The American College of Chest Physicians guidelines recommend agents such as aspirin and warfarin for stroke prevention.1 Each of these agents differs in terms of safety and efficacy and carries their own caveats. The mainstay of treatment for those at moderate risk for stroke is primarily warfarin, adjusted to an INR target of 2 to 3 to balance stroke reduction and bleeding risk. Newer anticoagulants do not require INR monitoring and are less susceptible to dietary and drug interactions compared to warfarin. Apixaban for example, a novel approach to anticoagulation, works by inhibiting factor Xa of the coagulation cascade and has been studied for prevention and treatment of venous thromboembolism (VTE) in orthopedic populations.2
The ARISTOTLE study is a randomized, double-blind trial that compared apixaban (at a dose of 5 mg twice daily) with warfarin (target INR 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The study showed that apixaban outperforms current standard of care in a worldwide, moderate-stroke risk population by revealing statistically significant benefit in both efficacy and safety. Apixaban was superior to warfarin in preventing stroke or systemic embolism (1.27% vs 1.60%, CI 0.66 to 0.95; P<.01; NNT/year=303), all-cause mortality (3.52% vs 3.94%; HR 0.89, CI 0.81-0.98; P= 0.047; NNT/year 238) and major bleeding (2.13% vs 3.09%, HR 0.69, CI 0.60 to 0.80; P<.001; NNH/year=105).3 Compared with previous trials of other novel anticoagulants such as dabigatran’s RE-LY trial and rivaroxaban’s ROCKET-AF trial, the ARISTOTLE trial presented stronger results that proved superiority rather than noninferiority in primary outcome (stroke or systemic embolism) and a statistically significant benefit in all-cause mortality.4,5
Other notable features of the ARISTOTLE trial include: an appropriately selected study comparator (i.e. dose adjusted warfarin with an adequately reported time in therapeutic range (TTR), a mean of 62%; a statistically significant benefit in the outcome of stroke or hemorrhagic stroke alone with beneficial trends in other non-significant outcomes, and also a strict definition for bleeding based on the International Society on Thrombosis and Haemostasis criteria.6 Areas of concern regarding this study include: the lack of investigation of other important risk factors, including obesity, smoking history, and race; the question of true experimental blinding due to reliance of a “sham INR” to ensure similar monitoring; a TTR calculation not based on entire study’s timeline; and most concerning, the subanalysis in the North American subgroup was unable to prove statistically significant noninferiority.3
In summary, the ARISTOTLE investigators have successfully executed a study that suggests that to the general, worldwide atrial fibrillation population with low to moderate stroke risk, that apixaban is more efficacious and safer than warfarin. However, further studies are necessary to determine true benefit to the North American and United States population. Furthermore, there may be some question regarding whether the comparator arm was optimally dosed. Providers must not overlook the long history of safe warfarin use when appropriately dosed and monitored, the availability of an antidote if bleeding events do occur, medication compliance for daily dosed warfarin versus twice daily apixaban, as well as cost. With current data at ...