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VIDEO: Rivaroxaban plus aspirin cut cardiovascular events in stable patients

Publish date: August 28, 2017

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Low-dose rivaroxaban benefits despite increased bleeding

The key message from COMPASS was that, although adding a very low dosage of rivaroxaban to aspirin in patients with stable coronary or peripheral artery disease resulted in a clear increase in major bleeding events, patients received an overall net beneficial effect from the combined regimen. The finding that clinches the net benefit from the rivaroxaban plus aspirin combination, compared with aspirin alone, was that the combined regimen produced a statistically significant relative risk reduction of 18% for all-cause mortality. This finding reinforces the idea that the primary outcome was beneficial despite an increase in major bleeding events.

The finding that rivaroxaban plus aspirin produced benefit with a modest increase in bleeding risk in patients with peripheral artery disease (PAD) is especially important because PAD is really difficult to treat. Very few interventions have previously been proven to have a beneficial effect for patients with PAD. It’s very important to find an intervention that can reduce critical limb ischemia events in addition to reducing coronary events, stroke, and overall mortality.

The very low dosage of rivaroxaban used in COMPASS, 2.5 mg twice daily, seems to be a very important part of the study’s design. This dosage appeared to hit the sweet spot of being large enough to reduce events but with a gentle enough anticoagulation effect to avoid a significant increase in fatal, intracerebral, or critical organ bleeds. However, the patients enrolled in COMPASS, like most patients who enter trials, were generally at a lower risk for bleeding complications than we usually see in routine practice in patients with stable coronary or peripheral artery disease. Presuming that the Food and Drug Administration will soon approve the 2.5-mg formulation of rivaroxaban used in COMPASS, clinicians will need to be careful using this regimen on patients at increased risk for bleeding, such as frail or elderly patients with a history of bleeding events or taking other treatments that could increase bleeding risk, such as nonsteroidal anti-inflammatory drugs. In general, clinicians are wary of using treatments that increase bleeding risk, and so they may hesitate to use this combination of rivaroxaban plus aspirin in patients with a high bleeding risk.

The success of the approach used in COMPASS became possible with the introduction of the new oral anticoagulant drugs. Now that this class of agents has been available for a few years, clinicians have grown increasingly comfortable with them, compared with warfarin. When the new oral anticoagulants first came out, many considered them similar to warfarin. Today, there is a better appreciation that these drugs are distinct from warfarin by really causing fewer bleeding complications.

Dr. Christopher B. Granger

Christopher B. Granger, MD , is a cardiologist and professor of medicine at Duke University in Durham, N.C. He has been a consultant to and has received research support from Bayer and from other drugs companies that market new oral anticoagulants. He made these comments in an interview.

AT THE ESC CONGRESS 2017

BARCELONA – Combined treatment with a very low dosage of the anticoagulant rivaroxaban plus low-dose aspirin produced significant cuts in major adverse coronary, cerebral, and peripheral artery disease events with just a modest rise in major bleeding events in patients with stable disease in the COMPASS pivotal, randomized trial with more than 27,000 patients.

The benefits from the rivaroxaban plus aspirin regimen included a statistically significant 24% relative risk reduction in the study’s primary, combined endpoint, and a significant 18% relative risk reduction in all-cause death compared with a standard regimen of aspirin only, John W. Eikelboom, MD, said at the annual congress of the European Society of Cardiology. In addition, analysis of the net clinical benefit from treatment that took into account both the major adverse cardiovascular events prevented and major bleeding events induced, showed that the rivaroxaban-plus-aspirin regimen cut these by a statistically significant 20%, compared with aspirin alone.

Other notable benefits documented by the findings included a statistically significant 42% relative risk reduction for stroke and a statistically significant 46% relative risk reduction in the incidence of major adverse limb events among the roughly one-quarter of enrolled patients who entered the study with evidence of peripheral artery disease.

These risk reductions are similar in magnitude to the secondary-prevention benefits produced by controlling hypertension or dyslipidemia, noted Dr. Eikelboom, a researcher at McMaster University in Hamilton, Ont. “In the future, rivaroxaban will take its place among the other foundational treatments for long-term, secondary prevention,” he predicted in a video interview.

