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(Stroke. 1997;28:946-950.)
© 1997 American Heart Association, Inc.

Articles

Stroke, Statins, and Cholesterol

A Meta-Analysis of Randomized, Placebo-Controlled, Double-Blind Trials With HMG-CoA Reductase Inhibitors

Gerard J. Blauw, MD, PhD; A. Margot Lagaay, MD, PhD; Augustinus H. M. Smelt, MD, PhD; Rudi G. J. Westendorp, MD, PhD

From the Departments of General Internal Medicine and Clinical Epidemiology (R.G.J.W.), Leiden (Netherlands) University Medical Centre.

Correspondence to Dr G.J. Blauw, MD, PhD, Department of General Internal Medicine, Section of Gerontology and Geriatrics, C1-R41, Leiden University Medical Centre, Albinusdreef 2, PO Box 9600, 2300 RC Leiden, Netherlands.

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Background and Purpose To estimate the effect of 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors ("statins") on stroke risk, we combined the data of the randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors published so far.

Methods The studies were identified using the Medline CD+ and Current Contents databases from January 1980 through May 1996, inclusive. All studies were evaluated on the use of a placebo control, monotherapy, and double blindness. When the type of stroke or the occurrence of clinical events or adverse effects were incompletely or not reported, the investigators were contacted personally. For each trial, the number of strokes in the treatment arm was compared with the number of strokes expected on all observations under the assumption that drug treatment had no effect.

Results A total of 462 strokes among 20 438 participants in 13 trials could be analyzed. A total of 181 strokes were observed in patients randomized to treatment with an HMG-CoA reductase inhibitor and 261 strokes in patients randomized to placebo. A lower than expected number of strokes was observed in the treatment groups of all but one trial (P=.001). Treatment with an HMG-CoA reductase inhibitor led to an overall risk reduction of 31% (odds ratio, 0.69; 95% confidence interval, 0.57 to 0.83).

Conclusions The combined data suggest that treatment with HMG-CoA reductase inhibitors prevents stroke in middle-aged persons. Because stroke is especially common in older age, these data reinforce the need for clinical trials to evaluate the effect of HMG-CoA reductase inhibitors in preventing stroke in the elderly.

Key Words: cholesterol • HMG-CoA reductase inhibitors • meta-analysis • stroke prevention

	Introduction

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Over the last 5 years, data have emerged on the beneficial effects of the HMG-CoA reductase inhibitors, the so-called "statins," in the prevention of coronary heart disease.^{1 2 3 4 5 6 7 8 9 10 11 12 13 14} The three large clinical intervention trials, the 4S, WOSCOP, and CARE studies, presented convincing evidence.^{15 16 17}

In contrast to the data on the reduction of ischemic heart disease, little is known about the effects of these drugs on other manifestations of atherosclerotic disease, such as stroke. To date, only in the 4S and CARE studies was a reduction of stroke observed.^{15 17} In other trials, such a beneficial effect could not be detected, most likely because the incidence of stroke in the studied groups was too low. Most of the participants were middle-aged men with signs and symptoms of coronary heart disease. Pooling the data from single trials may overcome this problem, as was done in the pravastatin atherosclerosis intervention program.⁶ This analysis suggested that pravastatin may reduce stroke risk.

Because stroke is a major cause of morbidity and mortality in older age and data from the single studies on the effect of the HMG-CoA reductase inhibitors are not conclusive yet, we combined the data on the occurrence of stroke in the randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors published so far.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Data on stroke were retrieved from published randomized, controlled trials with HMG-CoA reductase inhibitors. The studies were identified using the Medline CD+ (1980 through September 1996) and the Current Contents (Life Science addition, January through May 1996, inclusive) databases. The search strategy used the terms HMG-CoA reductase inhibitor, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, randomized controlled trial, and double-blind method, both as medical subject headings (MeSH) and text words. Reviews and preliminary reports were used for further references. All studies were evaluated on the use of placebo control, monotherapy, and double blindness by two of us (G.J.B. and R.G.J.W.) independently. The identified studies were searched for the occurrence of fatal or nonfatal strokes. Studies reporting no major adverse events or no major clinical events were classified as studies with no strokes. When the type of stroke, the occurrence of clinical events, or the occurrence of adverse events was incompletely or not reported in the original publications, the investigators of the studies were contacted by mail and telephone.

