COMPASS Analysis Explores Impact of Low-Dose Rivaroxaban Plus Aspirin on Stroke

LOS ANGELES, CA—Low-dose rivaroxaban plus low-dose aspirin may have a role for primary or secondary prevention of stroke in patients with stable atherosclerotic vascular disease, according to a substudy of the COMPASS trial.

As previously reported, the combination reduced risks of all strokes and ischemic/uncertain-type strokes, without increasing the risk of hemorrhagic stroke, compared with aspirin alone.

A new analysis presented by Mike Sharma, MD (Population Health Research Institute, Hamilton, Canada), today at the International Stroke Conference (ISC) here shows that the benefit appears to be particularly pronounced in patients who have a prior history of stroke. In that subgroup, the combination reduced the rate of all strokes from 3.4% to 0.7% per year (HR 0.42; 95% CI 0.19-0.92), resulting in a number needed to treat of 37, which “very attractive in prevention,” Sharma said at a press conference.

In addition, he said, “early disability was reduced, which we believe is due to a reduction in the stroke rate. This we feel represents a significant advance in prevention for people with existing disease.”

Sharma pointed out that patients with established cardiovascular disease receiving standard preventive therapies continue to have cardiovascular events at a rate of about 5% to 10% per year. Aspirin reduces that risk, but only modestly, he said.

COMPASS was designed to evaluate whether incorporation of a low dose of a non-vitamin K antagonist—in this case, rivaroxaban (Xarelto; Bayer/Janssen)—could improve on the performance of aspirin.

The trial enrolled 27,395 patients with stable CAD or PAD (including carotid disease) and randomized them to three groups:

• Aspirin 100 mg/day
• Rivaroxaban 5 mg twice daily
• Rivaroxaban 2.5 mg twice daily plus aspirin 100 mg/day

The trial was stopped due to efficacy after the first interim analysis. The mean follow-up was 1.9 years. The main trial results, presented at the European Society of Cardiology Congress last year, showed that the combination of rivaroxaban and aspirin reduced the risk of the primary composite endpoint of cardiovascular death, stroke, and MI compared with aspirin alone (4.1% vs 5.4%; HR 0.76; 95% CI 0.66-0.86). That benefit was accompanied by a higher risk of major bleeding (3.1% vs 1.9%; HR 1.70; 95% CI 1.40-2.05).

At the ISC meeting today, Sharma delved deeper into the stroke outcomes.

The combination lowered risks of all stroke (0.5% vs 0.8% per year; HR 0.58; 95% CI 0.44-0.76) and ischemic/uncertain-type stroke (0.4% vs 0.7% per year; HR 0.51; 95% CI 0.38-0.69). There were numerically more hemorrhagic strokes in the combination arm, but the difference did not reach statistical significance (0.09% vs 0.06% per year; HR 1.49; 95% CI 0.67-3.31).

Sharma said that oral anticoagulation typically would be expected to increase the risk of hemorrhagic transformation, but in COMPASS, the opposite was seen with the combination versus aspirin alone (0.03% vs 0.08% per year; HR 0.35; 95% CI 0.13-0.99).

The risk of death within 30 days of stroke was similar with rivaroxaban plus aspirin or aspirin alone (0.06% vs 0.07% per year; HR 0.84; 95% CI 0.38-1.88).

Looking at rivaroxaban monotherapy, the treatment did not reduce the risk of all stroke, although it showed a benefit for ischemic/uncertain-type stroke compared with aspirin alone (HR 0.66; 95% CI 0.50-0.88). The risk of hemorrhagic stroke, however, was higher with this approach (HR 2.70; 95% CI 1.31-5.58).

The researchers also investigated early functional outcomes following stroke—based on modified Rankin Scale scores—and found that the combination reduced risk of strokes resulting in mild deficits at 7 days or hospital discharge, as well as those resulting in more severe deficits or death.

“I think that these findings are going to fundamentally change the way we approach prevention,” Sharma said, noting that the effects of low-dose rivaroxaban and low-dose aspirin are probably synergistic. Rivaroxaban blocks factor Xa, which in turn blocks secondary activation of platelets that feed into the coagulation system. “What we’re seeing here with these results is: you really need to think about both if you’re going to have a big impact on stopping stroke,” he explained.

More Data Needed

American Stroke Association spokesperson Ralph Sacco, MD (University of Miami, FL), told TCTMD that more data are needed before recommending the approach studied in COMPASS to prevent stroke, particularly in the secondary-prevention setting. The proportion of trial participants with a prior stroke was small, he pointed out.

For primary prevention of stroke in this population, it’s possible that combining low-dose rivaroxaban with low-dose aspirin could be beneficial, although he noted that the dose used in the trial has not been approved for use in the United States and that more studies are needed to explore low-dose oral anticoagulants in this setting.

“We think of these drugs more for atrial fibrillation, but I think this shows promise in a non-atrial fibrillation population, where the outcome that seemed to show the greatest efficacy was a stroke outcome,” said Sacco, a former president of the American Heart Association. “I still feel like I need some more data before I can change practice, but it’s a very promising trial with interesting results.”

One concern with using this type of combination strategy is bleeding, Sacco added. “That’s always the rate-limiting step,” he said. “I think the good news here is that it’s low-dose aspirin and it’s low-dose rivaroxaban, and therefore it’s probably lower adverse effects in terms of bleeding. And if there is the efficacy there, this could be a promising approach.”