title: Dabigatran versus warfarin in patients with atrial fibrillation. Edoxaban versus warfarin in patients with atrial fibrillation. Physical Activity, Obesity, Weight Change, and Risk of Atrial Fibrillation: The Atherosclerosis Risk in Communities Study Influence of obesity on outcomes in atrial fibrillation: yet another obesity paradox. Low Body Weight Is Associated With the Incidence of Stroke in Atrial Fibrillation Patients - Insight From the Fushimi AF Registry. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. Cardiovascular risk in relation to body mass index and use of evidence-based preventive medications in patients with or at risk of atherothrombosis. Obesity and outcomes among patients with established atrial fibrillation. Apixaban versus warfarin in patients with atrial fibrillation. Relation of Nonvalvular Atrial Fibrillation to Body Mass Index (from the SPORTIF Trials). Body mass index and adverse events in patients with incident atrial fibrillation.
abstract: 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 . 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 . ) Background —Physical activity ( PA ) has previously been suggested to attenuate the risk of atrial fibrillation ( AF ) conferred by excess body weight and weight gain . We prospect ively examined the relationship between body size , weight change , and level of PA in a biracial cohort of middle-aged men and women . Methods and Results —Baseline characteristics on risk factor levels were obtained on 14 219 participants from the Atherosclerosis Risk in Communities Study . AF incidence was ascertained from 1987 to 2009 . Adjusted Cox proportional hazards models were used to estimate the associations between body mass index , waist circumference , relative weight change , and PA level with incident AF . During follow-up , there were 1775 cases of incident AF . Body mass index and waist circumference were positively associated with AF as was weight loss/gain of > 5 % initial body weight . An ideal level of PA had a small protective effect on AF risk and partially attenuated the risk of AF associated with excess weight in men but not women : compared with men with a normal body mass index , the risk of AF in obese men with an ideal , intermediate , and poor level of PA at baseline was increased by 37 % , 129 % , and 156 % ( Pinteraction=0.04 ) . During follow-up , PA did not modify the association between weight gain and risk of AF . Conclusions —Obesity and extreme weight change are risk factors for incident AF , whereas being physically active is associated with a small reduction in risk . In men only , being physically active offset some , but not all , of the risk incurred with excess body weight BACKGROUND Obese patients have favorable outcomes in congestive heart failure , hypertension , peripheral vascular disease , and coronary artery disease . Obesity also has been linked with increased incidence of atrial fibrillation , but its influence on outcomes in atrial fibrillation patients has not been investigated . The objective of this research is to investigate the effect of obesity on outcomes in atrial fibrillation . METHODS The Atrial Fibrillation Follow-up Investigation of Rhythm Management ( AFFIRM ) study was one of the largest multicenter trials of atrial fibrillation , with 4060 patients . Subjects were r and omized to rate versus rhythm-control strategy . We performed a post hoc analysis of the National Heart , Lung and Blood Institute limited access data set of atrial fibrillation patients who had body mass index ( BMI ) data available in the AFFIRM study . BMI data were not available on 1542 patients . Patients with BMI > or=18.5 were split into normal ( 18.5 - 25 ) , overweight ( 25 - 30 ) , and obese ( > 30 ) categories as per BMI ( kg/m(2 ) ) . Multivariate Cox proportional hazards regression was used on the eligible 2492 patients . End points were all-cause mortality and cardiovascular mortality . RESULTS Over three fourths of all patients in our cohort were overweight or obese . There were 304 deaths ( 103 among normal weight , 108 among overweight , and 93 among obese ) and 148 cardiovascular deaths ( 54 among normal weight , 41 among overweight , and 53 among obese ) over a mean period of 3 years of patient follow-up . On multivariate analysis , overweight ( hazard ratio [ HR ] 0.64 ; 95 % confidence interval [ CI ] , 0.48 - 0.84 ; P=.001 ) and obese ( HR 0.80 ; 95 % CI , 0.68 - 0.93 ; P=.005 ) categories were associated with lower all-cause mortality as compared with normal weight . Overweight ( HR 0.40 ; 95 % CI , 0.26 - 0.60 ; P < .001 ) and obese patients ( HR 0.77 ; 95 % CI , 0.62 - 0.95 ; P=.01 ) also had lower cardiovascular mortality as compared with the normal weight patients . CONCLUSIONS Although in prior studies , obesity has been associated with increased risk of atrial fibrillation , an obesity paradox exists for outcomes in