European Heart Journal (2002) 23, 183–184
doi:10.1053/euhj.2001.2959, available online at http://www.idealibrary.com on
Editorials
Statins and mortality
See page 207, doi:10.1053/euhj.2001.2775 for the article to which this Editorial refers
In this issue Simes et al. present pooled estimates for mortality from the Pravastatin Pooling Project (PPP)[1]. The two secondary prevention studies[2,3]
and the primary prevention trial[4] included in the
PPP enrolled together about 20 000 men and women aged 45–75 years with or without established cor-onary artery disease and a wide range of baseline lipid levels. As compared to placebo, in those allocated to pravastatin, LDL cholesterol was lowered by 24% and triglycerides by 9%, whereas HDL cholesterol increased by 5%. After a follow-up period of about 5 years, in the pravastatin arm, there was a relative risk reduction of 20% for total mortality, and 24% for coronary heart disease mortality. Moreover, non-cardiovascular mortality was non-significantly reduced by 12%, with no evidence for an increase in specific deaths. There was no statistical evidence for differences in the relative risk reduction between primary and secondary prevention, different age strata, or sex. Among cardiovascular disease end-points, the risk reduction was most impressive for fatal definite MI, with a risk reduction of 50%. Because of the similar relative risk reduction across different strata, the absolute risk reduction of pra-vastatin use was largely driven by the underlying mortality risk.
These results corroborate findings of single statin trials[2–6] and results of pooled combined
cardio-vascular end-points[7]. Compared to other
interven-tions and medicainterven-tions after myocardial infarction[8],
statins are among the most effective therapies in the reduction of subsequent cardiovascular events and mortality. Moreover, the results confirm that the relative risk reduction for different end-points is quite stable across different strata of baseline risk. As is known from many previous studies, the risk of mor-tality is several-fold increased among patients with established coronary heart disease[9], and accordingly, these patients derive the greatest benefit from statins with respect to absolute risk reduction. Despite the known large benefits, many patients with established
coronary heart disease still do not receive lipid-lowering drugs as recently demonstrated in the EUROASPIRE II study[10] which surveyed patients
up to 70 years of age after a hospital stay for coronary heart disease. In the PPP, the observed benefit was reached with a pravastatin dose of 40 mg per day, lowering cholesterol in a large proportion of participants to <5 mmol . l1. In daily practice, many treated patients do not reach this therapeutic goal[10], frequently due to underdosage of
lipid-lowering drugs. The current study, together with previous reports of statin trials, support the broad use of statins in appropriate doses for secondary prevention of coronary heart disease.
Among patients without coronary heart disease, the relative risk reduction for cardiovascular and total mortality did not significantly differ from those with a history of myocardial infarction. The primary prevention subjects included in this quantitative over-view were all male with moderate to high cardio-vascular risk, and therefore do not represent a typical sample of primary prevention subjects. Nevertheless, the relative risk reduction for combined end-points and mortality was also similar among subjects in the AFCAPS/TEXCAPS trial[6] that enrolled men and women with a far lower average risk. Among subjects without coronary heart disease in the PPP, the cor-onary mortality risk was about one third of that of patients with coronary heart disease, and in the AFCAPS/TEXCAPS study the coronary mortality risk was about 15 times lower than in the secondary prevention subjects of the PPP. Because of the wide range of cardiovascular and total mortality risk in primary prevention, decisions regarding statin therapy have to be tailored to the individual patient according to his/her risk for subsequent cardiovascu-lar events, as proposed in recent European[11] and US[12]guidelines.
Despite the growing body of evidence regarding the benefits of lipid lowering drugs, there are several issues that have to be clarified in further studies. First, the current analysis did not provide mortality results according to baseline lipid readings. These numbers would have been of interest because it is still not entirely clear whether there is a lower cut-off of LDL cholesterol for a benefit of lipid lowering drugs.
Published online 22 November 2001.
