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Apixaban Found Effective for Preventing Strokes

Laino, Charlene

doi: 10.1097/01.NT.0000406547.42622.8f
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Investigators reported that apixaban reduced the risk of stroke or systemic embolism by 21 percent, compared with warfarin. Additionally, it was associated with a 31 percent reduction in major bleeding and an 11 percent reduction in all-cause mortality versus the vitamin K antagonist.

PARIS—The ARISTOTLE trial took center stage at the recent European Society of Cardiology (ESC) Congress here, with results showing the experimental oral factor Xa inhibitor apixaban was superior to warfarin in patients with atrial fibrillation (AF).

Apixaban reduced the risk of stroke or systemic embolism, the primary endpoint, by 21 percent, compared with warfarin. Additionally, it was associated with a 31 percent reduction in major bleeding and an 11 percent reduction in all-cause mortality versus the vitamin K antagonist, reported Christopher B. Granger, MD, professor of medicine and director of the cardiac care unit at Duke University Medical Center in Durham, NC.

The results of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study was simultaneously published Aug. 28 in the online edition of The New England Journal of Medicine.

Ralph L. Sacco, MD, immediate past president of the American Heart Association/American Stroke Association, who was not involved with the trial, noted that at last year's ESC meeting, another trial — Apixaban versus Acetylsalicylic Acid to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) — showed that apixaban was more effective than aspirin at preventing stroke among patients who couldn't take warfarin. [The AVERROES trial was stopped early by an independent data monitoring committee because of the demonstrated clear benefit of apixaban.]

“So we have two strong trials of apixaban's effect on stroke prevention,” said Dr. Sacco, Olemberg Professor and chairman of neurology at the University of Miami Miller School of Medicine.

Two other oral anticoagulants in the race to find warfarin alternatives — dabigatran and rivaroxaban — have also shown benefits over the older treatment in clinical trials, Dr. Sacco said. But apixaban is the first to improve all three major outcome measures of stroke, deaths, and bleeds. [See “The Warfarin Alternatives: Three Major Studies.']

“Among neurologists, there is a lot of excitement and interest in novel anticoagulants to prevent stroke among patients with atrial fibrillation. For so many years, there was only warfarin,” he said.

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The ARISTOTLE study included 9,120 patients randomized to receive apixaban 5 mg twice daily; 2.5 mg was given to a subset of patients who had met at least two of the following criteria: age 80 years or older, weight 60 kg or less, and serum creatinine level of 1.5 mg/dL or more. A total of 9,081 patients were randomized to warfarin treated to target international normalized ratio (INR) of 2.0 to 3.0.

After a median follow-up period of 1.8 years, 1.3 percent of patients per year in the apixaban group suffered a stroke or systemic embolism vs. 1.6 percent per year in the warfarin group. The rate of major bleeds was 2.1 percent per year in the apixaban group vs. 3.1 percent per year in the warfarin group. And 3.5 percent of patients per year in the apixaban group died vs. 3.9 percent per year in the warfarin group.

This means that for every 1,000 patients treated for nearly two years, apixaban, as compared with warfarin, prevented six strokes, 15 major bleeds, and eight deaths, Dr. Granger said.

The benefit in stroke prevention was driven mainly by the difference in hemorrhagic strokes, with a rate of 0.24 percent per year for apixaban versus 0.47 percent for warfarin. The rate of ischemic stroke was similar in both groups: 0.9 percent per year for apixaban and 1.05 percent per year for warfarin, a nonsignificant difference.

Apixaban bested warfarin at preventing stroke and thromboembolism in all subgroups of patients studied, regardless of age, gender, body-mass index, prior use of warfarin or INR, among other characteristics, Dr. Granger said.

Importantly, the subgroup analyses showed apixaban was superior regardless of whether a patient had a former stroke or transient ischemic attack (TIA), Dr. Sacco added.

The median age of patients in ARISTOTLE was 70, and all had at least one additional risk factor for stroke. About 25 percent were treated at centers in North America, 40 percent in Europe, and the rest in Latin America or the Asian Pacific.

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There is a huge need for new anticoagulants, Dr. Sacco said, with studies suggesting that up to half of AF patients who could benefit from warfarin are not receiving the drug due to concerns such as bleeding, drug-drug interactions, and the need for frequent blood monitoring.

All three warfarin alternatives are wins for patients, Dr. Sacco said. He noted that they provide the same or better protection as warfarin, but without the need for frequent blood monitoring for anticoagulation and a lower risk of drug-drug interactions and intracranial bleeding events.

So far, the only new agent to gain FDA approval for the prevention of stroke and systemic embolism in AF patients has been dabigatran, based on results of the Randomized Evaluation of Long-Term Anti-Coagulation Therapy (RE-LY) trial, reported in the Sept. 19, 2009, edition of The New England Journal of Medicine. [See Neurology Today's “Dabigatran Slashes Risk of Brain Bleeding in Patients with Prior Stroke,”]

An FDA panel has recommended rivaroxaban for approval based on results of ROCKET-AF — Rivaroxaban Once Daily Oral Director Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism — which were reported in the Sept. 8 New England Journal of Medicine.

