Statins prevent coronary heart disease

COMMENTARY Statins prevent coronary heart disease Over the past two years, our policies regarding the management of patients with clinically manifest coronary heart disease (CHD) and hypercholesterolaemia have changed radically. This change came about when clinical trials showed that inhibitors of the 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase step in cholesterol synthesis, or "statins", led to less progression and more regression of pre-existing coronary atherosclerotic lesions,’-3 and to fewer subsequent clinical CHD events.4-6 In the seminal secondary prevention randomised clinical trial, known as 4S,4 4444 patients with angina pectoris or previous myocardial infarction were followed for 5-4 years. Compared with placebo-treated patients, simvastatin produced a 30% reduction in the relative risk of deaths from all causes, a 42% risk reduction in deaths from CHD, a 34% risk reduction in CHD morbidity, and a 37% risk reduction in myocardial revascularisation procedures. Mean changes in total cholesterol, lowdensity lipoprotein (LDL) cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol were -25%, - 35%, -15%, and +8%, respectively. The approximately 30% reduction of LDL cholesterol achieved with statins is a dimension never previously seen with other drugs or with diet. These drugs are the most powerful and consistent means available of lowering plasma cholesterol and have no adverse effects (at least within the 10 years of trials). Now our policy for people with mild or moderate increases in plasma cholesterol and additional CHD risk is also set to undergo a fundamental change. The results of the first large long-term primary prevention trial, the West of Scotland Study, have just been published.’ This trial was conducted in 6595 hypercholesterolaemic 45-65-year-old men over a mean of 4-9 years. Most were otherwise healthy; none had previous myocardial infarction; and only 5% had self-reported stable angina on admission to the trial. Randomisation was between pravastatin 40 mg at night and placebo. The criteria for entry8 to the trial were LDL cholesterol concentrations greater than 4-0 mmol/L (-155 mg/dL) at both key screening visits, or greater than 4-5 mmol/L at one of these screening visits, but less than 6-0 mmol/L. Pravastatin reduced total cholesterol by 20%, LDL cholesterol by 26%, and triglycerides by 12%; HDL cholesterol was raised by 5%. There were no side-effects or adverse reactions. In the pravastatin-treated group, the risk of CHD death or non-fatal myocardial infarction, and non-fatal infarction alone, was reduced by 31 %; deaths definitely due to CHD were reduced by 28% (pO-13), and from all causes by 22% (p=051); and the need for coronary angiography was reduced by 31% and for The angioplasty or bypass grafting by 37% (p<0001). clinical benefits of pravastatin treatment were equivalent in the 84% without and the 16% with pre-existing vascular risk. The West of Scotland trial is the fifth long-term randomised study to show benefit from reducing hypercholesterolaemia in healthy men at high risk for CHD and the first to use a statin. The results of the Los Angeles Veterans diet trial," the WHO clofibrate trials the Lipid Research Clinics cholestyramine trial," and the

