Association between C-reactive protein and adverse events in secondary cardiovascular prevention: A systematic review and meta-analysis of prognostic factor studies

Background and aims C-reactive protein (CRP) has been associated with an increased risk of cardiovascular events in the setting of primary prevention; however, its risk association in secondary cardiovascular prevention remains unclear. We evaluated the prognostic role of CRP across the spectrum of patients with established atherosclerotic cardiovascular disease (ASCVD). Methods We performed a systematic review and meta-analysis by screening Embase and MEDLINE databases from inception through November 2024. We included studies reporting adjusted risk associations between CRP and cardiovascular events among patients with ASCVD. Two reviewers extracted data and assessed the risk of bias. Data were extracted using an adaption of the Checklist for Critical Appraisal and Data Extraction for Systematic Review of Prediction Modelling Studies (CHARMS-PF). The primary analysis was conducted using a random-effects model within a Bayesian framework. Risk of bias was assessed using the Quality in Prognosis Studies tool. The GRADE (grading of recommendations assessment, development, and evaluation) approach was used to rate the certainty in the prognostic yield of CRP. The principal outcome was major adverse cardiovascular events. Additional outcomes included: all-cause death, myocardial infarction, cardiovascular death, and cerebrovascular events. Results We included 27 studies, published from 2002 to 2024, and involving 193,761 participants (65,204 or 34 % females). Higher CRP levels were defined accordingly to the included studies and ranged from 0.5 to 5.0 mg/L 26 studies adjusted for conventional cardiovascular risk factors (age, sex, smoking, diabetes, dyslipidemia, hypertension); one omitted smoking status but included the others. Higher CRP levels were associated with an increased risk of major adverse cardiovascular events (adjusted hazard ratio, aHR, 1.55, 95 % credible intervals, CrI, 1.39 to 1.73; tau = 0.24, 95 %CrI 0.14 to 0.34; high certainty), all-cause death (aHR 1.92, 95 %CrI 1.52 to 2.41; tau = 0.30, 95 %CrI 0.14 to 0.51; moderate certainty), myocardial infarction (aHR 1.40, 95 %CrI 1.22 to 1.63; tau = 0.066, 95 %CrI 0.001 to 0.28; moderate certainty), and cardiovascular death (aHR 1.35, 95 %CrI 0.98 to 1.84; tau = 0.20, 95 %CrI 0.001 to 0.54; low certainty) after adjustment for traditional risk factors. The association between CRP and the risk of cerebrovascular events was inconclusive (aHR 1.52, 95 %CrI 0.69 to 3.32; tau = 0.33 95 %CrI 0.001 to 0.85; very low certainty). Dose-response Bayesian meta-analysis showed a non-linear association between CRP and major cardiovascular events, with levels between 2 and 4 mg/L being associated with clinically relevant higher risk. A similar dose-response relationship was observed also for all-cause death. Conclusions Among patients with ASCVD, elevated levels of CRP are associated with an increased risk of cardiovascular events. Systematic screening of CRP in secondary cardiovascular prevention could improve the identification of patients at risk of recurrent cardiovascular events. Systematic review registration CRD42025636822.