C-Reactive Protein Concentration and the Vascular Benefits of Statin Therapy: An Analysis of 20 536 Patients in the Heart Protection Study

Study Questions:

What are the effects of statin therapy in relation to baseline concentrations of C-reactive protein (CRP) and low-density lipoprotein (LDL) cholesterol?


In 69 hospitals in the United Kingdom, 20,536 men and women ages 40-80 years at high risk of vascular events were randomly assigned to simvastatin 40 mg daily versus matching placebo for a mean of 5.0 years. Patients were categorized into six baseline CRP groups (<1.25, 1.25-1.99, 2.00-2.99, 3.00-4.99, 5.00-7.99, and ≥8.00 mg/L). The primary endpoint for subgroup analyses was major vascular events, defined as the composite of coronary death, myocardial infarction, stroke, or revascularization. Analysis was by intention to treat.


Overall, allocation to simvastatin resulted in a significant 24% (95% CI, 19-28) proportional reduction in the incidence of first major vascular event after randomization (2,033 [19.8%] allocated simvastatin vs. 2,585 [25.2%] allocated placebo). There was no evidence that the proportional reduction in this endpoint, or its components, varied with baseline CRP concentration (trend p = 0.41). Even in participants with baseline CRP concentration less than 1.25 mg/L, major vascular events were significantly reduced by 29% (99% CI, 12-43; p < 0.0001; 239 [14.1%] vs. 329 [19.4%]). No significant heterogeneity in the relative risk reduction was recorded between the four subgroups defined by the combination of low or high baseline concentrations of LDL cholesterol and CRP (p = 0.72). In particular, there was clear evidence of benefit in those with both low LDL cholesterol and low CRP (27% reduction; 99% CI, 11-40; p < 0.0001; 295 [15.6%] vs. 400 [20.9%]).


The authors concluded that this study does not lend support to the hypothesis that baseline CRP concentration modifies the vascular benefits of statin therapy materially.


In this study of more than 20,000 people at high risk of vascular events, statin therapy reduced the risk of a major vascular event by a quarter, but there was no indication that the proportional risk reduction was larger in those with higher baseline CRP concentration. Indeed, even in participants with baseline CRP concentration less than 1.25 mg/L, or with low baseline concentrations of both LDL cholesterol and CRP, there were significant reductions in the risk of major vascular events. It should be noted that the Heart Protection Study was conducted primarily in a secondary prevention population, and may not offer insight on the usefulness of CRP measurements in a primary prevention population. In the future, the most definitive way to test the inflammatory hypothesis of atherosclerosis will be to directly randomize patients to anti-inflammatory therapies, and such prospective studies may offer additional insight on CRP for risk stratification.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins, Statins

Keywords: Lipoproteins, LDL, Cholesterol, Incidence, Myocardial Infarction, Stroke, C-Reactive Protein, Atherosclerosis, Biological Markers, Cholesterol, LDL, Simvastatin, Biomedical Research

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