Published online before print October 2, 2008, doi: 10.1161/STROKEAHA.108.532606
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(Stroke. 2008;39:e181.)
© 2008 American Heart Association, Inc.
Letters to the Editor |
Response to Letter by Mascitelli et al
Department of Medicine (Neurology), Duke Center for Cerebrovascular Disease, Center for Clinical Health Policy Research, Duke University and Durham VA Medical Centers, Durham, NC
Response:
Dr Mascitelli and colleagues indicate that our exploratory analysis of the relative effects of high dose atorvastatin on secondary stroke prevention in men and women1 did not mention an increased risk of hemorrhagic stroke with treatment. The stroke outcomes included all strokes (ischemic and hemorrhagic). It is not appropriate to perform analyses of subgroups of subgroups.2 Caution must always be used when conducting exploratory analyses.3 In this report, we appropriately tested for statistical interactions between treatment and gender for the SPARCL prespecified primary and secondary end points and found no statistical heterogeneity in the benefit of treatment.
In raising the issue of hemorrhagic stroke in SPARCL, Dr Mascitelli and colleagues quote several of our own published reports that include thorough discussions of the topic.4–6 Although based on a post hoc analysis, we found that the overall 16% reduction in the time to fatal or nonfatal stroke with atorvastatin treatment in SPARCL (adjusted hazard ratio, 0.84; 95% CI, 0.71 to 0.99; P=0.03; unadjusted P=0.05) was partially attenuated by an increase in the risk of hemorrhage.3 Subsequent exploratory multivariable analyses found that the risk of hemorrhagic stroke increased with advancing age and was higher in those with a hemorrhagic stroke within the prior 1 to 6 months, in men and in those with uncontrolled hypertension.6 The identified factors, however, did not account "for the great majority of the increased risk of hemorrhagic strokes." As we wrote, the models explained 1% of the risk of hemorrhagic stroke suggesting most of the risk was related to unmeasured factors.6 The additional risk factors that were identified in these analyses had effects that were independent of treatment and treatment did not disproportionately increase the risks associated with any of these factors.6 Therefore, not only have we addressed the general issue of hemorrhagic stroke in SPARCL, but also reported that the risks associated with treatment were similar in men and women (ie, no significant statistical interaction was found between sex, treatment and the risk of brain hemorrhage).
Discussions in our prior publications also noted the results of the Heart Protection Study (HPS)7 in which post hoc analysis found no overall increase in the risk of brain hemorrhage with statin treatment. A further post hoc subgroup analysis found statistical heterogeneity in the occurrence of hemorrhagic stroke between those with and without a history of prior stroke (n=21, 1.3% with treatment versus n=11, 0.7%). HPS, however, was neither designed nor powered to address the question. The risk of hemorrhage after thrombolytic treatment associated with low LDL-cholesterol found in the cited retrospective study was unrelated to statin treatment.8
SPARCL shows that treatment with atorvastatin 80 mg per day reduces the risk of recurrent stroke in both men and women. Based on the available data, there is no basis for excluding women from treatment.
Acknowledgments
Disclosures
The SPARCL trial was funded by Pfizer. Dr Goldstein’s institution was compensated for his work as a member of the SPARCL steering committee. Dr Goldstein has also served as a consultant for Pfizer.
References
1. Goldstein LB, Amarenco P, LaMonte M, Gilbert S, Messig M, Callahan A, Hennerici M, Sillesen H, Welch KMA. 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. Stroke. 2008; 39: 2444–2448.
2. Pfeffer MA, Jarcho JA. The charisma of subgroups and the subgroups of CHARISMA. N Engl J Med. 2006; 354: 1744–1746.
3. Rothwell PM. Treating individuals 2. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. Lancet. 2005; 365: 176–186.[CrossRef][Medline] [Order article via Infotrieve]
4. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006; 355: 549–559.
5. Amarenco P, Goldstein LB, Szarek M, Sillesen H, Rudolph AE, Callahan A, Hennerici M, Simunovic L, Zivin JA, Welch KMA. Effects of intense low-density lipoprotein cholesterol reduction in patients with stroke or transient ischemic attack: The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke. 2007; 38: 3198–3204.
6. Goldstein LB, Amarenco P, Szarek M, Callahan A, Hennerici M, Sillesen H, Zivin J, Welch KMA. Secondary analysis of hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study. Neurology. 2008; 70: 2364–2370.
7. Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions. Lancet. 2004; 363: 757–767.[CrossRef][Medline] [Order article via Infotrieve]
8. Bang OY, Saver JL, Liebeskind DS, Starkman S, Villablanca P, Salamon N, Buck B, Ali L, Restrepo L, Vinuela F, Duckwiler G, Jahan R, Razinia T, Ovbiagele B. Cholesterol level and symptomatic hemorrhagic transformation after ischemic stroke thrombolysis. Neurology. 2007; 68: 737–742.
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