Hope Renewed for Novel Anticoagulant Use in ACS

A recent arrival to the anticoagulant scene—the oral factor Xa inhibitor rivaroxaban—may prove a useful adjunct to current therapy in treating patients with acute coronary syndromes (ACS), according to an announcement from the drug’s manufacturer on September 29, 2011.

After a string of lackluster results for novel anticoagulants in this population, finally some good news: The phase III ATLAS-ACS TIMI 51 (Addition to standard therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51) trial has met its primary efficacy endpoint for reducing ischemic events with rivaroxaban (Xarelto; Johnson & Johnson, New Brunswick, NJ; Bayer HealthCare, Leverkusen, Germany).

In telephone interviews with TCTMD, American Heart Association (AHA) president Gordon Tomaselli, MD, of Johns Hopkins University School of Medicine (Baltimore, MD), and John H. Alexander, MD, MHS, of Duke University Medical Center (Durham, NC), both seemed pleasantly surprised to hear the announcement. However, they questioned why ATLAS-ACS differed from its predecessors.

And in the absence of data, Dr. Tomaselli cautioned, “[i]t’s always a little dangerous to rely on a press announcement.”

Efficacy More Apparent Than Safety

The double-blind trial randomized more than 15,000 ACS patients against a background of standard therapy including low-dose aspirin. Subjects were stratified according to whether they did or did not also receive a thienopyridine (either clopidogrel or ticlopidine). Within each stratum, patients were assigned in a 1:1:1 ratio to twice daily doses of rivaroxaban 2.5 mg or 5 mg, or placebo.

A press release issued by Bayer indicates that rivaroxaban significantly reduced the composite of cardiovascular death, MI, or stroke but increased non-CABG-related TIMI major bleeding. For now, there are no specific numbers attached to that message, but details are expected at the upcoming AHA Scientific Sessions in Chicago, IL, where ATLAS-ACS TIMI 51 will be presented at a late breaking trial session on November 13, 2011.

From A-Fib to ACS

Rivaroxaban gained US Food and Drug Administration (FDA) approval for the prevention of deep vein thrombosis in patients undergoing knee or hip replacement surgery in July 2010. On September 8, 2011, an FDA advisory panel voted in support of another indication, the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (A-fib). Furthermore, an editorial published online October 5, 2011, ahead of print the New England Journal of Medicine reports that the agency is slated to make its decision regarding rivaroxaban and A-fib by November 5, 2011.

A-fib has thus far been the most successful venue for novel anticoagulants. Not only is the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim, Ridgefield, CT) already on the market but positive results were reported for the oral factor Xa inhibitor apixaban (Eliquis; Pfizer, New York, NY; Bristol-Myers Squibb, Princeton, NJ) at the European Society of Cardiology (ESC) Congress 2011 in Paris, France, on August 28.

In comparison, results for ACS patients have been disappointing. The RUBY-1 trial, also presented at ESC 2011, showed that the oral factor Xa inhibitor darexaban not only fails to decrease ischemic events compared with placebo in patients with recent high-risk ACS but also increases bleeding by up to fourfold at its highest dose. And the APPRAISE-2 trial, published in the New England Journal of Medicine in July 2011, found that apixaban more than doubles major bleeding when added to antiplatelet therapy in high-risk ACS patients. Efficacy outcomes were similar between the study’s treatment and placebo arms.

Bucking the Trend

So what could be so different about ATLAS-ACS? According to Dr. Alexander, who served as principal investigator for APPRAISE-2, there are several possible explanations including the choice of drug, the study population, and the dosing.

Dr. Alexander expressed doubt that rivaroxaban would behave that differently from apixaban but noted that the latter 2 factors could be important. “ATLAS has a lower-risk population and lower doses of rivaroxaban compared with what we studied in APPRAISE,” he noted.

Dr. Tomaselli, meanwhile, noted that rivaroxaban and apixaban may, in fact, behave differently. “These drugs are the same class. They’re both factor Xa inhibitors. But that doesn’t mean they’re going to have the same off-target effects or even the same relative [influence on] bleeding. They work by roughly the same mechanism, but there may be some differences,” he stressed.

Regardless, Dr. Tomaselli suggested that ATLAS-ACS may have obtained good results because it stratified patients by clopidogrel use. Dr. Alexander, though, was unconvinced by this explanation, since APPRAISE-2 found consistent results between patients receiving clopidogrel and those on aspirin alone. Without knowing the proportion of patients in ATLAS-ACS who were on a thienopyridine, he said, it is impossible to know which cohort drove the observed benefit.

Dr. Alexander estimated that, based on the ATLAS-ACS trial design and projected endpoints, there must have been a relative reduction of at least 15% to 20% in the primary efficacy endpoint. “Whether that’s important or not will really depend on which components of the primary endpoint were reduced and what the tradeoff for bleeding was,” including the type and severity of bleeding events, he concluded.

If the risk-benefit ratio is favorable, Dr. Alexander said, “then I imagine other anticoagulants that are further along the development pathway [such as] apixaban and dabigatran may revisit the ACS population.”

Dr. Tomaselli agreed that the most relevant question is whether ATLAS-ACS finds a net clinical benefit favoring rivaroxaban in terms of ischemic and bleeding outcomes.

Regardless of the actual trial results, he said, it is worth pursuing better outcomes for ACS patients. “The fact that there are still residual events [in this population] even after they are treated with the best medical therapy suggests that there may be something more we can do. But I don’t know that the something more is yet another drug,” Dr. Tomaselli explained, noting that there may be a limit to how few complications and subsequent events can be achieved pharmacologically. “The question is whether [rivaroxaban] is the therapy that’s going to allow for improved outcomes in these folks.”

More to Come on A-Fib

Another wrinkle is how the ATLAS-ACS results might extend to patients who have both A-fib and ACS. Dr. Alexander pointed out that ROCKET-AF, the pivotal trial backing rivaroxaban in A-fib patients, tested a 20-mg daily dose, while ATLAS-ACS used lower doses but gave them twice daily. The new findings are going to cause confusion about the best approach for this special-needs group, he said, “because now maybe we’ll have 1 drug we should treat them with but we won’t know [at] what dose.”


Bayer AG. Phase III study of Bayer’s rivaroxaban in patients with acute coronary syndrome meets primary efficacy endpoint. http://www.press.bayer.com/baynews/baynews.nsf/id/Bayer-AG-Phase-III-Study-Bayers-Rivaroxaban-Patients-Acute-Coronary-Syndrome-Meets-Primary-Efficacy?Open&ccm=001. Published September 30, 2011. Accessed October 3, 2011.



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  • Dr. Tomaselli reports no relevant conflicts of interest.
  • Dr. Alexander reports receiving research funding from and serving as a consultant to Bristol-Myers Squibb, Johnson & Johnson, and Pfizer.

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