Research Article: Are Markers of Inflammation More Strongly Associated with Risk for Fatal Than for Nonfatal Vascular Events?

Date Published: June 23, 2009

Publisher: Public Library of Science

Author(s): Naveed Sattar, Heather M. Murray, Paul Welsh, Gerard J. Blauw, Brendan M. Buckley, Stuart Cobbe, Anton J. M. de Craen, Gordon D. Lowe, J. Wouter Jukema, Peter W. Macfarlane, Michael B. Murphy, David J. Stott, Rudi G. J. Westendorp, James Shepherd, Ian Ford, Chris J. Packard, Fiona Mary Turnbull

Abstract: In a secondary analysis of a randomized trial comparing pravastatin versus placebo for the prevention of coronary and cerebral events in an elderly at-risk population, Naveed Sattar and colleagues find that inflammatory markers may be more strongly associated with risk of fatal vascular events than nonfatal vascular events.

Partial Text: Low-grade chronic inflammation is now 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. Recently we reported that whilst CRP was associated with subsequent combined nonfatal and fatal vascular events in the elderly at risk, the C-statistic was moderately (albeit significantly) increased with addition of CRP to traditional risk factors [5]. Other studies have reported similar findings in that all inflammatory markers appear to have moderate associations with risk of CHD events [6],[7], and provide minimal clinical utility to the C-statistic in risk scores [8]–[10].

The protocol of PROSPER has been published elsewhere [21],[22], and the methodology and outcome of the main trial has also been published [22].

Plasma IL-6 levels were obtained in 5,653 biobank samples (97.4%) of the original 5,804 patients. Of these, 667 (11.8%) had a nonfatal CVD event, 189 (3.3%) had a fatal CVD event, 37 (0.7%) died from other CVD causes (including 18 aneurysms, seven pulmonary embolisms, and three heart failures), and a further 299 (5.3%) had non-CVD deaths. Corresponding samples measured for CRP were 5,680 samples, 672 nonfatal CVD events, 190 fatal CVD events, 38 fatal other CVD events, and 300 non-CVD deaths. Fibrinogen was measured in 5,631 individuals. All other risk factor measurements were available in all individuals. 59 patients who had an incident nonfatal CVD went on to die from other events (vascular or otherwise). For the purpose of the present analysis, only the first event was included.

To our knowledge, this is the first study to directly and simultaneously compare prospectively the associations of a range of inflammatory markers separately with risks of fatal and nonfatal CVD events in a hypothesis driven manner. The results show that IL-6, CRP, and to a lesser extent, fibrinogen are more closely linked to risk of fatal MI or stroke (i.e., fatal CVD) than to nonfatal vascular events in the elderly at risk. In other words, we suggest that inflammatory markers are linked more closely to risk of death from CVD causes than to risk of nonfatal CVD events. We believe our findings may be a key feature of the inflammatory-vascular risk paradigm, which has been previously overlooked in the literature, but one that may have both important biological, clinical, and health implications.



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