Assessment of individual and combined ACC scientific statement-recommended inflammatory markers for long-term prognostication in coronary heart disease: a two-cohort study

Background Chronic inflammation and coronary artery disease(CAD) have been research hotspots in recent years. In 2025, the American College of Cardiology (ACC) issued a Scientific Statement highlighting a broader panel of inflammatory markers for risk refinement, including clinically accessible indicators, including the established high-sensitivity C-reactive protein (hsCRP), as well as neutrophil-to-lymphocyte ratio (NLR) and fibrinogen (FIB). Aims This study aimed to investigate the association of hsCRP, NLR, and FIB—individually and in combination—with the risks of major adverse cardiovascular and cerebrovascular events (MACCE) and cardiac death in patients with CAD, using two large independent cohorts with different follow-up durations. Methods We analyzed two independent cohorts of patients with CAD: a 10-year single-center cohort (n=10,724) and a 2-year multicenter cohort (n=18,701). After excluding patients without complete follow-up data or missing measurements of inflammatory markers, the final analytic sample included 5,663 and 15,804 patients, respectively. A total score (range 0–6) was calculated by summing the tertile-based scores of hsCRP, NLR, and FIB(T1=0, T2=1, T3=2). Patients were then categorized as low (score 0–2), intermediate (3–4), high (5), or very high (6) risk. The primary endpoint was MACCE, defined as a composite of all-cause death, myocardial infarction, coronary revascularization, and non-hemorrhagic stroke. The secondary endpoint was cardiac death. Results In the 10-year PCI cohort (n=5663, mean age 58.6±10.4 years, 77.7% male), MACCE and cardiac death occurred in 39.2% and 4.5%, respectively; in the 2-year cohort (n=15804, mean age 60.9±10.5 years, 74.9% male), rates were 10.7% and 1.9%. Each inflammatory marker independently predicted both outcomes (Figure2), with a clear dose-response pattern when assessed jointly via a tertile-based score. In the 10-year cohort, relative to the low-risk group, MACCE risk increased progressively across intermediate, high, and very high inflammatory burden groups (HR 1.14, 1.24, 1.45; all P < 0.05). A similar trend was observed for cardiac death (HR 1.61, 2.47, 3.52). In the 2-year cohort, MACCE risk also rose across groups (HR 1.13, 1.53, 1.90), with stronger associations for cardiac death (HR 1.99, 3.41, 5.99). Conclusion Based on two large cohort studies, we demonstrated that the three inflammatory markers recommended in the ACC scientific statement independently predicted MACCE and cardiac death in patients with CAD, with a consistent dose-response relationship across cohorts. This is the first study to jointly assess these markers, showing that increased inflammatory burden correlates with higher adverse event risk. These findings support routine combined assessment for enhanced risk stratification and highlight a very high-risk subgroup that may benefit from intensive monitoring and anti-inflammatory therapy.