***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background — Dabigatran , an oral thrombin inhibitor , and rivaroxaban and apixaban , oral factor Xa inhibitors , have been found to be safe and effective in reducing stroke risk in patients with atrial fibrillation . We sought to compare the efficacy and safety of the 3 new agents based on data from their published warfarin-controlled r and omized trials , using the method of adjusted indirect comparisons . Methods and Results — We included findings from 44 535 patients enrolled in 3 trials of the efficacy of dabigatran  ( R and omized Evaluation of Long-Term Anticoagulation Therapy [ RELY ] ) , apixaban ( Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation [ ARISTOTLE ] ) , and rivaroxaban ( Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ ROCKET-AF ] ) , each compared with warfarin . The primary efficacy end point was stroke or systemic embolism ; the safety end point we studied was major hemorrhage . To address a lack of comparability between trial population s caused by the restriction of ROCKET-AF to high-risk patients , we conducted a subgroup analysis in patients with a CHADS2 score ≥3 . We found no statistically significant efficacy differences among the 3 drugs , although apixaban and dabigatran were numerically superior to rivaroxaban . Apixaban produced significantly fewer major hemorrhages than dabigatran and rivaroxaban . Conclusions — An indirect comparison of new anticoagulants based on existing trial data indicates that in patients with a CHADS2 score ≥3  dabigatran 150 mg , apixaban 5 mg , and rivaroxaban 20 mg result ed in statistically similar rates of stroke and systemic embolism , but apixaban had a lower risk of major hemorrhage compared with dabigatran and rivaroxaban . Until head-to-head trials or large-scale observational studies that reflect routine use of these agents are available , such adjusted indirect comparisons based on trial data are one tool to guide initial therapeutic choices Background — Rivaroxaban and dabigatran are new oral anticoagulants that specifically inhibit factor Xa and thrombin , respectively . Clinical studies on the prevention and treatment of venous and arterial thromboembolism show promising results . A major disadvantage of these anticoagulants is the absence of an antidote in case of serious bleeding or when an emergency intervention needs immediate correction of coagulation . This study evaluated the potential of prothrombin complex concentrate ( PCC ) to reverse the anticoagulant effect of these drugs . Methods and Results — In a r and omized , double-blind , placebo-controlled study , 12 healthy male volunteers received rivaroxaban 20 mg twice daily ( n=6 ) or dabigatran 150 mg twice daily ( n=6 ) for 2½ days , followed by either a single bolus of 50 IU/kg PCC ( Cofact ) or a similar volume of saline . After a washout period , this procedure was repeated with the other anticoagulant treatment . Rivaroxaban induced a significant prolongation of the prothrombin time ( 15.8±1.3 versus 12.3±0.7 seconds at baseline ; P<0.001 ) that was immediately and completely reversed by PCC ( 12.8±1.0 ; P<0.001 ) . The endogenous thrombin potential was inhibited by rivaroxaban ( 51±22 % ; baseline , 92±22 % ; P=0.002 ) and normalized with PCC ( 114±26 % ; P<0.001 ) , whereas saline had no effect . Dabigatran  increased the activated partial thromboplastin time , ecarin clotting time ( ECT ) , and thrombin time . Administration of PCC did not restore these coagulation tests . Conclusion — Prothrombin complex concentrate immediately and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study . Clinical Trial Registration — URL : http://www.trialregister.nl . Unique identifier : NTR2272 Background — Oral anticoagulation ( OAC ) therapy is effective in atrial fibrillation but requires vigilance to maintain the international normalized ratio in the therapeutic range . This report examines how differences in time in therapeutic range ( TTR ) between centers and between countries affect the outcomes of OAC therapy . Methods and Results — In a posthoc analysis , the TTRs of patients on OAC in a r and omized trial of OAC versus clopidogrel plus aspirin  ( Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events [ ACTIVE W ] ) were used to calculate the mean TTR  for each of 526 centers and 15 countries . Proportional-hazards analysis , with and without adjustment for baseline variables , was performed , with patients stratified by TTR quartile and country . A wide variation in TTRs was found between centers , with mean TTRs for centers in the 4 quartiles of 44 % , 60 % , 69 % , and 78 % . For patients at centers below the median TTR ( 65 % ) , no treatment benefit was demonstrated as measured by relative risk for vascular events of clopidogrel plus aspirin versus OAC ( relative risk , 0.93 ; 95 % confidence interval , 0.70 to 1.24 ; P=0.61 ) . However , for patients at centers with a TTR above the study median , OAC had a marked benefit , reducing vascular events by > 2-fold ( relative risk , 2.14 ; 95 % confidence interval , 1.61 to 2.85 ; P<0.0001 ) . Mean TTR also varied between countries from 46 % to 78 % ; relative risk ( clopidogrel plus aspirin versus OAC ) varied from 0.6 to 3.6 ( a 5-fold difference ) . A population -average model predicted that a TTR of 58 % would be needed to be confident that patients would benefit from being on OAC . Conclusions — A wide variation exists in international normalized ratio control , as measured by TTR , between clinical centers and between countries , which has a major impact on the treatment benefit of OAC therapy . For centers and countries , a target threshold TTR exists ( estimated between 58 % and 65 % ) below which there appears to be little benefit of OAC over antiplatelet therapy Background and Purpose — Intracranial hemorrhage is the most devastating complication of anticoagulation . Outcomes associated with different sites of intracranial bleeding occurring with warfarin versus dabigatran have not been defined . Methods — Analysis of 18 113 participants with atrial fibrillation in the R and