the current prevalence of atrial fibrillation estimated in the developed countries was approximately 1.52% of the general population .
the incidence of atrial fibrillation increased with age , and it was estimated that both incidence and prevalence of atrial fibrillation were likely to rise from 2010 to 2030 due to the extension of survival .
such risk factors included heart failure , hypertension , age , diabetes , previous stroke , vascular disease , and sex category , which were expressed by the cha2ds2-vasc scores .
stroke increased the burden of economic cost on the healthcare system , so it was necessary to search for an effective preventive therapy .
however , with the disadvantages of the unstable international normalized ratio ( inr ) and high rates of bleeding , inr had to be frequently monitored , and dosages of warfarin had to be carefully adjusted according to it , which led to the poor medication adherence .
therefore , the novel oral anticoagulants ( noacs ) were developed as alternatives to warfarin , such as the direct thrombin inhibitor dabigatran , and the direct factor xa inhibitors apixaban , rivaroxaban , and edoxaban .
four large phase iii randomized controlled trials ( rcts ) , registering approximately 70  000 participants , demonstrated that noacs were noninferior to warfarin for the prevention of stroke or systemic embolism .
however , there was no head - to - head evidence to compare noacs with each other .
network meta - analysis ( nma ) was a statistical method to assess the degree of agreement between direct and indirect comparisons .
we therefore aimed to assess the relative efficacy and safety of interventions for stroke prevention using the nma approach .
we systematically searched for relevant rcts in cochrane , pubmed , embase , and medline from inception through april 2014 using the following keywords : nonvalvular atrial fibrillation , stroke prevention , novel oral anticoagulants , dabigatran , apixaban , rivaroxaban , edoxaban , and warfarin .
in addition , the reference lists of published articles and previous meta - analyses were manually searched .
this meta - analysis was carried out in accordance with the preferred reporting items for systematic reviews and meta - analyses .
studies were eligible to be included in the meta - analysis if they were prospective , randomized controlled , double - blinded or open - labeled , phase iii trials , comparing any of the following four noacs  dabigatran , apixaban , rivaroxaban , and edoxaban  with vitamin k antagonists in patients diagnosed with nonvalvular atrial fibrillation and at least one risk factor for stroke .
the reporting data of included studies were mainly on the relevant outcomes of stroke and bleeding .
we excluded nonrandomized studies , substudy of the rcts , ongoing trials , and those involving children ( < 18 years of age ) or patients who had a valvular atrial fibrillation , recent stroke , or a condition with a risk of bleeding .
two investigators ( w.f . , j.g . ) independently performed the literature search and assessed the relevance of the research objects .
disagreements were resolved by consensus or in consultation with a third author ( z.s . ) .
the quality of the studies was assessed by two authors ( w.f . , j.g . ) independently according to the criteria described in the cochrane handbook 5.1.0 .
the criteria included the following items : sequence generation , allocation sequence concealment , blinding of participants , incomplete outcome data , and selective outcome reporting .
yes ,  no , or  unclear , and the summary assessment of the risk of bias for each important outcome within and across studies was categorized as  low risk of bias ,  unclear risk of bias , or  high risk of bias. disagreements were resolved by discussion or in consultation with a third author ( z.s . ) .
we performed nma within a bayesian framework using markov chain monte carlo methods , which combined direct and indirect evidence for any given treatments in one joint analysis .
the analysis not only increased statistical power of the direct comparisons but also provided insights into the relative effectiveness of interventions that have never been directly compared . we did both fixed and random effects models and estimated the fitness by calculating the totresdev and deviance information criterion ( dic ) .
when totresdev equaled the total number of the original data , the model fit the best .
the values of dic and totresdev were similar for all results of fixed and random effects models , so there was almost no difference in model fitness . in analyses including a few studies , the random effects model will produce poor estimates of the variation .
given that the nma included only four rcts , we chose the fixed - effects model to avoid poor estimates of variation .
the odds ratios ( ors ) and appropriate 95% confidence intervals ( cis ) of outcomes were calculated to assess the compared interventions , and the p values below 0.05 were used to assess significance .