atrial fibrillation . Obese patients with atrial fibrillation appear to have better long-term outcomes than nonobese patients BACKGROUND Japanese patients with atrial fibrillation ( AF ) are generally small and lean , but knowledge of the clinical characteristics of those with low body weight ( LBW : ≤50 kg ) is limited . METHODS AND RESULTS The Fushimi AF Registry is a community-based prospect i ve survey of AF patients who visited the participating medical institutions in Fushmi-ku , Japan . The BW and follow-up data were available for 2,945 patients . We compared the background and the incidence of clinical events during a median follow-up of 746 days between a LBW and non-LBW group . Patients in the LBW group accounted for 26.8 % ( 788 patients ) of the total . The LBW group was more often female , older , and had higher CHADS2score . The incidence of stroke/systemic embolism ( SE ) during follow-up was higher in the LBW group ( hazard ratio ( HR ) : 2.19 , 95 % confidence interval ( CI ) : 1.57 - 3.04 ; P<0.01 ) , whereas that of major bleeding was comparable ( HR : 1.05 , 95 % CI : 0.64 - 1.68 ; P=0.84 ) . This trend was consistently observed in the subgroups stratified by age , sex , and oral anticoagulant prescription at baseline . Multivariate analysis as well as propensity-score matching analysis further supported the significance of LBW as a risk of stroke/SE . CONCLUSIONS Patients in the LBW group had high risk profiles and showed a higher incidence of stroke/SE , but the incidence of major bleeding was not particularly high 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 . ) AIM Explore the relation between body mass index ( BMI ) and cardiovascular disease , and the influence of optimal medical therapy ( OMT ) on this relationship . METHODS AND RESULTS Patients from the REACH cohort , an international , prospect i ve cohort of patients with or at high risk of atherosclerosis with documentation of potential confounders , including treatments and risk factors , were followed up to 4 years ( n = 54 285 ) . Patients were categorized according to baseline BMI ( ranging from underweight to Grade III obesity ) . Optimal medical therapy was defined as the use of the four cardioprotective medication classes ( statins , ACE inhibitors/angiotensin II receptor blockers , β-blockers , and antiplatelet agents ) . The main outcomes were all-cause mortality , cardiovascular ( CV ) mortality , and CV events . In primary and secondary prevention , a reverse J-shaped curve best described the relationship between BMI categories and the incidence of the various outcomes . In secondary prevention , the highest adjusted risks were observed for underweight patients ( 1.97 , P < 0.01 , and 1.29 , P = 0.03 , for CV mortality and CV events ) and the lowest HRs were observed , respectively , in Grade II and Grade III obese patients ( 0.73 , P < 0.01 and 0.80 , P < 0.01 ) . The proportion of patients on OMT increased with BMI from 10.1 to 36 % ( P < 0.001 ) . The apparent CV protection conferred by obesity persisted in patients receiving OMT . CONCLUSION An obesity paradox was observed in both primary and secondary CV prevention patients . The intensity of use of evidence -based preventive medications does not account for the paradoxical CV protection associated with obesity . At extremes of BMI , further interventions beyond OMT may be needed to reduce CV risk Atrial fibrillation ( AF ) and obesity have reached epidemic proportions . The impact of obesity on clinical outcomes in patients with established AF is unknown . We analyzed 2,492 patients in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management ( AFFIRM ) study .  Body mass index ( BMI ) was evaluated as a categorical variable ( normal 18.5 to < 25 kg/m(2 ) , overweight 25 to < 30 kg/m(2 ) , obese > or=30 kg/m(2 ) ) . Rate of death from any cause was higher in the normal BMI group ( 5.8 per 100 patient-years ) than in the overweight and obese groups ( 3.9 and 3.7 , respectively ) . Cardiovascular death rate was highest in the normal BMI group ( 3.1 per 100 patient-years ) , lowest in the overweight group ( 1.5 per 100 patient-years ) , and intermediate in the obese group ( 2.1 per 100 patient-years ) . After adjustment for baseline factors , differences in risk of death from any cause were no longer significant . However , overweight remained associated with a lower risk of cardiovascular death ( hazard ratio 0.47 , p = 0.002 ) . Obese patients were more likely to have an uncontrolled heart rate at rest , but rhythm-control strategy success was similar across BMI categories . In each BMI category , risk of death from any cause was similar for patients r and omized to a rhythm- or rate-control strategy . In conclusion , in patients with established AF , overweight and obesity do not adversely affect overall survival . Obesity does not appear to affect the relative benefit of a rate- or