omized Evaluation of Long-term anticoagulant therapY ( RE-LY ) trial assigned to adjusted-dose warfarin ( target international normalized ratio , 2–3 ) or dabigatran ( 150 mg or 110 mg , both twice daily ) . Results — During a mean of 2.0 years of follow-up ,  154 intracranial hemorrhages occurred in 153 participants : 46 % intracerebral ( 49 % mortality ) , 45 % subdural ( 24 % mortality ) , and 8 % subarachnoid ( 31 % mortality ) . The rates of intracranial hemorrhage were 0.76 % , 0.31 % , and 0.23 % per year among those assigned to warfarin , dabigatran 150 mg , and dabigatran 110 mg , respectively ( P<0.001 for either dabigatran dose versus warfarin ) . Fewer fatal intracranial hemorrhages occurred among those assigned dabigatran 150 mg and 110 mg ( n=13 and n=11 , respectively ) versus warfarin ( n=32 ; P<0.01 for both ) . Fewer traumatic intracranial hemorrhages occurred among those assigned to dabigatran ( 11 patients with each dose ) compared with warfarin ( 24 patients ; P<0.05 for both dabigatran doses versus warfarin ) . Independent predictors of intracranial hemorrhage were assignment to warfarin ( relative risk , 2.9 ; P<0.001 ) , aspirin use ( relative risk , 1.6 ; P=0.01 ) , age ( relative risk , 1.1 per year ; P<0.001 ) , and previous stroke/transient ischemic attack ( relative risk , 1.8 ; P=0.001 ) . Conclusions — The clinical spectrum of intracranial hemorrhage was similar for patients given warfarin and dabigatran . Absolute rates at all sites and both fatal and traumatic intracranial hemorrhages were lower with dabigatran than with warfarin . Concomitant aspirin use was the most important modifiable independent risk factor for intracranial hemorrhage BACKGROUND atrial fibrillation ( AF ) is the commonest chronic arrhythmia with a prevalence of 9 % in octogenarians and accounts for 24 % of the stroke risk in this population . Although trials demonstrate reductions in stroke with warfarin , audit data show that it is still underused . However , anti-coagulation in the very elderly is not without risk . METHODS r and omised open labelled prospect i ve study of primary thromboprophylaxis for AF . Patients aged > 80 and < 90 were r and omised to receive dose-adjusted warfarin ( INR 2.0 - 3.0 ) or aspirin 300 mg .  All patients had permanent AF , were ambulant , had Folstein mini mental score > 25 and had no contraindications to either treatment . Follow-up was for 1 year with 3 monthly visits . The primary outcome measure was a comparative frequency of combined endpoints comprising death , thromboembolism , serious bleeding and withdrawal from the study .  RESULTS seventy-five patients ( aspirin 39 ; warfarin 36 ) were entered ( mean age 83.9 , 47 % male ) . There were significantly more adverse events with aspirin ( 13/39 ; 33 % ) than warfarin ( 2/36 ; 6 % ) , P = 0.002 . 10/13 aspirin  adverse events were caused by side effects and serious bleeding ; there were three deaths ( two aspirin , one warfarin ) . CONCLUSION dose-adjusted warfarin was significantly better tolerated with fewer adverse events than aspirin 300 mg in this elderly population . Although aspirin 75 mg may have been better tolerated , there is no evidence for efficacy in AF at this dose Background and Purpose — The cost-effectiveness of dabigatran for stroke prevention in patients with atrial fibrillation and prior stroke or transient ischemic attack has not been directly assessed . Methods — A Markov decision model was constructed using data from the R and omized Evaluation of Long-Term Therapy ( RE-LY ) trial , other trials of warfarin therapy for atrial fibrillation , and the published cost of dabigatran . We compared the cost and quality -adjusted life expectancy associated with 150 mg dabigatran twice daily versus warfarin therapy targeted to an international normalized ratio of 2 to 3 . The target population was a cohort of patients aged ≥70 years with nonvalvular atrial fibrillation , prior stroke or transient ischemic attack , and no contraindication to anticoagulation . Results — In the base case , dabigatran was associated with 4.27 quality -adjusted life-years compared with 3.91 quality -adjusted life-years with warfarin . Dabigatran provided 0.36 additional quality -adjusted life-years at a cost of $ 9000 , yielding an incremental cost-effectiveness ratio of $ 25 000 . In sensitivity analyses , the cost-effectiveness of dabigatran was inversely related to the quality of international normalized ratio control achieved with warfarin therapy . In Monte Carlo analysis , dabigatran was cost-effective in 57 % of simulations using a threshold of $ 50 000 per quality -adjusted life-year and 78 % of simulations using a threshold of $ 100 000 per quality -adjusted life-year . Conclusions — Dabigatran appears to be cost-effective relative to warfarin for stroke prevention in patients with atrial fibrillation and prior stroke or transient ischemic attack . Our analysis is limited by its reliance on data from a sub study of a single r and omized trial , and our results may not apply in setting s with uncommonly good international normalized ratio control using warfarin ACCF : American College of Cardiology Foundation ACCP : American College of Chest Physicians ACS : acute coronary syndrome ACT : Atrial arrhythmia Conversion Trial ADONIS : American – Australian – African trial with DronedarONe In atrial fibrillation or flutter for the maintenance of Sinus rhythm AF : atrial fibrillation AHA : American Heart Association AND ROMEDA : ANtiarrhythmic trial with DROnedarone in Moderate-to-severe congestive heart failure Evaluating morbidity DecreAse APHRS : Asia Pacific Heart Rhythm Society aPTT : activated partial thromboplastin time ARB : angiotensin-receptor 
    Output:
    
Data from r and omized , Phase III clinical trials of the novel oral anticoagulants , dabigatran , a direct thrombin inhibitor , and rivaroxaban and apixaban , both factor Xa inhibitors , indicate these drugs are at least noninferior to warfarin for the prevention of stroke and systemic embolism .
They are easier to administer , and have an equivalent or lower risk of bleeding versus warfarin .