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Helsinki Heart trial with gemfibrozil’2 all pointed in the same direction but used measures that reduced LDL cholesterol by less than half that of the statins. The West of Scotland trial showed clinical benefit within a year of starting treatment with pravastatin. This result contrasts with those of the earlier primary prevention trials in which diet, fibrates, or cholestyramine were used, with benefit not established until 3 or 4 years of treatment. The speedier response may be a consequence of the greater extent of reduction of LDL cholesterol achieved by statins. It might also reflect rapid improvement in endothelial-dependent vasorelaxation," which is known to be impaired in men with hypercholesterolaemia, or that there is less platelet aggregation, rather than the stabilisation of atheromatous plaques since beneficial structural changes from equivalent LDL reduction take several years. 14 No certain conclusions can be drawn from these trials about non-cardiac mortality, since none had the statistical power to measure a change in incidence. But neither the West of Scotland trial nor 4 S showed any adverse trend. This question will probably not be resolved until the results of an ongoing mega trial are known. Decisions about intervention must depend not only on clinical priorities but also on assessment of risk, extent of benefit, and cost. The West of Scotland and 4 S trials have provided indisputable evidence that the incidence of CHD can be reduced by about a third in those at risk from hypercholesterolaemia, whether or not they already have clinically manifest CHD. Further, both studies?,15 have indicated that the benefits are no less for those with baseline plasma cholesterol concentrations between 5-5 and 6-5 mmol/L compared with 6-5-8 mmol/L. Until now, the usual advice has been to consider using drugs only when the concentration exceeds 6-5 mmol/L. These trial results suggest that most healthy people with a total cholesterol above 5-5 mmol/L together with additional CHD risk factors, and also every male patient (and perhaps also female patients, although the evidence is less solid) up to 70 years, should be considered for treatment with a statin. The question of whether men who have plasma cholesterol concentrations of greater than 5-5 mmol/L (or a total cholesterol/HDL ratio >5) but with no additional CHD risk factors should always be treated with statins will be debated intensively by physicians, health economists, and pharmaceutical companies. The usual recommendation for these men at lower risk is to decrease dietary saturated fat intake and increase the polyunsaturated/saturated fat ratio but this is often ineffective outside clinic conditions and therefore an effective and safe drug assumes more importance. Some additional perspective about the extent of benefit may help with these decisions. Of 1000 55-year-old men living in the UK at all categories of CHD risk, 87% will be alive 10 years later.16 CHD is the cause of 36% of the deaths occurring over this period and, since the West of Scotland trial indicates that one-third of these CHD deaths might be prevented, the 10-year overall survival might be improved by about 1-5% and the 5-year survival rate by rather less than 1%. Alternatively, one can estimate that, for middle-aged men, there will be 9 fewer deaths and about 20 fewer non-fatal myocardial infarcts per 1000 individuals treated with a statin over 5 years.

will have to be for life and a year’s with a statin costs k400-600 ($600-900), exclusive of physician or laboratory charges, my preference is to focus on those identified as being at higher risk (plasma cholesterol >6’5 mmol/L). Any temptation to extrapolate the results of the West of Scotland trial to those with a plasma cholesterol of less than 5-5 mmol/L should be resisted because there is no evidence of benefit so far and the CHD risk in such men is only slightly increased. These trials have shown clearly that inexorable progress of a ubiquitous chronic disease can be slowed and that there is a real prospect of better health for many at high risk. Since

treatment

treatment

M F Oliver National Heart & Lung Institute, Imperial College, London, UK 1 Waters D, Higginson L, Gladstone P, et al. Effects of monotherapy with an HMGCoA reductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography: the Canadian Coronary Atherosclerosis Intervention Trial. Circulation

1944; 89: 959-68.

Investigators. Effect of simvastatin on coronary atheroma: a multicentre antiatheroma study. Lancet 1994; 344: 633-38. 3 Jukema JW, Bruschke AVG, van Boven AJ, et al. Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels: the Regression Growth Evaluation Statin Study (REGRESS). Circulation 1995; 91: 2528-40. 4 Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 2 MAAS

1383-89. 5

Furberg CD, Adams HP, Applegate WB, et al. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation

6

Byington RP, Jukema JW, Salonen JT, et al. Reduction in cardiovascular events during pravastatin treatment. Circulation 1995;

1994; 90: 1679-87.

92: 2419-25. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301-07. 8 The West of Scotland Coronary Prevention Study Group. A coronary primary prevention study of Scottish men aged 45-64 years: trial design. Clin Epidemiol 1992; 45: 849-60. 9 Dayton S, Pearce ML, Hashimoto S, et al. A controlled clinical trial of a diet high in unsaturated fat preventing complications in atherosclerosis. Circulation 1969; 39/40 (suppl II): 63. 10 Report from Committee of Principal Investigators. A cooperative trial in the primary prevention of ischaemic heart disease using clofibrate. Br Heart J 1978; 40: 1069-18. 11 Lipid Research Clinics Coronary Prevention Trial. JAMA 1984; 251: 351-74. 12 Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidaemia. N Engl J Med 1987; 317: 1237-45. 13 Stroes ESG, Koomans HA, de Bruin TWA, Rabelink TJ. Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication. Lancet 1995; 346: 467-71. 14 Buchwald H, Varco RL, Matts JP, and the POSCH group. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. N Engl J Med 1990; 323: 946-55. 15 Scandinavian Simvastatin Survival Study Group. Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4 S). Lancet 1995; 345: 1274-75. 16 OPCS. Mortality statistics by cause (series DH 2). London: HM Stationery Office, 1993. 7

