigatran 150mg 0.77; edoxaban 60mg 0.87; rivaroxaban 0.86] except for dabigatran 110mg and edoxaban 30mg. Apixaban and edoxaban 30mg and 60mg had significantly fewer major bleeding events than dabigatran 150mg, ricvaroxaban, and vitamin K antagonists. All NOACs were similar in reducing secondary endpoints with the exception of dabigatran 110mg and 150mg which were associated with a significantly greater incidence of myocardial infarction compared to apixaban, edoxaban 60mg, and rivaroxaban.. Our indirect comparison with adjustment for study design suggests that the efficacy of the examined NOACs is similar across drugs, but that some differences in safety and risk of myocardial infarction exist, and that open label study designs appear to overestimate safety and treatment efficacy. Differences in study design should be taken into account in the interpretation of results from RCTs of NOACs.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Dabigatran; Hemorrhage; Humans; Myocardial Infarction; Odds Ratio; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiazoles; Thromboembolism; Treatment Outcome; Vitamin K

Although several new antithrombotic agents have been developed for stroke prevention in patients with nonvalvular atrial fibrillation (AF), many patients will continue to be treated with warfarin worldwide. We performed a meta-analysis of safety and efficacy outcomes in patients with AF treated with warfarin for stroke prevention in large contemporary randomized controlled trials (RCTs).. We searched the MEDLINE, EMBASE, and Cochrane databases for relevant studies; RCTs comparing warfarin with an alternative thromboprophylaxis strategy with at least 400 patients in the warfarin arm and reporting stroke as an efficacy outcome were included.. Eight RCTs with 55,789 patient-years of warfarin therapy follow-up were included. Overall time spent in the therapeutic range was 55% to 68%. The annual incidence of stroke or systemic embolism in patients with AF taking warfarin was estimated to be 1.66% (95% CI, 1.41%-1.91%). Major bleeding rates varied from 1.40% to 3.40% per year across the studies. The risk of stroke per year was significantly higher in elderly patients (2.27%), female patients (2.12%), patients with a history of stroke (2.64%), and patients reporting no previous exposure to vitamin K antagonists (1.96%). There was a significant increase in the annual incidence of stroke with progressively increasing CHADS(2) (congestive heart failure, hypertension, age, diabetes, and prior stroke) scores.. Current use of warfarin as a stroke prevention agent in patients with AF is associated with a low rate of residual stroke or systemic embolism estimated to be 1.66% per year. Compared with a previous meta-analysis, there has been significant improvement in the proportion of time spent in therapeutic anticoagulation, with a resultant decline in observed stroke rates.

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Brain Ischemia; Clopidogrel; Female; Humans; Incidence; Male; Oligosaccharides; Primary Prevention; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Stroke; Ticlopidine; Treatment Outcome; United States; Warfarin

Atrial fibrillation is already the most common clinically significant cardiac arrhythmia and a common cause of stroke. Vitamin K antagonists are very effective for the prevention of cardioembolic stroke but have numerous limitations that limit their uptake in eligible patients with AF and reduce their effectiveness in treated patients. Multiple new anticoagulants are under development as potential replacements for vitamin K antagonists. Most are small synthetic molecules that target factor IIa (e.g., dabigatran etexilate, AZD-0837) or factor Xa (e.g., rivaroxaban, apixaban, betrixaban, DU176b, idrabiotaparinux). These drugs have predictable pharmacokinetics that allow fixed dosing without laboratory monitoring, and are being compared with vitamin K antagonists or aspirin in phase III clinical trials [corrected]. A new vitamin K antagonist (ATI-5923) with improved pharmacological properties compared with warfarin is also being evaluated in a phase III trial. None of the new agents have as yet been approved for clinical use.

