Correspondence
Pravastatin Therapy and the Risk of Stroke
N Engl J Med 2000; 343:1894-1896December 21, 2000
- Article
To the Editor:
In their discussion of pravastatin therapy to reduce the risk of stroke, White et al. (Aug. 3 issue)1 cite several references erroneously and present their findings without appropriate qualifying language.
First, they note that “several trials of . . . statins have reported reductions of 25 to 30 percent in the rate of stroke.” To support this statement, they cite four references, three of which report on specific clinical trials. However, one of those trials (the West of Scotland study) showed no reduction in the rate of stroke; the risk after five years of follow-up was reported as 1.6 percent for both the pravastatin and placebo groups (P=0.57).2 A second cited study (the Air Force–Texas Coronary Atherosclerosis Prevention Study, or AFCAPS/TexCAPS) does not even list stroke as an individual end point; it is subsumed in the heterogeneous composite end point of “cardiovascular events.”3
Second, White et al. draw the following conclusion: “This study shows that lipid-lowering therapy with pravastatin reduces the risk of stroke in patients with known coronary heart disease.” However, the P value for the difference in stroke rate between the pravastatin and placebo groups (3.7 percent vs. 4.5 percent during six years of follow-up) was 0.05 on univariate analysis and 0.10 on multivariate analysis. Although the conventional standard of setting significance at P=0.05 can be viewed as somewhat arbitrary, it is nevertheless widely accepted; thus, the authors should at least have qualified their conclusion and acknowledged more openly the borderline statistical significance of their result.
In the aggregate, the data from several studies do suggest that statin therapy reduces the risk of stroke in selected high-risk patients. However, the irresistible urge to inflate the magnitude of the benefits found in trials of cholesterol-lowering drugs — a topic that I discussed in the pre-statin era4 — still seems evident.
4 ReferencesAllan S. Brett, M.D.
University of South Carolina School of Medicine, Columbia, SC 292031
White HD ,Simes RJ ,Anderson NE , et al. Pravastatin therapy and the risk of stroke. N Engl J Med 2000;343:317-326
Full Text | Web of Science | Medline2
Shepherd J ,Cobbe SM ,Ford I , et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301-1307
Full Text | Web of Science | Medline3
Downs JR ,Clearfield M ,Weis S , et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615-1622
CrossRef | Web of Science | Medline4
Brett AS . Treating hypercholesterolemia: how should practicing physicians interpret the published data for patients? N Engl J Med 1989;321:676-680
Full Text | Web of Science | Medline
To the Editor:
White et al. report on the effect of pravastatin therapy on the risk of stroke in patients with a previous myocardial infarction or unstable angina. From their data they conclude that pravastatin reduces the risk of stroke, especially nonhemorrhagic stroke, in this population of patients selected for a history of cardiovascular disease.
The effect they observed was small: the relative risk reduction of 19 percent emphasized by the authors translates to an absolute risk reduction of 0.8 percent over six years. This means that 750 patients must be treated for one year in order to prevent 1 stroke. This figure compares very unfavorably with the risk reduction possible with other preventive measures, such as aspirin. An equally modest effect on the incidence of stroke was reported in an earlier study of pravastatin in a similar study group.1 Even if one accepts the statistical methods and conclusions of the study by White et al., the question remains whether therapy with pravastatin is clinically useful in this selected group of patients when the primary goal is the prevention of stroke.
1 ReferencesJan F. Meilof, M.D., Ph.D.
Bernard M.I. Uitdehaag, M.D., Ph.D.
Academic Hospital Vrije Universiteit Amsterdam, 1007 MB Amsterdam, the Netherlands1
Plehn JF ,Davis BR ,Sacks FM , et al. Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. Circulation 1999;99:216-223
Web of Science | Medline
To the Editor:
White et al. report that in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study, pravastatin significantly reduced the risk of stroke in patients with a history of myocardial infarction or unstable angina. Although the qualifying diagnosis in nearly two thirds of the patients was myocardial infarction, the authors have ignored previous reports suggesting a post-infarction reduction in left ventricular function as an independent risk factor for stroke.1-3 Considering the well-established importance of such reduced function, I wonder whether the convincing conclusions that were drawn by White et al. would have been different if the two study groups in their trial had also been matched with respect to left ventricular ejection fraction.
