title: Economic Analysis of Apixaban Therapy for Patients With Atrial Fibrillation From a US Perspective: Results From the ARISTOTLE Randomized Clinical Trial Dabigatran vs. warfarin in relation to the presence of left ventricular hypertrophy in patients with atrial fibrillation— the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) study Chronic obstructive pulmonary disease in patients with atrial fibrillation: Insights from the ARISTOTLE trial. Dabigatran versus warfarin in patients with atrial fibrillation. Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: observations from the ARISTOTLE trial Anemia is associated with bleeding and mortality, but not stroke, in patients with atrial fibrillation: Insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial Edoxaban versus warfarin in patients with atrial fibrillation. Direct treatment cost of atrial fibrillation in the elderly American population: a Medicare perspective Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF Apixaban vs. warfarin with concomitant aspirin in patients with atrial fibrillation: insights from the ARISTOTLE trial. Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation. Efficacy and safety of edoxaban compared with warfarin in patients with atrial fibrillation and heart failure: insights from ENGAGE AF-TIMI 48. Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial Efficacy and Safety of Dabigatran Compared With Warfarin in Relation to Baseline Renal Function in Patients With Atrial Fibrillation: A RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) Trial Analysis The Long-Term Multicenter Observational Study of Dabigatran Treatment in Patients With Atrial Fibrillation (RELY-ABLE) Study Stroke severity in atrial fibrillation. The Framingham Study. Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: the 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 Trial). Concomitant Use of Single Antiplatelet Therapy With Edoxaban or Warfarin in Patients With Atrial Fibrillation: Analysis From the ENGAGE AF‐TIMI48 Trial Clinical outcomes in patients with atrial fibrillation according to sex during anticoagulation with apixaban or warfarin: a secondary analysis of a randomized controlled trial. Apixaban versus warfarin in patients with atrial fibrillation. Outcomes of apixaban vs. warfarin by type and duration of atrial fibrillation: results from the ARISTOTLE trial. On-Treatment Outcomes in Patients With Worsening Renal Function With Rivaroxaban Compared With Warfarin: Insights From ROCKET AF Efficacy and Safety of Apixaban Compared With Warfarin in Patients With Atrial Fibrillation and Peripheral Artery Disease: Insights From the ARISTOTLE Trial
abstract: Importance The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation ( ARISTOTLE ) trial reported that apixaban therapy was superior to warfarin therapy in preventing stroke and all-cause death while causing significantly fewer major bleeds . To establish the value proposition of substituting apixiban therapy for warfarin therapy in patients with atrial fibrillation , we performed a cost-effectiveness analysis using patient-level data from the ARISTOTLE trial . Objective To assess the cost and cost-effectiveness of apixaban therapy compared with warfarin therapy in patients with atrial fibrillation from the perspective of the US health care system . Design , Setting , and Participants This economic analysis uses patient-level re source use and clinical data collected in the ARISTOTLE trial , a multinational r and omized clinical trial that observed 18 201 patients ( 3417 US patients ) for a median of 1.8 years between 2006 and 2011 . Interventions Apixaban therapy vs warfarin therapy . Main Outcomes and Measures Within-trial re source use and cost were compared between treatments , using externally derived US cost weights . Life expectancies for US patients were estimated according to their baseline risk and treatment using time-based and age-based survival models developed using the overall ARISTOTLE population . Quality -of-life adjustment factors were obtained from external sources . Cost-effectiveness ( incremental cost per quality -adjusted life-year gained ) was evaluated from a US perspective , and extensive sensitivity analyses were performed . Results Of the 3417 US patients enrolled in ARISTOTLE , the mean ( SD ) age was 71 ( 10 ) years ; 2329 ( 68.2 % ) were male and 3264 ( 95.5 % ) were white . After 2 years of anticoagulation therapy , health care costs ( excluding the study drug ) of patients treated with apixaban therapy and warfarin therapy were not statistically different ( difference , −$60 ; 95 % CI , −$2728 to $ 2608 ) . Life expectancy , modeled from ARISTOTLE outcomes , was significantly longer with apixaban therapy vs warfarin therapy ( 7.94 vs 7.54 quality -adjusted life years ) . The incremental cost , including cost of anticoagulant and monitoring , of achieving these benefits was within accepted US norms ( $ 53 925 per quality -adjusted life year , with 98 % likelihood of meeting a $ 100 000 willingness-to-pay threshold ) . Results were generally consistent when model assumptions were varied , with lifetime cost-effectiveness most affected by the price of apixaban and the time horizon . Conclusions and Relevance Apixaban therapy for ARISTOTLE-eligible patients with atrial fibrillation provides clinical benefits at an incremental cost that represents reasonable value for money judged using US benchmarks for cost-effectiveness . Trial Registration clinical trials.gov Identifier : Abstract Aim We tested the hypothesis that left ventricular hypertrophy ( LVH ) interferes with the antithrombotic effects of dabigatran and warfarin in patients with atrial fibrillation ( AF ) . Methods and results This is a post-hoc analysis of the R and omized Evaluation of Long-term anticoagulation therapY ( RE-LY ) Study . We defined LVH by electrocardiography ( ECG ) and included patients with AF on the ECG tracing at entry .  