Topics: Anticoagulants; Atrial Fibrillation; Benzamides; Benzimidazoles; Biotin; Clinical Trials, Phase III as Topic; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Thiophenes; Vitamin K

Idraparinux is an analogue of fondaparinux binding with high affinity to antithrombin. It was designed for weekly, rather than daily, administration, with an exceptionally long half-life. One potential problem with small heparin-like fragments of this type is the difficulty of neutralising excessive activity in the case of side-effects or overdose. The efficacy of idraparinux was was proven in clinical studies with patients suffering from venous thromboembolism (VTE) or atrial fibrillation. Due to major bleeding events during treatment for more than six months the development of idraparinux was stopped. Idrabiotaparinux has an attached biotin moiety at the non-reducing end unit, which allows its neutralisation with avidin, an egg-derived protein with low antigenicity. This compound is currently investigated in clinical trials for prevention of recurrent VTE in patients with acute pulmonary embolism. The future of idrabiotaparinux depends also on the safety and efficacy of avidin.

Topics: Animals; Anticoagulants; Antithrombin III; Atrial Fibrillation; Avidin; Biotin; Carbohydrate Conformation; Carbohydrate Sequence; Drug Design; Drug Evaluation, Preclinical; Fondaparinux; Hemorrhage; Heparin Antagonists; Humans; Molecular Sequence Data; Molecular Structure; Oligosaccharides; Polysaccharides; Randomized Controlled Trials as Topic; Structure-Activity Relationship; Thrombosis; Treatment Outcome

Advances in antithrombotic therapy began when traditional anticoagulant agents such as heparin and the vitamin K antagonists like Coumadin became commercially available in the 1940s and 1950s. Inherent limitations of these compounds, including the need for monitoring and multiple food and drug interactions (with coumadin), spurred the development of newer parenteral compounds like low molecular weight heparin, the pentasaccharide fondaparinux, and direct thrombin inhibitors such as hirudin, argatroban and bivalirudin with advantages over traditional compounds. Despite the failure of the first oral anticoagulant in 50 years--the direct thrombin inhibitor ximelagatran--due to issues with liver toxicity, new oral agents such as the Factor Xa inhibitors rivaroxaban, apixaban, YM-150, and DU-176b and oral direct thrombin inhibitors such as dabigatran are in advanced stages of development, with dabigatran and rivaroxaban now approved for use outside of the United States for thromboprophylaxis in the setting of orthopedic surgery. These and other novel agents have the potential to greatly expand our armamentarium to treat thromboembolic disease, with more targeted approaches to specific procoagulant complexes, a predictable anticoagulant response that does not require monitoring, and use in both acute and long-term treatment settings.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Dabigatran; Drug Discovery; Factor Xa Inhibitors; Humans; Morpholines; Oligosaccharides; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism

Indirect systemic and direct oral factor Xa and direct oral factor IIa inhibitors with improved pharmacologic profiles compared with heparins and vitamin K antagonists are currently in clinical development. This overview focuses on the indirect antithrombin dependent pentasaccharide derivatives of idraparinux and on the most advanced oral direct inhibitors to factor Xa (rivaroxaban and apixaban) and IIa (dabigatran). Specifically, the results of dose-finding studies for the prevention of venous thromboembolism after elective orthopedic surgery, the results of dose-finding studies for treatment of acute venous thromboembolism including prolonged prophylaxis of recurrent events, and the designs of ongoing clinical trials are reviewed.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Glycine; Humans; Infusions, Parenteral; Morpholines; Oligosaccharides; Piperazines; Prothrombin; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Thrombosis; Venous Thromboembolism

