Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Lovastatin may have reduced the risk for cardiovascular events

ACP J Club. 1995 May-June;122:66. doi:10.7326/ACPJC-1995-122-3-066


Source Citation

Furberg CD, Adams HP, Applegate WB, et al. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation. 1994 Oct;90: 1679-87.


Abstract

Objective

To determine whether lovastatin reduces mortality, major cardiovascular events, and progression of subclinical atherosclerosis. (Warfarin was also studied, but the results were not included in this report.)

Design

Randomized, factorial, placebo-controlled trial (Asymptomatic Carotid Artery Progression Study) with mean follow-up of 34 months.

Setting

Clinics at 4 academic institutions.

Patients

Adults aged 40 to 79 years (mean age, 62 y; 52% men) with early carotid atherosclerosis, moderately elevated low-density lipoprotein (LDL) cholesterol levels, and no symptomatic cardiovascular disease. Exclusion criteria were myocardial infarction (MI), stroke, angina, or poor compliance. 15 415 patients were screened in a 3-stage process and 919 were studied. Follow-up was 95%.

Intervention

The warfarin dose was 1 mg/d; lovastatin was started at 20 mg/d and was increased or decreased by 10 mg/d to keep the LDL cholesterol level at 2.31 to 2.85 mmol/L. 229 patients received lovastatin and warfarin, 229 received warfarin only, 231 received lovastatin only, and 230 received placebo only. Aspirin was recommended for all patients.

Main Outcome Measures

Change in cholesterol levels and mean maximum intimal-medial thickness (IMT) assessed by B-mode ultrasonography across 12 preselected segments in the carotid arteries. Secondary outcomes were death, MI, and stroke. End-point assessment was blind.

Main Results

Warfarin had no effect on cholesterol levels. Lovastatin decreased LDL cholesterol levels by 25% (P < 0.001) (levels were unchanged in the placebo group). High-density lipoprotein (HDL) cholesterol changes did not differ when comparing lovastatin and placebo. Progression of IMT was lowest in the lovastatin group compared with the placebo-only group (- 0.009 vs. 0.006 mm/y; P < 0.001). The effect of lovastatin was not associated with sex, age, initial IMT, or cholesterol levels. Adverse events were not increased in the lovastatin group or in the warfarin group. 1 death occurred in patients receiving lovastatin and 8 deaths occurred in patients receiving lovastatin placebo (P = 0.02). 3% of the patients receiving lovastatin placebo had a major cardiovascular event (4 coronary heart disease deaths, 5 strokes, and 5 nonfatal MIs) compared with 1% receiving lovastatin (5 nonfatal MIs; P = 0.04).

Conclusion

Lovastatin reduced LDL cholesterol levels, slowed the progression of mean intimal-medial thickness of the common carotid arteries, and decreased mortality and major cardiovascular events in adults with early atherosclerosis.

Sources of funding: National Heart, Lung, and Blood Institute; Merck, Sharpe and Dohme (lovastatin); DuPont Pharmaceuticals (warfarin), and Sterling Drug Company (aspirin).

For article reprint: Dr. C.D. Furberg, Department of Public Health Sciences, Bowman Gray School of Medicine, Winston-Salem, NC 27157-1063. FAX 910-716-5425.


Commentary

Long-term simvastatin improved survival in coronary heart disease

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