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


Therapeutics

Review: HMGcoA reductase inhibitors reduce stroke, CHD, and all-cause mortality

ACP J Club. 1998 Jul-Aug;129:1. doi:10.7326/ACPJC-1998-129-1-001


Source Citation

Bucher HC, Griffith LE, Guyatt GH. Effect of HMGcoA reductase inhibitors on stroke. A meta-analysis of randomized, controlled trials. Ann Intern Med. 1998 Jan 15;128:89-95.


Abstract

Question

Are 3-hydroxy-3-methylglutaryl coenzyme A (HMGcoA) reductase inhibitors more effective than other lipid-lowering interventions for reducing fatal and nonfatal stroke?

Data sources

Studies were identified using MEDLINE and EMBASE (to October 1996) {with the search terms hypercholesterolemia; cholesterol; mortality; coronary heart disease; myocardial infarction; cerebrovascular disorder; and anti-cholesteremic drugs combined with quality filters, including randomized controlled trial and controlled clinical trial; through hand searches of current issues of cardiac journals}*; and by reviewing previously published meta-analyses and bibliographies of relevant papers.

Study selection

Studies were selected if they were randomized controlled trials that reported nonfatal and fatal strokes. Trials that were restricted to patients who had a previous stroke or heart transplant were excluded.

Data extraction

Data were extracted on study focus (primary or secondary prevention); intervention, including drug (HMGcoA, resins, and fibrates) and dietary information; duration of follow-up; patient characteristics; and outcomes. Studies were assessed for methodologic quality and given a summary score based on follow-up, concealment of randomization, blinding of caregivers and patients, and blinding during outcome assessment. Pooled treatment effects were calculated using a random effects model.

Main results

28 randomized controlled trials (8 trials of HMGcoA, 5 trials of fibrates, 3 trials of resins, 10 trials of dietary interventions, and 2 trials with multiple treatment arms) were included in the meta-analysis. The intervention groups included a total of 49 477 patients, and the control groups included 56 636 patients. HMGcoA reductase inhibitors reduced the risk for fatal and nonfatal stroke (relative risk [RR] 0.76, 95% CI 0.62 to 0.92, test for heterogeneity P > 0.2), death from coronary heart disease (RR 0.69, CI 0.59 to 0.80, test for heterogeneity P > 0.2), and all-cause mortality (RR 0.80, CI 0.71 to 0.90, test for heterogeneity P > 0.2) compared with all other interventions (P = 0.01, P = 0.003, and P = 0.03, respectively). Pooled estimates for fibrates, resins, and dietary interventions showed no effect on fatal and nonfatal stroke or all-cause mortality. Resins decreased risk for death from coronary heart disease (RR 0.69, CI 0.48 to 0.99), but fibrates and dietary interventions did not.

Conclusions

HMGcoA reductase inhibitors reduce risk for fatal and nonfatal stroke, coronary heart disease mortality, and all-cause mortality. Resins decrease risk for fatal coronary heart disease, but this effect has not been shown for fibrates or diet.

Source of funding: In part, the Swiss National Research Foundation.

For correspondence: Dr. H.C. Bucher, Medizinische Universit├Ąts-Poliklinik, Kantonsspital Basel, CH-4031 Basel, Switzerland. FAX 41-61-265-4300.

*Information supplied by author.


Commentary

The study by Bucher and colleagues is 1 of 3 recent meta-analyses of lipid level lowering and stroke. We are unlikely to see a large, randomized, placebo-controlled trial with stroke as a main outcome because of existing evidence that HMGcoA reductase inhibitors reduce morbidity and mortality related to coronary heart disease. We are therefore left with other sources of evidence, such as the current meta-analysis. Most myocardial infarction results from coronary atherosclerosis; the mechanism of stroke may be difficult to ascertain. Although epidemiologic evidence of an association between cholesterol levels and risk for stroke is weak (1), many of the smaller studies included in this meta-analysis and a meta-analysis by Hebert and colleagues (2) report modest reductions in carotid plaque thickness. The only trial that reported on nonembolic ischemic strokes found a 50% RR reduction.

On the basis of the results of the study by Bucher and colleagues, it is unlikely that other interventions to lower lipid levels reduce stroke. We do not know if this is because of an intrinsically different mechanism of action or because of the greater potency of statin agents.

In all patients, the effect of HMGcoA reductase inhibitors on coronary heart disease is larger than the effect on stroke. The reduction in coronary artery disease is often the basis for clinical decisions to use these drugs. Nevertheless, these findings may influence the treatment of patients who do not have coronary artery disease but do have known or suspected cerebrovascular atherosclerosis and elevations in low-density lipoprotein cholesterol levels. Carotid endarterectomy is clearly beneficial in symptomatic patients with high-grade stenoses, but this represents a small number of patients at risk for future stroke. Therefore, statin therapy may be appealing for other groups. Because other preventive interventions in noncardioembolic ischemic stroke only have modest effects, statin drugs should be a welcome addition to our armamentarium for stroke prevention.

Craig Redfern, DO
Providence Ambulatory Care and Education CenterPortland, Oregon, USA


References

1. Cholesterol, diastolic blood pressure, and stroke: 13 000 strokes in 450 000 people in 45 prospective cohorts. Prospective studies collaboration. Lancet. 1995;346:1647-53.

2. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials. JAMA. 1997;278:313-21.