Apixaban Increases Major Bleeding in High-Risk ACS Patients

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The oral, direct factor Xa inhibitor apixaban increases major bleeding more than twofold when added to antiplatelet therapy in high-risk patients who have suffered an acute coronary syndrome (ACS). It was on the basis of these results, published online July 24, 2011, ahead of print in the New England Journal of Medicine, that the phase 3 APPRAISE-2 trial was halted early in November 2010.

The findings also were presented simultaneously this week at the International Society on Thrombosis and Haemostasis Congress in Kyoto, Japan.

For the APPRAISE-2 (APixaban for PRevention of Acute Ischemic and Safety Events-2) trial, researchers led by John H. Alexander, MD, of Duke University Medical Center (Durham, NC), randomized 7,392 out of a planned 10,800 high-risk patients with recent ACS and at least 2 risk factors for recurrent ischemic events to apixaban (5 mg twice daily) or placebo in addition to standard antiplatelet therapy. Roughly 81% of patients were on dual antiplatelet therapy with the remainder on aspirin alone. In addition, 44% had received PCI and 55% medical management alone. About 40% of the patients presented with STEMI.

After an interim analysis (median follow-up of 241 days), the primary efficacy endpoint of CV death, MI, or ischemic stroke was similar in the apixaban and placebo groups while the primary safety endpoint of TIMI major bleeding was more than twice as high in the apixaban group (HR 2.59; 95% CI 1.50-4.46; table 1).

Table 1. APPRAISE-2 Primary Endpoints: Interim Analysis


(n = 3,705)

(n = 3,687)

P Value

CV Death, MI, Ischemic Stroke




TIMI Major Bleeding




Other efficacy outcomes including death, CV death, MI, and stent thrombosis were similar between groups.

It was the increase in TIMI major bleeding that caused the early trial stoppage, which was announced by the sponsors in late 2010. Other endpoints including intracranial bleeding (0.6% vs. 0.2%; P = 0.03) and fatal bleeding (0.3% vs. 0; P = NS) were also more common in apixaban patients, though there were so few fatal bleeding events that the difference was not statistically significant.

The primary efficacy and safety endpoints were consistent across multiple subgroups including those who did or did not receive PCI and those on dual antiplatelet therapy or aspirin monotherapy.

APPRAISE-2 was conducted despite increased bleeding rates in the earlier phase 2 APPRAISE trial. In that study, which assessed 4 different apixaban doses, the 2 highest (10 mg twice daily and 20 mg once daily) led to bleeding, causing those arms to be halted early. The 2 lower doses (2.5 mg twice daily and 10 mg once daily) were associated with nonsignificant trends for increased major or clinically relevant nonmajor bleeding but also decreased ischemic events.

Not a Fair Trade-Off

“We knew that adding an anticoagulant to dual antiplatelet therapy increases bleeding,” explained Dr. Alexander in a telephone interview with TCTMD. “What we were uncertain about was whether there was efficacy. So we enrolled a high-risk population and used a dose of apixaban that we thought would have the best chance of having a favorable trade-off between efficacy and bleeding. What we now know is it doesn’t reduce ischemic events, so there’s no signal here that would outweigh the increase in bleeding.”

However, the results should not automatically rule out this class of new anticoagulants in all ACS patients. Rather, the APPRAISE-2 data should be viewed as relevant only “for this drug in this dose with this population,” Dr. Alexander said. He added that another large randomized trial, ATLAS-ACS 2 TIMI 51, is testing a similar factor Xa inhibitor, rivaroxaban, in lower-risk ACS patients.

Hitinder S. Gurm, MD, of the University of Michigan Medical School (Ann Arbor, MI), was less optimistic. “We’ve not seen a signal from any of these trials that point to a reduction in major ischemic events. And if anything, there’s a considerable increase in bleeding,” he told TCTMD in a telephone interview. “Beyond [APPRAISE-2], these data should call into question the other similar trials that are being conducted.”

Hypothesis Called into Question

According to Dr. Gurm, the whole concept of adding an anticoagulant to long-term antiplatelet therapy for ACS patients should be shelved. “We think of ACS as being a thrombotic event secondary to plaque instability and by blocking thrombosis totally we could I guess reduce that, but that will come at the cost of increased bleeding,” he said. “So there is a balance point, and I think we’ve reached that balance point with good dual agent therapy. I don’t see a role for triple therapy for ACS.”

The prospect becomes even more doubtful when considering the more powerful antiplatelet agents—prasugrel and ticagrelor—that have recently been approved. “It’s another question that has to be studied, but I would think you’re less likely to see an additional benefit adding an anticoagulant to prasugrel or ticagrelor,” Dr. Alexander said.

Still, during a different phase of treatment, drugs like apixaban might make sense, Dr. Gurm amended. “Perhaps in the early phase,” he said. “Maybe we could come to a paradigm where instead of patients being started on heparin or enoxaparin, we would give them an oral factor Xa inhibitor, aspirin, and clopidogrel, then take them to the cath lab. Or especially if you’re waiting to take them to the cath lab, early therapy with oral drugs might make sense instead of using heparin. That could be where these drugs find a role, but I remain skeptical about long term therapy.”

Different Story in A-fib

The situation is altogether different in patients with venous thromboembolism (VTE) and atrial fibrillation (A-fib), where factor Xa inhibitors have proven effective, with rivaroxaban approved for deep vein thrombosis prevention and dabigatran approved for stroke prevention.

“I think APPRAISE-2 says much more about the population than the drug,” Dr. Alexander said. “Anticoagulants have very different effects in A-fib. We know warfarin is effective in A-fib, so it’s not too surprising that these novel anticoagulants are more likely to be effective, whereas in ACS, we don’t even know that warfarin is effective.”

“The way I see it, the factor Xa inhibitors have a bright future in the treatment of venous disease and patients with atrial fibrillation,” Dr. Gurm agreed. “I think that’s a great leap forward that we finally have therapies we can use in these patients.”

But not as long-term therapy in ACS patients, Dr. Alexander cautioned. “This doesn’t totally put the nail in the coffin for adding anticoagulants to antiplatelet therapy, but at least in this population at this dose with this background therapy, it doesn’t work,” he said. “And we can wait for ATLAS 2, but I’m not too optimistic.”


Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011.Epub ahead of print.



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Jason R. Kahn, the former News Editor of TCTMD, worked at CRF for 11 years until his death in 2014…

Read Full Bio
  • The trial was sponsored by Bristol-Myers Squibb and Pfizer.
  • Dr. Alexander reports serving as a consultant to and/or receiving honoraria from Bristol-Myers Squibb and Pfizer and serving as a consultant to AstraZeneca, Bayer, Boeringer Ingelheim, Merck-Schering Plough, Ortho-McNeil-Jannsen Pharmaceuticals, Polymedix, and Regado Biosciences.
  • Dr. Gurm reports no relevant conflicts of interest.