heterogeneity was assessed with the data including ttr , chads2 score , age , and sex .
two sensitivity analyses were performed including a meta - analysis of the factor xa inhibitors only , the thrombin inhibitor dabigatran removed , and an analysis combining all doses of all noacs .
statistical analyses were conducted using stata version 12.0 ( statacorp , college station , texas , usa ) , r version 2.15.0 ( r foundation for statistical computing , vienna , austria ) , and winbugs 1.4.3 ( mrc biostatistic unit , cambridge , uk ) through the package r2winbugs .
we systematically searched for relevant rcts in cochrane , pubmed , embase , and medline from inception through april 2014 using the following keywords : nonvalvular atrial fibrillation , stroke prevention , novel oral anticoagulants , dabigatran , apixaban , rivaroxaban , edoxaban , and warfarin .
in addition , the reference lists of published articles and previous meta - analyses were manually searched .
this meta - analysis was carried out in accordance with the preferred reporting items for systematic reviews and meta - analyses .
studies were eligible to be included in the meta - analysis if they were prospective , randomized controlled , double - blinded or open - labeled , phase iii trials , comparing any of the following four noacs  dabigatran , apixaban , rivaroxaban , and edoxaban  with vitamin k antagonists in patients diagnosed with nonvalvular atrial fibrillation and at least one risk factor for stroke .
the reporting data of included studies were mainly on the relevant outcomes of stroke and bleeding .
we excluded nonrandomized studies , substudy of the rcts , ongoing trials , and those involving children ( < 18 years of age ) or patients who had a valvular atrial fibrillation , recent stroke , or a condition with a risk of bleeding .
two investigators ( w.f . , j.g . ) independently performed the literature search and assessed the relevance of the research objects .
disagreements were resolved by consensus or in consultation with a third author ( z.s . ) .
the quality of the studies was assessed by two authors ( w.f . , j.g . ) independently according to the criteria described in the cochrane handbook 5.1.0 .
the criteria included the following items : sequence generation , allocation sequence concealment , blinding of participants , incomplete outcome data , and selective outcome reporting .
unclear , and the summary assessment of the risk of bias for each important outcome within and across studies was categorized as  low risk of bias ,  unclear risk of bias , or  high risk of bias. disagreements were resolved by discussion or in consultation with a third author ( z.s . ) .
we performed nma within a bayesian framework using markov chain monte carlo methods , which combined direct and indirect evidence for any given treatments in one joint analysis .
the analysis not only increased statistical power of the direct comparisons but also provided insights into the relative effectiveness of interventions that have never been directly compared .
we did both fixed and random effects models and estimated the fitness by calculating the totresdev and deviance information criterion ( dic ) .
when totresdev equaled the total number of the original data , the model fit the best .
dic was an estimate of expected predictive error . in the current nma , the values of dic and totresdev were similar for all results of fixed and random effects models , so there was almost no difference in model fitness . in analyses including a few studies , the random effects model will produce poor estimates of the variation . given that the nma included only four rcts , we chose the fixed - effects model to avoid poor estimates of variation .
the odds ratios ( ors ) and appropriate 95% confidence intervals ( cis ) of outcomes were calculated to assess the compared interventions , and the p values below 0.05 were used to assess significance .
heterogeneity was assessed with the data including ttr , chads2 score , age , and sex .
two sensitivity analyses were performed including a meta - analysis of the factor xa inhibitors only , the thrombin inhibitor dabigatran removed , and an analysis combining all doses of all noacs .
statistical analyses were conducted using stata version 12.0 ( statacorp , college station , texas , usa ) , r version 2.15.0 ( r foundation for statistical computing , vienna , austria ) , and winbugs 1.4.3 ( mrc biostatistic unit , cambridge , uk ) through the package r2winbugs .
our electronic searches yielded 4694 studies after elimination of duplicate results , through a review of titles and abstracts ; 4456 studies were rejected for laboratory studies , were review articles , or were irrelevant to the current analysis .
the remaining 238 articles were reviewed and assessed for satisfaction of the inclusion or exclusion criteria ( fig .
