The persisting risk of cardiovascular disease (CVD) events despite reaching targets for known CVD risk factor such as low density lipoprotein (LDL) cholesterol, blood pressure, glycemia, and body weight is summarized as residual CVD risk. Conditions that may contribute to a residual CVD risk include inflammation, pro-thrombotic imbalance of the coagulation system, and metabolic pathways. These risk modifiers that are usually underrecognized and not addressed in clinical practice may contribute to recurrent cardiovascular events. Previous studies (Table 1) have shown that addressing such contributors of residual risk results in a statistically significant and clinically meaningful reduction of major adverse cardiovascular and cerebrovascular events (MACCE) (2), (3), (4), (5), (6), (7), (8), (9). Treatment with aspirin in very high risk patients defined by the presence of established atherosclerotic cardiovascular disease (ASCVD) is based on robust evidence. The Antithrombotic Trialists' Collaboration, which included 16 randomized trials of about 17,000 patients in secondary prevention and could demonstrate that antiplatelet therapy is associated with a significant reduction of the risk of serious vascular events. However, this outcome still occurred in 6.7% aspirin treated patients, as compared with 8.2% in the placebo group (10). These data underscore the substantial residual thrombotic risk in secondary prevention patients treated with antiplatelet drugs as recommended by current guidelines (11). Consequently, there is interest in selection of patients that could benefit from intensification of antithrombotic and/or anticoagulation therapy for long-term secondary prevention. However, appropriate patient selection, and dosing of anticoagulants are critical when balancing efficacy and bleeding risk (12).

The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial could demonstrate that in a highly selected population at greatest risk of subsequent cardiovascular complications, low-dose rivaroxaban plus aspirin reduced the risk of cardiovascular events as compared with aspirin monotherapy but increased the risk of major bleeding events (13).

A number of previous studies have assessed external applicability of the COMPASS trial and most of these analyses included subsets of patients with ASCVD (14), (15), (16), (17), (18), (19) and thus have limitations including generalizability.

The REACH registry is prospective observational study investigating a cohort of approximately 68 thousand outpatients 45 years or older from 44 countries with three or more atherothrombotic risk factors and patients with established coronary artery disease (CAD), CVD, or peripheral artery disease (PAD) (20). Sufficient data to assess COMPASS eligible were available in almost 32 thousand patients with either CAD or PAD and 52-59% were estimated to have been COMPASS eligible (21).