A conversation with Mike Sharma, MD, MSc, FRCPC, Michael G. DeGroote Chair in Stroke Prevention and Associate Professor of Medicine (Neurology) at McMaster University/Population Health Research Institute and one of the co-authors of the COMPASS clinical trial, which studied the utility of combined low dose rivaroxaban and aspirin for cardiovascular disease prevention in patients with peripheral artery disease. Dr. Sharma presented a platform presentation on the findings of stroke prevention at the International Stroke Conference in February 2018 in Los Angeles, California.
Interviewed by Alexis N. Simpkins, Assistant Professor of Neurology, University of Florida School of Medicine.
They will be discussing the paper “Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease,” published in October 2017 in The New England Journal of Medicine (Eikelboom JW, et al. N Engl J Med 2017; 377:1319-30).
Dr. Simpkins: The rivaroxaban dose that was included in this clinical trial is different from the standard dosing used for secondary stroke prevention. How was the dose selected for primary prevention for this study?
Dr. Sharma: Rivaroxaban is indicated for stroke prevention in the setting of AF. The standard dose of rivaroxaban used for stroke prevention in atrial fibrillation was based on the pathophysiology of thrombosis in low flow, low shear stress systems like the venous circulation. The arterial system is a high flow, high shear stress system, and it was unclear that a dose for AF was appropriate for the prevention of events related to arterial disease. The doses used in COMPASS were first tested in the ATLAS trial of acute ACS — a better model of arterial disease. There was benefit in the acute setting of coronary disease, and the primary question in COMPASS was whether the benefit of these doses would also be seen in patients with chronic stable arterial disease.
Dr. Simpkins: The patients selected for the clinical trial had coronary artery disease, peripheral vascular disease, and carotid artery disease. Why was the addition of rivaroxaban so beneficial in the context of these co-morbidities?
Dr. Sharma: COMPASS shows us that our previous paradigm of using exclusively antiplatelets in arterial disease was incomplete. The addition of rivaroxaban at low dose to aspirin was significantly more effective than aspirin alone, suggesting that atherothrombotic disease causes more than just platelet activation. Of specific interest to stroke physicians, carotid stenosis was included in the definition of peripheral arterial disease, and the COMPASSS results would be consistent with a major effect of the trial interventions on artery-to-artery emboli, as well as a reduction in thrombi at sites of atherosclerotic plaque. In addition to the currently available results, the MRI, biomarker and genetic substudy of COMPASS (COMPASS MIND) may provide further pathomechanistic insights.
Dr. Simpkins: In the COMPASS trial, most of the patients enrolled were men, and rate of stroke was highest in patients of Asian descent. Were you able to compare stroke etiology in the patients that did have stroke to determine what kind of stroke the rivaroxaban was most effective at preventing?
Dr. Sharma: In our models of stroke predictors at baseline, the strongest independent predictor of stroke occurrence was a history of previous stroke. Asian ethnicity was correlated with an increased risk of ischemic and hemorrhagic stroke. While work to classify the etiology of the strokes that occurred in COMPASS is underway, the following observation may be helpful: AF was an exclusion for entry into the trial, and the rate of new-onset AF during the trial was low, suggesting that most ischemic strokes were arterial in origin.
Dr. Simpkins: Do you think that the benefit found in the study is specific to rivaroxaban, or could this be a dose response effect of the level of factor Xa inhibition?
Dr. Sharma: It is difficult to be sure without additional data involving another agent that inhibits factor Xa. There is some evidence suggesting a class effect based on strokes occurring in the APEX trial testing betrixaban, but the data are less clear than in COMPASS. The results of COMPASS in the context of other trials of rivaroxaban suggest that using the correct dose is crucial to ensure efficacy and safety.
Dr. Simpkins: What do you see are the next steps in investigating utility of low dose anti-coagulation for primary prevention in cardiovascular disease?
Dr. Sharma: We now have evidence that combination therapy can be quite effective for stroke prevention in patients with atherosclerosis — up to 50% more effective than aspirin alone — and trials testing this new paradigm are urgently needed. Our results suggest that dose-finding studies for anticoagulants combined with anti-platelets in arterial disease should be an integral part of drug development for future classes of anticoagulants.
Dr. Simpkins: How would you interpret these results in the context of primary stroke prevention versus secondary stroke prevention?
Dr. Sharma: Most COMPASS participants did not have a history of stroke, and, from that perspective, this represents primary prevention of stroke. From the perspective of the treating physicians of these patients, COMPASS was a trial of secondary prevention of vascular events in those with established CAD or PAD. In the approximately 1000 COMPASS participants with a history of stroke (i.e. secondary prevention of stroke), we noted a significant benefit for the combination of rivaroxaban 2.5 mg BID plus aspirin over aspirin. Importantly, a stroke within 1 month of randomization was an exclusion criterion, and we do not have data for the early post stroke period.
Dr. Simpkins: How you think your data might influence the way that we think about managing stroke prevention in patients with asymptomatic carotid artery disease?
Dr. Sharma: Asymptomatic carotid stenosis and previous carotid revascularization was defined as PAD in COMPASS, and almost 2000 patients were randomized with carotid disease. There was benefit in this subgroup consistent with the overall effect. So we have evidence of benefit in these 2 important subgroups — those with previous stroke and those with carotid disease.
Dr. Simpkins: Thank you very much for participating in the Blogging Stroke interview.