Breast

cancer

in female

flight

attendants

A recent study from Finland showed a significant excess of de novo breast cancer in 1577 female flight attendants followed for a mean of 13-9 years.’ In searching for an explanation for this observation the following variables

considered by the researchers: radiation exposure, lifestyle, reproductive factors, fat intake, social class, and alcohol consumption. None of these factors, separately or together, was thought sufficient to explain the increased incidence of breast cancer. The quality of the methods used was high, with complete documentation of personal identification numbers of the cohort and follow-up for death and emigration. Thus technical incompleteness was thought not to have biased the results. In particular, the mean cumulative dose equivalent of cosmic radiation received by the cabin attendants was deemed far too low to account for the increased incidence, giving a relative risk of 1-011 for breast cancer compared with 1-87 discovered. How might one explain this increase in breast cancer? We have recently reported evidence2 of immune promotion of oncogenesis in a substantial subset of women who develop breast cancer. Chronic immunosuppression of 25 914 women for 1-11 years in western Europe and North America resulted in a 25% overall reduction in de-novo breast cancer, with a 42% reduction among 13 003 women who received cyclosporin, azathioprine, and steroids, and a 51% reduction among 8166 recipients of renal grafts in North America. Low-level radiation in the dose range received by female flight attendants has been shown to stimulate ongoing immune responses both in animals and man.3,4 Moreover, controlled population studies in Chinas.6 and in health workers in an Austrian health spa’ have shown that there is enhanced immune reactivity in such groups exposed to low-level radiation. A logical step would be to determine whether female flight attendants have higher immune reactivity than a matched cohort of women who fly infrequently--eg, those who tend the ticket counters in airports. The results would either refute or support our prediction of enhanced reactivity. Two cases of Kaposi’s sarcoma-a rare cancer in Finland-were found in 187 Finnish male flight attendants over the same period. Growth of this tumour is promoted by immune cytokines in the immunoactive early phase of the disease, both in patients with AIDS and in those without.8,9 Enhanced immune reactivity could likewise be expected to increase promotion of this tumour. were

Thomas Stewart, Nicolas Stewart University of Ottawa, Ottawa, Ontario,

Ottawa General Hospital and Canada

Pukkala E, Auvinen A, Wahlberg G. Incidence of cancer among Finnish airline cabin attendants, 1967-92. BMJ 1995; 311: 649-52. 2 Stewart T, Tsai SCJ, Grayson H, Henderson R, Opelz G. Incidence of de-novo breast cancer in women chronically immunosuppressed after organ transplantation. Lancet 1995; 346: 796-98. 3 Luckey TD. Radiation hormesis. Boca Raton: CRC Press, 1991. 4 Cohen BL. Mini Review. Dose-response relationship for radiation carcinogenesis in the low-dose region. Int Arch Occup Environ Health 1994; 66: 71-75. 5 Liu SZ, Xv GZ, Li X, et al. Wang SK. A restudy of immune functions of the inhabitants in a high natural radioactivity area in Guangdon. Chinese J Radiol Med Protection 1985; 5: 124-27. 6 Liu SZ, Liu WH, Sun JB. Radiation hormesis: its expression in the immune system. Health Physics 1987; 52: 579-83. 7 Tuschl H, Altmann H, Kovac R, Topaloglov A, Egg D, Günther R. Effects of low dose radiation on repair processes in human lymphocytes. Radiation Res 1980; 81: 1-9. 8 Ensoli B, Barillari G, Gallo RC. Cytokines and growth factors in the pathogenesis of AIDS-associated Kaposi’s sarcoma. Immunol Rev 1

1992; 127: 147-55. 9

Levy JA. A new human herpes virus: KSHV or HHV8?

Lancet 1995;

346: 786.

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