since clinical and methodological diversity always occurs in a meta - analysis , statistical heterogeneity is inevitable .
there was also notable heterogeneity in the remaining articles . to decrease statistical heterogeneity and increase comparable ascertainment , we restricted phase iii trials comparing noacs with warfarin in the current study , and did not incorporate any phase ii dose - ranging studies because of their small sample size and short follow - up .
we did not include the j - rocket - af trial mainly because of its smaller sample size ( n  =  1278 ) compared with the global rocket - af ( n  =  14  264 ) . to minimize heterogeneity and confirm the reliability , we had to restrict rcts whose sample sizes were similar
. finally , four rcts ( n  =  71  683 ) fulfilled our inclusion criteria : the re - ly evaluated dabigatran , aristotle trial investigated apixaban , rocket - af evaluated rivaroxaban , and edoxaban investigated in engage af - timi 48 .
the qualitative assessment and risk of bias for each trial are reported in supplementary fig .
sensitivity analyses removing dabigatran and combining all doses of all noacs also showed similar results .
the results of noacs vs. warfarin and noac vs. noac are respectively summarized in table 2 and table 3 for the outcomes of stroke or systemic embolism , any stroke , hemorrhagic stroke , ischemic stroke , disabling or fatal stroke , all - cause mortality , myocardial infarction ( mi ) , major bleeding , gastrointestinal bleeding , intracranial hemorrhage ( ich ) , and any bleeding .
other than edoxaban 30  mg , the remaining noacs demonstrated numerically lower hazards of stroke or systemic embolism , and any stroke compared with warfarin .
it reached statistical significance for apixaban and dabigatran 150  mg in prevention of stroke or systemic embolism and any stroke , whereas edoxaban 60  mg only in stroke or systemic embolism .
all noacs were associated with a significant reduction in the risk of hemorrhagic stroke . compared with warfarin ,
dabigatran 150  mg could significantly reduce the risk of ischemic stroke , whereas edoxaban 30  mg could significantly increase the risk of ischemic stroke .
dabigatran 150  mg and apixaban could significantly reduce the risk of disabling and fatal stroke .
all - cause mortality was numerically reduced by all noacs , especially by apixaban and edoxaban 30  mg .
only dabigatran 150  mg could increase the risk of mi significantly . concerning the safety results , apixaban , dabigatran110  mg , and both doses of edoxaban exhibited lower rates of major bleeding and any bleeding compared with warfarin .
a significantly lower hazard for dabigatran 150  mg in any bleeding was also observed .
dabigatran 150  mg , rivaroxaban , and edoxaban 60  mg were associated with significantly increased gastrointestinal bleeding ; however , edoxaban 30  mg was the opposite .
compared with dabigatran 150  mg , rivaroxaban showed significantly higher hazards of stroke or systemic embolism , any stroke , and hemorrhagic stroke .
the hazards of stroke or systemic embolism , any stroke , ischemic stroke , and disabling or fatal stroke were significantly higher for edoxaban 30  mg compared with dabigatran 150  mg .
a similar pattern in any stroke was observed for edoxaban 60  mg compared with dabigatran 150  mg .
there were significantly higher risks of stroke or systemic embolism , any stroke , ischemic stroke , and disabling or fatal stroke for edoxaban 30  mg compared with apixaban . a similar pattern , with the exception of stroke or systemic embolism ,
the results of efficacy achieved no statistical significance for edoxaban 60  mg compared with apixaban , rivaroxaban , and dabigatran 110  mg , respectively .
edoxaban 60  mg had significantly lower risks of stroke or systemic embolism , any stroke , and ischemic stroke , than edoxaban 30  mg . lower risks of stroke or systemic embolism , any stroke , and ischemic stroke were observed in dabigatran 150  mg compared with dabigatran 110  mg .
apixaban , rivaroxaban , and edoxaban 60  mg could significantly reduce the risk of mi compared with dabigatran 150  mg . regarding the bleeding outcomes , the hazards of major bleeding , gastrointestinal bleeding , and any bleeding were significantly higher for rivaroxaban vs. apixaban and edoxaban 30  mg .
