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ARTICLES: S. Chaturvedi, J. Zivin, A. Breazna, P. Amarenco, A. Callahan, L. B. Goldstein, M. Hennerici, H. Sillesen, A. Rudolph, M. A. Welch, and For the SPARCL Investigators Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack Neurology 2008; 0: 01.wnl.0000327339.55844.1av1 [Abstract]

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Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack

William Landau   (22 June 2009)

Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack

Michael Strupp   (22 June 2009)

Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack

Matt T. Bianchi MD PhD, Brandon Westover, MD PhD   (22 June 2009)

Reply from the author

Seemant Chaturvedi MD, FAHA, FAAN   (22 June 2009)

Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack

Luis Castilla-Guerra, Maria del Carmen Fernandez-Moreno, MD, Maria Dolores Jimenez-Hernandez, MD, PhD   (15 January 2009)

Reply from the author

Seemant Chaturvedi   (15 January 2009)

Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack

Luca Mascitelli, Francesca Pezzetta MD, Tolmezzo, Italy, Mark R Goldstein, Bonita Springs, FL   (21 November 2008)

Reply from the author

Seemant Chaturvedi   (21 November 2008)

Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack 22 June 2009
William Landau, Washington University School of Medicine 660 S. Euclid Avenue, St. Louis, MO Send Correspondence to journal: Re: Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack landauw{at}neuro.wustl.edu William Landau	Hello, grandpa. How’s your wife? Compared with whom? -Ancient Vaudeville joke Before foxy grandpa spends $1300 per year for atorvastatin pills to prevent the disability of a second stroke—which he fears most—he needs more comparative numbers to set into a rational annual register. [1] The original study concluded that “the reduction in the risk of non fatal stroke was consistent with the treatment effect, but not significant“. [2] That stroke is a “coronary heart disease risk equivalent” is both statistically correct and common sense. The actual annual second stroke risk for elderly control patients (median age 72.5 years) was 3.3%, vs. those receiving atorvastatin (median age 72.3 years), 2.9%, which is a difference of 0.4%/year. The annual risk of not having a stroke and not taking this drug is 96.7%. A fifth of the study’s elderly patients were 75 years or older. The National Vital Statistic Life Table, based only on age, indicates the probability of dying during the next 365 days. (Table) For men aged 72-85, 0.4% annual decreased stroke risk must be compared with their 8- to 25- fold larger annual risk of non-survival (women have better odds). Twice as many of the treatment group’s strokes were hemorrhagic compared with the placebo; they had a larger death rate from all causes and more developed hepatic toxicity. A few developed rhabdomyolysis and some must have had muscular symptoms. Caveat emptor! Table The National Vital Statistic Life Table Age Male Female   Death Survival Death Survival 72 3.2% 96.8% 2.2% 97.8% 75 4.2% 95.8% 2.8% 97.2% 80 6.7% 93.3% 4.6% 95.4% 85 10.2% 89.8% 7.7% 92.3% References 1. Chaturvedi S, et al, for the SPARCL Investigators: Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack. Neurology 2009;72:688-694. 2. 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. Disclosure: The author reports no disclosures.
Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack 22 June 2009
Michael Strupp, University of Munich Marchioninistrasse 15, 81377 Munich Send Correspondence to journal: Re: Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack Michael.Strupp{at}med.uni-muenchen.de Michael Strupp	Chaturvedi and co-workers concluded that “the results support the use of atorvastatin in elderly patients with recent stroke or TIA.” [1] This conclusion can be questioned when the statistics and the results are reviewed. According to their study, the primary endpoint (fatal or non-fatal stroke) was reduced by 10% in elderly subjects (hazard ratio 0.90, 0.73 to 1.1 (p=0.33)). Non-significant p values were also found for the subgroup analysis of the primary outcome measures. They argue that a test of heterogeneity for a treatment-age interaction was not significant. From a biometrical point of view, this questionable test does not seem relevant because the primary statistical analysis was not significant. This data should be reanalyzed by other statisticians. The conclusions may have to be modified. This is not only of medical importance but also of major socioeconomic importance due to the high number of patients over the age of 65 who suffer from stroke. A treatment that is evidently not effective should not be approved or applied. Reference 1. Chaturvedi, S Zivin J, Amerenco P et al. Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack Neurology 2009; 72:688-694. Disclosure: The author reports no disclosures.
Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack 22 June 2009
Matt T. Bianchi MD PhD, Beth Israel Deaconess Medical Center Boston MA, Brandon Westover, MD PhD Send Correspondence to journal: Re: Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack mtbianchi{at}partners.org Matt T. Bianchi MD PhD, et al.	We read with interest the article by Chaturvedi et al. who retrospectively analyzed the SPARCL trial data to investigate whether statin therapy reduced future stroke risk in older (65+) patients with recent stroke or TIA. Whereas future stroke risk in young patients significantly differed from matched placebo controls (26% risk reduction), the risk reduction for older patients was not significant (10%, p=0.33). However, a test of heterogeneity showed no significant interaction between age and treatment effect (p=0.52). Thus, the accompanying commentary in that issue states, the authors “correctly conclude that statin benefits are shared equally in the two groups”. We feel that this conclusion is not justified. A priori, there are four possible interpretations of the 10% vs 26% age-dependent RRR including: 1) only young patients benefited (following the initial p-value results); 2) both young and old patients benefited (10% and 26% are indistinguishable and the 26% “wins”); 3) neither young nor old patients benefited (10% and 26% are indistinguishable and the 10% prevails); or 4) the question remains uncertain. Possibilities #2 and #3 are mutually exclusive, yet nothing compels us to choose #2 over #3, as the authors do, rather than the reverse. This leaves #1 and #4. To visualize the dilemma, consider the simulated data (Figure), which shows three groups (n=20 each) with means of 3, 4, or 5 (arbitrary units of benefit), and variance of 1, for placebo, old, or young patients, respectively. Here, placebo and old are statistically indistinguishable, as are placebo and young, but the young group is different from placebo (as in Chaturvedi et al). The dilemma is that the middle column (old) is statistically indistinguishable from the other two groups, but those groups differ from one another. One can imagine a chain of patient groups, A through Z, each with an incrementally but non-significantly larger benefit: If the smallest and largest means, A and Z, are statistically different, it seems unreasonable to conclude that B through Y are all equal to Z, and it seems equally unreasonable to conclude that B through Y are each equal to A. We find the logic of this paper, purporting to show that atorvastatin significantly reduces secondary stroke risk in the elderly, in need of further justification. A plausible conjecture consistent with the data, but not directly addressed by the authors, is that high-dose statin therapy provides stroke risk reduction that gradually diminishes with age. Figure Disclosure: The authors report no disclosures.
Reply from the author 22 June 2009
Seemant Chaturvedi MD, FAHA, FAAN, Wayne State University Detroit, MI 48201 Send Correspondence to journal: Re: Reply from the author schaturv{at}med.wayne.edu Seemant Chaturvedi MD, FAHA, FAAN	We appreciate the thrust of Dr. Landau’s comments, but disagree with several of his statements concerning our exploratory analysis. The primary trial was neither designed nor powered to detect a treatment effect in the subgroup of patients older than age 65 years. The 95% confidence interval around the hazard ratio in the elderly subgroup overlaps with that of younger subjects, and there was no age-related heterogeneity in the treatment effect. Although treatment was associated with an increase in hemorrhagic stroke, this was included in the primary endpoint showing benefit. The rates of myalgias, myopathy and hepatotoxicty were very low and did not differ between elderly and younger subjects. There was no significant difference in all cause mortality in the older subjects; they tended to have lower rates than the younger group. The absolute risk reduction for any cardiovascular event was 4.1% in the elderly vs. 3.0% in the younger group. SPARCL was a randomized trial and is internally valid. The application of vital statistics to this selected population is not appropriate. We stand by the conclusions as reflected in our publication. We also thank Dr. Strupp and Dr. Bianchi for their comments. As indicated in our response to Dr. Landau, the SPARCL trial was neither designed nor powered to detect subgroup treatment effects. When conducting exploratory subgroup analyses, the nominal subgroup p-value can be misleading, and other studies using this type of analysis have been appropriately criticized. [3] We used the recommended statistical approach: to test for a subgroup interaction based on the study pre-specified endpoints. [4] There was no heterogeneity between older and younger subjects for the SPARCL primary or any secondary endpoint. Our analysis was exploratory yet based on the results, it is not appropriate to deny an effective therapy to stroke patients based on their older age. References 3. Pfeffer MA, Jarcho JA. The charisma of subgroups and the subgroups of CHARISMA. New England Journal of Medicine. 