Idraparinux is a synthetic pentasaccharide that binds to antithrombin with high affinity. In view of its long half-life, it is suitable for once-a-week administration.. To review the evidence favoring the use of idraparinux for the acute and long-term treatment of patients with venous thromboembolism (VTE) and for the prevention of thromboembolic events in patients with atrial fibrillation (AF).. All preclinical and clinical studies carried out with the use of idraparinux were sought through electronic searches of MEDLINE from January 1, 1999 up to December 31, 2007.. The administration of idraparinux in subcutaneous fixed doses of 2.5 mg once weekly was found to be as effective and safe as conventional antithrombotic therapy in the initial treatment of patients with deep vein thrombosis, but less effective than standard therapy in the initial treatment of patients with primary pulmonary embolism. During a 6-month extension of thromboprophylaxis, idraparinux was effective in preventing recurrent VTE but was associated with an increased risk of bleeding versus placebo. Finally, in patients with AF the long-term treatment with idraparinux was as effective as vitamin K antagonists, but caused more bleeding.. In its current formulation, idraparinux can be recommended only for the initial treatment of patients with deep vein thrombosis. The bioequipotency of a biotinylated version of idraparinux (idrabiotaparinux), whose effects can be reversed by a neutralizing agent (avidin), is under investigation in the treatment of VTE at present, as is the use of lower doses in patients with AF.

Topics: Animals; Antithrombins; Atrial Fibrillation; Clinical Trials as Topic; Drug Administration Schedule; Drug Evaluation; Fibrinolytic Agents; Half-Life; Humans; Oligosaccharides; Protein Binding; Thromboembolism

Atrial fibrillation is the most common sustained arrhythmia in clinical practice and is associated to thromboembolic complications. Anticoagulation with vitamin K antagonists is clearly useful to reduce the incidence of emboli, but associated with important limitations. Therefore, there is an active search for medications that are more effective and simpler to prescribe and manage. Synthetic pentasaccharides of heparin such as idraparinux for parenteral use, showed promising results. Direct inhibitors of thrombin were also useful for the prevention of thromboembolism. However, they were withdrawn from the market due to potentially fatal adverse reactions. Other area of investigation has been the effectiveness of the combination of antiplatelet agents such as aspirin and clopidrogel. Although this combination is attractive, results of clinical trials must be awaited to have an opinion about its real usefulness. Finally, left atrial appendage transcatheter occlusion (PLAATO) is an effective and reasonably safe method for patients with contraindications for anticoagulation or those that continue to embolize despite well prescribed anticoagulation. The long term results of this intervention must also be awaited.

Topics: Anticoagulants; Atrial Fibrillation; Controlled Clinical Trials as Topic; Heparin; Humans; Multicenter Studies as Topic; Oligosaccharides; Platelet Aggregation Inhibitors; Thrombin; Thromboembolism

Shortcomings of the existing anticoagulants, vitamin K antagonists and heparins, have led to the development of newer anticoagulant therapies. In particular, Vitamin K antagonists' slow onset of action, numerous drug interactions, narrow therapeutic window and need for frequent monitoring make it the most obvious target for replacement. Targeting specific coagulation enzymes or steps in the coagulation pathway, new anticoagulants have been or are under evaluation in clinical trials for a number of clinical indications, namely the prevention and treatment of venous thromboembolism, the prevention of ischemic stroke in patients with atrial fibrillation, and in acute coronary syndromes. Following a brief review of pharmacological aspects, this article will summarize the results of Phase III clinical trials evaluating the novel anticoagulants fondaparinux, ximelagatran and idraparinux. At present, most attention is directed at developing an oral anticoagulant to replace vitamin K antagonists for prevention of systemic thromboembolism. A number of newer agents are in both early and advanced stages of investigation.

Topics: Anticoagulants; Atrial Fibrillation; Azetidines; Benzylamines; Clinical Trials, Phase III as Topic; Fondaparinux; Humans; Oligosaccharides; Polysaccharides; Thromboembolism; Thrombosis; Venous Thrombosis

