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) had 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, Dr. Christopher B. Granger reported Aug. 28 at the annual congress of the European Society of Cardiology, and in a published article that concurrently appeared online (N. Engl. J. Med. 2011 Aug. 28 [10.1056/NEJMoa1107039]).
Heidi Splete/Elsevier Global Medical News
Dr. Lars Wallentin (left) of Uppsala Clinical Research Center in Sweden, cochair of the study (right) Dr. Christopher Granger discuss findings from the ARISTOTLE study.
"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]).
In RE-LY, which tested two different dabigatran dosages, the 110-mg/b.i.d. dosage produced stroke and systemic embolism prevention that was noninferior to warfarin while leading to a statistically significant reduction in major bleeds, and the 150-mg/b.i.d. dosage (the primary dosage approved by the FDA) produced a statically significant reduction in strokes and systemic embolisms compared with warfarin while being noninferior to the comparator for major bleeds. In ROCKET-AF, once-daily treatment with rivaroxaban proved noninferior to warfarin for both the primary efficacy end point of fewer strokes and systemic embolisms and the safety end point of major bleeds.
"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 Dr. Lars Wallentin, 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 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.