For each trial, the number of strokes in the treatment arm was compared with the number of strokes expected on all observations under the assumption that drug treatment had no effect.¹⁷ The number of expected strokes can be calculated from the marginals of a 2x2 table of active- and placebo-treated subjects. For each trial, the number of observed strokes (O) minus the number of expected strokes (E), as well as the variance, can then be calculated and summed over all trials. The formal test statistic whether the number of O-E strokes differs from zero is the total of O-E over all trials divided by the standard deviation (square root of the summed variances), which follows a Z distribution. The pooled OR for stroke in treated subjects was approximated by the exponent of Z divided by the standard deviation.¹⁸

Heterogeneity between studies was evaluated with ² testing, subtracting Z² from the sum of (O-E)²/variance of (O-E) for each trial.¹⁸ Heterogeneity was also tested after pooling the data of the small trials, since a large number of small studies can obscure the true heterogeneity between a few large trials.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
From the above-mentioned strategy of using the Medline and the Current Contents databases, more than 400 studies were identified, of which 114 could be classified as randomized, placebo-controlled, double-blind trials (the total list of references is available on request to the authors). The remaining studies were reviews on the topic, did not describe original data, or failed to fulfill the preset criteria on the use of a placebo control, monotherapy, and double blindness and thus were excluded. The results of two other large ongoing intervention trials, the LIPID¹⁹ and the Oxford Cholesterol Study,²⁰ were not yet available.

From the 114 studies included in the analysis, additional information was obtained for 16 trials. One investigator did not respond.²¹ The investigators of four trials could not provide additional information on strokes because the original data were no longer accessible.^{14 22 23 24} One of these was the EXCEL Study, an efficacy and safety trial including 8245 participants with a follow-up of 48 weeks.^{14 15} In this trial, one hemorrhagic stroke was observed but could not be traced to one of the treatment arms (personal communication, R.H. Bradford and A. Langendörfer, 1996). The three other studies were small trials that included some 212 participants.^{22 23 24}

In 101 trials with a total of 5670 person-years, no strokes were observed (Table 1). These trials were not included in the analysis because they contribute no information on the possible effect of HMG-CoA reductase inhibitors on stroke risk. The participants in these trials were for the greater part healthy volunteers and asymptomatic subjects with dyslipidemia aged 20 to 65 years.

View this table: [in this window] [in a new window]   Table 1. Study Characteristics of All 114 Included Randomized, Placebo-Controlled, Double-Blind Trials With HMG-CoA Reductase Inhibitors

A total of 442 strokes in 20 438 subjects with an observation period of 87 481 person-years in 13 trials could be analyzed.^{2 3 4 5 6 7 8 9 10 11 12 15 16 17} Among these trials reporting on stroke, the Efficacy and Safety of Pravastatin (ESP)² represents part of a larger study, investigating the efficacy and safety of pravastatin. Nine trials were designed to determine the effect on the regression of atherosclerosis.^{3 4 5 6 7 8 9 10 11 12} The 4S,¹⁵ WOSCOP,¹⁶ and CARE studies¹⁷ were principally designed to determine the effect on clinical end points. The baseline characteristics of the trials reporting on stroke are shown in Table 2.

View this table: [in this window] [in a new window]   Table 2. Baseline Characteristics of 13 Randomized, Placebo-Controlled, Double-Blind Trials Reporting on Stroke

Overall, a total of 181 strokes were observed in the patients randomized to treatment with an HMG-CoA reductase inhibitor and 261 strokes in the patients randomized to placebo (Table 3). A lower than expected number of strokes was observed in all but one trial. Before pooling, we tested for heterogeneity between the treatment effects in the different trials. The test statistic was not significant (²₁₂=13.1, P=.3), indicating that the separate studies estimate a common underlying risk reduction. When the three large clinical intervention trials^{15 16 17} were analyzed together with the combined data of the 10 smaller trials,^{2 3 4 5 6 7 8 9 10 11 12} the test statistic became significant (²₃=8.3, P<.05). Heterogeneity between the 10 smaller trials was absent (²₉=5.0, P>.5). Thus, heterogeneity was present between the clinical intervention trials; the 4S, CARE, and WOSCOP studies; and the other trials,^{2 3 4 5 6 7 8 9 10 11 12} which is also reflected by the effect of the HMG-CoA reductase inhibitors on stroke risk (see below).

View this table: [in this window] [in a new window]   Table 3. Number of Strokes in Randomized Trials With HMG-CoA Reductase Inhibitors (Transient Ischemic Attacks Included)

The reduction in total strokes in the subjects treated with HMG-CoA reductase inhibitors was highly significant (Z=3.9, P<.001). The pooled data amounted to an overall risk reduction of 31% during treatment with an HMG-CoA reductase inhibitor (OR, 0.69; 95% CI, 0.57 to 0.83). The risk reduction in the 10 smaller trials was 72% (OR, 0.28; 95% CI, 0.14 to 0.56). A similar result was obtained from the six smaller trials using pravastatin (OR, 0.36; 95% CI, 0.16 to 0.81). The 4S¹⁵ and CARE studies¹⁷ showed a significant reduction of 30% and 31% in stroke risk, whereas in the WOSCOP study¹⁶ treatment decreased stroke risk by only 11%.

