Outcomes of Apixaban vs Warfarin by Type of AF
This study has three important findings. First, there was a consistent reduction in stroke or systemic embolism, all-cause mortality, and major bleeding with apixaban compared with warfarin regardless of the type of AF. Secondly, the superiority of apixaban over warfarin was consistent regardless of AF duration, defined as time from first documented occurrence of AF to randomization. Finally, in this study, persistent or permanent AF was associated with a higher risk of stroke or systemic embolism and a trend towards a higher risk of all-cause mortality than paroxysmal AF. These differences were maintained even after adjustment for differences in baseline characteristics that could influence the risk of these events.
Despite differences in baseline characteristics and outcomes by type of AF, there was a consistent reduction in stroke or systemic embolism, all-cause mortality, and major bleeding with apixaban compared with warfarin for both AF types. In an analysis of ACTIVE W (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events), compared with the combination of aspirin and clopidogrel, warfarin resulted in a lower risk of stroke or systemic embolism and a higher risk of bleeding, irrespective of the AF type. In RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy), and compared with warfarin, the higher studied dose of dabigatran showed superior efficacy for stroke prevention with comparable risk of major bleeding in patients with paroxysmal as well as patients with persistent and permanent AF. Thus, it seems likely that the results on stroke prevention with the new anticoagulants compared with warfarin will be consistent regardless of the type of AF.
In this study, apixaban was superior to warfarin, on average, and was consistent regardless of AF duration, defined as time from first documented occurrence of AF to randomization. To our knowledge, our study is the first to examine the effect of an anticoagulant by duration of AF in the context of a large, multicentre, randomized clinical trial. Similar analyses of ACTIVE W and RE-LY did not examine the benefit of study drug by duration of AF at study entry. Because of the potential clinical importance of this factor, it should be examined in future studies including secondary analyses of large contemporary clinical trials of AF. The association between longer duration of AF and reduction in the risk of death is intriguing; however, it likely reflects selection bias that resulted from inclusion in a clinical trial. In other words, patients with longer duration of AF have typically passed the initial first months of AF during which the risk of stroke and major bleeding is high and are more commonly warfarin experienced and more commonly had not had side-effects and complications on warfarin as such patients would have been excluded from participating in a randomized clinical trial.
Although some studies suggested lower event rates in patients with paroxysmal AF than patients with persistent or permanent AF, data from major clinical trials of warfarin as well as other anticoagulants failed to show any difference in clinical events related to AF by AF type. Our findings are in stark contrast with the findings of those studies and raise questions about potential reasons for these differences. Except for RE-LY, previous studies included substantially fewer patients than our study. Specifically, the pooled analysis of the SPAF trials included only 460 patients with paroxysmal AF and 1552 patients with sustained AF, the pooled analysis of the SPORTIF trials included 836 patients with paroxysmal AF and 6493 subjects with persistent AF, and the more recent ACTIVE W trial included 1202 patients with paroxysmal AF and 5495 patients with persistent or permanent AF. By including more patients (2786 patients with paroxysmal AF and 15 412 patients with persistent or permanent AF), our study had more statistical power to determine whether AF type is an independent risk factor for stroke or systemic embolism. Also, ARISTOTLE enrolled a greater proportion of patients with persistent/permanent AF than RE-LY (15 412 vs. 12 164). This may explain why our findings are different from the findings of RE-LY, as patients with persistent or permanent AF are typically more morbid than patients with paroxysmal AF. Although largely speculative, differences between our findings and those of RE-LY may relate to differences in patient characteristics, definitions of types of AF, and outcomes or overall management of patients. Analyses of outcomes by AF type in other large contemporary randomized clinical trials, such as ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) and ENGAGE-AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48), may help address this controversy.
Several caveats should be kept in mind when assessing our results. First, classifying AF is challenging especially given the nuances of the definitions of AF types and the transitioning of some patients from one type of AF to another at different time points. Secondly, although this was a pre-specified secondary analysis of the ARISTOTLE trial and several statistical models were used to adjust for confounding, residual confounding cannot be ruled out. However, our adjusted analysis was quite comprehensive, and therefore, our findings cannot be explained by imbalances in measured covariates. Although there may be unmeasured patient characteristics associated with type of AF that would explain the observed discrepancies, we adjusted for well-known comorbidities that are likely to influence outcomes. Thirdly, we were unable to analyse persistent and permanent AF separately because these were combined into one category during data collection. Because patients with these types of AF may be inherently different, combining them may have introduced some bias. In addition, the distinction between paroxysmal and non-paroxysmal AF is not always clear cut. Fourthly, because the majority of patients in our study had two or fewer ECGs reported in follow-up, these data could not be used to discern type of AF during the follow-up. However, it is somewhat reassuring that the proportion of patients with AF on all subsequent ECGs was substantially higher in the persistent/permanent AF group than in the paroxysmal AF group (81.6 vs. 17.5%). Fifthly, we were neither able to capture the effect of all rhythm-control therapies on AF type nor to assess the AF burden in the follow-up. Our results originated from a large clinical trial population. Notwithstanding the large number of included patients and countries, our results should be validated in other databases.