2006;354:1744-1746. 4. Rothwell PM. Treating individuals 2. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. Lancet. 2005;365:176-186. Disclosures: The study to which this Correspondence refers was sponsored by Pfizer. Dr. Chaturvedi has served as a consultant to Pfizer.
Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack 15 January 2009
Luis Castilla-Guerra, Departments of Internal Medicine and Neurology, Hospital de la Merced Juan Ramón Jimenez nº5. Castileja de Guzmán, 41908, Osuna, Seville, Spain, Maria del Carmen Fernandez-Moreno, MD, Maria Dolores Jimenez-Hernandez, MD, PhD Send Correspondence to journal: Re: Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack castillafernandez{at}hotmail.com Luis Castilla-Guerra, et al.	In their post-hoc analysis of data from the Stroke Prevention with Aggressive Reductions in Cholesterol Levels (SPARCL) trial, Chaturvedi et al. concluded that the findings support the use of atorvastatin in elderly patients with recent stroke and TIA. [1] However, a close scrutiny of the data shows that this is only partially true. The primary aim of the SPARCL trial was to investigate whether atorvastatin was more effective than placebo for reducing stroke in patients with recent stroke or TIA and no known coronary heart disease. [2] Unfortunately, in those aged 65 years or older, atorvastatin did not show a significant reduction in recurrent stroke rate (HR 0.90, 0.73-1.11, p=0.33). Furthermore, in elderly patients without carotid stenosis at baseline, atorvastatin showed no benefit on stroke recurrence (HR 1.00, 0.78-1.28, p=0.99). Only in patients with known carotid stenosis at baseline did the SPARCL trial reveal an almost significant reduction in the risk of stroke with atorvastatin (HR 0.67, 0.44-1.01, p=0.057). It seems that the real benefits of atorvastatin are related to stabilization in atherosclerotic plaques contributing to reduce new strokes or vascular events in other arteries. This concept is consistent with findings from many trials of statins in patients with unstable coronary events, in which plaque rupture in the culprit artery as well as in other arteries was stabilized by early statin therapy. In this sub-analysis of the SPARCL trial among the elderly, atorvastatin was also associated with a reduction in coronary events. [1] Likewise, a recent meta-analysis of nine trials involving a total of 19,569 patients with an age range of 65 to 82 years showed that statins reduced stroke incidence by 25% (RR 0.75; 0.56-0.94) in elderly patients with coronary heart disease. [3] We would argue against the administration of statin agents to all elderly patients with ischemic stroke to prevent recurrent stroke. However, regardless of stroke subtype, the prevalence of coronary atherosclerosis in patients with stroke is 75%. [4] In addition, after a first stroke the 5-year risk of myocardial infarction is 10%, which qualifies stroke as a coronary heart disease risk equivalent. [5] To conclude, we would argue for the use of statin agents in all elderly patients with ischemic stroke to prevent further vascular events. References 1. Chaturvedi S, Zivin J, Breazna A, et al. Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack. 2008 Sep 3. (Epub ahead of print). 2. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549-559. 3. Afilalo J, Duque G, Steele R, Jukema JW, de Craen AJM, Eisenberg MJ. Statins for secondary prevention in elderly patients. A hierarchical Bayesian meta-analysis. J Am Coll Cardiol 2008; 51: 37-45. 4. Gongora-Rivera F, Labreuche J, Jaramillo A, et al. The prevalence of coronary atherosclerosis in patients with stroke. Stroke 2007;38: 1203-1210. 5. Mazighi M, Lavallée PC, Labreuche J, Amarenco P. Statin therapy and stroke: what was known, what is new and what is next? Curr Opin Lipidol 2007;18:622-625. Disclosure: The authors report no disclosures.
Reply from the author 15 January 2009
