Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events?

Abstract

Background: Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI) and stroke.

Methods and findings: In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), baseline inflammatory markers in up to 5,680 men and women aged 70-82 y were related to risk for endpoints; nonfatal CVD (i.e., nonfatal MI and nonfatal stroke [n = 672]), fatal CVD (n = 190), death from other CV causes (n = 38), and non-CVD mortality (n = 300), over 3.2-y follow-up. Elevations in baseline IL-6 levels were significantly (p = 0.0009; competing risks model analysis) more strongly associated with fatal CVD (hazard ratio [HR] for 1 log unit increase in IL-6 1.75, 95% confidence interval [CI] 1.44-2.12) than with risk of nonfatal CVD (1.17, 95% CI 1.04-1.31), in analyses adjusted for treatment allocation. The findings were consistent in a fully adjusted model. These broad trends were similar for CRP and, to a lesser extent, for fibrinogen. The results were also similar in placebo and statin recipients (i.e., no interaction). The C-statistic for fatal CVD using traditional risk factors was significantly (+0.017; p<0.0001) improved by inclusion of IL-6 but not so for nonfatal CVD events (p = 0.20).

Conclusions: In PROSPER, inflammatory markers, in particular IL-6 and CRP, are more strongly associated with risk of fatal vascular events than nonfatal vascular events. These novel observations may have important implications for better understanding aetiology of CVD mortality, and have potential clinical relevance.

Figure 1. Kaplan-Meier time-to-event plots split by tertiles of IL-6 tertiles for (A) nonfatal CVD (n = 667 events), (B) fatal CVD (n = 189 deaths), (C) fatal other CV (n = 37 deaths), and (D) non-CVD mortality (n = 299 deaths).

Figure 2. Plot showing associations of 1-unit increase in log IL-6, log CRP, and fibrinogen with HR of endpoints on a log scale (after adjusting for randomized treatment, age, gender, LDL cholesterol, HDL cholesterol, triglycerides, BMI, systolic and diastolic blood pressure, current and exsmoking, diabetes, previous CVD, use of antihypertensive therapy, and country).