Hazard ratios ( HR ) for each dabigatran dose vs. warfarin were calculated in relation to LVH . LVH was present in 2353 ( 22.7 % ) out of 10 372 patients . In patients without LVH , the rates of primary outcome were 1.59%/year with warfarin , 1.60 % with dabigatran 110 mg ( HR vs. warfarin 1.01 , 95 % confidence interval ( CI ) 0.75–1.36 ) and 1.08 % with dabigatran 150 mg ( HR vs. warfarin 0.68 , 95 % CI 0.49–0.95 ) . In patients with LVH , the rates of primary outcome were 3.21%/year with warfarin , 1.69 % with dabigatran 110 mg ( HR vs. warfarin 0.52 , 95 % CI 0.32–0.84 ) and 1.55 % with 150 mg ( HR vs. warfarin 0.48 , 95 % CI 0.29–0.78 ) . The interaction between LVH status and dabigatran 110 mg vs. warfarin was significant for the primary outcome ( P = 0.021 ) and stroke ( P = 0.016 ) . LVH was associated with a higher event rate with warfarin , not with dabigatran . In the warfarin group , the time in therapeutic range was significantly lower in the presence than in the absence of LVH . Conclusions LVH was associated with a lower antithrombotic efficacy of warfarin , but not of dabigatran , in patients with AF . Consequently , the relative benefit of the lower dose of dabigatran compared to warfarin was enhanced in patients with LVH . The higher dose of dabigatran was superior to warfarin regardless of LVH status . Clinical trial registration http : www . clinical trials.gov . Unique identifier : NCT00262600 BACKGROUND Comorbid chronic obstructive pulmonary disease ( COPD ) is associated with poor outcomes among patients with cardiovascular disease . The risks of stroke and mortality associated with COPD among patients with atrial fibrillation are not well understood . METHODS We analyzed patients from ARISTOTLE , a r and omized trial of 18,201 patients with atrial fibrillation comparing the effects of apixaban versus warfarin on the risk of stroke or systemic embolism . Using Cox proportional hazards models , we assessed the associations between comorbid COPD and risk of stroke or systemic embolism and of mortality , adjusting for treatment allocation , smoking history and other risk factors . RESULTS COPD was present in 1950 ( 10.8 % ) of 18,134 patients with data on pulmonary disease history . After multivariable adjustment , COPD was not associated with risk of stroke or systemic embolism ( adjusted HR 0.85 [ 95 % CI 0.60 , 1.21 ] , p=0.356 ) . However , COPD was associated with a higher risk of all-cause mortality ( adjusted HR 1.60 [ 95 % CI 1.36 , 1.88 ] , p<0.001 ) and both cardiovascular and non-cardiovascular mortality . The benefit of apixaban over warfarin on stroke or systemic embolism was consistent among patients with and without COPD ( HR 0.92 [ 95 % CI 0.52 , 1.63 ] versus 0.78 [ 95 % CI 0.65 , 0.95 ] , interaction p=0.617 ) . CONCLUSIONS COPD was independently associated with increased risk of cardiovascular and non-cardiovascular mortality among patients with atrial fibrillation , but was not associated with risk of stroke or systemic embolism . The effect of apixaban on stroke or systemic embolism in COPD patients was consistent with its effect in the overall trial population BACKGROUND Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use . Dabigatran is a new oral direct thrombin inhibitor . METHODS In this noninferiority trial , we r and omly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive , in a blinded fashion , fixed doses of dabigatran--110 mg or 150 mg twice daily -- or , in an unblinded fashion , adjusted-dose warfarin . The median duration of the follow-up period was 2.0 years . The primary outcome was stroke or systemic embolism . RESULTS Rates of the primary outcome were 1.69 % per year in the warfarin group , as compared with 1.53 % per year in the group that received 110 mg of dabigatran ( relative risk with dabigatran , 0.91 ; 95 % confidence interval [ CI ] , 0.74 to 1.11 ; P<0.001 for noninferiority ) and 1.11 % per year in the group that received 150 mg of dabigatran ( relative risk , 0.66 ; 95 % CI , 0.53 to 0.82 ; P<0.001 for superiority ) . The rate of major bleeding was 3.36 % per year in the warfarin group , as compared with 2.71 % per year in the group receiving 110 mg of dabigatran ( P=0.003 ) and 3.11 % per year in the group receiving 150 mg of dabigatran ( P=0.31 ) . The rate of hemorrhagic stroke was 0.38 % per year in the warfarin group , as compared with 0.12 % per year with 110 mg of dabigatran ( P<0.001 ) and 0.10 % per year with 150 mg of dabigatran ( P<0.001 ) . The mortality rate was 4.13 % per year in the warfarin group , as compared with 3.75 % per year with 110 mg of dabigatran ( P=0.13 ) and 3.64 % per year with 150 mg of dabigatran ( P=0.051 ) . CONCLUSIONS In patients with atrial fibrillation , dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin , as well as lower rates of major hemorrhage .  Dabigatran administered at a dose of 150 mg , as compared with warfarin , was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage . ( Clinical Trials.gov number , NCT00262600 . Aims The risk of stroke in patients with atrial fibrillation ( AF ) increases with age . In the ARISTOTLE trial , apixaban when compared with warfarin reduced the rate of stroke , death , and bleeding . We evaluated these outcomes in relation to patient age . Methods and results A total of 18 201 patients with AF and a raised risk of stroke were r and omized  to warfarin or apixaban 5 mg b.d . with dose reduction to 2.5 mg b.d . or placebo in 831 patients with ≥2 of the following criteria : age ≥80 years , body weight ≤60 kg , or creatinine ≥133 μmol/L. We used Cox models to compare outcomes in relation to patient age during 1.8 years median follow-up . Of the trial population , 30 % were < 65 years , 39 % were 65 to < 75 , and 31 % were ≥75 years . The rates of stroke , all-cause death , and major bleeding were higher in the older age groups ( P < 0.001 for all ) . Apixaban was more effective than warfarin  in preventing stroke and reducing mortality across all age groups , and associated with less major bleeding , less total bleeding , and less intracranial haemorrhage regardless of age ( P interaction > 0.11 for all ) . Results were also consistent for the 13 % of patients ≥80 years . No significant interaction with apixaban dose was found with respect to treatment effect on major outcomes . Conclusion The benefits of apixaban vs. warfarin were consistent in patients with AF regardless of age . Owing to the higher risk at older age , the absolute benefits of apixaban were greater in the elderly Background Patients with atrial fibrillation ( AF ) are prone to cardiovascular events and anticoagulation‐related bleeding complications . We hypothesized that patients with anemia are at increased risk for these outcomes . Methods We performed a post hoc analysis of the ARISTOTLE trial , which included > 18,000 patients with AF r and omized to warfarin ( target international normalized ratio , 2.0‐3.0 ) or apixaban 5 mg twice daily .  Multivariable Cox regression analysis was used to determine if anemia ( defined as hemoglobin < 13.0 in men and < 12.0 g/dL in women ) was associated with future stroke , major bleeding , or mortality . Results Anemia was present at baseline in 12.6 % of the ARISTOTLE population . Patients with anemia were older , had higher mean CHADS2 and HAS‐BLED scores , and were more likely to have experienced previous bleeding events . Anemia was associated with major bleeding ( adjusted hazard ratio [ HR ] , 1.92 ; 95 % CI , 1.62‐2.28 ; P < .0001 ) and all‐cause mortality ( adjusted HR , 1.68 ; 95 % CI , 1.46‐1.93 ; P < .0001 ) but not stroke or systemic embolism ( adjusted HR , 0.92 ; 95 % CI , 0.70‐1.21 ) . The benefits of apixaban compared with warfarin  on the rates of stroke , mortality , and bleeding events were consistent in patients with and without anemia . Conclusions Chronic anemia is associated with a higher incidence of bleeding complications and mortality , but not of stroke , in anticoagulated patients with AF .  