Secondary Prevention of Antithrombotic Therapy in Patients with Stable Cardiovascular Disease at High Ischemic Risk: A Network Meta-Analysis of Randomized Controlled Trials

Backgroud: Antithrombotic secondary prevention in stable cardiovascular disease (SCVD) patients at high ischemic risk remains unclear. We compared aspirin monotherapy; ticagrelor monotherapy; clopidogrel monotherapy; rivaroxaban monotherapy; rivaroxaban plus aspirin; ticagrelor plus aspirin; and clopidogrel plus aspirin in cohorts at high ischemic risk such as coronary artery disease (CAD) with multi-vessel disease or history of miocardial infarction (MI), symptomatic peripheral artery disease (PAD) or limb revascularization or amputation, or asymptomatic carotid stenosis. Methods: Eleven randomized controlled trials were included. The primary outcomes were major cardiovascular and cerebrovascular events (MACEs) and major bleeding, which constituted net clinical benefit. A random effects model was used for frequency network meta-analysis. Odds ratio (OR) and 95% credible intervals (CI) were reported as a summary statistic. Results: Among 111737 patients, the median follow-up was 24 months. Compared with aspirin monotherapy, rivaroxaban plus aspirin [OR 0.79 (95% CI, 0.69, 0.89)], ticagrelor plus aspirin [0.88 (0.80, 0.98)], clopidogrel plus aspirin [0.56 (0.41, 0.77)] were associated with a reduced risk of MACEs, but rivaroxaban monotherapy [0.92 (0.79, 1.07)], ticagrelor monotherapy [0.68 (0.45, 1.05)], and clopidogrel monotherapy [0.67 (0.43,1.05)] showed no statistically significant difference. However, rivaroxaban monotherapy regimens and all dual antithrombotic strategies increased the risk of major bleeding to varying degrees, with ticagrelor plus aspirin associated with the highest risk of major bleeding. The net clinical benefit favored clopidogrel monotherapy or ticagrelor monotherapy, which have a mild anti-ischemic effect without an increase in bleeding risk. Rivaroxaban plus aspirin favored a reduction in all-cause or cardiovascular death or ischemic stroke, and P2Y12 inhibitors favored a reduced risk of MI. The results for the efficacy and safety outcomes in the CAD and PAD subgroups were similar to the results for the whole cohort. Conclusions: The present network meta-analysis suggests that clopidogrel or ticagrelor monotherapy may be recommended first in this cohort of SCVD at high ischemic risk. But clopidogrel plus aspirin or rivaroxaban plus aspirin can still be considered for use in patients with recurrent MACEs. Funding: This study was supported by the Science Technology Department of Zhejiang Province (2019C03SA100640), the Zhejiang Health Commission (2021KY916), and the Hangzhou Science and Technology Bureau (A20200624 and 20201203B178). The sponsors played no role in the study design, data collection and analysis, or decision to submit the article for publication. Declaration of Interest: None to declare.