Atrial fibrillation, the most commonly encountered arrhythmia in clinical practice, is associated with substantial morbidity and mortality. Its incidence and prevalence are increasing, and it represents a growing clinical and economic burden. Recent research has highlighted new approaches to both pharmacological and non-pharmacological management. Pooled data from trials comparing antithrombotic treatment with placebo show that warfarin reduces the risk of stroke by 62% and that aspirin alone reduces the risk by 22%. Overall, in high-risk patients, warfarin was better than aspirin in preventing strokes, with a relative risk reduction of 36%, but the risk of major hemorrhage with warfarin was twice that with aspirin. Anticoagulation treatment needs to be tailored individually for patients on the basis of age, comorbidities, and contraindications. However, warfarin remains under-prescribed in clinical practice, for reasons related to patients (comorbidities) and physicians. The limitations of warfarin treatment have prompted the development of new anticoagulants with predictable pharmacokinetics that do not require as frequent monitoring. Ximelagatran, an oral direct thrombin inhibitor, was compared with warfarin in the SPORTIF program, which found both agents to be broadly effective in the prevention of embolic events, but observed abnormal liver function tests in 6% of patients on ximelagatran. Liver function monitoring during treatment is thus needed. Idraparinux, a factor Xa inhibitor administered by once weekly subcutaneous injections, is being evaluated in patients with atrial fibrillation. The ACTIVE trial is currently assessing the role of aspirin plus clopidogrel, compared with adjusted dose warfarin, in the prevention of vascular events in high-risk patients with atrial fibrillation. Angiotensin-converting enzyme inhibitors and angiotensin II receptor-blocking drugs interfere with atrial remodeling and show promise in atrial fibrillation, as suggested in the LIFE trial. Preliminary studies suggest that statins may reduce the risk of recurrence after electrical cardioversion. Finally, percutaneous methods for occlusion of the left atrial appendage are currently under investigation in patients at high risk of thromboembolism but with contraindications for chronic warfarin.

Topics: Administration, Oral; Age Factors; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Clopidogrel; Drug Therapy, Combination; Electric Countershock; Humans; Hypolipidemic Agents; Incidence; Injections, Subcutaneous; Middle Aged; Oligosaccharides; Placebos; Platelet Aggregation Inhibitors; Prevalence; Prodrugs; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Stroke; Ticlopidine; Warfarin

Several antithrombotic agents in development have the potential to greatly simplify the management of patients with AF or at risk for DVT/PE. Ximelagatran has already completed several phase 3 clinical studies in both of these high-risk, high-cost clinical settings and is poised to become the first practical alternative to warfarin. Although the exact therapeutic roles of ximelagatran and other novel antithrombotics further back in the pipeline remain to be determined, the impact of these nonwarfarin alternatives on the current labor-intensive system of anticoagulation clinics seems certain. Most important, the introduction of safer and equally effective oral anticoagulants that do not require monitoring may increase the percentage of high-risk patients who actually receive preventive therapy. If the institutional energy and resources previously spent on anticoagulation clinics, thrombotic disease management, and quality benchmarking can now be redirected to the delivery of the new generation of easier-to-administer and safer antithrombotic agents, the potential to increase rates of preventive therapy initiation and adherence in managed care populations may be within reach. Given the proven clinical value of anticoagulation, this potential increase in the rate of prophylaxis suggests the possibility that, even in the face of a rapidly aging US population, we are nonetheless entering into a period of reduced morbidity, mortality, and costs from stroke and DVT/PE.

Topics: Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; Clopidogrel; Fibrinolytic Agents; Fondaparinux; Humans; Oligosaccharides; Platelet Aggregation Inhibitors; Polysaccharides; Prodrugs; Pyridines; Stroke; Ticlopidine

Warfarin therapy achieving an International Normalized Ratio between 2 and 3 has been shown to be effective in preventing stroke. However, warfarin administration is problematic because of its variable dose, interaction with numerous foods and drugs, narrow therapeutic range, need for chronic anticoagulation monitoring, and long onset and offset of action, which all contribute to the significant underuse of warfarin in patients with atrial fibrillation at risk for stroke despite clear indication for its use. This has led to new approaches. Studies with idraparinux (AMADEUS), a factor 10a inhibitor, and with aspirin and clopidogrel (ACTIVE), both platelet inhibitors, are on-going. Studies with ximelagatran (Stroke Prevention by Oral Thrombin Inhibition in Atrial Fibrillation [SPORTIF] trials III and V), an oral direct thrombin inhibitor, have been completed. They compared ximelagatran with warfarin in patients with nonvalvular atrial fibrillation at risk for stroke. The studies demonstrated that ximelagatran is not inferior to warfarin. Moreover, ximelagatran has rapid onset and offset of action, fixed oral dosing without the need for anticoagulation monitoring, low potential for food and drug interactions, and a therapeutic margin wider than that of warfarin. We anticipate further studies to demonstrate definitively that the small percentage of patients (0.5%) with elevation of both alanine aminotransferase (ALT) and bilirubin levels can be managed safely, thereby making ximelagatran a promising option for preventing thromboembolism in patients with atrial fibrillation at risk for stroke.

