This article presents current opinions on the role of antithrombotic therapy in secondary prevention of cardiovascular diseases (CVD) in patients after noncardioembolic stroke or a transient ischemic attack on the background of sinus rhythm. This review analytically analyses evidence-based data on antithrombotic drugs used for this secondary prevention. Despite the fact that acetylsalicylic acid (ASA) is still a “gold standard” for prevention of noncardioembolic stroke, the search for rational combinations of antithrombotic drugs to increase the effectiveness of preventive treatment is relevant. The question whether the rivaroxaban treatment as monotherapy or in combination with ASA is more effective than the ASA monotherapy for secondary prevention of cardiovascular complications (CVC) was addressed in the COMPASS study. In that study, three regimens of antithrombotic therapy were compared in patients with stable atherosclerotic CVD: rivaroxaban (2.5 mg twice a day) in combination with ASA (100 mg/day); rivaroxaban (5 mg twice a day); and ASA (100 mg/day). Risk for development of major CVC (death, stroke, myocardial infarction (IM)) was lower (p<0.001) in the rivaroxaban+ASA combination treatment group than in the ASA monotherapy group; however, the risk of major bleedings was somewhat higher. Total risk based on the definition of “pure clinical benefit” was lower for the rivaroxaban+ASA combination treatment than for the ASA monotherapy. The rivaroxaban monotherapy did not result in a significant decrease in the risk of major CVC compared to the ASA monotherapy but significantly increased the risk of major bleedings. Incidence of repeated ischemic stroke for a year was 1.1% for the combination therapy, 2.6% for the rivaroxaban therapy, and 3.4% for the ASA monotherapy with significant differences between the combination treatment group and the ASA monotherapy group (p<0.01). Relative risk of repeated stroke was 67% lower for the combination therapy group compared to the ASA monotherapy group. The combination of rivaroxaban (2.5 mg twice a day) and ASA (100 mg) opens a new epoch of antithrombotic treatment for primary and secondary prevention of stroke in patients with a stable atherosclerotic CVD and sinus rhythm.