Seemant Chaturvedi, Wayne State University 8C-UHC, 4201 St. Antoine, Detroit, MI 48201 Send Correspondence to journal: Re: Reply from the author SChaturv{at}med.wayne.edu Seemant Chaturvedi	Dr. Castilla-Guerra and colleagues comment on our post-hoc SPARCL study analysis exploring the impact of atorvastatin treatment in elderly compared to younger patients with recent stroke or TIA. We disagree with their assertion that the analysis showed no reduction in stroke for the elderly group. SPARCL showed an overall 16% reduction in the study’s primary endpoint (time to the occurrence of a first non-fatal or fatal stroke). [6] The test for statistical heterogeneity of the treatment effect between older and younger SPARCL subjects for the SPARCL primary endpoint (combined risk of non-fatal and fatal stroke) was not significant (p=0.52). Therefore, there was not a significant difference in the treatment effect based on the subjects age. We encourage Castilla-Guerra et al. to consider another exploratory analysis of SPARCL data in subjects with carotid atherosclerosis. [7] References 6. Amarenco AP, Bogousslavsky J, Callahan A, et al. High-dose atorvastatin after stroke or transient ischemic attack. New England Journal of Medicine 2006; 355: 549-559. 7. Sillesen H, Amarenco P, Hennerici MG, et al. Atorvastatin reduces the risk of cardiovascular events in patients with carotid atherosclerosis. A Secondary Analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke 2008;39:3297- 3302 Disclosures: The article to which this correspondence refers includes the following disclosures- This study was sponsored by Pfizer Inc., which was involved in the design and conduct of the study; collection, management, and analysis of the data; and review of the manuscript. Seemant Chaturvedi has acted as a consultant for Pfizer. The honorarium received did not exceed $10,000. Justin Zivin has received honoraria from Pfizer during the course of this study. The honoraria did not exceed $10,000/year. Andrei Breazna is an employee of Pfizer and has an equity or ownership interest in the sponsor of the study. Statistical analysis was performed by Andrei Breazna. Pierre Amarenco has received grants from Pfizer for other research or activities not reported in this research exceeding $10,000/year and honoraria from Pfizer in excess of $10,000/year during the course of this study. Alfred Callahan has received honoraria from Pfizer in excess of $10,000 during the course of this study. Larry Goldstein has received honoraria from Pfizer during the course of this study. The honoraria did not exceed $10,000/year. 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/year. Henrik Sillesen has received grants from Pfizer for other research or activities not reported in this research/article in excess of $10,000/year and honoraria exceeding $10,000/year during the course of this study. Amy Rudolph is an employee of Pfizer and has an equity or ownership interest in the sponsor of the study. K. Michael Welch has received honoraria from Pfizer during the course of the study in excess of $10,000/year.
Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack 21 November 2008
Luca Mascitelli, Comando Brigata Alpina Julia 8 Via S. Agostino, Udine 33100 Italy, Francesca Pezzetta MD, Tolmezzo, Italy, Mark R Goldstein, Bonita Springs, FL Send Correspondence to journal: Re: Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack lumasci{at}libero.it Luca Mascitelli, et al.	In this post-hoc analysis of data from the Stroke Prevention with Aggressive Reductions in Cholesterol Levels (SPARCL) trial, Chaturvedi et al. attempt to determine the effects of atorvastatin treatment in patients without known coronary heart disease who had recent stroke or transient ischemic attack. [1] We are concerned about the efficacy and safety of high-dose statins in the secondary prevention of stroke, especially in the elderly. Their post-hoc analysis found that, compared to placebo, the use of high-dose atorvastatin was associated with a non-significant relative risk reduction of the combined endpoint of fatal and nonfatal stroke and with no effect on all-cause mortality. However, the risk of hemorrhagic stroke was not mentioned. It has been shown in patients with a history of cerebrovascular disease that statins decrease the risk of future strokes. However, this beneficial effect is relatively small as a result of an associated increased risk of hemorrhagic stroke. [2] In the SPARCL trial, the cause-specific adjusted hazard ratios in the atorvastatin group compared to the placebo group were 0.78 for ischemic stroke and 1.66 for hemorrhagic stroke. [3] In addition to treatment with atorvastatin, an exploratory analysis of the same trial found that the risk of hemorrhagic stroke increased with age. [4] Furthermore, lower low-density lipoprotein cholesterol levels with or without statin treatment have also been shown to be strongly and independently related to a higher risk of symptomatic hemorrhagic transformation after ischemic stroke thrombolysis. [5] We would urge caution when treating elderly patients with high-dose statins for the secondary prevention of stroke. References 1. Chaturvedi S, Zivin J, Breazna A, et al; For the SPARCL Investigators. Effect of atorvastatin in elderly patients with a recent stroke or transient ischemic attack. Neurology 2008 Sep 3. [Epub ahead of print]. 