Net Clinical Benefit of Extended Dual Pathway Inhibition in Chronic Coronary Syndrome as Classified by the 2024 ESC Criteria: a COMPASS Substudy

Abstract Background and Aims Extended dual pathway inhibition (DPI) with aspirin and rivaroxaban is recommended in high-risk patients with chronic coronary syndrome (CCS). In the 2024 update of the European Society of Cardiology guidelines on CCS, the high-risk criteria were revised. In the COMPASS cohort, we evaluated net clinical benefit of DPI according to baseline risk as defined by the ESC criteria in CCS patients. Methods CCS patients randomized to aspirin alone or DPI (n=15,429) were risk stratified using the 2024 ESC criteria. Endpoints included major adverse cardiovascular events (MACE), all-cause death, fatal/critical organ bleeding, and composite adverse events (MACE and bleeding). Net clinical benefit was the 30-month absolute risk difference combining MACE and bleeding. Results High-risk status was associated with higher 30-month incidences of MACE (6.4% vs. 5.0%, HR 1.33, 95% CI 1.09−1.63) and composite adverse events (7.1% vs. 5.7%, HR 1.31 [1.09–1.58]), but not all-cause death or bleeding. DPI reduced MACE (low-risk: HR 0.66 [0.45−0.95]; high-risk: HR 0.77 [0.66.−0.91]; p-value for interaction 0.42) and all-cause death (low-risk: 0.78 [0.53−1.14]; high-risk: HR 0.78 [0.64−0.94], p-value for interaction 0.99). DPI provided similar net clinical benefit in low-risk (30-month risk difference -1.77% [-3.88−0.33], HR 0.79 [0.56−1.11]) and high-risk patients (30-month risk difference -2.06% [-3.20−-0.91], HR 0.80 [0.69−0.93]; p-value for interaction 0.94). Conclusions In CCS patients, DPI reduced all-cause death and MACE while increasing major bleeding. The 2024 ESC criteria performed poorly in terms of distinguishing patients at high vs. low ischemic risk, making them inadequate to provide guidance for DPI use.