Discussion
This study has three important findings. First, there was a consistent reduction in stroke or systemic embolism, all-cause mortality, and major bleeding with apixaban compared with warfarin regardless of the type of AF. Secondly, the superiority of apixaban over warfarin was consistent regardless of AF duration, defined as time from first documented occurrence of AF to randomization. Finally, in this study, persistent or permanent AF was associated with a higher risk of stroke or systemic embolism and a trend towards a higher risk of all-cause mortality than paroxysmal AF. These differences were maintained even after adjustment for differences in baseline characteristics that could influence the risk of these events.
Despite differences in baseline characteristics and outcomes by type of AF, there was a consistent reduction in stroke or systemic embolism, all-cause mortality, and major bleeding with apixaban compared with warfarin for both AF types. In an analysis of ACTIVE W (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events), compared with the combination of aspirin and clopidogrel, warfarin resulted in a lower risk of stroke or systemic embolism and a higher risk of bleeding, irrespective of the AF type. In RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy), and compared with warfarin, the higher studied dose of dabigatran showed superior efficacy for stroke prevention with comparable risk of major bleeding in patients with paroxysmal as well as patients with persistent and permanent AF. Thus, it seems likely that the results on stroke prevention with the new anticoagulants compared with warfarin will be consistent regardless of the type of AF.
In this study, apixaban was superior to warfarin, on average, and was consistent regardless of AF duration, defined as time from first documented occurrence of AF to randomization. To our knowledge, our study is the first to examine the effect of an anticoagulant by duration of AF in the context of a large, multicentre, randomized clinical trial. Similar analyses of ACTIVE W and RE-LY did not examine the benefit of study drug by duration of AF at study entry. Because of the potential clinical importance of this factor, it should be examined in future studies including secondary analyses of large contemporary clinical trials of AF. The association between longer duration of AF and reduction in the risk of death is intriguing; however, it likely reflects selection bias that resulted from inclusion in a clinical trial. In other words, patients with longer duration of AF have typically passed the initial first months of AF during which the risk of stroke and major bleeding is high and are more commonly warfarin experienced and more commonly had not had side-effects and complications on warfarin as such patients would have been excluded from participating in a randomized clinical trial.
Although some studies suggested lower event rates in patients with paroxysmal AF than patients with persistent or permanent AF, data from major clinical trials of warfarin as well as other anticoagulants failed to show any difference in clinical events related to AF by AF type. Our findings are in stark contrast with the findings of those studies and raise questions about potential reasons for these differences. Except for RE-LY, previous studies included substantially fewer patients than our study. Specifically, the pooled analysis of the SPAF trials included only 460 patients with paroxysmal AF and 1552 patients with sustained AF, the pooled analysis of the SPORTIF trials included 836 patients with paroxysmal AF and 6493 subjects with persistent AF, and the more recent ACTIVE W trial included 1202 patients with paroxysmal AF and 5495 patients with persistent or permanent AF. By including more patients (2786 patients with paroxysmal AF and 15 412 patients with persistent or permanent AF), our study had more statistical power to determine whether AF type is an independent risk factor for stroke or systemic embolism. Also, ARISTOTLE enrolled a greater proportion of patients with persistent/permanent AF than RE-LY (15 412 vs. 12 164). This may explain why our findings are different from the findings of RE-LY, as patients with persistent or permanent AF are typically more morbid than patients with paroxysmal AF. Although largely speculative, differences between our findings and those of RE-LY may relate to differences in patient characteristics, definitions of types of AF, and outcomes or overall management of patients. Analyses of outcomes by AF type in other large contemporary randomized clinical trials, such as ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) and ENGAGE-AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48), may help address this controversy.
Several caveats should be kept in mind when assessing our results. First, classifying AF is challenging especially given the nuances of the definitions of AF types and the transitioning of some patients from one type of AF to another at different time points. Secondly, although this was a pre-specified secondary analysis of the ARISTOTLE trial and several statistical models were used to adjust for confounding, residual confounding cannot be ruled out. However, our adjusted analysis was quite comprehensive, and therefore, our findings cannot be explained by imbalances in measured covariates. Although there may be unmeasured patient characteristics associated with type of AF that would explain the observed discrepancies, we adjusted for well-known comorbidities that are likely to influence outcomes. Thirdly, we were unable to analyse persistent and permanent AF separately because these were combined into one category during data collection. Because patients with these types of AF may be inherently different, combining them may have introduced some bias. In addition, the distinction between paroxysmal and non-paroxysmal AF is not always clear cut. Fourthly, because the majority of patients in our study had two or fewer ECGs reported in follow-up, these data could not be used to discern type of AF during the follow-up. However, it is somewhat reassuring that the proportion of patients with AF on all subsequent ECGs was substantially higher in the persistent/permanent AF group than in the paroxysmal AF group (81.6 vs. 17.5%). Fifthly, we were neither able to capture the effect of all rhythm-control therapies on AF type nor to assess the AF burden in the follow-up. Our results originated from a large clinical trial population. Notwithstanding the large number of included patients and countries, our results should be validated in other databases.
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