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(Stroke. 2008;39:2444.)
© 2008 American Heart Association, Inc.

Original Contributions

Relative Effects of Statin Therapy on Stroke and Cardiovascular Events in Men and Women

Secondary Analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study

Larry B. Goldstein, MD; Pierre Amarenco, MD; Marian LaMonte, MD; Steven Gilbert, PhD; Michael Messig, PhD; Alfred Callahan, MD; Michael Hennerici, MD, PhD; Henrik Sillesen, MD, MSc; K. Michael A. Welch, MB, ChB on behalf of the SPARCL Investigators

From Duke University and VA Medical Centers (L.B.G.), Durham, NC; Denis Diderot University (P.A.), Paris; the University of Maryland (M.L.), Baltimore, Md; Rho Inc (S.G.), Newton, Mass; Pfizer, (M.M..) New York; Neurologic Consultants (A.C.), Nashville, Tenn; the University of Heidelberg (M.H.), Mannheim, Germany; the University of Copenhagen (H.S.), Denmark; and Rosalind Franklin University of Medicine and Science (K.M.A.W.), North Chicago, Ill.

Correspondence to Larry B. Goldstein, Box 3651, Duke University Medical Center, Durham, NC 27710. E-mail golds004{at}mc.duke.edu

	Abstract

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Background and Purpose— In SPARCL, treatment with atorvastatin 80 mg daily reduced stroke risk in patients with recent stroke or TIA and no known coronary heart disease by 16% versus placebo over 4.9 years of follow-up. The purpose of this secondary analysis was to determine whether men and women similarly benefited from randomization to statin treatment.

Methods— The effect of sex on treatment-related reductions in stroke and other cardiovascular outcomes were analyzed with Cox regression modeling testing for sex by treatment interactions.

Results— Women (n=1908) constituted 40% of the SPARCL study population. At baseline, men (n=2823) were younger (62.0±0.21versus 63.9±0.27 years), had lower systolic BPs (138.1±0.35 versus 139.5±0.47 mm Hg), higher diastolic BPs (82.2±0.20 versus 81.0±0.25 mm Hg), more frequently had a history of smoking (73% versus 38%), and had lower total cholesterol (207.0±0.54 versus 218.9±0.67 mg/dL) and LDL-C levels (132±0.45 versus 134±0.57 mg/dL) than women. Use of antithrombotics and antihypertensives were similar. After prespecified adjustment for region, entry event, time since event, and age, there were no sex by treatment interactions for the combined risk of nonfatal and fatal stroke (treatment Hazard Ratio, HR=0.84, 95% CI 0.68, 1.02 in men versus HR=0.84, 95% CI 0.63, 1.11 in women; treatmentxsex interaction P=0.99), major cardiac events (HR=0.61, 95% CI 0.42, 0.87 in men versus HR=0.76, 95% CI 0.48, 1.21 in women; P=0.45), major cardiovascular events (HR=0.78, 95% CI 0.65, 0.93 in men versus HR=0.84, 95% CI 0.65, 1.07 in women; P=0.63), revascularization procedures (HR=0.50, 95% CI 0.37, 0.67 in men versus HR=0.76, 95% CI 0.46, 1.24 in women; P=0.17), or any CHD event (HR=0.54, 95% CI 0.41, 0.72 in men versus 0.67 95% CI 0.46, 0.98 in women; P=0.40).

Conclusion— Stroke and other cardiovascular events are similarly reduced with atorvastatin 80 mg/d in men and women with recent stroke or TIA.

Key Words: stroke • TIA • prevention • lipids • statins • sex

	Introduction

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Meta-analysis of 14 trials of statins including more than 90 000 subjects, most of whom had coronary heart disease (CHD) or major CHD risk factors, found men and women had similar treatment-associated reductions in both major coronary events and major vascular events.¹ Consistent with these results, the Prospective Pravastatin Pooling Project and the Heart Protection Study found statin treatment was associated with similar reductions in the occurrence of predominately first strokes regardless of sex.^2,3 A secondary analysis of subjects with CHD enrolled in 3 clinical trials of oral glycoprotein IIb/IIIa inhibitors found no significant difference in statin-associated stroke reductions between men and women.⁴

Whether statin treatment is equally effective for secondary stroke prevention in men and women has not been addressed. The Stroke Prevention with Aggressive Reductions in Cholesterol Levels (SPARCL) trial showed that treating patients with recent stroke or TIA and no known coronary heart disease with a statin (atorvastatin 80 mg per day) reduced the combined risk of fatal and nonfatal stroke as well as other cardiovascular events.⁵ The purpose of this post hoc analysis of data from the SPARCL trial was to determine whether men and women similarly benefited from randomization to statin treatment.