Apixaban is an attractive anticoagulant for stroke prevention in patients with AF with or without anemia BACKGROUND Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects . The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known . METHODS We conducted a r and omized , double-blind , double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation ( median follow-up , 2.8 years ) . The primary efficacy end point was stroke or systemic embolism . Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period . The principal safety end point was major bleeding . RESULTS The annualized rate of the primary end point during treatment was 1.50 % with warfarin ( median time in the therapeutic range , 68.4 % ) , as compared with 1.18 % with high-dose edoxaban ( hazard ratio , 0.79 ; 97.5 % confidence interval [ CI ] , 0.63 to 0.99 ; P<0.001 for noninferiority ) and 1.61 % with low-dose edoxaban ( hazard ratio , 1.07 ; 97.5 % CI , 0.87 to 1.31 ; P=0.005 for noninferiority ) . In the intention-to-treat analysis , there was a trend favoring high-dose edoxaban versus warfarin ( hazard ratio , 0.87 ; 97.5 % CI , 0.73 to 1.04 ; P=0.08 ) and an unfavorable trend with low-dose edoxaban versus warfarin ( hazard ratio , 1.13 ; 97.5 % CI , 0.96 to 1.34 ; P=0.10 ) . The annualized rate of major bleeding was 3.43 % with warfarin versus 2.75 % with high-dose edoxaban ( hazard ratio , 0.80 ; 95 % CI , 0.71 to 0.91 ; P<0.001 ) and 1.61 % with low-dose edoxaban ( hazard ratio , 0.47 ; 95 % CI , 0.41 to 0.55 ; P<0.001 ) . The corresponding annualized rates of death from cardiovascular causes were 3.17 % versus 2.74 % ( hazard ratio , 0.86 ; 95 % CI , 0.77 to 0.97 ; P=0.01 ) , and 2.71 % ( hazard ratio , 0.85 ; 95 % CI , 0.76 to 0.96 ; P=0.008 ) , and the corresponding rates of the key secondary end point ( a composite of stroke , systemic embolism , or death from cardiovascular causes ) were 4.43 % versus 3.85 % ( hazard ratio , 0.87 ; 95 % CI , 0.78 to 0.96 ; P=0.005 ) , and 4.23 % ( hazard ratio , 0.95 ; 95 % CI , 0.86 to 1.05 ; P=0.32 ) . CONCLUSIONS Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes . ( Funded by Daiichi Sankyo Pharma Development ; ENGAGE AF-TIMI 48 Clinical Trials.gov number , NCT00781391 . ) Abstract Objective : Although atrial fibrillation ( AF ) is the most commonly sustained arrhythmia in adults , few studies have examined the direct treatment cost of AF . Methods : A Medicare data base of a 5 % r and om national sample of all beneficiaries was used to identify patients diagnosed with AF in 2003 and to follow them for 1 year after diagnosis . These patients were matched on a 1:1 basis by age , gender and race . The incremental cost of treating AF was calculated with multivariate regression models adjusting for covariates . Results : In total , 55,260 subjects developed new AF , of which 69 % were ≥75 years old , 54 % were female and 91 % were White .  The adjusted mean incremental treatment cost of AF was $ 14,199 ( 95 % confidence interval $ 13,201–15,001 ; p<0.01 ) . Some of this cost was attributable to the incidence of stroke and heart failure at the 1-year post-AF diagnosis . A significantly higher proportion of AF patients experienced stroke ( 23.1 vs. 13.3 % ; p<0.01 ) and heart failure ( 36.7 vs. 10.4 % ; p<0.01 ) compared with Medicare beneficiaries without AF . Conclusions : Mean incremental direct treatment costs for Medicare beneficiaries with AF were higher than previously reported . Interventions that can reduce the incidence of AF and its complications may also reduce the national economic impact of AF AIMS We investigated the prevalence of prior myocardial infa rct ion ( MI ) and incidence of ischaemic cardiovascular ( CV ) events among atrial fibrillation ( AF ) patients . METHODS AND RESULTS In ROCKET AF , 14 264 patients with nonvalvular AF were r and omized to rivaroxaban or warfarin . The key efficacy outcome for these analyses was CV death , MI , and unstable angina ( UA ) . This pre-specified analysis was performed on patients while on treatment . Rates are per 100 patient-years . Overall , 2468 ( 17 % ) patients had prior MI at enrollment . Compared with patients without prior MI , these patients were more likely to be male ( 75 vs. 57 % ) , on aspirin at baseline ( 47 vs. 34 % ) , have prior congestive heart failure ( 78 vs. 59 % ) , diabetes ( 47 vs. 39 % ) , hypertension ( 94 vs. 90 % ) , higher mean CHADS2 score ( 3.64 vs. 3.43 ) , and fewer prior strokes or transient ischaemic attacks ( 46 vs. 54 % ) . CV death , MI , or UA rates tended to be lower in patients assigned rivaroxaban compared with warfarin [ 2.70 vs. 3.15 ; hazard ratio ( HR ) 0.86 , 95 % confidence interval ( CI ) 0.73 - 1.00 ; P = 0.0509 ] . CV death , MI , or UA rates were higher in those with prior MI compared with no prior MI ( 6.68 vs. 2.19 ; HR 3.04 , 95 % CI 2.59 - 3.56 ) with consistent results for CV death , MI , or UA for rivaroxaban compared with warfarin in prior MI compared with no prior MI ( P interaction = 0.10 ) . CONCLUSION Prior MI was common and associated with substantial risk for subsequent cardiac events . Patients with prior MI assigned rivaroxaban compared with warfarin had a non-significant 14 % reduction of ischaemic cardiac events BACKGROUND In ROCKET AF , rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation ( AF ) . We aim ed to investigate whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack ( TIA ) . METHODS In ROCKET AF , patients with AF who were at increased risk of stroke were r and omly assigned ( 1:1 ) in a double-blind manner to rivaroxaban 20 mg daily or adjusted dose warfarin ( international normalised ratio 2·0 - 3·0 ) . Patients and investigators were masked to treatment allocation . Between Dec 18 , 2006 , and June 17 , 2009 , 14 264 patients from 1178 centres in 45 countries were r and omly assigned . The primary endpoint was the composite of stroke or non-CNS systemic embolism . In this sub study we assessed the interaction of the treatment effects of rivaroxaban and warfarin among patients with and without previous stroke or TIA . Efficacy analyses were by intention to treat and safety analyses were done in the on-treatment population . ROCKET AF is registered with Clinical Trials.gov , number NCT00403767 . FINDINGS 7468 ( 52 % ) patients had a previous stroke ( n=4907 ) or TIA ( n=2561 ) and 6796 ( 48 % ) had no previous stroke or TIA .  