Despite the high number of subjects included in the PPP, the number of women enrolled was low, and no female subjects were included in primary prevention. Although there is no clear evidence that the mortality reduction by statin use differs among women and men, the small number of female subjects does not permit the drawing of clear conclusions, in particular with respect to total mortality. However, in second-ary prevention, the risk reduction for combined fatal and non-fatal end-points was similar among both genders[7]. Although the included secondary preven-tion studies enrolled patients up to a relatively high age of 75 years, it would be important to have more data on patients at a more advanced age, particularly whether they benefit from statin therapy with respect to quality of life.
An additional point is the duration of drug treat-ment. The majority of patients receiving statins for secondary prevention are older than 50 or 60 years of age, and have a particularly high cardiovascular mortality risk. Therefore, it is not likely that with increased follow-up the benefits for cardiovascular risk reduction could be offset by any long-term harm from treatment. In primary prevention, however, the question of whether to treat or not to treat more frequently arises in subjects at younger age, with the consequence that lipid lowering therapy would have to be taken potentially for decades. So far, there is no evidence that statins increase the rate of non-cardiovascular disease incidence or mortality, and in the current pooled estimates the risk tended to be decreased. Although this is reassuring, certain dis-eases like cancer have a long latent period before clinical manifestations become apparent. Therefore, more data are needed regarding potential harm in the very long-term. Thus, the ongoing follow-up of the WOSCOP and LIPID population will provide important additional information with respect to this issue.
In summary, the accrued evidence clearly indicates a large benefit of lipid lowering drugs in most subjects at high risk for cardiovascular events. Moreover, the results demonstrate a similar relative risk reduction among groups irrespective of baseline risk, with an absolute risk reduction proportional to the under-lying baseline risk. Despite the convincing results so far published, additional data would be very helpful to optimize treatment decisions, such as results from primary prevention trials including subjects with an intermediate risk, data on long-term use, as well as
more study results on treatment effects among women and among patients at very advanced age.
J. MUNTWYLER1
F. GUTZWILLER2
1Department of Internal Medicine,
University Hospital of Zu¨rich, Switzerland
2Institute of Social and Preventive Medicine,
University of Zu¨rich, Switzerland
References
[1] Simes J, Furberg CD, Braunwald E et al. Effects of pra-vastatin on mortality in patients with and without coronary heart disease across a broad range of cholesterol levels: the Prospective Pravastatin Pooling project. Eur Heart J 2002; 23: 207–15, doi:10.1053/euhj.2001.2775.
[2] Sacks FM, Pfeffer MA, Moye LA et al. The effect of pra-vastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335: 1001–9.
[3] The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: 1349–57.
[4] Shepherd J, Cobbe SM, Ford I et al. Prevention of coronary heart disease with pravastatin in men with hypercholestero-lemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995; 333: 1301–7.
[5] Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–9.
[6] Downs JR, Clearfield M, Weis S et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998; 279: 1615–22.
[7] Sacks FM, Tonkin AM, Shepherd J et al. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project. Circulation 2000; 102: 1893–900.
[8] Merz CN, Rozanski A, Forrester JS. The secondary prevention of coronary artery disease. Am J Med 1997; 102: 572–81.
[9] Lotufo PA, Gaziano JM, Chae CU et al. Diabetes and all-cause and coronary heart disease mortality among US male physicians. Arch Intern Med 2001; 161: 242–7. [10] EUROASPIRE I and II Group. Clinical reality of coronary
prevention guidelines: a comparison of EUROASPIRE I and II in nine countries. European Action on Secondary Preven-tion by IntervenPreven-tion to Reduce Events. Lancet 2001; 357: 995–1001.
[11] Prevention of coronary heart disease in clinical practice. Recommendations of the Second Joint Task Force of European and other Societies on coronary prevention. Eur Heart J 1998; 19: 1434–503.
[12] Executive summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Choles-terol in Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486–97.
184 Editorials