Topics: Anticoagulants; Aspirin; Atrial Fibrillation; Azetidines; Benzylamines; Clopidogrel; Humans; Oligosaccharides; Platelet Aggregation Inhibitors; Stroke; Ticlopidine; Warfarin

Obesity has been associated with increased cardiovascular risk in atrial fibrillation, but little is known in elderly patients with atrial fibrillation.. Post hoc analysis of data from the AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) trial.. We studied 1588 elderly patients, who were categorized as normal body mass index (BMI, 18.5-25 kg/m(2); n=515 [32.4%]), overweight (BMI, 25-30 kg/m(2); n=711 [44.8%]), and obese (BMI≥30 kg/m(2); n=362 [22.8%]). There was a significant reduction in the composite outcome of cardiovascular death and stroke/systemic embolism with increasing BMI category, being 5.0%, 3.2%, and 1.5% per 100 patient-years, respectively (P for trend=0.01). Cox proportional hazards analysis found obesity to be associated with a lower risk of the primary composite outcome (hazard ratio, 0.29; 95% confidence interval, 0.11-0.77; P=0.01). In the warfarin arm (n=814), multivariate logistic regression analysis demonstrated that obesity was independently related to higher odds of time in therapeutic range ≥60% (odds ratio, 1.84; 95% confidence interval, 1.21-2.80; P=0.004).. Obesity was associated with a lower stroke and mortality rate in elderly anticoagulated atrial fibrillation patients. Obesity was related to good quality anticoagulation control.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Body Mass Index; Cardiovascular Diseases; Case-Control Studies; Comorbidity; Embolism; Factor Xa Inhibitors; Female; Humans; Logistic Models; Male; Multivariate Analysis; Obesity; Oligosaccharides; Overweight; Proportional Hazards Models; Risk Factors; Stroke; Warfarin

Simple bleeding risk scores have been proposed to predict bleeding events, in patients anticoagulated using non-warfarin anticoagulants. We compared the relative predictive values of two bleeding risk scores, HAS-BLED and ORBIT, in non-warfarin anticoagulated patients with atrial fibrillation (AF).. In a post-hoc ancillary analysis of 'clinically relevant bleeding' events amongst 2283 patients in the idraparinux arm in the AMADEUS trial. The two scores performed modestly in predicting both bleeding outcomes, although there was a trend for better HAS-BLED score performance in predicting any clinically relevant bleeding [c-indexes in HAS-BLED vs. ORBIT; 0.61 (95% CI; 0.58-0.64) vs. 0.58 (95% CI; 0.55-0.61); c-index difference=0.03, z-score=1.84, p=0.06)]. Using the HAS-BLED score compared with the ORBIT score correctly and significantly reclassified 15.6% of the population (95% CI: 4.3 to 27.0; p=0.007). Decision curve analyses confirmed the increasing ability to correctly identify patients who would bleed using the HAS-BLED score versus the ORBIT score, over a wide range of thresholds for any clinically relevant bleeding risk predictions.. In this comparison of the HAS-BLED and ORBIT scores in a cohort of non-warfarin anticoagulated patients with AF, we show that the HAS-BLED score more accurately predicted any clinically relevant bleeding amongst patients with AF who were anticoagulated with a non-warfarin anticoagulant, when compared with the ORBIT score.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Blood Coagulation; Female; Hemorrhage; Humans; Male; Middle Aged; Oligosaccharides; Predictive Value of Tests; Research Design; Risk Assessment; Stroke

