Protecting the Heart: A Practical Review of the Statin Studies

H. T. Ong, MBBS (Mal), MRCP (UK), M Med (Sing), FRCP (Glasg, Edin), FCCP (USA), FAMM (Mal)

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In This Article

The Beginnings: 4S, WOSCOPS, and CARE

4S ushered in the era of megatrials on hypolipidemic therapy.[3] In hindsight, this was a very well conceived trial because it addressed the question for which a positive answer was most likely. It looked at patients who were already suffering from IHD and had definitely elevated cholesterol levels, and investigated whether lowering the cholesterol levels in these patients would bring benefit. A total of 4444 patients with angina or prior myocardial infarction and serum cholesterol between 5.5 and 8.0 mmol/L were put on either simvastatin or placebo and followed up for a median of 5.4 years. Total cholesterol was reduced by 25%, and low-density lipoprotein (LDL) cholesterol by 35% in the treatment group. Treatment with simvastatin reduced major coronary events (defined as coronary death, myocardial infarction, or resuscitated cardiac arrest, relative risk [RR] 0.66, 95% confidence interval [CI] 0.59-0.75), reduced coronary mortality (RR 0.58, 95% CI 0.46-0.73), and reduced total mortality (RR 0.70, 95% CI 0.58-0.85). Furthermore, therapy also reduced the need for coronary revascularization with bypass surgery or angioplasty (RR 0.63, 95% CI 0.54-0.74). There was no difference in noncardiovascular deaths in the treated and placebo groups. This study established clearly that hypolipidemic therapy is safe and it reduces morbidity and mortality in hypercholesterolemic patients with IHD. It is thus reasonable to conclude that all patients with significantly elevated cholesterol levels and known prior cardiovascular heart disease should have their hypercholesterolemia treated to reduce future adverse events. A subsequent substudy confirmed the value of therapy in diabetic patients.[4]

The next major study,[5] chronologically, was WOSCOPS. This addressed a different question from 4S and investigated whether hypolipidemic therapy was beneficial in hypercholesterolemic men without a prior history of myocardial infarction. A total of 6595 men aged 45-64 years were put on either pravastatin 40 mg per day or placebo, and followed up over an average of 4.9 years. Total cholesterol was reduced by 20% and LDL cholesterol reduced by 26% with treatment. Although this was a primary prevention study, the subjects enrolled were actually at high risk for coronary events, being middle-aged men with markedly elevated cholesterol levels (total cholesterol 7.03 +/- 0.57 mmol/L), elevated body mass index (26 +/- 3.1 kg/m2), and more than a third were current smokers. In this high-risk group, pravastatin therapy reduced coronary events by 31% (95% CI 17% to 43%), revascularization procedures by 37% (95% CI 11% to 56%), and cardiovascular mortality by 32% (95% CI 3% to 53%). There was no difference in noncardiovascular mortality, and the reduction in total mortality of 22% was of borderline significance (P = .051). This suggests that in these subjects with no definite prior IHD, treatment of elevated lipid levels does not bring about as great a benefit as it would in a population known definitely to have cardiovascular disease, as in the 4S population. Nevertheless, the reduction of adverse coronary events in WOSCOPS is impressive and the message has been made that the high-risk hypercholesterolemic patient who was not previously known to have IHD would benefit from treatment of hyperlipidemia. The goal post has been moved -- the message is out to seek out the high-risk hypercholesterolemic patient who has now been shown to benefit from statin therapy.

The following year saw the publication of the CARE study.[6] This study was on patients with a past history of a myocardial infarction but who had average cholesterol levels (5.4 +/- 0.4 mmol/L). A total of 4159 patients had a median follow-up of 5 years. Total cholesterol was reduced by 20% and LDL cholesterol by 28%. Compared with placebo, pravastatin therapy reduced the primary end point (defined as coronary death or nonfatal myocardial infarction) by 24% (95% CI 9% to 36%). In this study, there was no significant difference in cardiovascular, noncardiovascular, or total mortality; it was myocardial infarction that was markedly reduced, and this accounted for the significant reduction in primary end point. The need for revascularization procedures and the incidence of strokes were also lowered significantly with pravastatin therapy. The inescapable conclusion was that in patients with a prior myocardial infarction (secondary prevention), hypolipidemic therapy is important even if cholesterol levels are not highly elevated. However, the absence of coronary mortality reduction and the lower percentage reduction of major coronary events in the CARE study compared with 4S suggests that it is the hyperlipidemic and high-risk patient who will benefit most from therapy.

The historical impact of these 3 trials, published over a 2-year period, is especially remarkable when one considers what was available in the 2 decades prior to their appearance. Hypocholesterolemic drug trials achieved only modest reduction of total cholesterol levels of about 10% compared with a 20% to 30% reduction with the statins. These drugs produce significant unpleasant adverse effects, suggested an increase of noncardiac mortality, and appeared to have no impact on total mortality.[7,8,9,10] The disappointing results of drug trials then made dietary and lifestyle studies appear impressive.[11,12] However, dietary and lifestyle changes are difficult to implement and maintain on a large scale. Moreover, the difference between a diet with under 10% of total calories from saturated fat and one with under 7% of total calories from saturated fat may be more significant to the researcher than to the clinician or the patient. Today, we argue for a therapeutic lifestyle and for healthy eating habits, but the safety, efficacy, and tolerability of the statins are so well established that the latest clinical guidelines all devote much more attention to pharmacologic therapy than to dietary advice in the primary and secondary prevention of cardiovascular disease.[13,14,15] It was these 3 statin trials that laid the foundation of our fundamental change in practice habits.

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