Apixaban: Hailing Warfarin's Demise?

With the publication of "Apixaban versus Warfarin in Patients with Atrial Fibrillation" (the ARISTOLE trial) in the New England Journal of Medicine, the third drug in a series of medications designed to attack thrombin in the clotting cascade. The study was announced with quite a fanfare in Europe as cardiologists, financial analysts and reporters gushed forth with 'mega-blockbuster' praise this past weekend.

And for good reason.

This is the first trial to conclude that this direct Factor Xa inhibitor demonstrated a mortality superiority over warfarin when treating patients with non-rheumatic atrial fibrillation (Two earlier trials showed a trend that way, but only reached mortality equivalency, not superiority: the direct thrombin inhibitor dabigratran's Re-LY Trial and rival direct Factor Xa inbibitor rivaroxaban's ROCKET-AF trial). Specifically, the 18,201-patient ARTISTOLE trial showed

The rate of the primary outcome (major bleeding) was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42).

(Although registration is required, please see the excellent review by Larry Husten over at the Cardioexchange blog).

So is warfarin now passé in the treatment of non-rheumatic atrial fibrillation?

Not quite yet.

There remain some significant caveats for doctors and patients that should be remembered now that these advantages to apixaban have been published.

• While aspirin was used in about 30% of the patients placed on apixaban in this study, only 1.9% of the patients were also taking the common antiplatelet agent clopidogrel. Recall that the study protocol stated "Patients taking a thienopyridine at baseline were not eligible for inclusion in the study, although these drugs could be prescribed during the study if an indication emerged." The risks for bleeding for patients already on aspirin and clopidogrel (or its more potent cousin prasugrel) may be significant. Certainly the lack of antidote to the anticoagulating effect of this medication may make this "trifecta" of anticoagulants particularly hazardous as long as an antidote to this new class of thrombin-inhibiting drugs does not exist.
• It is important to remember that patients with prosthetic valves were not included in any of the Factor Xa/thrombin inhibitor studies. Warfarin will still be required for those patients - at least until proof of their safety in this cohort of patients surfaces.
• As with dabigatran that has shown some challenges with its limited available dosages in the elderly, clinical experience will dictate whether a drug with a "one dose fits all" like apixaban is as safe as touted. Also, we can only hope that we don't find little "storage and handling issues" for apixaban after release like we did for dabigatran.
• Finally, we are yet to discover apixaban's price (soon to be marketed under the brand name of Eliquis®). Cost remains a significant consideration for patients wanting to make the switch to these newer thrombin-inhibiting medications. With greater cost-shifting for health care and medications being placed on patients, patients with limited monthly budgets will still be slow to switch to these agents.

So while we're seeing the dawn of a new era of anticoagulation for patients with atrial fibrillation, both doctors and patients should recall that there remain considerable limitations to the adoption of this new class of medication that should be carefully considered.

-Wes