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


Therapeutics

Pravastatin reduced nonfatal MI without increasing noncardiovascular death in men with hypercholesterolemia

ACP J Club. 1996 Mar-April;124:40. doi:10.7326/ACPJC-1996-124-2-040


Source Citation

Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995 Nov 16;333:1301-7. [PubMed ID: 7566020]


Abstract

Objective

To evaluate the effectiveness of pravastatin in preventing coronary events in men with moderate hypercholesterolemia and no history of myocardial infarction (MI).

Design

Randomized, double-blind, placebo-controlled trial with a mean 4.9-year follow-up.

Setting

Coronary screening clinics throughout the West of Scotland.

Patients

6595 men (mean age 55 y) with a fasting low-density lipoprotein (LDL) cholesterol level ≥ 4.0 mmol/L during the second and third baseline visits, with at least 1 value ≥ 4.5 mmol/L and 1 value ≤ 6.0 mmol/L; no serious electrocardiogram abnormalities; and no history of MI or other serious illnesses.

Intervention

3302 patients were allocated to pravastatin, 40 mg each evening, and 3293 to placebo. Patients were seen at 3-month intervals, and lipid-lowering dietary advice was reinforced at each visit.

Main Outcome Measures

Nonfatal MI or death from coronary heart disease (CHD), cardiovascular and total mortality, revascularization procedures, and changes in plasma cholesterol and LDL cholesterol levels.

Main Results

Analysis was by intention to treat. Pravastatin decreased plasma cholesterol levels by 20% and LDL cholesterol levels by 26% in patients who took their medication. No changes occurred with placebo. Pravastatin led to fewer definite nonfatal MIs and deaths from CHD at a mean follow-up of 4.9 years than did placebo (P < 0.001) (Table). When this combined outcome was separated, pravastatin led to fewer definite MIs than did placebo (P < 0.001) (Table) but not to fewer deaths definitely from CHD (1.2% vs 1.7%, P = 0.13). The rate of death from all cardiovascular causes was lower in the pravastatin group than in the placebo group (1.6% vs 2.3%, P = 0.03). No difference in noncardiovascular deaths was observed (P = 0.54). Total mortality was 3.2% in the pravastatin group and 4.1% for placebo (P = 0.051). At year 5, cumulative rates of withdrawal from treatment in the placebo and pravastatin groups were 31% and 30%, respectively.

Conclusion

In men with moderate hypercholesterolemia and no history of myocardial infarction, pravastatin when compared with placebo reduced the incidence of either nonfatal myocardial infarction or death from coronary heart disease and did not increase the risk for death from noncardiovascular causes.

Source of funding: Bristol-Myers Squibb Pharmaceutical Research Institute, USA.

For article reprint: Dr. I. Ford, Robertson Centre for Biostatistics, Boyd Orr Building, University of Glasgow, Glasgow G12 8QQ, Scotland, UK. FAX 44-141-330-5094.


Table. Pravastatin vs placebo for reducing nonfatal myocardial infarction (MI) or death from coronary heart disease (CHD)*

Outcomes at mean of 4.9 y Pravastatin Placebo RRR (95% CI) NNT (CI)
Nonfatal MI or death from CHD 6% 8% 31% (17 to 43) 42 (28 to 94)
Nonfatal MI 5% 7% 31% (15 to 45) 53 (33 to 130)

*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

In this trial, a 20% reduction in blood cholesterol levels was associated with a reduction in the risk for coronary death and nonfatal MI and the need for revascularization procedures. The results of this trial and the evidence from the 4S Group (1) confirm that intensive efforts to reduce blood cholesterol levels reduce the risk for CHD, particularly among patients who are at high risk for CHD. Despite the substantial proportionate benefits with these potent cholesterol-lowering drugs, the absolute 5-year risk in the trial for any coronary event among the nonsmokers in the placebo group was still lower than that among the smokers in the treated group. Although the rate of death from noncardiovascular causes did not increase among the treated patients, the trial lacked the statistical power to assess whether cholesterol reduction affects noncardiovascular mortality. Instituting drug therapy to reduce cholesterol is clearly worthwhile in patients with a high absolute risk for CHD. Some uncertainty remains, however, about the balance between the benefits and hazards of prolonged drug therapy in patients at lower risk. The question of whether lowering cholesterol in patients at high and intermediate risk for CHD produces an improvement in survival is being addressed in several ongoing trials. Neither this trial by Shepherd and colleagues nor the 4S trial can assess the types of hazard that some investigators have been claiming with cholesterol-lowering treatments (e.g., 20% increase in non-CHD mortality or cancer). Reliable evidence about the balance between benefits and risks will emerge from further large trials (2) and in particular an overview of such trials (3).

Robert Clarke, MD
University of OxfordOxford, England, UK


References

1. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:383-9.

2. Collins R, Keech A, Peto R, et al. Cholesterol and total mortality: need for larger trials. BMJ. 1992;304:1689.

3. Cholesterol Treatment Trialists Collaboration. Protocol for a prospective collaborative overview of all current and planned randomized trials of cholesterol treatment regimens. Am J Cardiol. 1995;75:1130-4