	Methods

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The methods of the SPARCL study have been described in detail previously.^5,6 The local research ethics committee or institutional review board at each participating study center approved the study protocol, and all patients gave written informed consent. The primary hypothesis of the SPARCL trial was that treatment with 80 mg of atorvastatin per day would reduce the combined risk of fatal and nonfatal stroke among patients with a history of stroke or TIA. Eligible patients were men and women over 18 years of age who had had an ischemic or hemorrhagic stroke or a TIA (diagnosed by a neurologist within 30 days after the event) 1 to 6 months before randomization. Stroke was defined by focal clinical signs of central nervous system dysfunction of vascular origin that lasted for at least 24 hours; TIA was defined by the loss of cerebral or ocular function for less than 24 hours. Patients had to be ambulatory, with a modified Rankin score of no more than 3 (scores can range from 0 to 5, with higher scores indicating more severe disability), and to have an LDL cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter) and no more than 190 mg per deciliter (4.9 mmol per liter; 15 of 205 centers excluded otherwise suitable patients with an LDL cholesterol level above 160 mg per deciliter [4.1 mmol per liter], as required by their institutional review boards). Excluded patients otherwise included those with atrial fibrillation, mechanical prosthetic heart valves, severe mitral valve stenosis, or subarachnoid hemorrhage. Patients with hemorrhagic stroke (2% of the study population) could be included if they were deemed by the investigator to be at risk for ischemic stroke or coronary heart disease. Subjects were enrolled between September 1998 and March 2001.

The primary outcome for the SPARCL trial was the time from randomization to a first nonfatal or fatal stroke. There were 7 prespecified secondary composite outcomes: stroke or TIA; major coronary event (cardiac death, nonfatal myocardial infarction [MI] or resuscitated cardiac arrest); major cardiovascular event (stroke plus any major coronary event); any CHD event (major coronary event, plus coronary revascularization procedure, unstable angina or angina/ischemia requiring emergent hospitalization); revascularization procedure (coronary, carotid or peripheral); and any cardiovascular event (any of the former plus clinically significant peripheral vascular disease). An independent end point committee adjudicated all potential end points without knowledge of the patients’ treatment status or cholesterol levels.

For this post hoc analyses, we evaluated the relative effects of intention to treat with atorvastatin 80 mg per day in men and women on the primary and each secondary SPARCL outcome in separate Cox regression models with prespecified adjustment for region (7 dummy variables), entry event, time since event, and age (each requiring 1 degree of freedom). Adjustment was made in the regression models for potential confounding by inclusion of covariates.

A second set of analyses to control for additional possible confounders was performed to validate the primary analysis by using a logistic regression model to reduce the dimensionality of the data (a logistic regression predicting sex was fitted to baseline covariates including age, days since qualifying event, type of qualifying event, geographic region baseline lipid levels, systolic and diastolic blood pressure, body mass index, smoking and hypertension history).⁷ Because of sample size limitations, all potential covariates could not be directly added to the Cox regression models.⁸ Because exploratory analyses revealed possible nonlinear relationships, the model was also allowed to fit the squared and square root transformed versions of the listed continuous variables based on a forward selection procedure. The resulting model had a c-statistic of 0.821. The linear predictor from this model was then saved and grouped by quintile. The data were then stratified by sex and quintile of the linear predictor from the previous logistic regression. Patients who could not be included in the logistic regression model because of missing data were assigned to their own strata. This resulted in a total of 12 strata. The data for all patients were then analyzed using a stratified Cox regression model with covariate terms for age, days since qualifying event, qualifying event, and geographic region.

The SPARCL steering committee developed the study protocol with the sponsor and takes responsibility for the data and data analyses. Medpace (Cincinnati) managed all data. Medpace, Charles River Laboratories Clinical Services (Brussels), and the sponsor provided site monitoring throughout the study. A data and safety monitoring board with independent statistical support performed interim monitoring analyses for safety and efficacy.

