Summary

In a follow-up to a 5-year study, investigators report a significant reduction in coronary artery events (heart attack, cardiac death) in statin-treated subjects after a further 10 years.

Introduction

The latest thinking about the development and progression of atherosclerosis is that inflammatory changes arise in the innermost artery cells (the intima cells) associated with an influx of low-density lipoprotein (LDL) cholesterol. The central role of LDL cholesterol is borne out by the success achieved by lowering this lipid in preventing coronary artery thrombosis, or heart attack. Three large clinical studies examined this approach in the late 1990s.¹ They were all what's called 'primary prevention' studies - that is to say they examine trials to lower the risk of an initial event (e.g. a heart attack). Secondary prevention is lowering the risk of an event (e.g. sudden cardiac death) following survival of an initial event (e.g. a heart attack).

The results were unequivocal in demonstrating the clinical benefit of lowering LDL cholesterol levels. The WOSCOPS trial entered people with the highest levels of cholesterol - men aged 45 to 64, without a prior heart attack, with an average LDL level of 192 mg/dL. Pravastatin (40mg Pravachol® daily) lowered this by 26%. After 5 years there was a significant difference in all-cause and coronary heart disease mortality; this was 5.5% for the pravastatin group and 7.9%for the placebo group.

Now an additional 10 years' follow-up of the WOSCOPS trial survivors has been published in the New England Journal of Medicine.²

The Long-Term Follow-up Study

The survivors of the original 5-year study were followed for the next 10 years, with recording of all deaths, hospitalizations, and cancer occurrences, using the national (Scotland) computerized record-linkage system. There was a statistically significant reduction in death from coronary heart disease or non-fatal heart attack from 10.3% in those originally assigned to receive placebo to 8.6% in those originally assigned to pravastatin. There were no excess cancer deaths in the pravastatin group compared with the placebo.

This study is important as it shows the effects of statin treatment persist in the long term. But there are still two practical questions for the patient and the prescribing physician. How early should treatment be started, and what should the LDL cholesterol target be?

Prescribing Statins

The WOSCOPS follow-up study showed that the group originally assigned to receive pravastatin had better outcomes after 15 years, although the placebo group subjects were allowed to take pravastatin after the original 5-year trial ended. This suggests that earlier initiation of treatment had a long-lasting effect. So physicians should not hesitate unduly to start patients on a statin, especially in those who may have a genetic risk for hypercholesterolemia.

Many studies - epidemiologic and clinical - have shown a graded association between serum LDL cholesterol and the heart disease rate, but they haven't been able to demonstrate a level below which further lowering of LDL cholesterol fails to further reduce coronary events. There's little information about subjects with LDL cholesterol levels below 90 mg/dL. Arctic Eskimos, however, may provide a model. Their LDL cholesterol levels are commonly in the range of 50 to 70 mg/dL, and both clinical and postmortem studies have shown an absence of atherosclerosis, even in older subjects.

In the TNT (Treating to New Targets) study patients with stable coronary artery disease were given either 10 or 80 mg atorvastatin (Lipitor®) for 5 years. Those given the higher dose achieved an average LDL cholesterol level of 77 mg/dL, and had a coronary event risk level 22% lower than those given the low atorvastatin dose.³

Next steps

The editorialist who wrote the source article for this piece calls for further clinical trials of treatments designed to lower LDL cholesterol levels still further, using existing medications. He then states: "One possible result is that sufficient lowering will reduce the incidence of coronary disease to the point that it becomes a relatively uncommon diagnosis".

Before we embrace the concept of reducing LDL cholesterol to extremely low levels and keeping it there, we should be aware of a caution raised by an analysis of adverse event reports from 20-odd statin studies. The authors reported a link between cancer incidence and the actual LDL levels achieved, although there was no such link between percentage LDL reduction or the size of the reduction.⁴ Even the authors of the study, however, state that the findings are far from conclusive. Maybe we must wait for further findings from long-term studies before giving statins a completely clean bill of health. But there's no doubt that, in general, their benefits greatly exceed any possible risks.