Efficacy and Safety of Rivaroxaban Versus Aspirin in Embolic Stroke of Undetermined Source and Carotid Atherosclerosis.

Background and Purpose- The sources of emboli in patients with embolic stroke of undetermined source (ESUS) are multiple and may not respond uniformly to anticoagulation. In this exploratory subgroup analysis of patients with carotid atherosclerosis in the NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism)-ESUS trial, we assessed whether the treatment effect in this subgroup is consistent with the overall trial population and investigated the association of carotid atherosclerosis with recurrent ischemic stroke. Methods- Carotid atherosclerosis was analyzed either as the presence of mild (ie, 20%-49%) atherosclerotic stenosis or, separately, as the presence of carotid plaque. Primary efficacy outcome was ischemic stroke recurrence. Safety outcomes were major bleeding and symptomatic intracerebral bleeding. Results- Carotid plaque was present in 40% of participants and mild carotid stenosis in 11%. There was no significant difference in ischemic stroke recurrence between rivaroxaban- and aspirin-treated patients among 490 patients with carotid stenosis (5.0 versus 5.9/100 patient-years, respectively, hazard ratio [HR], 0.85; 95% CI, 0.39-1.87; P for interaction of treatment effect with patients without carotid stenosis 0.78) and among 2905 patients with carotid plaques (5.9 versus 4.9/100 patient-years, respectively, HR, 1.20; 95% CI, 0.86-1.68; P for interaction of treatment effect with patients without carotid stenosis 0.2). Among patients with carotid plaque, major bleeding was more frequent in rivaroxaban-treated patients compared with aspirin-treated (2.0 versus 0.5/100 patient-years, HR, 3.75; 95% CI, 1.63-8.65). Patients with carotid stenosis had similar rate of ischemic stroke recurrence compared with those without (5.4 versus 4.9/100 patient-years, respectively, HR, 1.11; 95% CI, 0.73-1.69), but there was a strong trend of higher rate of ischemic stroke recurrence in patients with carotid plaque compared with those without (5.4 versus 4.3/100 patient-years, respectively, HR, 1.23; 95% CI, 0.99-1.54). Conclusions- In ESUS patients with carotid atherosclerosis, we found no difference in efficacy between rivaroxaban and aspirin for prevention of recurrent stroke, but aspirin was safer, consistent with the overall trial results. Carotid plaque was much more often present ipsilateral to the qualifying ischemic stroke than contralateral, supporting an important etiological role of nonstenotic carotid disease in ESUS. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

Atherosclerotic Risk Factors in Patients with Ischemic Cerebrovascular Disease.

Aggressive treatment of atherosclerotic risk factors can substantially reduce stroke risk in patients with a history of stroke or transient ischemic attack. Data from several recent large clinical trials provide convincing evidence of benefit for a number of specific therapies directed at this population. The authors recommend treatment with ramipril alone or perindopril plus indapamide regardless of blood pressure, provided there is no contraindication. For patients already taking a different angiotensin- converting enzyme (ACE) inhibitor, the authors do not routinely switch agents. The authors recommend use of simvastatin 40 mg per day in patients with a total cholesterol level of 135 mg/dL or greater, provided no contraindication exists. The authors also recommend consideration of gemfibrozil in patients with isolated low high- density lipoprotein levels. In patients with diabetes mellitus, tight glycemic control has not been shown to reduce macrovascular complications such as stroke, but does reduce microvascular complications. However, diabetics should receive especially aggressive treatment of other vascular risk factors. There is no role for post-menopausal hormone replacement therapy in prevention of stroke. Weight loss for overweight patients, regular exercise, and a diet rich in fruits, vegetables, cereals, and fish, as well as low in fat and cholesterol, should be a standard recommendation for this group of patients. Treatment with folic acid, B(6), and B(12) for patients with elevated homocysteine appears rational, though this is unproven. However, there is no benefit to vitamin E, vitamin C, or beta-carotene supplementation. Smokers should stop. For every 43 smokers who quit, one stroke is prevented. Moderate consumption of alcohol (one to two drinks a day) may be beneficial, but heavy alcohol use (more than five drinks a day) increases stroke risk.