Prospective evaluation of the relationship between C-reactive protein, D-dimer and progression of peripheral arterial disease

Objective: Elevated levels of C-reactive protein (CRP) and D-dimer (DD) have been associated with the presence and progression of various forms of atherosclerotic disease, particularly coronary heart disease. We hypothesize that there is a relationship between elevated levels of baseline CRP and DD and progression of peripheral arterial disease (PAD) in patients with symptomatic PAD. The current study is a prospective evaluation of this hypothesis. Methods: Between 1996 and 2003, 384 subjects were enrolled in a National Institutes of Health-sponsored blinded, prospective trial evaluating the effects of multiple atherosclerotic risk factors on progression of symptomatic PAD. Baseline levels of CRP and D-dimer were obtained in 332 subjects. Subjects were followed every 6 months with clinical history and exam, ankle-brachial pressure index (ABI), and carotid artery duplex scanning (CDS). The primary study end point was a composite of ABI progression, CDS progression, stroke, myocardial infarction, amputation, and death from cardiovascular disease. Secondary end points included each of the components of the primary end point. The relationship between time to the various endpoints and baseline CRP and DD levels was examined by life-table analysis and Cox proportional hazards analysis. Results: Adequate baseline samples for CRP and DD were available in 332 subjects (mean age, 67 years; 57.8% men) with mean follow-up of 38.4 months (range, 1 to 99 months). Mean baseline levels (± SD) for CRP were 0.8 ± 1.14 (range, 0.03 to 13.0), and mean DD levels were 227.4 ± 303.3 (range, 1.9 to 2744.8). Progression, as defined by the primary end point, occurred in 48.5% of subjects. Subjects with elevated CRP (highest tertile) were no more likely to have any of the progression end points than those with the lowest values (lowest tertile) (P = NS, log-rank test, for all comparisons). By univariate analysis, subjects with elevated DD (highest tertile) were significantly more likely to die from any cause compared with subjects with the lowest DD values (lowest tertile) (P = .03, log-rank test). They were, however, no more likely to reach any of the other progression end points, including the primary end point (P = NS, log-rank test for all other comparisons). Multivariate analysis showed that DD level was a significant independent variable associated with occurrence of myocardial infarction (hazard ratio, 2.3; P = .02). Conclusions: In subjects with symptomatic PAD, elevated baseline DD, a marker of thrombotic activity, was significantly associated with the occurrence of myocardial infarction. This study did not confirm a relationship between progression of PAD and baseline DD or CRP during the first 3 years. Baseline DD and CRP do not provide useful risk stratification in patients at high risk for progression of symptomatic PAD. Future studies should evaluate serial levels of these markers to assess their utility in predicting progression of symptomatic PAD.