Measurement of C-Reactive Protein for the targeting of statin therapy in the primary prevention of acute coronary events

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Measurement of C-Reactive Protein for the targeting of statin therapy in the primary prevention of acute coronary events.

Dr F. Haverkate and Dr M.P.M. de Maat, Leiden The Netherlands

Statins known to lower cholesterol levels reduce the risk of cardiovascular events. The reduction in risk cannot be completely explained by the effects of statins on cholesterol, and it became apparent some years ago that statins do more than just lowering cholesterol. They have effects on immune function, macrophage metabolism and cell proliferation independently of changes in plasma LDL concentrations (1).Ridker et al (2) addressed the question of whether statins might prevent coronary events in persons with low cholesterol, but high levels of C-Reactive protein (CRP), a sensitive acute-phase reactant and inflammatory marker. The interest in CRP is based on its well-established function as a cardiovascular risk factor, a discovery by the ECAT Angina Pectoris Group (3,4). The relationship between CRP and cardiovascular risk is independent of lipid levels (5,6) and an increased risk is observed in subjects with high CRP and low cholesterol levels as compared with low levels of both CRP and cholesterol.

In Ridker's study (2) 5742 apparently healthy persons were included in a randomized, placebo-controlled trial of lovostatin (20 or 40 mg daily). CRP and lipid levels determined at baseline were correlated with the risk of primary coronary events during a 5-year follow-up period. In line with results of previous studies lovostatin reduced the number of events; moreover high CRP as well as high lipid levels indicated the overall risk independently of each other. The study of Ridker et al describes a reduction of CRP by lovostatin of approximately 15 %, as compared with the placebo group. The reduction was not related to the effect of the statin on lipids. This is in line with the reduction of CRP on pravastatin, recently also published by Ridker et al (7).

The most interesting observation of Ridker et al (2) is that lovostatin was clinically effective among those with high CRP, while LDL cholesterol or the ratio of total to HDL cholesterol was low. It confirms that (a) there is an independent relationship between CRP and cardiovascular risk and also between cholesterol and the risk, and (b) statins have an effect on inflammatory reactions besides their lipid-lowering effect. The results of this study suggest that CRP screening may provide an additional tool for targeting the use of statins, particularly when cholesterol levels are normal or low. With respect to the CRP-lowering effect of other statins (7,8), the effect described here may not be limited to lovostatin.

As statins and fibrates reduce both cholesterol levels and the risk of disease, a causal action of cholesterol in cardiovascular disease is generally accepted. Can we now also conclude that there is a causal action of CRP? Such an exciting hypothesis cannot be proven yet. Although CRP activates the complement system, causes tissue damage and subsequently contributes to cardiovascular disease (9), it is too early to put CRP on the same level of clinical usefulness as cholesterol.

As levels of fibrinogen, also an acute-phase protein, are not reduced by statins (10), the effect of CRP found may be associated with a specific inflammatory response, notably through particular cytokines.

The findings of Ridker et al. are a breakthrough in the field. However, precautions have to be taken. The event rate in their study with 85 events (number not explicitly mentioned in the study) is rather small. The subdivision in 4 subgroups of events creates per group a rather low number of events ranging from 15 to 34. In the subgroup with high CRP and low lipids the number of events is too low for definite conclusions. Moreover it is an enigma why the subgroup with both high CRP and high lipids shows a smaller risk reduction than the subgroup with high CRP, but low lipids.

The results of this study immediately raise the question of what will happen in secondary prevention. There is a clear demand for studies in high-risk groups with a higher event rate, for instance in patients with angina. If Ridker's results can be confirmed in such studies, CRP may become an additional diagnostic tool in cardiovascular disease. If a causal relationship appears to exist, therapeutic intervention with specific anti-inflammatory drugs may be envisaged.

Dr F. Haverkate and Dr M.P.M. de Maat


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2. Ridker PM, Rifai N, Chearfield M, Downs JR, Weis SE, Miles JS, Gotto AM for the Air Force/Texas Coronary Atherosclerosis Prevention Study. Measurement of C-Reactive Protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med 2001; 344:1959-1965.

3. Haverkate F. Low-grade acute-phase reactions in arteriosclerosis and the consequences for haemostatic risk factors. Fibrinolysis 1992; 6 suppl 3:17-18.

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10. De Maat MP, Kluft C. Determinants of C-Reactive Protein concentration in blood. Ital Heart J 2001; 100:96-102.

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