	Results

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Table 1 compares baseline characteristics between men (n=2823) and women (n=1908). Men were younger, had lower systolic BP, higher diastolic BP, less frequently had a history of hypertension, and more frequently had a history of smoking. Men also had lower total cholesterol, LDL-C, HDL-C, and Apolipoprotein A1 levels than women. Use of antithrombotics and antihypertensives were similar. Table 2 gives the mean percent change from baseline to the last study visit for each lipid measure for atorvastatin and placebo treated men and women. There were no sex-based treatment differences in lipid profiles between men and women (LDL-cholesterol, P=0.986; total cholesterol, P=0.452; HDL-cholesterol, P=0.126; triglycerides, P=0.8437; Apo A1, P=0.135; Apo B, P=0.955).

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics by Sex

View this table: [in this window] [in a new window]   Table 2. Baseline, End of Treatment, and Percent Change From Baseline Lipid Levels by Sex

Table 3 gives adjusted hazard ratios, Wald probability values, and treatment by sex interaction probability values for each of the SPARCL trial primary and secondary outcomes. The separate results for men and women were generated by removing the sex term from the model (since each model includes either all men or all women). Men and women had similar treatment-associated benefits for each study end point (ie, there were no significant treatment by sex interactions for the combined risk of nonfatal and fatal stroke, nonfatal stroke, fatal stroke, stroke or TIA, major cardiac events, major cardiovascular events, revascularization procedures, or any CHD event). The treatment by sex interaction term for all cause mortality is marginally significant (P=0.06). The second set of analyses using Cox regression models with stratification to control for additional potential confounders provided almost identical results (data not shown).

View this table: [in this window] [in a new window]   Table 3. Stroke and Cardiovascular Outcomes and All-Cause Mortality by Sex

Table 4 gives safety data by treatment and sex. Atorvastatin 80 mg per day was similarly tolerated in men and women.

View this table: [in this window] [in a new window]   Table 4. SPARCL Safety by Sex

	Discussion

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This analysis of data from the SPARCL trial found similar statin-related reductions in stroke and other cardiovascular events in men and women who had a recent stroke or TIA and no known coronary heart disease at the time of study enrollment. To reduce the chances of spurious associations in this post hoc analysis, we tested treatment by sex interactions for the SPARCL primary end point (first occurrence of a nonfatal or fatal stroke) as well as for all of the study’s prespecified secondary endpoints.

This analysis is a combination of a randomized trial and an observational study (ie, randomized treatment effects and nonrandom subgroups defined by sex). In Table 3, the adjusted hazard ratios by sex were obtained by running separate analyses on men and women controlling for age, qualifying event, days since qualifying event, and geographic region. Because treatment was randomized, these provide unbiased estimates of treatment effects for men and women. Other baseline variables such as age, baseline lipids, and blood pressure, however, differed between men and women (Table 1). To assure that any possible sex differences were not explained by differences in the baseline covariates, a second set of more complex analyses were performed with results not substantially different than those given in Table 3. It should be recognized, however, that the SPARCL trial was not designed to detect differences in event rates between men and women, and that statistical power of this analysis may be limited.

As shown in Table 3, the treatment by sex interaction term for all cause mortality is marginally significant. Although a relative treatment-related reduction in all cause mortality in women as compared to men cannot be excluded, the individual treatment effects are not significant (HR=1.14, 95% CI 0.90 to 1.45, P=0.28 for men and HR=0.78, 95% CI 0.57 to 1.07, P=0.12 for women).

The Heart Protection Study (HPS) compared the effects of simvastatin and placebo in a broad spectrum of patients that included 3280 subjects with prior cerebrovascular disease.³ As in SPARCL,⁵ the HPS found a reduction in major vascular events in patients with prior cerebrovascular disease treated with a statin, but in contrast to SPARCL, there was no reduction in recurrent stroke (and no analysis for a treatment-related difference in recurrent stroke based on sex). Some potential reasons for the difference between the trial results have been discussed previously and include later enrollment after the index event in HPS, smaller treatment-related reductions in lipid levels, and lack of power because of a small number of outcome strokes.⁵ In HPS, there was not a specific analysis to determine whether the effects of the statin on the occurrence of major vascular events differed between men and women with prior stroke.³

Several studies provide data assessing potential sex-related differences in the effects of statins for primary stroke prevention. The HPS found similar reductions in the frequencies of a first stroke with statin treatment in men and women.³ At least 2 other randomized placebo-controlled statin trials have provided subgroup analyses of stroke outcomes stratified by sex.⁴ The Cholesterol and Recurrent Events (CARE) study found a nonsignificant 35% reduction of stroke with statin treatment in women but no difference between men and women.⁹ The Long-Term Intervention With Pravastatin in Ischemic Disease (LIPID) study found that more women in the statin group (4.4%) than in the placebo group (3.6%) had strokes with a beneficial effect in men (3.6% with statin treatment versus 4.7% with placebo).¹⁰ When the data from these 2 trials was pooled with data from the West of Scotland Coronary Prevention Study (WOSCOPS), there was no statistical interaction between sex and statin treatment on the occurrence of stroke events.² Therefore, there is no evidence for a sex-related difference in the effects of statins in primary stroke prevention in the setting of known coronary heart disease or in other primary prevention populations.