The total number of fatal strokes was considerably smaller and not different between active- and placebo-treated subjects (30 and 27 patients, respectively; OR, 1.09; 95% CI, 0.65 to 1.84). When the data were analyzed after the exclusion of transient ischemic attacks in four studies,^{2 4 9 15} the risk reduction was 30% (OR, 0.70; 95% CI, 0.57 to 0.85).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
This meta-analysis shows that HMG-CoA reductase inhibitors ("statins") reduce stroke risk by 31%, similar to the effects on coronary heart disease. We found a large number of placebo-controlled, double-blind trials with statins in the literature. For most of these trials, no evidence was found for the occurrence of stroke. It may be reasoned that only the beneficial effects on stroke risk are reported in the literature, whereas the adverse effects remained unpublished. However, most of these trials were relatively small studies, conducted over a short period of time with a complete follow-up, investigating the biochemical or (patho)physiological effects of the statins. Most of the participants were healthy volunteers or asymptomatic hyperlipidemic subjects. Virtually all strokes occurred in the clinical intervention trials, all of which were included in the analysis. It is therefore unlikely that large number of strokes remained unreported. If the original publication was not clear on this point, we contacted the authors for clarification. Using this method, we have no indication that publication bias has seriously influenced the present findings.

A statistically significant risk reduction was observed in two of the three large clinical trials, 4S¹⁵ and CARE,¹⁷ as well as in the combination of the smaller trials.^{2 3 4 5 6 7 8 9 10 11 12} In contrast, only a modest effect of pravastatin was observed in the WOSCOP study.¹⁶ Formal heterogeneity testing confirmed that this effect of pravastatin in the WOSCOP study might be at odds with the overall estimate of 31% reduction in stroke risk. The fact that the CARE study, as well as the combined data from all other trials with pravastatin, shows a significant reduction of stroke risk makes it unlikely that the lack of effect in WOSCOP is drug specific. A possible explanation for the observed difference is that the WOSCOP study was basically designed as a primary prevention trial, whereas the other trials were secondary prevention trials. The subjects enrolled in WOSCOP differ significantly from those in the 4S,¹⁵ CARE,¹⁷ and other studies.^{2 3 4 5 6 7 8 9 10 11 12} The participants in WOSCOP were not selected on clinical end points of atherosclerosis but on risk factors. It may thus be hypothesized that other pathophysiological mechanisms underlie the occurrence of strokes in the participants of the 4S, CARE, and WOSCOP studies.

The present findings can be interpreted as evidence for cholesterol being a causal determinant of stroke. In the recent analysis of cohort studies, an overall association between total blood cholesterol and stroke was absent.²⁵ Also noteworthy, most of the observations in these cohort studies concerned fatal stroke. In accordance with this, we did not find a risk reduction by statins on fatal stroke.

Alternatively, in view of the findings of the above-mentioned analysis of cohort studies,²⁵ the presented data can also be interpreted as evidence for a cholesterol-independent effect of statins on cerebrovascular disease. Experimental data indicate that the statins may inhibit cell proliferation and G proteins.^{26 27 28} In animal experiments, it has been shown that lovastatin has a direct vasodilating effect.²⁹ Several clinical observations corroborate these experimental data in the published clinical intervention trials. The reduction of coronary events starts almost immediately during treatment,^{15 16} and the risk reduction is independent of the cholesterol level at baseline^{18 30} and is not correlated with the regression of coronary atherosclerosis.⁸

The presented data suggest that some 40 strokes may be prevented when treating 10 000 patients with coronary artery disease with statins for a considerable length of time. These patients are likely a subset of the population susceptible for stroke. Among this subset of patients, a large proportion of the strokes is caused by ischemia, likely due to ongoing atherosclerotic disease. As such, the effect of lipid control is likely to be beneficial. Age is a powerful risk factor for atherosclerotic disease, and the incidence of ischemic stroke increases progressively after the age of 70 years. Therefore, a large number of elderly persons with atherosclerosis may benefit from treatment with statins. In contrast to expectation, however, hypercholesterolemia is not an independent risk factor for cardiovascular disease beyond the age of 70 years. These data reinforce the need for clinical trials to evaluate the effect of statins to prevent stroke and coronary artery disease in the elderly with clinical signs and symptoms of atherosclerosis.