Limited data are available on the impact of renal function on the outcome of patients with atrial fibrillation (AF).. AMADEUS was a multicentre, randomized, open-label non-inferiority study that compared fixed-dose idraparinux with conventional anticoagulation by dose-adjusted vitamin K antagonists. We performed a post hoc analysis to assess the impact of renal function on the outcomes of anticoagulated AF patients. The primary efficacy outcome was the composite of stroke/systemic embolism (SE). The principal safety outcome of this analysis was major bleeding. We calculated c-indexes, reflecting the ability for discriminating diseased vs. non-diseased patients, and the net reclassification improvement (NRI, an index of inferior/superior performance of risk estimation scores). Of 4576 patients, 45 strokes and 103 major bleeding events occurred following an average follow-up of 325 ± 164 days. Patients with CrCl >90 mL/min had an annual stroke/SE rate of 0.6% compared with 0.8% for those with CrCl 60-90 mL/min and 2.2% for those with CrCl <60 mL/min (P < 0.001 for linear association). After adjusting for stroke risk factors, patients with CrCl <60 mL/min had more than two-fold higher risk of stroke/SE and almost 60% higher risk of major bleeding compared with those with CrCl ≥60. In patients with the CHA2DS2VASc score 1-2, CrCl <60 mL/min was associated with eight-fold higher stroke risk. When added to the CHA2DS2VASc or CHADS2 scores, CrCl <60 mL/min did not improve the c-indexes for CHADS2 (P = 0.054) or CHA2DS2VASc (P = 0.63) but resulted in significant NRI (0.26, P = 0.02) in this anticoagulated trial cohort.. Renal impairment (CrCl <60 mL/min) doubles the risk of stroke and increased the risk of major bleeding by almost 60% in anticoagulated patients with AF. Renal impairment was additive to stroke risk prediction scores based on a significant NRI, but no significant improvement in discrimination ability (based on c-indexes) for CHA2DS2VASc or CHADS2 was observed.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Oligosaccharides; Renal Insufficiency, Chronic; Risk Assessment; ROC Curve; Stroke; Vitamin K

The aim of the current analysis was to identify independent predictors of the overall clinical outcome of patients with atrial fibrillation (AF), including both stroke/thromboembolism and/or major bleeding. Given the overlap between stroke and bleeding risk factors, a composite risk-stratification score for stroke/thromboembolism or bleeding could potentially be developed.. We used data from the vitamin K antagonist (VKA) arm (n = 2,293; 65% men; mean age 70 ± 9 years) of the AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) trial, which was a multicenter, randomized, open-label noninferiority study that compared fixed-dose idraparinux with VKA in patients with AF. We defined two composite end points: end point 1 was the combination of stroke/thromboembolism or major bleeding; end point 2 was defined as the combination of stroke, systemic or venous embolism, myocardial infarction, cardiovascular death, or major bleeding.. The independent predictors for composite end point 1 were age (P = .014), previous stroke/transient ischemic attack (P = .049), aspirin use (P = .002), and time in therapeutic range (P = .007). For composite end point 2, similar predictors were evident, plus left ventricular dysfunction (P = .011). Based on the regression models, two novel composite risk-prediction scores were developed and were validated externally in a "real-world" cohort of 441 outpatients with AF receiving anticoagulation treatment. Both composite scores 1 and 2 demonstrated numerically higher discriminatory performance (area under the curve [AUC], 0.728; 95% CI, 0.659-0.798 and AUC, 0.707; 95% CI, 0.655-0.758, for end points 1 and 2, respectively) and a positive net reclassification when compared with currently used risk models (CHADS2 [congestive heart failure, hypertension, age ≥ 75 years, diabetes, prior stroke or transient ischemic attack], CHA2DS2VASc [cardiac failure or dysfunction, hypertension, age ≥ 75 years [doubled], diabetes, stroke (doubled)-vascular disease, age 65 to 74 years, and sex category (female)], and HAS-BLED [hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly]), but the differences were not statistically significant.. We have developed and validated two novel composite scores for stroke/thromboembolism/bleeding that offer good discriminatory and predictive performance. However, these composite risk scores did not perform better than the easier and more practical "traditional" stroke and bleeding risk scores that are currently in use, which allow greater practicality and a more personalized balancing of risks.