rhythm-control strategy 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 . ) Obesity is well-established as a major cardiovascular ( CV ) risk factor . Obesity confers a greater risk for developing atrial fibrillation ( AF ) , but the relation between obesity and established nonvalvular AF for stroke and all-cause death is still unclear . To ascertain the prevalence of overweight and obesity in patients with nonvalvular AF , their influence on adverse events , and the relation with anticoagulation control , we performed this post hoc analysis of the pooled Stroke Prevention using an Oral Thrombin Inhibitor in patients with atrial Fibrillation ( SPORTIF ) III and V data sets . For this study , we analyzed all patients assigned to the warfarin arm with data on body mass index ( BMI ) . Time in therapeutic range was used as an index of the quality of anticoagulation control . The 3,630 patients eligible for this analysis were categorized as follows : ( 1 ) BMI 18.5 to 24.9 ( " normal weight " ) in 24.1 % ; ( 2 ) BMI 25.0 to 29.9 ( " overweight " ) in 39.8 % ; and BMI ≥30 ( " obese " ) in 36.1 % . Both overweight ( hazard ratio [ HR ] 0.70 ) and obese ( HR 0.59 ) categories were inversely associated with the composite outcome of stroke/all-cause death . A similar inverse association was seen for the end point of stroke ( HR 0.61 and 0.47 , respectively ) . Good anticoagulation control also attenuated the association between BMI categories and outcomes . In patients with time in therapeutic range > 70 % , BMI category was not significantly associated with the composite outcome of stroke/death and stroke . Stroke and all-cause death progressively reduced in overweight and obese anticoagulated patients with AF . The inverse relation of BMI categories to the risk of stroke and all-cause death was mitigated by good anticoagulation control BACKGROUND Obesity is associated with the development of atrial fibrillation and may impact atrial fibrillation-related outcomes . To date , no anthropometric measure is included in any risk stratification scheme for stroke and death in atrial fibrillation patients . METHODS The prospect i ve Danish Diet , Cancer and Health study is a cohort including 57,053 participants ( 27,178 men and 29,875 women ) aged between 50 and 64 years . The study population for this study included the 3135 patients ( 2025 men and 1110 women ) who developed incident atrial fibrillation during follow-up . RESULTS Of the subjects with atrial fibrillation , 1414 ( 45 % ) had a body mass index ( BMI ) in the overweight category ( BMI 25 to < 30 kg/m(2 ) ) and 767 ( 24 % ) were categorized as obese ( BMI ≥30 kg/m(2 ) ) . During a median follow-up of 4.9 years , 609 deaths and 216 thromboembolic events ( 98 % ischemic strokes ) occurred . Using normal-weight patients as reference , the risk of a composite end point of " ischemic stroke , thromboembolism , or death " was significantly higher in overweight ( crude hazard ratio [ HR ] 1.31 ; 95 % confidence interval [ CI ] , 1.09 - 1.56 ) and obese patients ( crude HR 1.55 ; 95 % CI 1.27 - 1.90 ) . After adjustment for CHADS2 and CHA2DS2-VASc scores , the HRs for the composite end point were 1.21 ( 95 % CI 1.02 - 1.45 ) and 1.31 ( 95 % CI 1.10 - 1.56 ) , respectively , for overweight and 1.25 ( 95 % CI 1.03 - 1.53 ) and 1.36 ( 95 % CI 1.11 - 1.65 ) , respectively , for obese . Continuous analyses of BMI stratified by sex identified obese men and normal-weight women as the sex-specific " high-risk " categories . CONCLUSION Overweight and obesity are risk factors for " ischemic stroke , thromboembolism or death " in patients with atrial fibrillation , even after adjustment for CHADS2 and CHA2DS2-VASc scores . The association between BMI and outcomes among atrial fibrillation patients may be modified by sex
target: Results — An obesity paradox was found for cardiovascular death and all-cause death in the subgroup analyses of r and omized trial cohorts ; however , observational studies fail to show this relationship .
  Conclusions — There may be an obesity paradox in atrial fibrillation patients , particularly for all-cause and cardiovascular death outcomes .
  An obesity paradox was also evident for stroke/systemic embolic event outcome in NOAC trials , with a treatment effect favoring NOACs over warfarin for both efficacy and safety that was significant only for normal weight patients
background: Background and Purpose — Obesity is a risk factor for all-cause and cardiovascular death but , despite this , an inverse relationship between overweight or obesity and a better cardiovascular prognosis in long-term follow-up studies has been observed ; this phenomenon , described as obesity paradox , has also been found evident in atrial fibrillation cohorts .
  Methods — We performed a systematic review on the relationship between body mass index and major adverse outcomes in atrial fibrillation patients .