There are several stroke risk factors that are unique to women, and new areas of research offer the possibility of developing preventive therapies aimed at reducing a woman’s chances of having a first or recurrent stroke.¹¹ As reflected in the baseline data from the SPARCL trial, even traditional stroke risk factor profiles for men and women can differ. Despite these differences, this secondary analysis of SPARCL trial data suggests that statin treatment similarly reduces the likelihood of stroke and other cardiovascular events in men and women with recent TIA or stroke.

Supplemental Appendix
SPARCL Investigators and Committees
Steering Committee
K.M.A. Welch (Chair), USA; P. Amarenco, France; J. Bogousslavsky, Switzerland; A. Callahan III, USA; L. B. Goldstein, USA; M.G. Hennerici, Germany; H. Sillesen, Denmark; J. Zivin, USA.

Publication Subcommittee
H. Sillesen, Denmark (Chair); W. Clark, USA; A. Dávalos, Spain; L.B. Goldstein, USA; M. Kaste, Finland; L. Leiter, Canada; J. Zivin, USA.

Retention Subcommittee
P. Amarenco (Cochair), France; A. Callahan III (Cochair), USA; I. Altafullah, USA; G. Graham, USA; J. Glahn, Germany; D. Jiménez Hernández, Spain; R. MacWalter, UK; R. Scott, New Zealand; A. Shuaib, Canada; J. Sivenius, Finland; R. Stipal, Czech Republic.

Safety Committee
R. Hart (Chair), USA; J. Marsh, USA; B. Norrving, Sweden; S. Pocock, UK; R. Sacco, USA.

Cerebrovascular End Point Committee
J. Easton (Chair), USA; M. Brown, UK; Z. Nagy, Hungary; J. Whisnant, USA.

Cardiovascular End Point Committee
B. O'Neill (Chair), Canada; F. Kleber, Germany; J.-M. LaBlanche, France; F. Welty, Boston, USA.