Topics: Acenocoumarol; Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Area Under Curve; Atrial Fibrillation; Female; Hemorrhage; Humans; Male; Middle Aged; Models, Statistical; Oligosaccharides; Regression Analysis; Reproducibility of Results; Risk Factors; Stroke; Warfarin

This study aimed to assess the impact of combination antithrombotic therapy on stroke and bleeding risk compared with anticoagulation therapy only in patients with atrial fibrillation (AF).. Post hoc analysis of 4,576 patients with AF (mean ± SD age, 70.1 ± 9.1 years; men, 66.5%) enrolled in the Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation (AMADEUS) trial were randomized to receive either subcutaneous idraparinux (2.5 mg weekly) (n = 2,283) or dose-adjusted vitamin K antagonists (VKAs) (international normalized ratio, 2.0-3.0) (n = 2,293). Of these patients, 848 (18.5%) received antiplatelet therapy (aspirin, clopidogrel, ticlopidine, etc) in addition to anticoagulation treatment (combination antithrombotic therapy).. A total of 572 (15.3% per year) clinically relevant bleeding and 103 (2.6% per year) major bleeding events occurred. Patients receiving combination antithrombotic therapy had a 2.3- to 2.5-fold increased risk of clinically relevant bleeding events and major bleeding events, respectively, compared with those receiving anticoagulation therapy only. Multivariate analyses (hazard ratio, 95% CI) revealed that the risk of clinically relevant bleeding was significantly increased by age 65 to 74 years (1.44, 1.14-1.82) and ≥ 75 years (1.59, 1.24-2.04, P = .001) and by combination antithrombotic therapy (2.47, 2.07-2.96, P < .0001). The same held true for major bleeding events, with analogous figures for age 65 to 74 years (2.26, 1.08-4.71) and ≥ 75 years (4.19, 1.98-8.87, P = .0004) and for combination antithrombotic therapy (2.23, 1.49-3.34, P < .0001). Combination antithrombotic therapy was not associated with a decrease in ischemic stroke risk compared with anticoagulation therapy only (11 [1.4% per year] vs 22 [0.7% per year]; adjusted hazard ratio, 2.01; 95% CI, 0.94-4.30; P = .07).. Combination antithrombotic therapy increases the risk of clinically relevant bleeding and major bleeding in patients with AF and does not appear to reduce the risk of stroke.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Dose-Response Relationship, Drug; Drug Therapy, Combination; England; Female; Hemorrhage; Humans; Incidence; Injections, Subcutaneous; Male; Oligosaccharides; Platelet Aggregation Inhibitors; Prognosis; Risk Assessment; Risk Factors; Stroke; Warfarin

Idraparinux, a long-acting synthetic pentasaccharide, is a specific antithrombin-dependent inhibitor of activated factor X that has been investigated in the treatment and prevention of thromboembolic events.. To characterize the population pharmacokinetic profile of idraparinux in patients enrolled in van Gogh and Amadeus Phase III clinical trials.. Idraparinux was administered once-weekly subcutaneously at a dose of 2.5 mg, or 2.5 mg (first dose) and then 1.5 mg for patients with severe renal insufficiency (creatinine clearance<30 mL min(-1)). A population pharmacokinetic model was developed using data from 704 patients with acute deep-vein thrombosis or pulmonary embolism, 1310 patients suffering from atrial fibrillation, and 40 healthy subjects. Potential covariates analyzed included demographics (age, sex, weight and ethnicity), and serum creatinine and creatinine clearance determinations.. A three-compartment model best described idraparinux pharmacokinetics, with interindividual variability on clearance, central volume of distribution, and absorption rate constant; residual variability was low. Typical clearance, central volume of distribution, absorption rate constant and volume of distribution at steady-state were 0.0255 L h(-1), 3.36 L, 1.37 h and 30.8 L, respectively. Peak concentration was reached at 2.5 h. The terminal half-life was 66.3 days and time to steady-state was 35 weeks. At steady-state, exposures were similar for patients without and with severe renal impairment receiving adjusted-dose. Creatinine clearance was the most important covariate affecting idraparinux clearance. The particular characteristics of idraparinux--rapid onset of action and long-acting anticoagulant effect--offer interesting clinical perspectives currently under investigation with idrabiotaparinux, the reversible biotinylated form of idraparinux.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Atrial Fibrillation; Child; Child, Preschool; Factor Xa Inhibitors; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Middle Aged; Oligosaccharides; Pharmacokinetics; Pulmonary Embolism; Renal Insufficiency; Secondary Prevention; Single-Blind Method; Venous Thrombosis; Young Adult