3 ReferencesOren Fruchter, M.D.
29 Greenbaum St., Haifa 34987, Israel1
Kyrle PA ,Korninger C ,Gossinger H , et al. Prevention of arterial and pulmonary embolism by oral anticoagulants in patients with dilated cardiomyopathy. Thromb Haemost 1985;54:521-523
Web of Science | Medline2
Dunkman WB ,Johnson GR ,Carson PE ,Bhat G ,Farrell L ,Cohn JN . Incidence of thromboembolic events in congestive heart failure. Circulation 1993;87:Suppl:VI-943
Loh E ,St John Sutton M ,Wun CC , et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. N Engl J Med 1997;336:251-257
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: A meta-analysis of eight trials of statins published prior to the LIPID study calculated a risk ratio for stroke of 0.76 (95 percent confidence interval, 0.62 to 0.92).1 Dr. Brett correctly states that some individual studies within the meta-analysis do not show as large an effect.
Our prespecified primary analysis of the reduction in the rate of stroke from any cause with pravastatin had a P value of 0.048, whereas the adjusted P value in the multivariate analysis was 0.10. We agree that these results provide only some evidence of an effect of the treatment in reducing the rate of stroke from any cause. However, there was clear evidence of a reduction in nonhemorrhagic stroke, the other prespecified outcome, whether the analysis was unadjusted (P=0.02) or was adjusted for significant base-line factors (P=0.03). When LIPID is considered in the context of other trials of statins, the evidence of a treatment benefit is stronger, and when LIPID is included in the meta-analysis, the risk ratio for stroke is 0.78 (95 percent confidence interval, 0.68 to 0.90; P<0.001). If the meta-analysis is restricted to trials of pravastatin, the risk ratio is 0.78 (95 percent confidence interval, 0.67 to 0.92; P=0.003). Thus, our conclusion that treatment with pravastatin reduces the risk of stroke in patients with coronary heart disease is entirely appropriate.
We agree with Drs. Meilof and Uitdehaag that the absolute benefits of pravastatin treatment in reducing the risk of stroke are moderate, as stated in our abstract. Nevertheless, these benefits are in addition to the benefit of pravastatin in the prevention of coronary events. Consequently, fewer patients would need to be treated to prevent an event than to prevent a stroke. Treatment of 1000 patients for six years, for example, would prevent 30 deaths, 28 nonfatal myocardial infarctions, and 9 strokes in 48 patients. Treatment of 21 patients for six years would prevent 1 patient from having one or more of these events.2 Furthermore, the absolute benefits of treatment in terms of a reduction in the rate of stroke alone are greater in patients who are at higher risk of stroke.
We agree with Dr. Fruchter that reduced left ventricular function is an independent risk factor for stroke. However, patients with ejection fractions of 25 percent or less were excluded from LIPID, and since left ventricular function was not routinely assessed, we were unable to include it in our risk model.
In conclusion, the effects of treatment with pravastatin in reducing the rate of stroke in patients with coronary heart disease are moderate in absolute terms, but they are greater in patients who are at higher risk of stroke. Although the primary goal of lipid modification in these patients is to reduce mortality, the fact that pravastatin also helps to prevent stroke is an added benefit. In a population of patients in which the prevention of stroke is the primary goal of treatment, the role of statins needs further definition.
2 ReferencesHarvey D. White, D.Sc.
Green Lane Hospital, Auckland 1030, New ZealandR. John Simes, M.D.
University of Sydney, Sydney NSW 2020, AustraliaAndrew M. Tonkin, M.D.
National Heart Foundation of Australia, Melbourne, VIC 3003, Australiafor the LIPID Study Group
1
Bucher HC ,Griffith LE ,Guyatt GH . Effect of HMGcoA reductase inhibitors on stroke: a meta-analysis of randomized, controlled trials. Ann Intern Med 1998;128:89-95
Web of Science | Medline2
The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group
Full Text | Web of Science | Medline
