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ARTICLES: L. B. Goldstein, P. Amarenco, M. Szarek, A. Callahan, III, M. Hennerici, H. Sillesen, J. A. Zivin, K.M.A. Welch On behalf of the SPARCL Investigators Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study Neurology 2008; 70: 2364-2370 [Abstract] [Full text] [PDF]

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Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study

Mervyn D.I. Vergouwen, M. Vermeulen, Yvo B.W.E.M. Roos   (15 August 2008)

Reply from the author

Larry B. Goldstein   (15 August 2008)

Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study

Mark R. Goldstein, MD, FACP, Luca Mascitelli, MD, Medical Service, Comando Brigata alpina "Julia", Udine, Italy; Francesca Pezzetta, MD, Cardiology Service, Ospedale di Tolmezzo, Tolmezzo, Italy   (8 August 2008)

Reply from the author to Goldstein

Larry B. Goldstein   (8 August 2008)

Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study 15 August 2008
Mervyn D.I. Vergouwen, Academic Medical Center, Department of Neurology H2-218, Meibergdreef 9, 1005 AZ Amsterdam, The Netherlands, M. Vermeulen, Yvo B.W.E.M. Roos Send Correspondence to journal: Re: Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study m.d.vergouwen{at}amc.uva.nl Mervyn D.I. Vergouwen, et al.	The investigators of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study analyze the increased risk of hemorrhagic stroke in patients with a history of cerebrovascular disease treated with statins. [1] Since statin use is associated with an increased risk of hemorrhagic stroke in patients with a history of cerebrovascular disease, this study is important because it identifies at-risk subgroups of patients. [2] The authors emphasize that hemorrhagic stroke as an entry event is associated with hemorrhagic stroke during follow-up. Since patients with hemorrhagic stroke are usually not treated with statins for secondary prevention, this observation is of minor clinical importance. Far more interesting is the increased risk of hemorrhagic stroke in patients with lacunar stroke, caused by cerebral small vessel disease (HR 4.99, 95% CI 1.71 to 14.61), treated with statins. The authors discuss that increased hemorrhagic strokes in small vessel disease might lack validity, because secondary outcomes in isolated subgroups have a high risk of false-positive findings. Although we agree with the authors from a statistical point of view, we believe that future investigations should focus on whether statin treatment might be contra-indicated in patients with small vessel disease. Patients with cerebral small-vessel disease often have intracerebral microhemorrhages. [3] These microhemorrhages may change into macrohemorrhages if patients are treated with statins. Statins exert pleiotropic effects on, for example, the coagulation cascade and fibrinolytic system. It is still unclear from the SPARCL study whether statins in patients with small vessel disease prevent only minor (lacunar) strokes and whether the risk of fatal hemorrhagic stroke is increased in this group of patients. We would ask the SPARCL investigators to present data on benefit versus complications in the subgroup of patients with small vessel disease (lacunar stroke). References 1. Goldstein LB, Amarenco P, Szarek M, et al. On behalf of the SPARCL investigators. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study. Neurology 2008;70:2364-2370. 2. Vergouwen MD, de Haan RJ, Vermeulen M, Roos YB. Statin treatment and the occurrence of hemorrhagic stroke in patients with a history of cerebrovascular disease. Stroke 2008;39:497-502. 3. Kwa VI, Franke CL, Verbeeten B Jr, Stam J. Silent intracerebral microhemorrhages in patients with ischemic stroke. Amsterdam Vascular Medicine Group. Ann Neurol 1998;44:372-377. Disclosures: The authors have no disclosures.
Reply from the author 15 August 2008
Larry B. Goldstein, Duke University Medical Center Box 3651-DUMC, Durham, NC 27710 Send Correspondence to journal: Re: Reply from the author golds004{at}mc.duke.edu Larry B. Goldstein	Dr. Vergouwen and colleagues reiterate our caution that our report was exploratory and that drawing conclusions based on analyses of isolated subgroups is hazardous. [1] We further cautioned that baseline stroke subtype categorization in SPARCL was based on the clinical impression of the investigator and was not otherwise standardized or adjudicated. [1] With these important caveats stated, we did find an increased risk of outcome hemorrhagic strokes in subjects with an investigator-designated small vessel stroke at baseline. The validity of this post hoc observation is worthy of further study. Dr. Vergouwen and colleagues requested that we provide data reflecting the benefit versus complications in the subgroup of patients with small vessel disease. These data are given in the report (Table 1). [1] Subjects with a baseline small-vessel stroke who were randomized to treatment with atorvastatin 80 mg per day had a benefit in the primary endpoint (combined risk of any fatal or non-fatal stroke, HR 0.84, 95% CI 0.64 to 1.11)1 that was virtually identical to the benefit in the overall study population (HR 0.84, 95% CI 0.71 to 0.99). [4] There was no overall treatment-related difference in the frequency of fatal hemorrhages (17 in the active treatment and 18 in the placebo groups). [4] There are too few subjects and too many potential confounders to perform any further meaningful analyses of these data. We do not have data from SPARCL to address their conjectures regarding the possible importance of cerebral microhemorrhages or the pleiotropic effects of statins in this setting. As further discussed in the editorial that accompanied our report, “The true mechanism linking statins to brain hemorrhage (in patients with a history of recent stroke or TIA) remains a mystery.” [5] References 4. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. New England Journal of Medicine. 2006;355:549-559 5. Jacobs BS, Greenberg SM. Statins, low cholesterol, and hemorrhagic stroke. An uncertain triangle. Neurology 2008;70:2355-2356. Disclosure: Steering Committee for the SPARCL study which was supported by Pfizer and a consultant for Pfizer.
Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study 8 August 2008