a similar pattern was observed for both doses of dabigatran vs. edoxaban 30  mg and for dabigatran 150  mg vs. apixaban .
the hazards of major bleeding , ich , and any bleeding were significantly higher for rivaroxaban vs. dabigatran 110  mg .
the hazards of major bleeding were significantly lower for edoxaban 30  mg than apixaban , and similar results were observed in edoxaban 60  mg vs. rivaroxaban .
the hazard of ich was significantly lower for edoxaban 30  mg than for rivaroxaban .
the hazard of any bleeding was significantly higher for edoxaban 60  mg than for dabigatran 110  mg , and similar results were observed in rivaroxaban vs. dabigatran 150  mg , edoxaban 60  mg vs. apixaban , and rivaroxaban vs. edoxaban 60  mg .
the hazards of major bleeding , gastrointestinal bleeding , and any bleeding were significantly higher for edoxaban 60  mg than edoxaban 30  mg ; the hazard of any bleeding was significantly higher for dabigatran 150  mg compared with dabigatran 110  mg .
our electronic searches yielded 4694 studies after elimination of duplicate results , through a review of titles and abstracts ; 4456 studies were rejected for laboratory studies , were review articles , or were irrelevant to the current analysis .
the remaining 238 articles were reviewed and assessed for satisfaction of the inclusion or exclusion criteria ( fig .
since clinical and methodological diversity always occurs in a meta - analysis , statistical heterogeneity is inevitable .
there was also notable heterogeneity in the remaining articles . to decrease statistical heterogeneity and increase comparable ascertainment , we restricted phase iii trials comparing noacs with warfarin in the current study , and did not incorporate any phase ii dose - ranging studies because of their small sample size and short follow - up .
we did not include the j - rocket - af trial mainly because of its smaller sample size ( n  =  1278 ) compared with the global rocket - af ( n  =  14  264 ) . to minimize heterogeneity and confirm the reliability , we had to restrict rcts whose sample sizes were similar
. finally , four rcts ( n  =  71  683 ) fulfilled our inclusion criteria : the re - ly evaluated dabigatran , aristotle trial investigated apixaban , rocket - af evaluated rivaroxaban , and edoxaban investigated in engage af - timi 48 .
the qualitative assessment and risk of bias for each trial are reported in supplementary fig .
sensitivity analyses removing dabigatran and combining all doses of all noacs also showed similar results .
the results of noacs vs. warfarin and noac vs. noac are respectively summarized in table 2 and table 3 for the outcomes of stroke or systemic embolism , any stroke , hemorrhagic stroke , ischemic stroke , disabling or fatal stroke , all - cause mortality , myocardial infarction ( mi ) , major bleeding , gastrointestinal bleeding , intracranial hemorrhage ( ich ) , and any bleeding .
other than edoxaban 30  mg , the remaining noacs demonstrated numerically lower hazards of stroke or systemic embolism , and any stroke compared with warfarin .
it reached statistical significance for apixaban and dabigatran 150  mg in prevention of stroke or systemic embolism and any stroke , whereas edoxaban 60  mg only in stroke or systemic embolism .
all noacs were associated with a significant reduction in the risk of hemorrhagic stroke . compared with warfarin ,
dabigatran 150  mg could significantly reduce the risk of ischemic stroke , whereas edoxaban 30  mg could significantly increase the risk of ischemic stroke .
dabigatran 150  mg and apixaban could significantly reduce the risk of disabling and fatal stroke .
all - cause mortality was numerically reduced by all noacs , especially by apixaban and edoxaban 30  mg . only dabigatran 150  mg could increase the risk of mi significantly . concerning the safety results , apixaban , dabigatran110  mg , and both doses of edoxaban exhibited lower rates of major bleeding and any bleeding compared with warfarin .
a significantly lower hazard for dabigatran 150  mg in any bleeding was also observed .
dabigatran 150  mg , rivaroxaban , and edoxaban 60  mg were associated with significantly increased gastrointestinal bleeding ; however , edoxaban 30  mg was the opposite .
