LOS ANGELES — Combining the anticoagulant rivaroxaban (Xarelto, Bayer) with aspirin cuts the ischemic stroke rate by almost half without significantly increasing the risk for intracerebral hemorrhage (ICH) compared with aspirin alone in patients with stable atherosclerotic vascular disease, new research shows.
The combination was particularly effective for secondary stroke prevention, researchers report. These new results represent a significant advance in stroke prevention, author Mike Sharma, MD, associate professor of medicine (neurology), McMaster University, Hamilton, Ontario, Canada, told Medscape Medical News.
"What we have seen here is an additional benefit on top of aspirin, which essentially doubles the effect," said Dr Sharma. "If we can increase the effectiveness, have fewer strokes, the better off we'll be."
Updated results of the study — Effect of Rivaroxaban with Aspirin on Stroke Outcomes in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) — were presented here at the International Stroke Conference (ISC) 2018.
Patients with established cardiovascular disease have a high rate of additional events, between 5% and 10%, despite modern preventive therapies, said Dr Sharma. Aspirin has long been the standard antithrombotic treatment for prevention.
"We have been stuck with aspirin for decades," but it's only modestly effective for stroke prevention, said Dr Sharma. "If you haven't had an event before, it reduces your risk by about 12%, but even if you have already had a stroke or heart attack, it reduces your risk only by about 19%, so the rest of the risk is untouched."
Rivaroxaban is a selective direct factor Xa inhibitor. It's already approved by the US Food and Drug Administration, indicated (at a dose of 15 mg or 20 mg) for prevention of deep-vein thrombosis in the legs and for prevention of stroke in the setting of atrial fibrillation (AF).
COMPASS enrolled 27,395 patients at 602 centers in 32 countries. Participants had coronary artery disease and could have had a myocardial infarction (MI) within 20 years or multivessel disease, or they had peripheral artery disease (PAD), which included those who had surgery for PAD or intermittent claudication with carotid stenosis (where at least 50% were asymptomatic) and carotid revascularization.
Of the total study population, 1032 patients had previously had a stroke. Patients with AF were excluded from the study.
The trial had three treatment groups: aspirin 100 mg a day, rivaroxaban 5 mg twice daily, and a combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg per day.
The study was designed to run up to 4 years but was stopped early at 23 months, after an interim analysis uncovered "overwhelming efficacy" of the combination therapy, said Dr Sharma.
Primary results for a composite endpoint of cardiovascular death, stroke, or MI, were published online August 27 in the New England Journal of Medicine and presented at that time at the European Society of Cardiology meeting.
That analysis showed that event rates were 4.1% for the combination therapy and 5.4% for aspirin (hazard ratio [HR] for combination vs aspirin, 0.76; 95% confidence interval [CI], 0.66 - 0.86; P < .0001), but major bleeding events occurred in more patients in the combination group (3.1% vs 1.9%; HR, 1.70; 95% CI, 1.40 - 2.05; P < .001).
Intracranial or fatal bleeding did not significantly differ between these two groups. Rivaroxaban by itself did not show a benefit over aspirin alone.
The current analysis looked specifically at stroke endpoints and found that for the combined stroke outcome (ischemic and hemorrhagic), there was a significant reduction for the combination therapy compared with aspirin alone (HR, 0.58; 95% CI, 0.44 - 0.76; P < .0001). The HR with rivaroxaban alone was 0.82 (95% CI, 0.65 - 1.05; P = .12)
"As you can see from the Kaplan-Meier curves, there is an early and consistent separation of the combination arm of rivaroxaban plus aspirin over aspirin," Dr Sharma said at a media briefing.
"Rivaroxaban alone stays very close to the aspirin arm and separates at about 18 months. We're not sure of the reason for that; it does not show significant benefit."
For ischemic stroke, the risk was cut almost in half for the combination therapy (HR, 0.51), with a "robust early separation of the curves" for the combination therapy over aspirin, said Dr Sharma.
"Once again, rivaroxaban by itself stays very close to the aspirin arm to 18 months or so and then separates."
The analysis showed that the rate of hemorrhagic transformation (bleeding into areas of infarct) was reduced in patients taking the combination therapy compared with those taking aspirin (HR, 0.35; 95% CI, 0.13 - 0.99; P = .04).
"We would expect this to be increased with anticoagulation," commented Dr Sharma.
There was no statistically significant increase in hemorrhagic stroke with the combined approach compared with the aspirin alone (P = .33), However, more hemorrhages occurred with combination than with aspirin therapy (15 vs 10).
"Any time you affect blood coagulation, you're going to get some bleeding," said Dr Sharma. "With all factor Xa inhibitors, there is an increase in bleeding in the [gastrointestinal] tract. In this trial, with the combination therapy, we saw a slight increase in bleeding outside the brain but happily no real increase inside the brain."
The 30-day mortality did not significantly differ between the groups.
As for the chance of being disabled or dead (modified Rankin Scale [mRS] score of 3 to 6) at 7 days or at hospital discharge, the combined therapy again came out on top (HR, 0.58; 95% CI, 0.37 - 0.89; P = .01)
"We think this was due to a reduction in the event rate for strokes altogether," said Dr Sharma. He noted that there was a similar reduction in the hazard of having a stroke with an mRS score of 0 to 2.
The biggest predictor of having any kind of stroke was having had one in the past (2.6% per year; P = .0001). A previous MI did not significantly increase the risk for stroke. Having carotid stenosis, or having undergone previous carotid surgery or stenting, increased the risk for ischemic stroke but not hemorrhagic stroke.
While an estimated 77% of strokes occur in patients who have never had a stroke, the researchers wanted to look at the risk in those with a history of stroke. In this secondary prevention population, those on aspirin had strokes at a rate of 3.4% per year, but among those with combination therapy, the rate was reduced to 0.7% per year (HR, 0.42; 95% CI, 0.19 - 0.92; P = .03).
The absolute risk reduction was 2.7 percentage points per year, and the number needed to treat was 37.
Dr Sharma stressed that this combination approach is not for every patient. "If you've got coronary artery disease, had a previous heart attack, or have peripheral vessel disease or carotid stenosis, then this is absolutely a combination to consider; but if you don't have those, we're not sure it will have the same benefit," he said, adding that this is also true for aspirin alone.
"If you're a 32-year-old healthy man, I don't think there's any benefit," he added.
Commenting on the study for Medscape Medical News, Larry B. Goldstein, MD, Ruth L Works Professor and chairman, Department of Neurology, University of Kentucky, Lexington, said he found it somewhat challenging to determine the impact of the combination therapy on secondary stroke prevention because patients with a prior stroke made up only a subpopulation.
"These were mostly patients with coronary heart disease, and the study was evaluating a combined outcome: stroke/MI and death together, so that makes it a little difficult to tease that out."
The "big concern," said Dr Goldstein, is that adding any anticoagulant to aspirin will increase the risk for bleeding in those who have had a stroke.
"Almost all these drugs have a narrow potential index between decreasing recurrent ischemic events, decreased blood clots, and causing bleeding."
The study was funded by Bayer. Dr Sharma reports being a consultant for Bayer, BMS, BI, and Daiichi Sankyo. Dr Goldstein has disclosed no relevant financial relationships.
International Stroke Conference (ISC) 2018. Late-breaking abstract 7. Presented January 25, 2018.
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Cite this: Rivaroxaban Plus Aspirin Cuts Stroke Rate in Half - Medscape - Jan 31, 2018.