Mark R. Goldstein, MD, FACP, Medical Director, Fountain Medical Court 9410 Fountain Medical Court, Suite A-200, Bonita Springs, FL 34135, USA, Luca Mascitelli, MD, Medical Service, Comando Brigata alpina "Julia", Udine, Italy; Francesca Pezzetta, MD, Cardiology Service, Ospedale di Tolmezzo, Tolmezzo, Italy Send Correspondence to journal: Re: Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study markrgoldstein{at}comcast.net Mark R. Goldstein, MD, FACP, et al.	The SPARCL study investigators further analyze the risk versus beneift of high-dose atorvastatin. [1] This is important since there has been a push to use high-dose statin therapy in wide segments of the population in order to achieve aggressive cholesterol-lowering goals. [2] The new SPARCL analysis suggests that individuals free of coronary heart disease with a history of hemorrhagic stroke, or any history of stroke and stage 2 hypertension, should not be treated with high dose atorvastatin therapy because of a six-fold risk of subsequent hemorrhagic stroke. Additionally, the risk appears to be magnified with advancing age. Furthermore, there is no mortality benefit of high-dose atorvastatin therapy among individuals free of coronary heart disease, despite having a prior stroke. [3] Although statin treatment may be effective in the prevention of stroke in patients with known coronary heart disease but without a history of cerebrovascular disease, some concerns remain when considering high doses of statins in certain segments of the population. High-dose compared to low-dose atorvastatin therapy in women with stable coronary heart disease increased all-cause mortality, fueled by a large and significant increase in cancer mortality. [4] Similarly, high-dose compared to low-dose atorvastatin therapy in elderly subjects with stable coronary heart disease is associated with a trend towards increased all-cause mortality, mainly from increased cancer mortality. [5] We believe that high-dose atorvastatin therapy should be not be used in elderly women, individuals with prior hemorrhagic stroke, or those with stage 2 hypertension and any prior stroke. References 1. Goldstein LB, Amarenco P, Szarek M, et al. on behalf of the SPARCL Investigators. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study. Neurology 2008;70:2364 -2370. 2. O’Keefe JH Jr, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low -density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol 2004;43:2142-2146. 3. 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. 4. Wenger NK, Lewis SJ, Welty FK, et al. on behalf of the TNT Steering Committee and Investigators. Beneficial effects of aggressive low -density lipoprotein cholesterol lowering in women with stable coronary heart disease in the Treating to New Targets (TNT) study. Heart 2008;94:434-439. 5. Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK, for the Treating to New Targets Study Steering Committee and Investigators. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med 2007;147:1-9. Disclosures: The authors have no disclosures.
Reply from the author to Goldstein 8 August 2008
Larry B. Goldstein, Duke University Medical Center Box 3651-DUMC, Durham, NC 27710 Send Correspondence to journal: Re: Reply from the author to Goldstein golds004{at}mc.duke.edu Larry B. Goldstein	Dr. Goldstein et al. assert that our report suggests, "individuals...with a history of hemorrhagic stroke, or any history of stroke and stage 2 hypertension, should not be treated with high dose atorvastatin therapy because of a six-fold risk of subsequent hemorrhagic stroke." It is first important to reiterate that our report was exploratory and that drawing firm conclusions based on unplanned, post hoc analyses is hazardous. Furthermore, there were no statistical interactions between any of the identified factors—including having a hemorrhagic stroke at baseline—and the risk of an outcome hemorrhagic stroke. The risk of hemorrhage was not disproportionately increased by treatment. [1] However, we did point out that there was no evidence that those with a baseline hemorrhagic stroke benefited from treatment. [1] The increased risk of hemorrhagic stroke associated with stage 2 hypertension was independent of treatment. Rather than being an indication for avoiding statins, these data reinforce the need to aggressively treat hypertension as part of secondary stroke prevention management. [6] The SPARCL trial was neither designed nor powered to detect a difference in all cause mortality. [3] We have also conducted a secondary analysis of SPARCL data comparing the relative effects of treatment on stroke and cardiovascular events in men and women. [7] Women constituted 40% of the SPARCL population. There were no sex by treatment interactions for the SPARCL primary endpoint (combined risk of nonfatal and fatal stroke; interaction p=0.99) or for the occurrence of any of the SPARCL secondary endpoints (major cardiac events, p=0.45; major cardiovascular events, p=0.63; revascularization procedures, p=0.17; any coronary heart event, p=0.40). There was a statistically marginal (p=0.06) sex by treatment interaction for all cause mortality, suggesting a possible benefit in women. In another analysis, we reported no statistical heterogeneity in the benefits associated with treatment between younger and older SPARCL subjects yet younger subjects benefited more. [8] The cited TNT trial analysis revealed no statistically significant age by treatment interaction for all cause mortality. [5] This included a small difference in cancer deaths between the two groups (2.8% for high dose vs. 2.1% for low dose). As always, physicians need to weigh the benefits against the risks of treatment in individual patients. Our exploratory analysis suggests this is particularly true for the use of statins in patients with a recent brain hemorrhage. The data, however, do not support the view that high-dose atorvastatin therapy should not be used in the elderly, in women, or in those with stage 2 hypertension and any prior stroke. References 6. Sacco RL, Adams R, Albers G, et al.. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack .Stroke. 2006;37:577-617 7. Goldstein LB, Amarenco P, LaMonte M, et al. Relative effects of statin therapy on stroke and cardiovascular events in man and women. Secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study. Stroke. 2008;39 (publish ahead of print, DOI 10.1161/STROKEAHA.107.512747). 8. Chaturvedi S, Zivin J, Breazna A, et al. Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack. Neurology 2008 (IN PRESS). Disclosure: Steering Committee for the SPARCL study which was supported by Pfizer and a consultant for Pfizer.