compared with dabigatran 150  mg , rivaroxaban showed significantly higher hazards of stroke or systemic embolism , any stroke , and hemorrhagic stroke .
the hazards of stroke or systemic embolism , any stroke , ischemic stroke , and disabling or fatal stroke were significantly higher for edoxaban 30  mg compared with dabigatran 150  mg .
a similar pattern in any stroke was observed for edoxaban 60  mg compared with dabigatran 150  mg .
there were significantly higher risks of stroke or systemic embolism , any stroke , ischemic stroke , and disabling or fatal stroke for edoxaban 30  mg compared with apixaban .
a similar pattern , with the exception of stroke or systemic embolism , was seen in the comparison of edoxaban 30  mg and rivaroxaban .
the results of efficacy achieved no statistical significance for edoxaban 60  mg compared with apixaban , rivaroxaban , and dabigatran 110  mg , respectively .
edoxaban 60  mg had significantly lower risks of stroke or systemic embolism , any stroke , and ischemic stroke , than edoxaban 30  mg . lower risks of stroke or systemic embolism , any stroke , and ischemic stroke were observed in dabigatran 150  mg compared with dabigatran 110  mg .
apixaban , rivaroxaban , and edoxaban 60  mg could significantly reduce the risk of mi compared with dabigatran 150  mg . regarding the bleeding outcomes , the hazards of major bleeding , gastrointestinal bleeding , and any bleeding were significantly higher for rivaroxaban vs. apixaban and edoxaban 30  mg .
a similar pattern was observed for both doses of dabigatran vs. edoxaban 30  mg and for dabigatran 150  mg vs. apixaban .
the hazards of major bleeding , ich , and any bleeding were significantly higher for rivaroxaban vs. dabigatran 110  mg .
the hazards of major bleeding were significantly lower for edoxaban 30  mg than apixaban , and similar results were observed in edoxaban 60  mg vs. rivaroxaban .
the hazard of ich was significantly lower for edoxaban 30  mg than for rivaroxaban .
the hazard of any bleeding was significantly higher for edoxaban 60  mg than for dabigatran 110  mg , and similar results were observed in rivaroxaban vs. dabigatran 150  mg , edoxaban 60  mg vs. apixaban , and rivaroxaban vs. edoxaban 60  mg .
the hazards of major bleeding , gastrointestinal bleeding , and any bleeding were significantly higher for edoxaban 60  mg than edoxaban 30  mg ; the hazard of any bleeding was significantly higher for dabigatran 150  mg compared with dabigatran 110  mg .
other than edoxaban 30  mg , the remaining noacs demonstrated numerically lower hazards of stroke or systemic embolism , and any stroke compared with warfarin .
it reached statistical significance for apixaban and dabigatran 150  mg in prevention of stroke or systemic embolism and any stroke , whereas edoxaban 60  mg only in stroke or systemic embolism .
all noacs were associated with a significant reduction in the risk of hemorrhagic stroke . compared with warfarin ,
dabigatran 150  mg could significantly reduce the risk of ischemic stroke , whereas edoxaban 30  mg could significantly increase the risk of ischemic stroke .
dabigatran 150  mg and apixaban could significantly reduce the risk of disabling and fatal stroke .
all - cause mortality was numerically reduced by all noacs , especially by apixaban and edoxaban 30  mg . only dabigatran 150  mg could increase the risk of mi significantly . concerning the safety results , apixaban , dabigatran110  mg , and both doses of edoxaban exhibited lower rates of major bleeding and any bleeding compared with warfarin .
a significantly lower hazard for dabigatran 150  mg in any bleeding was also observed .
dabigatran 150  mg , rivaroxaban , and edoxaban 60  mg were associated with significantly increased gastrointestinal bleeding ; however , edoxaban 30  mg was the opposite .
compared with dabigatran 150  mg , rivaroxaban showed significantly higher hazards of stroke or systemic embolism , any stroke , and hemorrhagic stroke .
the hazards of stroke or systemic embolism , any stroke , ischemic stroke , and disabling or fatal stroke were significantly higher for edoxaban 30  mg compared with dabigatran 150  mg .