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. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. 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. Goldstein LB, Amarenco P, Szarek M, et al; SPARCL Investigators. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study. Neurology 2008;70:2364-2370. 5. Bang OY, Saver JL, Liebeskind DS, et al. Cholesterol level and symptomatic hemorrhagic transformation after ischemic stroke thrombolysis. Neurology 2007;68:737-742. [Erratum in: Neurology 2007;68:1547]. Disclosure: The authors report no disclosures.
Reply from the author 21 November 2008
Seemant Chaturvedi, Wayne State University Send Correspondence to journal: Re: Reply from the author SChaturv{at}med.wayne.edu Seemant Chaturvedi	We thank Dr. Mascitelli et al. for their comments. As we reported, the test for heterogeneity for the SPARCL primary endpoint based on age group was not significant. [1] This means that there was no difference in treatment effect based on age. SPARCL was not powered to analyze treatment effects in subgroups. Therefore, the confidence intervals are wide. Consistent with the test for heterogeneity, the confidence intervals surrounding the point estimates for the two age groups overlap. SPARCL was not designed to test for an effect on all cause mortality. The primary publication of the SPARCL trial results reported the observation that the overall benefit of treatment on the primary endpoint included an increased risk of hemorrhagic stroke. [6] The subsequent exploratory analysis of brain hemorrhage in SPARCL found that, in addition to treatment, the hemorrhage rate increased with several factors, including age. However, there was no interaction between any of these factors, including age, with treatment, and risk of hemorrhage. To further clarify, treatment did not disproportionately increase the risk of hemorrhage in older vs. younger SPARCL patients. [3] The secondary analysis of brain hemorrhage in SPARCL also found no relationship between LDL-C levels and the risk of hemorrhage in atorvastatin-treated patients. [3] A further secondary analysis found that, compared to SPARCL subjects having no change or an increase in LDL-C, those with > a 50% LDL-C reduction had a 31% reduction in stroke risk (hazard ratio, 0.69, 95% CI, 0.55 to 0.87, P=0.0016), a 33% reduction in ischemic stroke (P=0.0018), but no statistically significant increase in hemorrhagic stroke (P=0.8864). [7] Further adjustment for age, gender, time-varying systolic blood pressure, cigarette smoking, diabetes, compliance to study drug, and antihypertensive and antiplatelet agents use did not modify these findings. [7] The relationship between low LDL-C and the risk of hemorrhage based on epidemiological studies was not found in SPARCL. References 6. 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. 7. Amarenco P, Goldstein LB, Szarek M et al. 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. Disclosures: The article to which this correspondence refers includes the following disclosures- This study was sponsored by Pfizer Inc., which was involved in the design and conduct of the study; collection, management, and analysis of the data; and review of the manuscript. Seemant Chaturvedi has acted as a consultant for Pfizer. The honorarium received did not exceed $10,000. Justin Zivin has received honoraria from Pfizer during the course of this study. The honoraria did not exceed $10,000/year. Andrei Breazna is an employee of Pfizer and has an equity or ownership interest in the sponsor of the study. Statistical analysis was performed by Andrei Breazna. Pierre Amarenco has received grants from Pfizer for other research or activities not reported in this research exceeding $10,000/year and honoraria from Pfizer in excess of $10,000/year during the course of this study. Alfred Callahan has received honoraria from Pfizer in excess of $10,000 during the course of this study. Larry Goldstein has received honoraria from Pfizer during the course of this study. The honoraria did not exceed $10,000/year. 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/year. Henrik Sillesen has received grants from Pfizer for other research or activities not reported in this research/article in excess of $10,000/year and honoraria exceeding $10,000/year during the course of this study. Amy Rudolph is an employee of Pfizer and has an equity or ownership interest in the sponsor of the study. K. Michael Welch has received honoraria from Pfizer during the course of the study in excess of $10,000/year.