Lower patients' cholesterol nowBMJ 1995; 310 doi: https://doi.org/10.1136/bmj.310.6990.1280 (Published 20 May 1995) Cite this as: BMJ 1995;310:1280
- Michael Oliver,
- Philip Poole-Wilson,
- James Shepherd,
- Matti J Tikkanen
- Professor emeritus Professor of cardiac medicine National Heart and Lung Institute, London SW3 6LY
- Professor of pathological chemistry Royal Infirmary, Glasgow G4 0SF
- Professor of medicine Department of Medicine, Division of Cardiology, Helsinki University, Central Hospital, SF-00290 Helsinki 29, Finland
Trial evidence shows clear benefits from secondary prevention
The first principle of the lipid hypothesis is that raised plasma cholesterol concentrations are associated with a high incidence of atherosclerosis and an increased risk of coronary heart disease. That assertion no longer stirs argument in medical circles. But the second principle—that both this risk and total mortality can be reduced by lowering plasma cholesterol concentrations—remains controversial. Polarisation of views has led over the past 20 years to the emergence of enthusiasts for whom cholesterol lowering and the prevention of coronary heart disease are almost synonymous and sceptics who attribute to lipid reduction more harm than good. This lack of consensus has been widely publicised by the media, and many people believe that the case for treating raised cholesterol concentrations is flawed and can be disregarded. The publication in 1994 of the results of several new trials has shown that this attitude is no longer tenable for one clearly defined category of patients—those who have already developed coronary heart disease.
Clinical decisions are rarely black or white. More often than not they are made with incomplete knowledge. This is certainly true in the prevention of cardiovascular disease. No one would challenge a policy aimed at reducing cigarette smoking, even in the absence of formal evidence from trials of a positive effect on the incidence of coronary heart disease. Consensus also exists that reducing the blood pressure decreases the frequency of cerebral vascular events. Cholesterol reduction is the one issue that has remained unresolved until now. The key questions are whether and when to treat raised cholesterol concentrations and to prescribe cholesterol lowering drugs—do thedrawbacks of treatment outweigh its benefits? Faced with this dilemma—and mistakenly believing that the whole cholesterol lowering concept is still under debate—many practitioners choose to do nothing.
The new trial evidence has clarified the picture.1 2 3 4 5 6 There is no longer any doubt about the benefit and safety of treating hypercholesterolaemia in patients who have had a myocardial infarction.7 We shall summarise the recent data.
The largest secondary prevention trial, the Scandinavian simvastatin survival study, studied 4444 patients and showed that a 25% reduction in plasma cholesterol concentrations initially between 5.5 and 8.0 mmol/l (and a reduction in low density lipoprotein cholesterol by 35%) resulted after 5.4 years in 30% fewer deaths and 42% fewer coronary deaths.1 No increase was seen in non-cardiovascular deaths. Two trials of the effects of a statin drug on coronary atheroma (considered together) showed that a decrease in cholesterol of 25-30% was associated with lessening of atheromatous obstruction. In one of these studies, the multicentre antiatheroma study conducted over four years in patients with raised cholesterol concentrations, three serial coronary angiograms showed less progression of lesions, including fewer new lesions and total occlusions, and more regression in those treated with simvastatin than in controls.2 Neither in this nor in the Canadian trial was any overall improvement seen in clinical events.3 Neither, however, was designed to enable a change in such events to be appraised with confidence. The fourth study was a three year trial of lovastatin in asymptomatic hypercholesterolaemic men and women with early carotid atherosclerosis, who were followed with ultrasonography.4 The results showed a favourable but not significant effect on the thickening of the intimal media and fewer major cardiovascular events compared with the placebo group. A further small three year trial of pravastatin was also associated with fewer coronary events.5 Finally, a small double blind trial, the Harvard atherosclerosis regression project, added some additional perspective by suggesting that patients with more normal cholesterol concentrations (between 4.5 and 6.0 mmol/l) might not benefit (at least within three years) from statin treatment.
The favourable results of these secondary prevention trials go some way to resolve one of the central concerns of the cholesterol controversy. This is the suggestion—derived from earlier primary prevention trials—that lowering the cholesterol concentration might itself increase the risk of non-coronary death.8 We can take some comfort from the Scandinavian simvastatin survival study, which showed that substantial reductions in circulating cholesterol—greater than those achieved in the earlier trials—were not associated with any evident increase in non-coronary mortality in patients known to have coronary heart disease, at least within five years of treatment. These results support the outcome of the longer program on the surgical control of the hyperlipidemias (POSCH) study, in which comparably large reductions in cholesterol were achieved by regional ileal bypass. The treated patients had no increase in non-coronary mortality after 12 years of follow up.9 Any true adverse biological effect would be expected to be evident from these two trials.
The new studies do not, however, resolve the possibility of an increase in non-cardiac mortality with cholesterol lowering in people without over coronary heart disease. That question is unlikely to be settled finally until a trial with the statistical power to address this specific issue is completed.10 If, as expected, the results of such megatrials show that lowering cholesterol reduces the incidence of coronary heart disease in those at high initial risk then the use of drugs to treat those at less high risk would still require the most careful appraisal.11
Jury still out on benefits in primary prevention
Conservatism in primary prevention is still justified. But it is no longer acceptable in the treatment of raised cholesterol concentrations in most patients with coronary heart disease after a myocardial infarction. The recently published joint guidelines of the European Atherosclerosis Society, the European Society of Cardiology, and the European Society of Hypertension reflect these findings by recommending treatment with cholesterol lowering drugs for patients with coronary heart disease and a plasma cholesterol concentration of over 6 mmol/l—but only if three to six months careful dietary counselling has failed.12 To what extent these recommendations might apply to high risk healthy people without manifest coronary heart disease may become clearer with the publication within a year of the first long term primary prevention trial in which reduction of plasma cholesterol by 25-30% has been achieved by the use of a statin drug.13
The risks of continuing high cholesterol concentrations in patients after myocardial infarction are unequivocal, but they are still often ignored in several European countries, including Britain. The consequence is undertreatment. While treatment with the statin drugs is expensive, this cost should be set against the strength of evidence for and the magnitude of the benefit shown in the recently published clinical trials. There is no longer any controversy about what to do for these patients and no justification for inertia.