a similar pattern in any stroke was observed for edoxaban 60  mg compared with dabigatran 150  mg .
there were significantly higher risks of stroke or systemic embolism , any stroke , ischemic stroke , and disabling or fatal stroke for edoxaban 30  mg compared with apixaban .
a similar pattern , with the exception of stroke or systemic embolism , was seen in the comparison of edoxaban 30  mg and rivaroxaban .
the results of efficacy achieved no statistical significance for edoxaban 60  mg compared with apixaban , rivaroxaban , and dabigatran 110  mg , respectively .
edoxaban 60  mg had significantly lower risks of stroke or systemic embolism , any stroke , and ischemic stroke , than edoxaban 30  mg . lower risks of stroke or systemic embolism , any stroke , and ischemic stroke were observed in dabigatran 150  mg compared with dabigatran 110  mg .
apixaban , rivaroxaban , and edoxaban 60  mg could significantly reduce the risk of mi compared with dabigatran 150  mg . regarding the bleeding outcomes , the hazards of major bleeding , gastrointestinal bleeding , and any bleeding were significantly higher for rivaroxaban vs. apixaban and edoxaban 30  mg .
a similar pattern was observed for both doses of dabigatran vs. edoxaban 30  mg and for dabigatran 150  mg vs. apixaban .
the hazards of major bleeding , ich , and any bleeding were significantly higher for rivaroxaban vs. dabigatran 110  mg .
the hazards of major bleeding were significantly lower for edoxaban 30  mg than apixaban , and similar results were observed in edoxaban 60  mg vs. rivaroxaban .
the hazard of ich was significantly lower for edoxaban 30  mg than for rivaroxaban .
the hazard of any bleeding was significantly higher for edoxaban 60  mg than for dabigatran 110  mg , and similar results were observed in rivaroxaban vs. dabigatran 150  mg , edoxaban 60  mg vs. apixaban , and rivaroxaban vs. edoxaban 60  mg .
the hazards of major bleeding , gastrointestinal bleeding , and any bleeding were significantly higher for edoxaban 60  mg than edoxaban 30  mg ; the hazard of any bleeding was significantly higher for dabigatran 150  mg compared with dabigatran 110  mg .
the current nma aimed to compare the efficacy and safety of noacs for stroke prevention in patients with nonvalvular atrial fibrillation .
nma is necessary as no studies compared noacs with each other head - to - head , and such a trial is difficult to implement due to a large number of involved population and expense .
the results of indirect comparison are usually , but not always , consistent with the direct ones .
when direct evidence of rcts is insufficient , indirect comparison can provide useful complementary information .
therefore , to minimize heterogeneity and confirm reliability , the current nma was restricted to four rcts whose outcomes were sufficiently similar and balanced .
the results comparing noacs and warfarin from the current analysis were consistent with the direct ones and confirmed the findings from direct analysis .
the application and development of anticoagulant drugs aim at seeking balances between hemorrhage and thrombosis , as higher efficacy in stroke prevention is related to higher risk of major bleeding events .
therefore , when we evaluated new treatments , both results of stroke prevention and bleeding had to be carefully considered , rather than estimating clinical efficacy in isolation . according to the results of the nma , apixaban , edoxaban 60  mg , and dabigatran 150  mg were found to have significantly better efficacy in prevention of stroke or systemic embolism than warfarin .
similarly , apixaban , both doses of edoxaban , and dabigatran 110  mg have significantly demonstrated lower hazards of major bleeding .
moreover , a meta - analysis including the four rcts was published recently , which demonstrated similar results for the four noacs compared with warfarin , but there were no comparisons among noacs .
although an indirect comparison analysis among noacs has been recently published , it used the so - called bucher method , which can only be used for testing with two arms .
however , the bayesian model used in the current nma did not have such a limitation . moreover
, in the four included trials , there were direct comparisons between two doses of dabigatran and edoxaban .
three arms partly existed in the network geometry , so we think the results in our analysis were more robust . similar results between the two methods were observed , but the ci was larger in our analysis .
