Abstract
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. 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). 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.
Highlights
Low-grade chronic inflammation is widely thought to play an important role in the process of atherogenesis [1], and levels of inflammatory markers such as C-reactive protein (CRP) [2], interleukin (IL)-6 [3], and fibrinogen [4] are moderately associated with risk of coronary heart disease (CHD) events
In PROSPER [21], a clinical trial of pravastatin in the elderly at risk, with more than 850 incident cardiovascular disease (CVD) events including 190 fatal CVD events, we had the potential to explore for differential associations of IL-6, CRP, and fibrinogen with subsequent prespecified vascular events, as well as examine whether such associations were independent of traditional risk factors
The results show that IL-6, CRP, and to a lesser extent, fibrinogen are more closely linked to risk of fatal myocardial infarction (MI) or stroke than to nonfatal vascular events in the elderly at risk
Summary
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 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)
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