There aren't any studies directly comparing the three newer drugs. So assuming apixaban and rivaroxaban are eventually approved by the FDA, how will clinicians seeking a warfarin alternative choose between the three new oral anticoagulants – and perhaps a fourth, edoxaban, that is currently being tested in a phase 3 ENGAGE study? In phase 2 trials with AF patients and those with venous thromboembolic events, edoxaban given at 30 mg once-daily and 60 mg once-daily had a similar or better safety profile compared with dose-adjusted warfarin.

Indirect comparisons, while far from ideal, will likely be made across the trials, and specific agents chosen based on patient characteristics and patient and physician preferences, experts told Neurology Today. [See “The Pros/Cons of Warfarin Alternatives.”]

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All the newer agents have some potential downsides, compared with warfarin. Cost is one potential issue: The estimated price of warfarin is about $40 a month versus $160 a month for dabigatran.

Also, there's no antidote for the newer drugs, while vitamin K is an antidote for warfarin. “That's not a trivial issue. The rate of major bleeds in patients on anticoagulants is 2 percent to 3 percent per year,” said Ralph Brindis, MD, senior regional advisor for cardiovascular disease at Kaiser Permanente in Oakland, CA, and immediate past president of the American College of Cardiology.

More important for neurologists treating stroke patients is that the INR guides tissue plasminogen activator (tPA) treatment, Dr. Sacco said.

“With warfarin, we can test the INR and we know if the patient's clotting levels fall within the accepted normal range,” he explained. “I am told that at some point, there will be a point-of-care test to provide rapid assessment and help guide treatment with the new anticoagulants,” he said.

Although the FDA approved dabigatran last October, the prescriptions are lower than predicted, with estimates showing it has less than 10 percent of the market share.

Dr. Sacco said that it often takes a while for new medications to catch on, especially if they are first-in-class. “Even our latest AHA/ASA recommendations are still not updated to include the new drugs for stroke prevention,” he said.

ARISTOTLE was funded by Bristol-Myers Squibb and Pfizer. A spokesperson for Bristol-Myers said the companies plan to apply for FDA approval later this year.

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DR. RALPH L. SACCO: BOTH THE RE-LY trial of dabigatran and the ARISTOTLE trial of apixaban appear to have “stronger” results than the ROCKET-AF trial of rivaroxaban. That's because both dabigatran and apixaban proved superior to warfarin at reducing stroke risk, while rivaroxaban failed to demonstrate superiority in the intention-to-treat analysis that included all randomized patients followed until the end of the study. (Rivaroxaban was noninferior to warfarin in preventing stroke, and demonstrated superiority in an “as-treated” analysis.) The intention-to-treat analysis is the gold standard.

Meanwhile, warfarin-treated patients in ARISTOTLE and RE-LY had INRs in the therapeutic range 62 percent and 64 percent of the time, respectively, compared with 54 percent in ROCKET-AF. The low figure led to criticism about whether warfarin was a fair comparator at the recent FDA panel hearing of rivaroxaban.

DR. CHRISTOPHER B. GRANGER: APIXABAN has the advantage of being the only drug so far to significantly reduce mortality risk. However, both of the other drugs — dabigatran and rivaroxaban — “strongly trended” towards a reduction in mortality as compared to warfarin. The mortality reduction is just clearer from a clinical perspective in ARISTOTLE.

As for safety events, both dabigatran and rivaroxaban were associated with an increase in gastrointestinal bleeding, while apixaban was not. So in a patient with a history of major GI bleeds, apixaban would have a major advantage.

Also, RE-LY suggested that dabigatran-treated patients had higher rates of myocardial infarction; this was not seen with apixaban.

But dabigatran is the only drug to lower the rate of ischemic stroke compared with warfarin. So in a young patient with AF, where you're less concerned about bleeding and more about ischemic stroke, that might be a good choice.

DR. RALPH BRINDIS: CONCERNS about compliance may be making some physicians hesitant to prescribe the warfarin alternatives. Rivaroxaban only has to be taken once a day, which could improve compliance, while the other drugs have to be taken twice daily.

One of the strengths of warfarin is we know patients are complying because we do blood tests every three weeks or so. The new drugs do not require international normalized ratio monitoring.

The newer agents will probably prove most useful for patients being prescribed anticoagulants for the first time and those for whom warfarin dosing proves problematic. If warfarin has been working, and the patient is well controlled and isn't upset about all the blood work, there is no reason to switch.

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Granger CB, Alexander JH, Wallentin L, et al, for the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fi brillation. N Engl J Med 2011; E-pub 2011 Aug. 28.
Patel MR, Mahaffy KW, Califf RM, et al, for the ROCKET AF Steering Committee, for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fi brillation. N Engl J Med 2011; 365:883-891.
Connolly SJ, Eikelboom J, Yusuf S, et al, for the AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fi brillation. N Engl J Med 2011;364(9):806-817.
Connolly SJ, Ezekowitz MD, Wallentin L, et al, for the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fi brillation; N Engl J Med 2009;361:1139-1151.
©2011 American Academy of Neurology