To get some protection against stroke in atrial fibrillation, we, along with our patients have been living with the hassles of warfarin, because we have to. But warfarin may not be our only choice for much longer.
In this week’s NEJM, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial was published. The trial showed that, for patients with non-valvular atrial fibrillation, the investigational drug, apixaban was superior to warfarin for the combined endpoint of stroke (both ischemic and hemorrhagic), and the prevention of systemic thromboembolism.
In this double-blind, double-dummy trial, over eighteen thousand patients with atrial fibrillation and at least one stroke risk factor were randomized to either dose-adjusted warfarin, or twice-daily apixaban, a direct Factor Xa inhibitor. Secondary outcomes included major bleeding and death.
Apixaban, compared to warfarin, reduced the risk of stroke or embolism by 21%, decreased the rate of bleeding by 31%, and reduced the rate of death by 11%. Each outcome met criteria for statistical significance.
A few caveats on the results. The primary outcome notably combined ischemic and hemorrhagic stroke. It is the marked reduction in hemorrhagic stroke, rather than in systemic embolization, that drove the primary endpoint. Another notable detail was that patients in the warfarin group had an INR in the therapeutic range around 62% of the time. Skeptics argue that the less time patients in the warfarin group stay therapeutic, the more likely it is that the study drug will prove superior. But if we want trials with real world implications, what challenge could be more emblematic of life as we know it than keeping patients’ INRs between 2-3?
This is the third large clinical trial published in the Journal among patients with non-valvular atrial fibrillation to demonstrate the non-inferiority of a pharmacologic agent for stroke as compared to warfarin. RE-LY studied the direct thrombin inhibitor, dabigatran, while ROCKET AF studied the Factor Xa inhibitor rivaroxaban. Despite some differences in study design and patients enrolled, all three trials demonstrated a significant decrease in hemorrhagic stroke with the study drug as compared to warfarin. ARISTOTLE, however, was the first trial to show a significant reduction in all-cause mortality with the novel anticoagulant.
Despite the success of all three agents, lingering questions remain.
Cost is critical. Pharmacoeconomic analyses will have to account not just for the much greater expense of these new drugs, but also potential savings wrought by ease of administration and fewer bleeding complications. But bleeds remain a concern. With no way to reverse these agents, what will we do for patients on these drugs who need urgent surgery or present with major bleeds? Finally, warfarin, despite the hassles, does one thing very well: it keeps patients in touch with their medical team. Is it possible that regular INR monitoring fosters adherence not just to thromboembolic prevention, but also to other essential medications? Will the level of therapeutic benefit seen in these three trials be sustained in the real world setting?
Only time will tell. Do you think these drugs are enough of an advance to use one of them or would you stick with warfarin with its long track record?