Vitamin K antagonists, the current standard treatment for prophylaxis against stroke and systemic embolism in patients with atrial fibrillation, require regular monitoring and dose adjustment; an unmonitored, fixed-dose anticoagulant regimen would be preferable. The aim of this randomised, open-label non-inferiority trial was to compare the efficacy and safety of idraparinux with vitamin K antagonists.. Patients with atrial fibrillation at risk for thromboembolism were randomly assigned to receive either subcutaneous idraparinux (2.5 mg weekly) or adjusted-dose vitamin K antagonists (target of an international normalised ratio of 2-3). Assessment of outcome was done blinded to treatment. The primary efficacy outcome was the cumulative incidence of all stroke and systemic embolism. The principal safety outcome was clinically relevant bleeding. Analyses were done by intention to treat; the non-inferiority hazard ratio was set at 1.5. This trial is registered with ClinicalTrials.gov, number NCT00070655.. The trial was stopped after randomisation of 4576 patients (2283 to receive idraparinux, 2293 to receive vitamin K antagonists) and a mean follow-up period of 10.7 (SD 5.4) months because of excess clinically relevant bleeding with idraparinux (346 cases vs 226 cases; 19.7 vs 11.3 per 100 patient-years; p<0.0001). There were 21 instances of intracranial bleeding with idraparinux and nine with vitamin K antagonists (1.1 vs 0.4 per 100 patient-years; p=0.014); elderly patients and those with renal impairment were at greater risk of such complications. There were 18 cases of thromboembolism with idraparinux and 27 cases with vitamin K antagonists (0.9 vs 1.3 per 100 patient-years; hazard ratio 0.71, 95% CI 0.39-1.30; p=0.007), satisfying the non-inferiority criterion. There were 62 deaths with idraparinux and 61 with vitamin K anatagonists (3.2 vs 2.9 per 100 patient-years; p=0.49).. In patients with atrial fibrillation at risk for thromboembolism, long-term treatment with idraparinux was no worse than vitamin K antagonists in terms of efficacy, but caused significantly more bleeding.

Topics: Acenocoumarol; Aged; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Oligosaccharides; Risk Factors; Single-Blind Method; Stroke; Thromboembolism; Treatment Outcome; Vitamin K; Warfarin

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Female; Hemorrhage; Humans; Male; Middle Aged; Oligosaccharides; Outcome Assessment, Health Care; Predictive Value of Tests; Proportional Hazards Models; Risk Assessment

Topics: Anticoagulants; Atrial Fibrillation; Hemorrhage; Humans; Oligosaccharides; Stroke; Thromboembolism; Vitamin K; Warfarin

Topics: Atrial Fibrillation; Fibrinolytic Agents; Humans; Oligosaccharides; Stroke

Topics: Aged; Anticoagulants; Atrial Fibrillation; Biopsy, Fine-Needle; Drainage; Drugs, Investigational; Factor VIIa; Hemoptysis; Hemorrhage; Humans; International Normalized Ratio; Lung; Lung Neoplasms; Male; Oligosaccharides; Pulmonary Embolism; Recombinant Proteins; Thoracic Diseases