The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA ( 2·79 % rivaroxaban vs 2·96 % warfarin ; hazard ratio [ HR ] 0·94 , 95 % CI 0·77 - 1·16 ) and those without ( 1·44%vs 1·88 % ; 0·77 , 0·58 - 1·01 ; interaction p=0·23 ) . The number of major and non-major clinical ly relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA ( 13·31 % rivaroxaban vs 13·87 % warfarin ; HR 0·96 , 95 % CI 0·87 - 1·07 ) and those without ( 16·69%vs 15·19 % ; 1·10 , 0·99 - 1·21 ; interaction p=0·08 ) . INTERPRETATION There was no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin was different between patients who had a previous stroke or TIA and those who had no previous stroke or TIA . These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF . FUNDING Johnson and Johnson Pharmaceutical Research and Development and Bayer HealthCare AIMS We assessed the effect of concomitant aspirin use on the efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation ( AF ) . METHODS AND RESULTS In ARISTOTLE , 18 201 patients were r and omized to apixaban 5 mg twice daily or warfarin . Concomitant aspirin use was left to the discretion of the treating physician . In this predefined analysis , simple and marginal structured models were used to adjust for baseline and time-dependent confounders associated with aspirin use . Outcome measures included stroke or systemic embolism , ischaemic stroke , myocardial infa rct ion , mortality , major bleeding , haemorrhagic stroke , major or clinical ly relevant non-major bleeding , and any bleeding . On Day 1 , 4434 ( 24 % ) patients were taking aspirin . Irrespective of concomitant aspirin use , apixaban reduced stroke or systemic embolism [ with aspirin : apixaban 1.12 % vs. warfarin 1.91 % , hazard ratio ( HR ) 0.58 , 95 % confidence interval ( CI ) 0.39 - 0.85 vs. without aspirin : apixaban 1.11 % vs. warfarin 1.32 % , HR 0.84 , 95 % CI 0.66 - 1.07 ; P interaction = 0.10 ] and caused less major bleeding than warfarin ( with aspirin : apixaban 3.10 % vs. warfarin 3.92 % , HR 0.77 , 95 % CI 0.60 - 0.99 vs. without aspirin : apixaban 1.82 % vs. warfarin 2.78 % , HR without aspirin 0.65 , 95 % CI 0.55 - 0.78 ; P interaction = 0.29 ) . Similar results were seen in the subgroups of patients with and without arterial vascular disease . CONCLUSION Apixaban had similar beneficial effects on stroke or systemic embolism and major bleeding compared with warfarin , irrespective of concomitant aspirin use Importance Dabigatran and rivaroxaban are non-vitamin K oral anticoagulants approved for stroke prevention in patients with nonvalvular atrial fibrillation ( AF ) . There are no r and omized head-to-head comparisons of these drugs for stroke , bleeding , or mortality outcomes . Objective To compare risks of thromboembolic stroke , intracranial hemorrhage ( ICH ) , major extracranial bleeding including major gastrointestinal bleeding , and mortality in patients with nonvalvular AF who initiated dabigatran or rivaroxaban treatment for stroke prevention . Design , Setting , and Participants Retrospective new-user cohort study of 118 891 patients with nonvalvular AF who were 65 years or older , enrolled in fee-for-service Medicare , and who initiated treatment with dabigatran or rivaroxaban from November 4 , 2011 , through June 30 , 2014 . Differences in baseline characteristics were adjusted using stabilized inverse probability of treatment weights based on propensity scores . The data analysis was performed from May 7 , 2015 , through June 30 , 2016 . Exposures Dabigatran , 150 mg , twice daily ; rivaroxaban , 20 mg , once daily . Main Outcomes and Measures Adjusted hazard ratios ( HRs ) for the primary outcomes of thromboembolic stroke , ICH , major extracranial bleeding including major gastrointestinal bleeding , and mortality , with dabigatran as reference . Adjusted incidence rate differences ( AIRDs ) were also estimated . Results A total of 52 240 dabigatran-treated and 66 651  rivaroxaban-treated patients ( 47 % female ) contributed 15 524 and 20 199 person-years of on-treatment follow-up , respectively , during which 2537 primary outcome events occurred . Rivaroxaban use was associated with a statistically nonsignificant reduction in thromboembolic stroke ( HR , 0.81 ; 95 % CI , 0.65 - 1.01 ; P = .07 ; AIRD = 1.8 fewer cases/1000 person-years ) , statistically significant increases in ICH ( HR , 1.65 ; 95 % CI , 1.20 - 2.26 ; P = .002 ; AIRD = 2.3 excess cases/1000 person-years ) and major extracranial bleeding ( HR , 1.48 ; 95 % CI , 1.32 - 1.67 ; P < .001 ; AIRD = 13.0 excess cases/1000 person-years ) , including major gastrointestinal bleeding ( HR , 1.40 ; 95 % CI , 1.23 - 1.59 ; P < .001 ; AIRD = 9.4 excess cases/1000 person-years ) , and with a statistically nonsignificant increase in mortality ( HR , 1.15 ; 95 % CI , 1.00 - 1.32 ; P = .051 ; AIRD = 3.1 excess cases/1000 person-years ) . In patients 75 years or older or with CHADS2 score greater than 2 , rivaroxaban use was associated with significantly increased mortality compared with dabigatran use . The excess rate of ICH with rivaroxaban use exceeded its reduced rate of thromboembolic stroke . Conclusions and Relevance Treatment with rivaroxaban 20 mg once daily was associated with statistically significant increases in ICH and major extracranial bleeding , including major gastrointestinal bleeding , compared with dabigatran 150 mg twice daily AIMS In the ENGAGE AF-TIMI 48 trial , edoxaban , a factor Xa inhibitor , was not found to be inferior to warfarin for the prevention of stroke or systemic embolic events ( SEE ) in patients with atrial fibrillation ( AF ) and was associated with significantly less bleeding . The higher-dose edoxaban regimen ( HDER ; 60 mg dose-reduced to 30 mg once daily ) has been approved in various countries in Europe , the USA , and Japan . Among patients treated with vitamin K antagonists ( VKAs ) , symptomatic heart failure ( HF ) is an independent risk factor for lower time-in-therapeutic range , which reduces the efficacy and safety of VKA therapy . We evaluated the efficacy and safety of edoxaban compared with warfarin across the spectrum of HF severity in the ENGAGE AF-TIMI 48 trial . METHODS AND RESULTS Of 14 071 patients r and omized to well-controlled warfarin or the HDER , 5926 ( 42 % ) had no history of HF , 6344 ( 45 % ) were in New York Heart Association ( NYHA ) class I-II , and 1801 ( 13 % ) were in NYHA class III-IV . The efficacy of edoxaban compared with warfarin in preventing stroke/SEE was similar in patients without and with HF regardless of the severity of HF ; [ HDER vs. warfarin : No-HF : hazard ratio ( HR ) 0.87 , 95 % confidence interval ( CI ) 0.69 - 1.11 ; NYHA class I-II : HR 0.88 , 95 % CI 0.69 - 1.12 ; NYHA class III-IV : HR 0.83 , 95 % CI 0.55 - 1.25 ; Pinteraction = 0.97 ] . Compared with warfarin , HDER was consistently associated with lower risk of major bleeding ( No-HF : HR 0.82 , 95 % CI 0.68 - 0.99 ; NYHA class I-II : HR 0.79 , 95 % CI 0.65 - 0.96 ; NYHA class III-IV : HR 0.79 , 95 % CI 0.54 - 1.17 ; Pinteraction = 0.96 ) . CONCLUSION The relative efficacy and safety of HDER compared with well-managed warfarin in AF patients with HF were similar to those without HF We investigated the frequency and characteristics of  intracranial hemorrhage ( ICH )  , the factors associated with the risk of ICH , and outcomes post-ICH overall and by r and omized treatment . We identified patients with ICH from the overall trial population enrolled in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial who received ≥1 dose of the study drug ( n = 18 140 ) . ICH was adjudicated by a central committee . Cox