	Selected Abbreviations and Acronyms

 

4S = Scandinavian Simvastatin Survival Study CARE = Cholesterol and Recurrent Events Trial CI = confidence interval EXCEL = Expanded Clinical Evaluation of Lovastatin HMG-CoA = 3-hydroxy-3-methylglutaryl–coenzyme A LIPID Study = Long-term Intervention With Pravastatin in Ischemic Disease Study OR = odds ratio WOSCOP = West of Scotland Coronary Prevention Study

Received November 21, 1996; revision received January 31, 1997; accepted February 19, 1997.

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				J.-N. Trochu, S. Mital, X.-p. Zhang, X. Xu, M. Ochoa, J. K Liao, F. A Recchia, and T. H Hintze Preservation of NO production by statins in the treatment of heart failure Cardiovasc Res, November 1, 2003; 60(2): 250 - 258. [Abstract] [Full Text] [PDF]

				D. Pierre-Paul and V. Gahtan Noncholesterol-Lowering Effects of Statins Vascular and Endovascular Surgery, September 1, 2003; 37(5): 301 - 313. [Abstract] [PDF]

				W. Balduini, E. Mazzoni, S. Carloni, M. G. De Simoni, C. Perego, L. Sironi, and M. Cimino Prophylactic but Not Delayed Administration of Simvastatin Protects Against Long-Lasting Cognitive and Morphological Consequences of Neonatal Hypoxic-Ischemic Brain Injury, Reduces Interleukin-1{beta} and Tumor Necrosis Factor-{alpha} mRNA Induction, and Does Not Affect Endothelial Nitric Oxide Synthase Expression Stroke, August 1, 2003; 34(8): 2007 - 2012. [Abstract] [Full Text] [PDF]

				A. W. E. Weverling-Rijnsburger, I. J. A. M. Jonkers, E. van Exel, J. Gussekloo, and R. G. J. Westendorp High-Density vs Low-Density Lipoprotein Cholesterol as the Risk Factor for Coronary Artery Disease and Stroke in Old Age Arch Intern Med, July 14, 2003; 163(13): 1549 - 1554. [Abstract] [Full Text] [PDF]

				M R Law, N J Wald, and A R Rudnicka Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis BMJ, June 25, 2003; 326(7404): 1423. [Abstract] [Full Text] [PDF]

				B. M Buckley Review: Lipids and stroke The British Journal of Diabetes & Vascular Disease, May 1, 2003; 3(3): 170 - 176. [Abstract] [PDF]

				J.-C. Corvol, A. Bouzamondo, M. Sirol, J.-S. Hulot, P. Sanchez, and P. Lechat Differential Effects of Lipid-Lowering Therapies on Stroke Prevention: A Meta-analysis of Randomized Trials Arch Intern Med, March 24, 2003; 163(6): 669 - 676. [Abstract] [Full Text] [PDF]

				E. Shahar, L. E. Chambless, W. D. Rosamond, L. L. Boland, C. M. Ballantyne, P. G. McGovern, and A. R. Sharrett Plasma Lipid Profile and Incident Ischemic Stroke: The Atherosclerosis Risk in Communities (ARIC) Study Stroke, March 1, 2003; 34(3): 623 - 631. [Abstract] [Full Text] [PDF]

				L. Sironi, M. Cimino, U. Guerrini, A. M. Calvio, B. Lodetti, M. Asdente, W. Balduini, R. Paoletti, and E. Tremoli Treatment With Statins After Induction of Focal Ischemia in Rats Reduces the Extent of Brain Damage Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 322 - 327. [Abstract] [Full Text] [PDF]

				W. Lalouschek, W. Lang, S. Greisenegger, and M. Mullner Determination of Lipid Profiles and Use of Statins in Patients With Ischemic Stroke or Transient Ischemic Attack Stroke, January 1, 2003; 34(1): 105 - 110. [Abstract] [Full Text] [PDF]

				P. Di Napoli, A.A. Taccardi, M. Oliver, and R. De Caterina Statins and stroke: evidence for cholesterol-independent effects Eur. Heart J., December 2, 2002; 23(24): 1908 - 1921. [PDF]

				T. Marshall and A. Rouse Resource implications and health benefits of primary prevention strategies for cardiovascular disease in people aged 30 to 74: mathematical modelling study BMJ, July 27, 2002; 325(7357): 197 - 197. [Abstract] [Full Text] [PDF]

N. Koren-Morag, D. Tanne, E. Graff, U. Goldbourt, and for the Bezafibrate Infarction Prevention Study Gr Low- and High-Density Lipoprotein Cholesterol and Ischemic Cerebrovascular Disease: The Bezafibrate Infarction Prevention Registry Arch Intern Med, May 13, 2002; 162(9): 993 - 999. [Abstract] [Full Text] [PD