12/08/11

PARIS – The growing list of oral anticoagulant drugs jockeying to replace warfarin as the go-to agent for stroke prevention in patients with atrial fibrillation added a new candidate, apixaban, that appeared to immediately take the lead on the strength of strikingly impressive results in an 18,000-patient trial.

When matched against warfarin, atrial fibrillation (AF) patients treated with apixaban (Bristol-Myers Squibb, Pfizer, to be known as Eliquis but still pending FDA approval) demonstrated significantly lower rates of stroke and systemic embolism, major bleeding complication, and overall mortality, compared with patients randomized to warfarin during a median follow-up of 1.8 years, Christopher B. Granger, MD, reported at the annual congress of the European Society of Cardiology, and in a published article that concurrently appeared online in the New England Journal of Medicine (10.1056/NEJMoa1107039).

"Treatment with apixaban as compared with warfarin in patients with AF and at least one additional risk factor for stroke reduces stroke and systemic embolism by [a relative] 21%, reduces major bleeding by [a relative] 31%, and reduces mortality by [a relative] 11%," all statistically significant differences, reported Dr. Granger, director of the cardiac care unit at Duke University in Durham, N.C.

"I view the study as a home run. It is incredibly important, and it put another stake in the heart of warfarin in the management of atrial fibrillation to prevent stroke," commented Dr. Ralph Brindis, senior adviser for cardiovascular diseases at Northern California Kaiser.

Apixaban’s accomplishment in significantly surpassing warfarin’s performance for the trio of stroke prevention, bleeding safety, and overall mortality in its pivotal trial, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study, appeared to vault it ahead of dabigatran (Pradaxa, Boehringer Ingelheim), which received Food and Drug Administration approval for stroke prevention in AF patients last October, and the still-investigational agent rivaroxaban (Xarelto, Janssen), which the FDA is currently reviewing for a similar AF indication.

Neither dabigatran nor rivaroxaban could match apixaban’s performance in their respective pivotal AF trials: the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) study that matched dabigatran against warfarin in 18,113 randomized patients (N. Engl. J. Med. 2009;361:1139-51), and the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study that pitted rivaroxaban against warfarin in 14,264 randomized patients (N. Engl. J. Med. 2011 Aug. 10 [10.1056/NEJMoa1009638]).

"We think we hit the sweet spot in terms of the [apixaban] dose" in ARISTOTLE, said Dr. Granger, and although he and other experts warned against the pitfalls of cross-trial comparisons, many also acknowledged that mental calculations comparing the demonstrated pros and cons of each of these three new drugs are inevitable once all three drugs become routinely available. Results from a study directly comparing two or all three of these drugs won’t be available soon, leaving it to clinicians to take into account not only the efficacy and safety performance of the three agents in these studies but other considerations as well, such as their prices, dosing convenience, adverse effects, and individual patient reactions.

"Apixaban has a certain edge because of its safety; [it] reduced all types of bleeding and had impressive tolerability," said Lars Wallentin, MD, PhD, professor and head of cardiology research at Uppsala University in Sweden, and a coinvestigator in both the ARISTOTLE and RE-LY trials. Apixaban also has the attraction of having another major stroke-prevention in AF study under its belt, the Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) study, which randomized 5,599 patients (N. Engl. J. Med. 2011;364:806-17). "We have two [apixaban] trials [in] a large program, showing this safety. In AVERROES the bleeding risk with apixaban was the same as with low-dose aspirin," Dr. Wallentin said in an interview.

"I think it will be very competitive" among the three new drugs, said Michael D. Ezekowitz, MD, professor of medicine at Thomas Jefferson University in Philadelphia and a lead investigator of the RE-LY trial. "That’s what we want; multiple agents competing, each one finding their niche in the huge field of atrial fibrillation treatment. The companies [that make these new drugs] will compete at multiple levels."

ARISTOTLE’s results showed that among patients randomized to apixaban, the rate of the primary stroke and systemic end point during follow-up was 1.27%, major bleeds occurred in 2.13%, the rate of death from any cause was 3.52%, and 0.24% of patients developed a hemorrhagic stroke. In patients randomized to warfarin, strokes or embolisms occurred in 1.60%, major bleeds in 3.09%, all-cause death in 3.94%, and hemorrhagic stroke in 0.47%. All of the differences between the two treatment groups were statistically significant. Over the median 1.8-year follow-up of the study, treatment of 1,000 patients with apixaban prevented on average six strokes (four hemorrhagic and two ischemic or unknown type), 15 major bleeds, and eight deaths compared with patients treated with warfarin.

Ready to Switch?

Apixaban treatment produced better outcomes in atrial fibrillation patients compared with warfarin in the ARISTOTLE trial, regardless of the quality of warfarin treatment the comparator patients received, raising the possibility that all atrial fibrillation patients might benefit by switching from warfarin to apixaban.

"The benefits of apixaban over warfarin in preventing stroke, reducing bleeding, and improving survival appear consistent regardless of a center’s quality of INR [international normalized ratio] control. Therefore, in patients with atrial fibrillation, apixaban is a safer and more effective treatment than warfarin across a wide range of warfarin management," Dr. Wallentin said at the congress. Assessment of apixaban’s efficacy and safety relative to warfarin across the range of warfarin care that was delivered was one of the trial’s prespecified analyses.

Dr. Granger said that he has received grants and consultant fees from numerous pharmaceutical companies, including Boehringer Ingelheim. Dr. Brindis said that he had no disclosures. Dr. Wallentin has received research grants from Bristol-Myers Squibb, Pfizer, Boehringer-Ingelheim, AstraZeneca, GlaxoSmithKline, Roche, and Merck-Schering Plough, and has been an adviser or consultant to Portola, CSL Behring, Evola, Athera, and Regado. Dr. Ezekowitz said that he has been a consultant to and has received grants from numerous companies including Boehringer Ingelheim. CfA

Mitchel L. Zoler is with the Philadelphia bureau of Elsevier Global Medical News.