other early published nmas only provided comparisons in the outcomes of stroke or systemic embolism and major bleeding . according to the results from indirect comparisons , edoxaban
60  mg and apixaban were better than dabigatran 150  mg and rivaroxaban in bleeding events , and were more favorable compared with dabigatran 110  mg and edoxaban 30  mg with respect to stroke prevention .
apixaban significantly revealed better results than edoxaban 60  mg in any bleeding events . in conclusion ,
apixaban was considered to have an advantage over the other noacs in terms of safety .
it is , however , still necessary to further investigate these findings by real - world applications and studies .
although the similarity assessment was conducted by inclusion criteria applied for the selection of studies , there remained to be some study - designed differences between the included trials .
aristotle , rocket - af , and engage af - timi 48 were designed as double - blinded , double - dummy trials .
only re - ly was an open - labeled study that might have increased selection bias and overestimated the therapeutic effect .
moreover , aristotle and re - ly studies enrolled patients who had a chads2 score of at least 1 , whereas patients with higher risk ( chads2 score of 2 ) were enrolled in rocket - af and engage af - timi 48 .
the therapeutic ranges ( ttr ) of 2.03.0 for warfarin were different in all the four trials . efficacy and safety analyses of the re - ly study
however , in the other three trials , efficacy analyses were conducted on the itt population and safety analyses on the on - treatment population .
moreover , the network geometry was not well connected to form a closed loop ; thus , the results were possibly inconsistent .
although the similarity assessment was conducted by inclusion criteria applied for the selection of studies , there remained to be some study - designed differences between the included trials .
aristotle , rocket - af , and engage af - timi 48 were designed as double - blinded , double - dummy trials .
only re - ly was an open - labeled study that might have increased selection bias and overestimated the therapeutic effect .
moreover , aristotle and re - ly studies enrolled patients who had a chads2 score of at least 1 , whereas patients with higher risk ( chads2 score of 2 ) were enrolled in rocket - af and engage af - timi 48 .
the therapeutic ranges ( ttr ) of 2.03.0 for warfarin were different in all the four trials .
efficacy and safety analyses of the re - ly study were based on the intention - to - treat ( itt ) population .
however , in the other three trials , efficacy analyses were conducted on the itt population and safety analyses on the on - treatment population . moreover , the network geometry was not well connected to form a closed loop ; thus , the results were possibly inconsistent .
the study was supported by grants from the medical and health research fund project of pla ( no.3202410 ) .
 backgroundmuch direct evidence has proved that the novel oral anticoagulants ( noacs ) are noninferior or superior to warfarin for stroke prevention in patients with nonvalvular atrial fibrillation , and lead to a relevant decrease in bleeding profiles . 
 however , no study has compared noacs with each other head - to - head . 
 the current study is a network meta - analysis aiming to assess the efficacy and safety of noacs.methodscochrane library , pubmed ncbi , embase and medline were systematically searched for randomized controlled trials that assessed the efficacy and safety profiles of noacs compared with warfarin . 
 the primary outcome was the rate of stroke or systemic embolism , and the secondary outcome was the rate of bleeding events . 
 network meta - analysis was performed using markov chain monte carlo methods.resultsa total of four phase iii randomized controlled trials ( n  =  71683 ) met the inclusion criteria . 
 all noacs except low dose of edoxaban showed noninferior efficacies to warfarin in stroke prevention . in the field of hemorrhage , apixaban was safer than edoxaban 60  mg in any bleeding events and had fewer major bleeding events compared with dabigatran 150  mg and rivaroxaban.conclusionnoacs are promising candidates for stroke prevention in patients with nonvalvular atrial fibrillation due to a favorable risk  benefit profile . 
 all noacs other than edoxaban 30  mg had parallel efficacies with respect to stroke prevention . 
 apixaban had an advantage over the other noacs in safety . 
Background
Method
Literature search
Study selection and data extraction
Qualitative assessment
Statistical analysis
Results
Study selection and description
Network meta-analysis
Novel oral anticoagulants versus warfarin
Indirect comparisons among novel oral anticoagulants
Discussion
Limitations
Acknowledgements
Supplementary Material