C-reactive protein concentration and the vascular benefits of statin therapy: an analysis of 20,536 patients in the Heart Protection Study

Abstract

Background: It has been suggested that inflammation status, as assessed by C-reactive protein (CRP) concentration, modifies the vascular protective effects of statin therapy. In particular, there have been claims that statins might be more beneficial in people with raised CRP concentrations, and might even be ineffective in people with low concentrations of both CRP and LDL cholesterol. This study aimed to test this hypothesis.

Methods: In 69 UK hospitals, 20,536 men and women aged 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 categorised 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 revascularisation. Analysis was by intention to treat. This study is registered, number ISRCTN48489393.

Findings: Overall, allocation to simvastatin resulted in a significant 24% (95% CI 19-28) proportional reduction in the incidence of first major vascular event after randomisation (2033 [19·8%] allocated simvastatin vs 2585 [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%]).

Interpretation: Evidence from this large-scale randomised trial does not lend support to the hypothesis that baseline CRP concentration modifies the vascular benefits of statin therapy materially.

Funding: UK Medical Research Council, British Heart Foundation, Merck, Roche Vitamins, and GlaxoSmithKline.

Figure 1

Effect of simvastatin allocation on vascular events by baseline concentration of C-reactive protein

Figure 2

Effect of simvastatin allocation on vascular and non-vascular death by concentration of baseline C-reactive protein

Figure 3

Effect of simvastatin allocation on first major vascular event during follow-up by baseline concentrations of LDL cholesterol and CRP Test for heterogeneity between four groups, excluding participants with missing data for baseline CRP concentration. Threshold values used to define low and high concentrations of LDL cholesterol and CRP are from the median values in the hypothesis-generating trial. CRP=C-reactive protein.