麻豆传媒

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BARCELONA -- For stable atherosclerotic vascular disease, an ultra-low dose of rivaroxaban (Xarelto) improved cardiovascular outcomes when added to aspirin, although it also increased major bleeds, the COMPASS trial showed.

A 2.5-mg dose twice daily cut the composite of cardiovascular death, stroke, or MI to a rate of 4.1% versus 5.4% with aspirin alone (HR 0.76, 95% CI 0.66-0.86), meeting the threshold for superiority. Mortality was numerically reduced, too, although the P-value didn't reach the high bar set for significance (3.4% versus 4.1%, HR 0.82, P=0.01 versus threshold of 0.0025 required).

However, 5 mg twice daily alone (without aspirin) did not improve the composite primary outcome (HR 0.90, 95% CI 0.79-1.03), reported John Eikelboom, MBBS, of McMaster University in Hamilton, Ontario, here at the meeting and online in the New England Journal of Medicine.

Use of rivaroxaban significantly raised risk of major bleeding in both treatment arms. For rivaroxaban plus aspirin, that was an absolute risk of 3.1% versus 1.9% (HR 1.70, 95% CI 1.40-2.05) but with no significant difference in intracranial or fatal bleeding compared with aspirin alone.

Composite net-clinical-benefit -- cardiovascular death, stroke, MI, fatal bleeding, or symptomatic bleeding into a critical organ -- still favored rivaroxaban plus aspirin over aspirin alone (4.7% versus 5.9%, HR 0.80, 95% CI 0.70-0.91).

"This trial represents an important step forward in thrombocardiology, and it is likely to change practice guidelines," Eugene Braunwald, MD, of Brigham and Women's Hospital in Boston, wrote in an accompanying editorial.

But given the bleeding risk, though, it might not to be a universal recommendation, suggested Sekar Kathiresan, MD, of the Broad Institute and Massachusetts General Hospital in Boston. "Clinicians will need to think through in which patient is the net-benefit calculus the greatest. Hopefully, additional analyses from the COMPASS trial will shed light on this," he stated.

"The results are compelling such that a large portion of our patients with established cardiovascular disease should be on the combination of low-dose rivaroxaban and aspirin, if cost was not an issue," commented Christopher Granger, MD, of the Duke Clinical Research Institute in Durham, N.C. However, "cost would definitely be an issue."

Also, rivaroxaban in the U.S. is sold only in tablets of 10, 15, or 20 mg. A 2.5-mg dose has been tested and worked for prevention in recent acute coronary syndrome patients in the ATLAS ACS 2 trial, but the FDA did not subsequently approve an indication for it.

Deepak Bhatt, MD, MPH, who was involved in both ATLAS ACS 2 and COMPASS, noted that the FDA panel questioned why the lowest rivaroxaban dose would work better than the intermediate 5-mg dose against a true placebo in ATLAS ACS 2. In that trial, both rivaroxaban doses bested placebo for major adverse cardiovascular events (MACE), but only 2.5-mg rivaroxaban held a mortality advantage.

As to why the combination arm worked better than low-dose rivaroxaban alone in COMPASS, "I think it has to do with antagonizing two pathways," Bhatt, of Brigham and Women's Hospital in Boston, told 麻豆传媒. "I think it's better to antagonize two pathways a little bit than to antagonize one a lot. That's the right cocktail."

While bleeding was elevated as an adverse event, it may also have been part of the reason for the extra efficacy, Bhatt suggested.

"Some of it might be bleeding, because bleeding is complex," Bhatt suggested. "Bleeding could effect MACE, because if you have a nosebleed you might stop aspirin." The bottom line was that the two trials were "very consistent ... that 2.5 is a good dose for this indication."

Freek W. A. Verheugt, MD, of University Hospital in Nijmegen, the Netherlands, agreed, calling it no surprise that there was a narrow therapeutic window, as has been the case with other oral anticoagulants like warfarin.

"The problem with oral anticoagulation is the proper dosing. Anticoagulants have a narrow therapeutic window so you have to look for the sweet spot," he said in an interview. The mechanism likely involves bleeding, "because if you get bleeding, doctors and patients stop the treatment. And they don't just stop the aspirin, they stop the statin, they stop the ACE inhibitor, they stop beta-blockers."

The double-blind Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial included 27,395 participants with stable atherosclerotic vascular disease, about 60% of whom were post-MI. Participants were randomly assigned to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The trial was stopped for superiority of the rivaroxaban plus aspirin group after a mean follow-up of 23 months.

A substudy of just the 7,470 patients with peripheral arterial disease showed that MACE again was significantly reduced only with the rivaroxaban plus aspirin combination (HR 0.72 vs aspirin alone, 95% CI 0.57-0.90). That combination also substantially reduced risk of major adverse limb events (HR 0.54, 95% CI 0.35-0.84) and of major amputation (HR 0.30, 95% CI 0.11-0.80).

Before COMPASS, “no pharmacological therapy has clearly reduced both major cardiovascular events … and major adverse limb events,” Sonia Anand, MD, PhD, of McMaster, noted at a press conference where she presented the results from the PAD substudy.

While the 100-mg dose of aspirin used in the trial isn't the most common used in the U.S., the exact dose likely doesn't make a difference, Bhatt noted. He pointed to similar efficacy in contemporary trials between 325-mg and 81-mg aspirin.

However, generalizability to other non-vitamin K oral anticoagulants is questionable, because dosing is so specific to each anticoagulant, Verheugt pointed out. Trials with those agents should be done too, he suggested.

Braunwald called "a head-to-head comparison between the addition to aspirin of a second antiplatelet drug versus a very low dose of a factor Xa inhibitor" of great interest.

COMPASS represents "a major advance in our understanding of antithrombotic treatment," Bhatt said. "Conceptually, it opens a door for research into other compounds."