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Therapeutics

Long-term simvastatin improved survival in coronary heart disease

ACP J Club. 1995 May-June;122:67. doi:10.7326/ACPJC-1995-122-3-067


Source Citation

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 Nov 19;344;1383-9.


Abstract

Objective

To determine whether long-term simvastatin is safe, improves survival, and decreases atherosclerotic events in patients with coronary artery disease (CAD).

Design

Randomized controlled trial (Scandinavian Simvastatin Survival Study) with median follow-up of 5.4 years.

Setting

94 clinical centers in Scandinavia.

Patients

Patients with angina or acute myocardial infarction (MI) aged 35 to 70 years (52% ≥ 60 y; 82% men) with serum cholesterol levels of 5.5 to 8.0 mmol/L and serum triglyceride levels ≤ 2.5 mmol/L. Exclusion criteria were potential for pregnancy, unstable angina, secondary hypercholesterolemia, tendon xanthomata, planned coronary artery surgery, recent MI, antiarrhythmic therapy, congestive heart failure requiring medication, previous stroke, impaired hepatic function, atrial fibrillation, cardiomegaly, valvular heart disease, partial ileal bypass, history of substance abuse, use of or contraindications to study drugs, or other serious disease.

Intervention

After 2 months of observation that included dietary advice, patients were allocated to simvastatin, 20 mg/d (n = 2221), or to placebo (n = 2223). The doses were adjusted to 10 mg/d or 40 mg/d to reduce total cholesterol levels to between 3.0 and 5.2 mmol/L.

Main Outcome Measures

End points were total mortality (primary end point) and major coronary events (secondary).

Main Results

The study was stopped early on the basis of predetermined criteria (440 deaths). Patients receiving simvastatin compared with those receiving placebo had greater mean changes from baseline in levels of total cholesterol, triglycerides, and low- and high-density lipoprotein (LDL and HDL) cholesterol. The patients receiving simvastatin also had 3.3% lower mortality (8.2% vs. 11.5%; {95% CI for the 3.3% absolute risk reduction [ARR], 1.6% to 5.1%; P < 0.001; relative risk reduction [RRR], 28.8%; number needed to treat [NNT], 30; CI, 20 to 64}*) and 6.7% fewer major coronary events (15.9% vs. 22.6%; {CI for the 6.7% ARR, 4.4% to 9.0%; P < 0.001; RRR, 29.6%; CI, 20.4% to 37.7%, NNT, 15; CI, 11 to 23}*). The results did not differ for age. Risk reduction in women was confined to fewer major coronary events. The groups did not differ for discontinuation of therapy or adverse effects.

Conclusions

Long-term simvastatin reduced mortality and major coronary events and improved lipid levels in patients with coronary artery disease.

Source of funding: Merck Research Laboratories.

For article reprint: Dr. T.R. Pedersen, Cardiology Section, Medical Department, Aker Hospital, N0514 Oslo, Norway. FAX 47-2289-4008.

*Numbers calculated from data in article.


Commentary

Lovastatin may have reduced the risk for cardiovascular events

Despite the many randomized controlled trials done over the past 3 decades, the debate about the advantages of cholesterol-lowering therapy has continued worldwide (1). These trials have clearly shown a reduction in the risk for nonfatal coronary events, but overall mortality was largely unaffected. When decreased cardiovascular mortality was seen, it was often counterbalanced by an increase in noncardiovascular mortality. Total mortality is insensitive for monitoring the effect of a therapeutic intervention, but it is the most reliable end point. This is particularly relevant in primary intervention trials where the benefit must outweigh the potential risk. Finally, the benefit of cholesterol-lowering therapy in women and elderly persons remains even more inconclusive because most trials were confined to middle-aged men.

A recent meta-analysis (2) of 22 trials estimated that a cholesterol reduction of > 5% to 10% is required to show a reduction in overall mortality in a single trial of practical size. The very modest average 5% reduction in total cholesterol levels achieved in these trials suggests that a more aggressive cholesterol-lowering approach will result in reduced overall mortality.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) have generally a greater cholesterol-lowering effect and better patient acceptability than the older agents (fibrates, resins, and niacin) used in all previous drug trials. Several primary and secondary prevention trials with statins are now assessing their increased lipid-lowering potential on cardiovascular morbidity and mortality.

Recent improvements in imaging technology have allowed better definition of the atherosclerotic process by quantitative angiographic and ultrasonographic assessments. Most of the current research has focused on angiographic changes in patients with established CAD. In these trials, intensive lipid-lowering therapy with various agents for 1 to 3 years resulted in a substantial reduction of both total and LDL cholesterol levels. This was associated with a slowing or arrest of CAD progression in almost half of the patients in the treatment group and with regression in relatively few patients.

The study by Furberg and colleagues exemplifies these "regression" studies. Together with the Pravastatin, Lipids, and Atherosclerosis in the Carotids (PLAC-2) trial (3, 4), these studies show, for the first time, the reliability of ultrasonography as a surrogate marker of progressive early carotid atherosclerosis. The noninvasive nature of ultrasonography is clearly attractive, but some doubt remains about its reproducibility in a routine clinical setting. The therapeutic implications also should be interpreted with some caution. Although reduction of cardiovascular events and all-cause mortality is impressive, the small sample size and low numbers of outcome events in this trial preclude generalization (as discussed by the authors). Finally, the therapeutic role of warfarin in these patients is uncertain because this component of the trial awaits publication. For now, this study reassures the practitioner about the great lipid-lowering potential and safety of statins in men and women with moderately elevated cholesterol levels. Nonetheless, confirmation of the clinical benefits in large-scale trials is needed before this approach can be recommended for a large group of asymptomatic persons.

On the other hand, results of the Scandinavian Simvastatin Survival Study are likely to have immediate, practical clinical consequences. This well-designed secondary prevention trial conclusively shows the benefit and safety of long-term therapy with simvastatin. For the first time, overall risk for death was reduced, in addition to the previously reported risk reduction in coronary events and death. It seems reasonable to assume that this benefit is not unique to simvastatin but is a class effect of statins. Dietary intervention and correction of other cardiovascular risk factors were not rigorously assessed in this trial; nevertheless, it appears that HMG CoA reductase inhibitors can now be regarded as another option (along with aspirin, β-blockers, and angiotensin-converting-enzyme inhibitors) for reducing the risk for future cardiovascular events (5). The fact that only slightly more than a third of all patients in this trial were receiving aspirin, however, should remind us that well-published advances are often not translated into clinical practice.

Wolfgang J. Weise, MD
University of Vermont Burlington, Vermont