regression models were used to identify factors associated with ICH . ICH occurred in 174 patients ; most ICH events were spontaneous ( 71.7 % ) versus traumatic ( 28.3 % ) . Apixaban result ed in significantly less ICH ( 0.33 % per year ) , regardless of type and location , than warfarin ( 0.80 % per year ) . Independent factors associated with increased risk of ICH were enrollment in Asia or Latin America , older age , prior stroke/transient ischemic attack , and aspirin use at baseline . Among warfarin-treated patients , the median ( 25th , 75th percentiles ) time from most recent international normalized ratio ( INR ) to ICH was 13 days ( 6 , 21 days ) . Median INR prior to ICH was 2.6 ( 2.1 , 3.0 ) ; 78.5 % of patients had a pre-ICH INR < 3.0 . After ICH , the modified Rankin scale score at discharge was ≥4 in 55.7 % of patients , and the overall mortality rate at 30 days was 43.3 % with no difference between apixaban- and warfarin-treated patients . ICH occurred at a rate of 0.80 % per year with warfarin regardless of INR control and at a rate of 0.33 % per year with apixaban and was associated with high short-term morbidity and mortality . This highlights the clinical relevance of reducing ICH by using apixaban rather than warfarin and avoiding concomitant aspirin , especially in patients of older age . This trial was registered at www . clinical trials.gov as # NCT00412984 BACKGROUND The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment . Rivaroxaban , an oral factor Xa inhibitor , may provide more consistent and predictable anticoagulation than warfarin . METHODS In a double-blind trial , we r and omly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban ( at a daily dose of 20 mg ) or dose-adjusted warfarin . The per- protocol , as-treated primary analysis was design ed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism . RESULTS In the primary analysis , the primary end point occurred in 188 patients in the rivaroxaban group ( 1.7 % per year ) and in 241 in the warfarin group ( 2.2 % per year ) ( hazard ratio in the rivaroxaban group , 0.79 ; 95 % confidence interval [ CI ] , 0.66 to 0.96 ; P<0.001 for noninferiority ) . In the intention-to-treat analysis , the primary end point occurred in 269 patients in the rivaroxaban group ( 2.1 % per year ) and in 306 patients in the warfarin group ( 2.4 % per year ) ( hazard ratio , 0.88 ; 95 % CI , 0.74 to 1.03 ; P<0.001 for noninferiority ; P=0.12 for superiority ) . Major and nonmajor clinical ly relevant bleeding occurred in 1475 patients in the rivaroxaban group ( 14.9 % per year ) and in 1449 in the warfarin group ( 14.5 % per year ) ( hazard ratio , 1.03 ; 95 % CI , 0.96 to 1.11 ; P=0.44 ) , with significant reductions in intracranial hemorrhage ( 0.5 % vs. 0.7 % , P=0.02 ) and fatal bleeding ( 0.2 % vs. 0.5 % , P=0.003 ) in the rivaroxaban group . CONCLUSIONS In patients with atrial fibrillation , rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism . There was no significant between-group difference in the risk of major bleeding , although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group . ( Funded by Johnson & Johnson and Bayer ; ROCKET AF Clinical Trials.gov number , NCT00403767 . ) BACKGROUND In the ARISTOTLE trial , the rate of stroke or systemic embolism was reduced by apixaban compared with warfarin in patients with atrial fibrillation ( AF ) . Patients with AF and previous stroke or transient ischaemic attack ( TIA ) have a high risk of stroke . We therefore aim ed to assess the efficacy and safety of apixaban compared with warfarin in prespecified subgroups of patients with and without previous stroke or TIA . METHODS Between Dec 19 , 2006 , and April 2 , 2010 , patients were enrolled in the ARISTOTLE trial at 1034 clinical sites in 39 countries . 18,201 patients with AF or atrial flutter were r and omly assigned to receive apixaban 5 mg twice daily or warfarin ( target international normalised ratio 2·0 - 3·0 ) . The median duration of follow-up was 1·8 years ( IQR 1·4 - 2·3 ) . The primary efficacy outcome was stroke or systemic embolism , analysed by intention to treat . The primary safety outcome was major bleeding in the on-treatment population . All participants , investigators , and sponsors were masked to treatment assignments . In this subgroup analysis , we estimated event rates and used Cox models to compare outcomes in patients with and without previous stroke or TIA . The ARISTOTLE trial is registered with Clinical Trials.gov , number NTC00412984 . FINDINGS Of the trial population , 3436 ( 19 % ) had a previous stroke or TIA . In the subgroup of patients with previous stroke or TIA , the rate of stroke or systemic embolism was 2·46 per 100 patient-years of follow-up in the apixaban group and 3·24 in the warfarin group ( hazard ratio [ HR ] 0·76 , 95 % CI 0·56 to 1·03 ) ; in the subgroup of patients without previous stroke or TIA , the rate of stroke or systemic embolism was 1·01 per 100 patient-years of follow-up with apixaban and 1·23 with warfarin ( HR 0·82 , 95 % CI 0·65 to 1·03 ; p for interaction=0·71 ) . The absolute reduction in the rate of stroke and systemic embolism  with apixaban versus warfarin was 0·77 per 100 patient-years of follow-up ( 95 % CI -0·08 to 1·63 ) in patients with and 0·22 ( -0·03 to 0·47 ) in those without previous stroke or TIA . The difference in major bleeding with apixaban compared with warfarin was 1·07 per 100 patient-years ( 95 % CI 0·09 - 2·04 ) in patients with and 0·93 ( 0·54 - 1·32 ) in those without previous stroke or TIA . INTERPRETATION The effects of apixaban versus warfarin were consistent in patients with AF with and without previous stroke or TIA . Owing to the higher risk of these outcomes in patients with previous stroke or TIA , the absolute benefits of apixaban might be greater in this population . FUNDING Bristol-Myers Squibb and Pfizer Background — Renal impairment increases the risk of stroke and bleeding in patients with atrial fibrillation . In the R and omized Evaluation of Long-Term Anticoagulant Therapy ( RELY ) trial , dabigatran , with ≈80 % renal elimination , displayed superiority over warfarin for prevention of stroke and systemic embolism in the 150-mg dose and significantly less major bleeding in the 110-mg dose in 18 113 patients with nonvalvular atrial fibrillation . This prespecified study investigated these outcomes in relation to renal function . Methods and Results — Glomerular filtration rate was estimated with the Cockcroft-Gault , Chronic Kidney Disease Epidemiology Collaboration ( CKD-EPI ) , and Modification of Diet in Renal Disease ( MDRD ) equations in all r and omized patients with available creatinine at baseline ( n=17 951 ) , and cystatin C – based glomerular filtration rate was estimated in a sub population with measurements available ( n=6190 ) . A glomerular filtration rate ≥80 , 50 to < 80 , and < 50 mL/min was estimated in 32.6 % , 47.6 % , and 19.8 % and in 21.6 % , 59.6 % , and 18.8 % of patients based on Cockcroft-Gault and CKD-EPI , respectively . Rates of stroke or systemic embolism , major bleeding , and all-cause mortality increased as renal function decreased . The rates of stroke or systemic embolism were lower with dabigatran 150 mg and similar with 110 mg twice daily compared with warfarin , without significant heterogeneity in subgroups defined by renal function ( interaction P>0.1 for all ) . For the outcome of major bleeding , there were significant interactions between treatment and renal function according to CKD-EPI and MDRD equations , respectively ( P<0.05 ) . The relative reduction in major bleeding with either dabigatran dose compared with warfarin was greater in patients with glomerular filtration rate ≥80 mL/min . Conclusions — The efficacy of both dosages of dabigatran was consistent with the overall trial irrespective of renal function . However , with the CKD-EPI and MDRD equations , both dabigatran dosages displayed significantly lower rates of major bleeding in patients with glomerular filtration rate ≥80 mL/min . