The clinical trials being compared for this analysis are summarized in (Table 1), with their primary safety and efficacy endpoints summarized in Online Table 2.
Summary patient characteristics and risk differences (with confidence intervals) are presented for the entire study population in (Table 2). As expected, there were important differences between the studies, particularly for the CHADS2 score (>50 percentage point difference between ROCKET-AF and the other trials) and the proportion of secondary prevention (approximately 35 percentage point difference between ROCKET-AF and the other trials). Mean/median age was broadly similar, as were the proportions of female patients. There were more patients with paroxysmal AF in RE-LY (36.4%) compared with ROCKET-AF and ARISTOTLE (approximately 15 to 17 percentage point difference). The prevalence of prior heart failure, diabetes, and hypertension was highest in ROCKET-AF (62.5%, 40%, and 90.5%, respectively) compared with the other 2 trials. Prior warfarin use was 62.4% in ROCKET-AF, compared with 50% in RE-LY (by design) and 57% in ARISTOTLE. The proportions with prior MI and prior aspirin use were broadly similar in the 3 trials.
When data with dabigatran 150 mg BID were used for the weighted average effects analysis, the new OACs as a whole were associated with lower stroke or systemic embolism (21%, p < 0.001), lower stroke (23% p < 0.001), and lower hemorrhagic stroke (53%, p < 0.001) than warfarin. All-cause mortality was lower for any new OAC (by 12%, p < 0.001). Major and intracranial bleeding were lower for any new OAC by 13% (p < 0.001) and 51% (p < 0.001) respectively. Weighted average hazard ratio and confidence intervals are given in (Table 3).
Relative Efficacy of Dabigatran, Apixaban, and Rivaroxaban
There was a significantly lower risk of stroke and systemic embolism (by 26%) for dabigatran (150 mg BID) compared with rivaroxaban, as well as less hemorrhagic stroke (by 56%, p = 0.039) and nondisabling stroke (by 40%, p = 0.038). There were no significant differences for apixaban versus dabigatran (both doses) or rivaroxaban, or rivaroxaban versus dabigatran 110 mg BID, in preventing stroke and systemic embolism. For the ischemic stroke endpoint, there were no significant differences between the new OACs.
Relative Safety of Dabigatran, Apixaban, and Rivaroxaban
Major bleeding was significantly lower with apixaban compared with dabigatran 150 mg BID (by 26%, p = 0.003) and rivaroxaban (by 34%, p < 0.001), but was not significantly different from dabigatran 110 mg BID ((Table 4), Fig. 1). Gastrointestinal and extracranial bleeding was also significantly less with apixaban compared with dabigatran 150 mg BID, by 41% (p = 0.003) and 26% (p = 0.007), respectively. There were no significant differences between apixaban and dabigatran 110 mg BID in safety endpoints.
Apixaban Versus Dabigatran 110 mg BID, Dabigatran 150 mg BID, and Rivaroxaban
Apixaban also had lower major or clinically relevant bleeding (by 34%, p < 0.001) compared with rivaroxaban. There was an increase (278%, p = 0.027) in systemic embolism for apixaban compared with rivaroxaban with lower bound of 95% confidence interval at 16% increase. Gastrointestinal bleeds were only reported numerically in ROCKET-AF and therefore not used in this analysis.
When compared with rivaroxaban, dabigatran 110 mg BID was associated with less major bleeding (by 23%, p = 0.011) and intracranial bleeding (by 54%, p = 0.006) ((Table 4), Fig. 2).
Rivaroxaban Versus Apixaban, Dabigatran 110 mg BID, and Dabigatran 150 mg BID
Our indirect comparison analysis did not find any significant differences in MI events between dabigatran (both doses) and apixaban but more MI events were seen with dabigatran (>50%) compared to rivaroxaban ((Table 4), Fig.2 ).