The COMPASS trial produced “unambiguous results that should change guidelines and the management of stable coronary artery disease,” commented Eugene Braunwald, MD, designated discussant for Dr. Eikelboom’s report. The results are “an important step for thrombocardiology,” said Dr. Braunwald, professor of medicine at Harvard Medical School in Boston.

Concurrently with Dr. Eikelboom’s report the results appeared in an article published online (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMoa1709118). This publication also include an editorial by Dr. Braunwald (N Engl J Med. 2017 Aug 27. doi: 10.1056/NEJMe1710241).

^{Mitchel L. Zoler/Frontline Medical News}

Dr. Eugene Braunwald

The Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) trial enrolled 27,395 patients with stable coronary, carotid, or peripheral artery disease, or a combination of two or more of these, at 602 centers in 33 countries. About 90% of enrolled patients had coronary artery disease and 27% had peripheral artery disease. The enrolled patients averaged 68 year old and were an average of 7 years removed from their index arterial event. Randomization assigned patients to receive 2.5 mg rivaroxaban (Xarelto) twice daily plus 100 mg aspirin daily, 5 mg rivaroxaban twice daily, or 100 mg aspirin once daily. The trial stopped early, after an average follow-up of 23 months, because of the overwhelming benefit seen for the rivaroxaban plus aspirin combination. The rivaroxaban-monotherapy arm failed to show any statistically significant benefits, compared with the aspirin-monotherapy control group.

The study’s primary endpoint – the combined rate of cardiovascular disease death, nonfatal stroke, and nonfatal MI – occurred in 4.1% of patients in the rivaroxaban-plus-aspirin group and in 5.4% of patients on aspirin alone. The rate of major bleeding events was 3.1% among patients on rivaroxaban plus aspirin and 1.9% in those who received aspirin only, a 51% relative increase among patients on the dual regimen, but the results showed no statistically significant increase in the rates of fatal bleeds, intracerebral bleeds, or bleeding in other critical organs.

Sonia Anand, MD, a colleague of Dr. Eikelboom’s at McMaster, presented a separate set of analyses that focused on the 7,470 enrolled patients who had been diagnosed at enrollment with peripheral artery disease. In this subgroup, the rivaroxaban-plus-aspirin regimen produced a statistically significant 28% relative risk reduction in the rate of the primary endpoint, compared with the aspirin control group. The dual regimen also produced a statistically significant 46% relative risk reduction in major adverse limb events and a significant 70% relative reduction in the incidence of major lower-extremity amputations, reported Dr. Anand, professor of medicine and director of the vascular medicine clinic at McMaster.

^{Mitchel L. Zoler/Frontline Medical News}

Dr. Sonia Anand

The COMPASS findings follow a 2012 published report from the ATLAS ACS 2-TIMI 51 trial showing that treatment with the same low-dose rivaroxaban regimen plus aspirin and a thienopyridine (clopidogrel or ticlopidine) reduced the same combined triple endpoint by a statistically significant 16%, compared with aspirin and a thienopyridine alone, in patients with a recent acute coronary syndrome event (N Engl J Med. 2012 Jan 5;366[1]:9-19). Despite this evidence, the Food and Drug Administration never approved the 2.5-mg formulation of rivaroxaban, nor did it approve marketing of rivaroxaban for this acute coronary syndrome population. This decision may have been driven in part by a problem with incomplete follow-up of several of the enrolled patients.

The COMPASS results were “very consistent” with the ATLAS ACS 2-TIMI 51 results. noted Dr. Eikelboom. “I think it’s time to look at these two trials in combination,” he suggested. Availability of the 2.5-mg rivaroxaban formulation used in both trials would allow “a treatment strategy that could start early after an acute coronary syndrome event and then extend long term,” he said.

COMPASS was sponsored by Bayer, which markets rivaroxaban (Xarelto). Dr. Eikelboom has received research support from Bayer and also from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, Janssen, Pfizer, Portola, and Sanofi. Dr. Anand has received speaking honoraria from several drug compnies. Dr. Braunwald had no disclosures.