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00262600 Background — During follow-up of between 1 and 3 years in the R and omized Evaluation of Long-term Anticoagulation Therapy ( RE-LY ) trial , 2 doses of dabigatran etexilate were shown to be effective and safe for the prevention of stroke or systemic embolism in patients with atrial fibrillation . There is a need for longer-term follow-up of patients on dabigatran and for further data comparing the 2 dabigatran doses . Methods and Results — Patients r and omly assigned to dabigatran in RE-LY were eligible for the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation ( RELY-ABLE ) trial if they had not permanently discontinued study medication at the time of their final RE-LY study visit . Enrolled patients continued to receive the double-blind dabigatran dose received in RE-LY , for up to 28 months of follow up after RE-LY ( median follow-up , 2.3 years ) . There were 5851 patients enrolled , representing 48 % of patients originally r and omly assigned to receive dabigatran in RE-LY and 86 % of RELY-ABLE – eligible patients .  Rates of stroke or systemic embolism were 1.46 % and 1.60%/y on dabigatran 150 and 110 mg twice daily , respectively ( hazard ratio , 0.91 ; 95 % confidence interval , 0.69–1.20 ) . Rates of major hemorrhage were 3.74 % and 2.99%/y on dabigatran 150 and 110 mg ( hazard ratio , 1.26 ; 95 % confidence interval , 1.04–1.53 ) . Rates of death were 3.02 % and 3.10%/y ( hazard ratio , 0.97 ; 95 % confidence interval , 0.80–1.19 ) . Rates of hemorrhagic stroke were 0.13 % and 0.14%/y . Conclusions — During 2.3 years of continued treatment with dabigatran after RE-LY , there was a higher rate of major bleeding with dabigatran 150 mg twice daily in comparison with 110 mg , and similar rates of stroke and death . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00808067 BACKGROUND AND PURPOSE Stroke occurring with atrial fibrillation ( AF )  is more likely to be fatal or more severe than non-AF stroke based on clinical series , but data from prospect i ve epidemiological studies are sparse and inconsistent . METHODS Over 40-year follow-up of the original 5070 Framingham cohort , 501 initial ischemic strokes , including 103 with AF , were analyzed . Stroke severity was rated as none , mild , moderate , severe , or fatal . Since 1981 , functional status indicated by the Barthel index has been evaluated acutely and at 3 , 6 , and 12 months . Severity and functional status of AF strokes were compared with non-AF strokes using chi 2 test and Student 's t test . Thirty-day mortality was assessed by logistic regression analyses . RESULTS AF was associated with increased stroke severity ( P = .048 ) . Thirty-day mortality was greater in AF strokes than in non-AF strokes ( 25 % versus 14 % ) . The multivariate-adjusted odds ratio for 30-day mortality for AF subjects was 1.84 ( 95 % confidence interval , 1.04 to 3.27 ) . Since 1981 , follow-up was available for 150 initial ischemic strokes , including 30 with AF . Compared with the non-AF group , the AF group had poorer survival and more recurrences during 1 year of follow-up . The AF subjects had lower mean Barthel index scores acutely ( 29.6 versus 58.6 , P < .001 ) and at 3 months ( P = .005 ) , 6 months ( P = .003 ) , and 12 months ( P = .130 ) after stroke among survivors . CONCLUSIONS Ischemic stroke associated with AF was nearly twice as likely to be fatal as non-AF stroke . Recurrence was more frequent , and functional deficits were more likely to be severe among survivors . Since stroke is usually the initial manifestation of embolism in AF , prevention is critical to reducing disability and mortality BACKGROUND The prevalence of both atrial fibrillation ( AF ) and diabetes mellitus ( DM ) are rising , and these conditions often occur together . Also , DM is an independent risk factor for stroke in patients with AF . We aim ed to examine the safety and efficacy of rivaroxaban vs warfarin in patients with nonvalvular AF and DM in a prespecified secondary analysis of the ROCKET AF trial . METHODS We stratified the ROCKET AF population by DM status , assessed associations with risk of outcomes by DM status and r and omized treatment using Cox proportional hazards models , and tested for interactions between r and omized treatments . For efficacy , primary outcomes were stroke ( ischemic or hemorrhagic ) or non- central nervous system embolism . For safety , the primary outcome was major or nonmajor clinical ly relevant bleeding . RESULTS The 5,695 patients with DM ( 40 % ) in ROCKET AF were younger , were more obese , and had more persistent AF  , but fewer had previous stroke  ( the CHADS2 score includes DM and stroke ) . The relative efficacy of  rivaroxaban and  warfarin for prevention of stroke and systemic embolism was similar in patients with ( 1.74 vs 2.14/100 patient-years , hazard ratio [ HR ] 0.82 ) and without ( 2.12 vs 2.32/100 patient-years , HR 0.92 ) DM ( interaction P = .53 ) . The safety of rivaroxaban vs warfarin regarding major bleeding ( HRs 1.00 and 1.12 for patients with and without DM , respectively ; interaction P = .43 ) , major or nonmajor clinical ly relevant bleeding ( HRs 0.98 and 1.09 ; interaction P = .17 ) , and intracerebral hemorrhage ( HRs 0.62 and 0.72 ; interaction P = .67 ) was independent of DM status . Adjusted exploratory analyses suggested 1.3- , 1.5- , and 1.9-fold higher 2-year rates of stroke , vascular mortality , and myocardial infa rct ion in DM patients . CONCLUSIONS AND RELEVANCE The relative efficacy and safety of rivaroxaban vs warfarin was similar in patients with and without DM , supporting use of rivaroxaban as an alternative to warfarin in diabetic patients with AF Background We studied the concomitant use of single antiplatelet therapy ( SAPT ) on the efficacy and safety of the anti‐Xa agent edoxaban in patients with atrial fibrillation ( AF ) . Methods and Results ENGAGE AF‐TIMI 48 was a