Investigators (number of randomized patients in parentheses):
Australia (167 patients): D. Crimmins, S. Davis, S. Dimmitt, G. Donnan, J. Frayne, D. Freilich, A. Zagami; Austria (87 patients): J. Mikocki, C. Schmidauer, R. Schmidt; Belgium (41 patients): J. De Bleecker, F. Deceuninck, P. Tack, V. Thijs; Brazil (8 patients): J. Gomes Fernandes; Canada (295 patients): M. Beaudry, R. Cote, K. Hoyte, L.-H. Lebrun, A. Mackey, D. Sahlas, D. Selchen, A. Shuaib, J.D. Spence, P. Teal, M. Winger; Chile (10 patients): G. Matamala; Czech Republic (222 patients): R. Cifkova, Z. Kalita, I. Rektor, H. Rosolova, R. Stipal, D. Vaclavik; Denmark (57 patients): G. Boysen, H. Klingenberg, Iversen, H. Sillesen; Finland (385 patients): M. Hillbom, M. Kaste, H. Numminen, A. Pilke, A. Salmivaara, J. Sivenius; France (161 patients): S. Alamowitch, P. Amarenco, J. Boulliat, T. De Broucker, F. Chollet, M.-H. Mahagne, L. Milandre, T. Moulin; Germany (284 patients): U. Bogdahn, H.-C. Diener, M. Dichgans, J. Glahn, R. Haberl, L. Harms, M.G. Hennerici, S. Knecht, G. Kroczek, C. Lichy, D. Sander, D. Schneider; Greece (39 patients): A. Kazis, C. Karageorgiou, I. Milonas, P. Stathis, D. Vogiatzoglou; Israel (61 patients): N. Bornstein, S. Honigman, Y. Lampl, J. Streifler; Italy (75 patients) : A. Capurso, G. Comi, C. Ferrarese, C. Gandolfo, M. Poloni, U. Senin; Mexico (9 patients): R. Rangel Guerra; Netherlands (171 patients): A.M. Boon, J.H.A. De Keyser, P.L.M. De Kort, J.A. Haas, D.J. Kamphuis, P-J. Koudstaal; New Zealand (219 patients): N. Anderson, R. Scott, G. Singh; Poland (249 patients): A. Czlonkowska, W. Drozdowski, Z. Gralewski, W. Kozubski, A. Kuczynska-Zardzewialy, R. Podemski, Z. Stelmasiak, A. Szczudlik; Portugal (102 patients): C. Da Costa Correia, J. Ferro, L. Salgueiro e Cunha; Slovakia (37 patients): J. Lietava, K. Raslova; South Africa (93 patients): J. Carr, J. Gardiner, A. Kruger; Spain (744 patients): J. Alvarez-Sabin, A. Chamorro, E. Diez-Tejedor, O. Fernández, J. Trejo Gabriel y Galán, J. González Marcos, J. Egido Herrero, M. Jiménez Martínez, A. Lago Martin, E. Mostacero Miguel, J. Vivancos Mora, J. Moltó, J. Viguera Romero, E. Cuartero Rodriguez, F. Rubio, J. Serena; Sweden (121 patients): A.C. Laska, B. Leijd, T. Strand, A. Terent, A. Waegner, T. Wallén; Switzerland (86 patients): R. Baumgartner, J. Bogousslavsky, H. Hungerbühler, P. Lyrer, H. Mattle; United Kingdom (146 patients): P.M. Bath, E.B. Ekpo, A. Freeman, K.R. Lees, M.J. MacLeod, R.S. MacWalter, A.K. Sharma, H.G.M. Shetty; United States (853 patients): G. Albers, I. Altafullah, O. Benavente, D. Book, J. Broderick, A. Callahan III, C. Calder, W. Carlini, S. Chaturvedi, T. Chippendale, W. Clark, B. Coull, P. Davis, T. Devlin, A. Dick, G. Dooneief, R. Duff, N. Estronza, A. Forteza, M. Frankel, J. Frey, G. Friday, G. Graham, J. Goldstein, M. Hammer, J. Harris, W. Harper, B. Hendin, D. Hess, R. Hinton, J. Hollander, R. Hughes, S. Kasner, T. Kent, L. Kim, H. Kirshner, M. LaMonte, L. Ledbetter, P. Lee-Kwen, K. Levin, R. Libman, J. Matlock, P. McDowell, F. McGee Jr, B. Meyer, A. Minagar, M. Moussouttas, R. Munson, M. Nash, A. Nassief, S. Orr, G. Ratinov, V. Salanga, S. Silliman, R. Singer, D. Smith, H. Sullivan, G. Tietjen, D. Thaler, M. Tuchman, D. Uskavitch, P. Verro, R. Vicari, R. Weinstein, J. Wilterdink, R. Zweifler; Venezuela (9 patients): M. De Bastos.

	Acknowledgments

 
Sources of Funding

The SPARCL trial was funded by Pfizer. Employees of Pfizer contributed to the design and conduct of the SPARCL trial, the collection, management, analysis, and interpretation of the data, and reviewed the manuscript.

Disclosures

Larry Goldstein has received honoraria from Pfizer during the course of this study. The honoraria did not exceed $10 000/yr. Pierre Amarenco has received grants from Pfizer for other research or activities not reported in this research exceeding $10 000/yr and honoraria from Pfizer in excess of $10 000/yr during the course of this study. Marian LaMonte declares no conflicts aside from participation as a site investigator in the SPARCL trial. Steven Gilbert is employed by Rho Inc, a company that provides statistical consultation for Pfizer. Michael Messig is an employee of Pfizer and owns Pfizer stock. Alfred Callahan has received research support and honoraria from Pfizer in excess of $10 000/yr during the course of this study. Michael Hennerici has received grants from Pfizer for other research or activities not reported in this research/article and honoraria from Pfizer during the course of the study. Neither the grants nor the honoraria exceeded $10 000/yr. Henrik Sillesen has received grants from Pfizer for other research or activities not reported in this research/article in excess of $10 000/yr and honoraria exceeding $10 000/yr during the course of this study. K. Michael Welch has received honoraria from Pfizer during the course of the study in excess of $10 000/yr and research support less than $10 000/yr.

Received December 31, 2007; accepted January 28, 2008.

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This Article Abstract Full Text (PDF) All Versions of this Article: 39/9/2444    most recent STROKEAHA.107.513747v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goldstein, L. B. Search for Related Content PubMed PubMed Citation Articles by Goldstein, L. B. Related Collections Secondary prevention Acute Stroke Syndromes Other Stroke Treatment - Medical