Apixaban Bleeding Risks Prompt Pfizer/Bristol-Myers Squibb to Halt Appraise-2 ACS Trial

November 19, 2010

November 19, 2010 (Princeton, New Jersey and New York, New York — Bristol-Myers Squibb and Pfizer have decided to discontinue the phase 3 APPRAISE-2 trial of apixaban in high-risk patients with recent acute coronary syndrome after it became clear that the increase in bleeding risk in patients randomized to apixaban would not be offset by reductions in ischemic events [1].

The trial, which randomized patients to 5.0 mg twice daily of the factor-Xa inhibitor or to placebo, in addition to mono or dual antiplatelet therapy, was stopped based on the recommendation of an independent data safety monitoring committee (DSMC). The trial had been planned for 10 800 patients in 40 countries, coordinated by the Duke Clinical Research Institute, in Durham, NC, and Uppsala Clinical Research Institute, in Sweden.

The trial's primary investigator, Dr John Alexander (Duke University Medical Center, Durham, NC), told heartwire , "We knew from the phase 2 [APPRAISE] trial with apixaban that we were likely to see more bleeding, but we were hoping that we'd chosen a dose where we would not see an intolerable amount of additional bleeding and that it would be offset by a reduction in ischemic events, which is the whole reason for studying these drugs."

However, earlier this week the DSMB that has been continuously reviewing the APPRAISE-2 data notified the study investigators that it was seeing an increase in serious bleeding, including bleeding requiring blood transfusions, and a small but significant number of significant bleeds as measured by the TIMI and GUSTO bleeding scales, including intracranial and fatal bleeding.

To judge whether the additional risk of bleeding with apixaban was offset by a reduction in ischemic events, the investigators made "apples-to-apples" comparisons of specific types of bleeding events with ischemic events of comparable severity, Alexander explained. For example, the rate of cardiovascular death was compared with the rate of fatal bleeding, intracranial bleeding was compared with stroke, and less severe major bleeding was compared with nonfatal MI. So the investigators, the DSMB, and the sponsors agreed to stop the trial and take all of the patients off the drug. "The risk/benefit profile here didn't favor what we thought would be an approvable or usable regimen on top of contemporary antiplatelet therapy in this population."

The trial had enrolled almost 7500 of a planned 10 800 patients in 40 countries. The trial's steering committee cochairs are Dr Robert Harrington of (Duke University Medical Center) and Dr Lars Wallentin (Uppsala University, Sweden).

The investigators will continue to evaluate the data to understand apixaban's effects in this population and publish their findings, it is hoped by early next year. "We set out to answer a question, and I'm sure that we've answered one, but I'm not exactly sure what question we answered," Alexander said. "All of the investigators and the steering committee are looking forward to getting into these data further once they're cleaned and complete so that we can really understand this."

The DSMC for APPRAISE Japan, a phase 2 study of two different doses of apixaban in ACS patients, has also recommended that the investigators discontinue that study.

We set out to answer a question, and I'm sure that we've answered one, but I'm not exactly sure what question we answered.

In a release, Bristol-Myers Squibb and Pfizer, which are jointly developing apixaban, say they remain committed to developing this factor-Xa inhibitor for other patient populations. Apixaban is being investigated within the EXPANSE clinical-trials program in eight other completed or ongoing randomized phase 3 trials expected to enroll a total of nearly 60 000 patients.

These disappointing results from APPRAISE-2 do not mean apixaban--or any other the factor-Xa inhibitor--cannot benefit ACS patients, Alexander said. "This isn't necessarily the answer to all post–acute coronary syndrome anticoagulation. It's really just this dose on this background therapy in this population," he said. "There was, and I think to some extent still is, a lot of hope about reducing these recurrent ischemic events in this population."

He emphasized that the APPRAISE-2 population was "enriched" to be especially high risk due to advanced age, diabetes, comorbidities, renal insufficiency, and patients who had not been previously revascularized. "This is not an all-comer post-ACS population, so one of the things we're interested in when we get the complete data set is trying to tease out subgroups where the risk/benefit profile is more attractive or is worse than we saw in the overall population."

Apixaban is one of several new anticoagulant drugs being tested in the acute coronary syndrome population. The REDEEM trial showed that dabigatran (Pradaxa, Boehringer Ingelheim) was associated with acceptable bleeding rates in acute coronary syndrome patients and, as reported by heartwire, Johnson & Johnson/Bayer are sponsoring a follow-up trial to the ATLAS ACS-TIMI 46 trial comparing two doses of rivaroxaban (Xarelto) with placebo in patients for acute coronary syndrome.

 

Studies in AF patients continue

Stroke prevention in AF patients is a major focus for the developers of warfarin alternatives. As reported by heartwire , the 5600-patient AVERROES trial showed that, compared with aspirin, apixaban significantly lowered the risk of stroke and systemic embolic events in atrial-fibrillation patients unsuitable for warfarin and did not cause more bleeding or intracranial hemorrhage. The companies are currently submitting data as they become available to the FDA to support the stroke indication. Bristol-Myers Squibb and Pfizer are also sponsoring the Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation (ARISTOTLE) trial comparing apixaban 5.0 mg twice daily with warfarin adjusted to an INR of 2.5 in patients with atrial fibrillation. Results of the trial are expected in April 2011.

Dabigatran was recently approved in the US and Canada to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. And, earlier this week, the ROCKET AF trial showed that rivaroxaban was noninferior to dose-adjusted warfarin for the end points of all-cause stroke and non–central nervous system embolism in patients in patients with nonvalvular atrial fibrillation.

Alexander pointed out that the ACS patients are probably a higher-risk group than the AF patients because they often are on dual antiplatelet therapy, whereas many AF patients are taking aspirin alone or no antiplatelet drugs.

Although the AF trials are different from the ACS trials, there is a lot of overlap between the two populations, Alexander said. "There are a substantial portion of patients with acute coronary syndrome who have atrial fibrillation, and there are a substantial number of patients with atrial fibrillation who develop acute coronary syndrome, so [the APPRAISE-2] data are also going to be really important to understanding how to use these drugs in the atrial-fibrillation population."

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