r and omized trial that compared 2 dose regimens of edoxaban with warfarin . We studied both the approved high‐dose edoxaban regimen ( HDER ; 60 mg daily reduced by one half in patients with anticipated increased drug exposure ) , as well as a lower‐dose edoxaban regimen ( LDER ; 30 mg daily , also reduced by one half in patients with anticipated increased drug regimen ) . SAPT ( aspirin in 92.5 % ) was administered at the discretion of the treating physician . Cox proportional hazard regressions stratified by SAPT at 3 months with treatment as a covariate were performed . The 4912 patients who received SAPT were more frequently male , with histories of coronary artery disease and diabetes , and had higher CHADS 2Vasc and HAS BLED scores than did the 14 977 patients not receiving SAPT . When compared to patients not receiving SAPT , those receiving SAPT had a higher incidence of major bleeding ; ( adjusted hazard ratio [ HR adj]=1.46 ; 95 % CI , 1.27–1.67 , P<0.001 ) . SAPT did not alter the relative efficacy of edoxaban compared to warfarin  in preventing stroke or systemic embolic events ( SEEs ) : edoxaban versus warfarin without SAPT , hazard ratio ( HR adj for HDER)=0.94 ; ( 95 % CI : 0.77–1.15 ) with SAPT , HR adj=0.70 ( 95 % CI : 0.50–0.98 ) , P interaction ( P int)=0.14 . ( HR adj for LDER versus warfarin without SAPT=1.19 ( 95 % CI 0.99–1.43 ) With SAPT , 1.03 ( 95 % CI , 0.76–1.39 ) P int=0.42 . Major bleeding was lower with edoxaban than warfarin both without SAPT , HR adj for HDER=0.80 ( 95 % CI , 0.68–0.95 ) , and with SAPT , HR adj=0.82 ( 95 % CI , 0.65–1.03 ; P int=0.91 ) . For LDER without SAPT ( HR adj=0.56 [ 95 % CI 0.46–0.67 ] ) and with SAPT ( HR adj=0.51 [ 95 % CI 0.39–0.66 ] ) . Conclusions Patients with AF who were selected by their physicians to receive SAPT in addition to an anticoagulant had a similar risk of stroke/SEE and higher rates of bleeding than those not receiving SAPT . Edoxaban exhibited similar relative efficacy and reduced bleeding compared to warfarin , with or without concomitant SAPT . Clinical Trial Registration URL : http://www . clinical trials.gov/. Unique identifier : NCT00781391 AIM To assess clinical outcomes , efficacy , and safety according to sex during anticoagulation with apixaban compared with warfarin in patients with atrial fibrillation . METHODS AND RESULTS Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation ( ARISTOTLE ) was a r and omized , double-blind , placebo-controlled , multicentre trial that included 11 785 ( 64.7 % ) men and 6416 ( 35.3 % ) women with atrial fibrillation or flutter r and omized to receive either warfarin or apixaban .  The primary efficacy endpoint was stroke or systemic embolism ; secondary efficacy endpoints were death from any cause and cardiovascular death . The primary safety endpoint was major bleeding ; secondary safety endpoints were a composite of major bleeding and non-major clinical ly relevant bleeding . The risk of stroke or systemic embolism was similar in women vs. men [ adjusted hazard ratio ( adjHR ) : 0.91 ; 95 % confidence interval ( CI ) : 0.74 - 1.12 ; P = 0.38 ] . However , among patients with history of stroke or transient ischaemic attack , women had a lower risk of recurrent stroke compared with men ( adjHR : 0.70 ; 95 % CI : 0.50 - 0.97 ; P = 0.036 ) . Women also had a lower risk of all-cause death ( adjHR : 0.63 ; 95 % CI : 0.55 - 0.73 ; P < 0.0001 ) and cardiovascular death ( adjHR : 0.62 ; 95 % CI : 0.51 - 0.75 ; P < 0.0001 ) , and a trend towards less major bleeding ( adjHR : 0.86 ; 95 % CI : 0.74 - 1.01 ; P = 0.066 ) and major or non-major clinical ly relevant bleeding ( adjHR : 0.89 ; 95 % CI : 0.80 - 1.00 ; P = 0.049 ) . The efficacy and safety benefits of apixaban compared with warfarin were consistent regardless of sex . CONCLUSION In the ARISTOTLE trial , women had a similar rate of stroke or systemic embolism but a lower risk of mortality and less clinical ly relevant bleeding than men . The efficacy and safety benefits of apixaban compared with warfarin were consistent in men and women . TRIAL REGISTRATION ARISTOTLE Clinical Trials.gov number , NCT00412984 BACKGROUND Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations . Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin . METHODS In this r and omized , double-blind trial , we compared apixaban ( at a dose of 5 mg twice daily ) with warfarin ( target international normalized ratio , 2.0 to 3.0 ) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke . The primary outcome was ischemic or hemorrhagic stroke or systemic embolism . The trial was design ed to test for noninferiority , with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause . RESULTS The median duration of follow-up was 1.8 years . The rate of the primary outcome was 1.27 % per year in the apixaban group , as compared with 1.60 % per year in the warfarin group ( hazard ratio with apixaban , 0.79 ; 95 % confidence interval [ CI ] , 0.66 to 0.95 ; P<0.001 for noninferiority ; P=0.01 for superiority ) . The rate of major bleeding was 2.13 % per year in the apixaban group , as compared with 3.09 % per year in the warfarin group ( hazard ratio , 0.69 ; 95 % CI , 0.60 to 0.80 ; P<0.001 ) , and the rates of death from any cause were 3.52 % and 3.94 % , respectively ( hazard ratio , 0.89 ; 95 % CI , 0.80 to 0.99 ; P=0.047 ) . The rate of hemorrhagic stroke was 0.24 % per year in the apixaban group , as compared with 0.47 % per year in the warfarin group ( hazard ratio , 0.51 ; 95 % CI , 0.35 to 0.75 ; P<0.001 ) , and the rate of ischemic or uncertain type of stroke was 0.97 % per year in the apixaban group and 1.05 % per year in the warfarin group ( hazard ratio , 0.92 ; 95 % CI , 0.74 to 1.13 ; P=0.42 ) . CONCLUSIONS In patients with atrial fibrillation , apixaban was superior to warfarin in preventing stroke or systemic embolism , caused less bleeding , and result ed in lower mortality . ( Funded by Bristol-Myers Squibb and Pfizer ; ARISTOTLE Clinical Trials.gov number , NCT00412984 . ) AIMS It is uncertain whether the benefit from apixaban varies by type and duration of atrial fibrillation ( AF ) . METHODS AND RESULTS A total of 18 201 patients with AF [ 2786 ( 15.3 % ) with paroxysmal and 15 412 ( 84.7 % ) with persistent or permanent ] were r and omized to apixaban or warfarin .  In this pre-specified secondary analysis , we compared outcomes and treatment effect of apixaban vs. warfarin by AF type and duration . The primary efficacy endpoint was a composite of ischaemic or haemorrhagic stroke or systemic embolism . The secondary efficacy endpoint was all-cause mortality . There was a consistent reduction in stroke or systemic embolism ( P for interaction = 0.71 ) , all-cause mortality ( P for interaction = 0.75 ) , and major bleeding ( P for interaction = 0.50 ) with apixaban compared with warfarin for both AF types . Apixaban was superior to warfarin in all studied endpoints , regardless of AF duration at study entry ( P for all interactions > 0.13 ) . The rate of stroke or systemic embolism was significantly higher in patients with persistent or permanent AF than patients with paroxysmal AF ( 1.52 vs. 0.98 % ; P = 0.003 , adjusted P = 0.015 ) . There was also a trend towards higher mortality in patients with persistent or permanent AF ( 3.90 vs. 2.81 % ; P = 0.0002 , adjusted P = 0.066 ) . CONCLUSION The risks of stroke , mortality , and major bleeding were lower with apixaban than warfarin regardless of AF type and duration . Although the risk of stroke or systemic embolism was lower in paroxysmal than persistent or permanent AF , apixaban is an attractive alternative to warfarin in patients with AF and at least one other risk factor for stroke , regardless of the type or duration of AF Background : Despite rapid clinical adoption of novel anticoagulants , it is unknown whether outcomes differ among patients with worsening renal function ( WRF ) taking these new drugs compared with warfarin .  We aim ed to determine whether the primary efficacy ( stroke or systemic embolism ) and safety ( major bleeding and nonmajor clinical ly relevant bleeding ) end points from the ROCKET AF trial ( Rivaroxaban Once-Daily , Oral , Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation trial ) differed among participants with WRF taking rivaroxaban and those taking warfarin .  Methods : After excluding patients without at least 1 follow-up creatinine measurement ( n=1624 ) , we included all remaining patients ( n=12 612 ) r and omly assigned to either rivaroxaban or dose-adjusted warfarin . On-treatment WRF ( a decrease of > 20 % from screening creatinine clearance measurement at any time point during the study ) was evaluated as a time-dependent covariate in Cox proportional hazards models . Results : Baseline characteristics were generally similar between patients with stable renal function ( n=9292 ) and WRF ( n=3320 ) .  Rates of stroke or systemic embolism , myocardial infa rct ion , and bleeding were also similar , but WRF patients experienced a higher incidence of vascular death versus stable renal function ( 2.21 versus 1.41 events per 100 patient-years ; P=0.026 ) . WRF patients who were r and omized to receive rivaroxaban had a reduction in stroke or systemic embolism compared with those taking warfarin ( 1.54 versus 3.25 events per 100 patient-years ) that was not seen in patients with stable renal function who were r and omized to receive rivaroxaban ( P=0.050 for interaction ) . There was no difference in major or nonmajor clinical ly relevant bleeding among WRF patients r and omized to warfarin versus rivaroxaban . Conclusions : Among patients with on-treatment WRF , rivaroxaban was associated with lower rates of stroke and systemic embolism compared with warfarin , without an increase in the composite bleeding end point . Clinical Trial Registration : URL : http://www . clinical trials.gov . Unique identifier : NCT00403767 Background We studied ( 1 ) the rates of stroke or systemic embolism and bleeding in patients with atrial fibrillation and peripheral artery disease ( PAD ) and ( 2 ) the efficacy and safety of apixaban versus warfarin in patients with atrial fibrillation with and without PAD . Methods and Results The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation ( ARISTOTLE ) trial r and omized 18 201 patients with atrial fibrillation to apixaban or warfarin for stroke/systemic embolism prevention ; 884 ( 4.9 % ) patients had PAD at baseline . Patients with PAD had higher unadjusted rates of stroke and systemic embolism ( hazard ratio [ HR ] 1.73 , 95 % CI 1.22–2.45 ; P=0.002 ) and major bleeding ( HR 1.34 , 95 % CI 1.00–1.81 ; P=0.05 ) , but after adjustment , no differences existed in rates of stroke and systemic embolism ( HR 1.32 , 95 % CI 0.93–1.88 ; P=0.12 ) and major bleeding ( HR 1.03 , 95 % CI 0.76–1.40 ; P=0.83 ) compared with patients without PAD . The risk of stroke or systemic embolism was similar in patients assigned to apixaban and warfarin with PAD ( HR 0.63 , 95 % CI 0.32–1.25 ) and without PAD ( HR 0.80 , 95 % CI 0.66–0.96 ; interaction P=0.52 ) . Patients with PAD did not have a statistically significant reduction in major or clinical ly relevant nonmajor bleeding with apixaban compared with warfarin ( HR 1.05 , 95 % CI 0.69–1.58 ) , whereas those without PAD had a statistically significant reduction ( HR 0.65 , 95 % CI 0.58–0.73 ; interaction P=0.03 ) . Conclusions Patients with PAD in ARISTOTLE had a higher crude risk of stroke or systemic embolism compared with patients without PAD that was not present after adjustment . The benefits of apixaban versus warfarin for stroke and systemic embolism were similar in patients with and without PAD . These findings highlight the need to optimize the treatment of patients with atrial fibrillation and PAD . Clinical Trial Registration URL : http://www . clinical trials.gov . Unique identifier : NCT00412984
target: Warfarin Versus Thrombin Inhibitor ( Dabigatran ) The RE-LY trial ( 9 , 18 ) showed that treatment with dabigatran , 150 mg , is superior to warfarin in reducing the incidence of the composite outcome of stroke or systemic embolism .
  No statistically significant difference was observed between the 2 therapies with regard to major bleeding , myocardial infa rct ion , or
background: Atrial fibrillation ( AF ) is characterized by uncoordinated atrial activation with consequent deterioration of mechanical function ( 1 ) .
  It is the most common sustained cardiac arrhythmia , and according to estimates , 12.1 million Americans will have AF by 2050 ( 2 ) .
  Patients with AF have increased risk for embolic stroke , heart failure , and cognitive impairment ; reduced quality of life ; and higher overall mortality ( 35 ) .
  Strokes related to AF have been characterized as more severe ( 6 , 7 ) and translate to a substantial economic burden , costing Medicare approximately $ 8 billion annually ( 8) .
  Antithrombotic therapies are the mainstays for preventing thromboembolic events in patients with AF .
  Oral anticoagulation with vitamin K antagonists ( VKAs ) has long been the gold st and ard therapy for stroke prevention in these patients .
  However , the challenges of monitoring VKA therapy and the many associated food and drug interactions have fueled the development of novel therapeutic options .
  Currently , 4 direct-acting oral anticoagulants ( DOACs ) are approved for stroke prevention in patients with nonvalvular AF : the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban , rivaroxaban , and edoxaban .
  In addition , procedural interventions , such as left atrial appendage ( LAA ) occlusion devices , are an alternative treatment for patients who are at high risk for bleeding while receiving anticoagulation therapy .
  This systematic review up date s previous review s ( 13 ) and aims to compare the effectiveness of the available medical and procedural therapies in preventing thromboembolic events and bleeding complications in patients with AF .