Correspondence
Statin Therapy after Stroke or Transient Ischemic Attack
N Engl J Med 2006; 355:2368-2371November 30, 2006
- Article
To the Editor:
In the August 10 issue, Amarenco et al. report the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study.1 The study of high-dose atorvastatin for stroke offers promising results, but also raises some serious concerns. One concern is that 55 patients who received high-dose atorvastatin, as compared with 11 who received placebo, had liver enzyme elevations that were more than three times the upper limit of the normal range. These results mirror those of a previous study of high-dose atorvastatin in which liver enzyme elevations occurred six times more often with high-dose atorvastatin than with placebo.2 Because statin hepatotoxicity is dose-related, we need information about the specific liver enzyme elevations that occurred in these studies.
In his accompanying editorial, Kent3 notes the 66% increase in the relative risk of hemorrhagic stroke among the patients receiving high-dose atorvastatin. Because statins have antithrombotic effects, one wonders why these patients were included in this study.3 Finally, this is the second major clinical study involving high-dose atorvastatin in which deaths from cardiovascular causes decreased, but deaths from other causes increased, resulting in no change in overall mortality. In 2005, Pitt considered this effect on outcome “a matter of concern” and cautioned, “We need further reassurance as to the safety of this approach.”4
These concerns about safety remain.
4 ReferencesJay S. Cohen, M.D.
University of California, San Diego, La Jolla, CA 92039
jacohen@ucsd.edu 1
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators
Full Text | Web of Science | Medline2
LaRosa JC ,Grundy SM ,Waters DD , et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-1435
Full Text | Web of Science | Medline3
Kent DM . Stroke -- an equal opportunity for the initiation of statin therapy. N Engl J Med 2006;355:613-615
Full Text | Web of Science | Medline4
Pitt B . Low-density lipoprotein cholesterol in patients with stable coronary heart disease -- is it time to shift our goals? N Engl J Med 2005;352:1483-1484
Full Text | Web of Science | Medline
To the Editor:
The SPARCL investigators suggest that high-dose atorvastatin may reduce the risk of fatal or nonfatal stroke. The trial did not have the statistical power to assess the risk of death, but the number of fatal strokes was significantly reduced, and the smaller number of nonfatal strokes was “consistent with the treatment effect” (P=0.11). There was also a nonsignificant reduction in deaths from cardiovascular disease in the treatment group (P=0.11, adjusted); however, the overall death rate was slightly lower in the placebo group, with a larger difference in favor of placebo when deaths from causes other than cardiovascular disease were considered (113 vs. 138, 4.8% vs. 5.8%, P=0.10).
Failure to reduce the overall death rates in some groups of patients and an increase in deaths from causes other than cardiovascular disease have been reported in other studies of lower-dose statins.1,2 This issue is important, since statins are given to increasing numbers of patients who are at low risk for cardiovascular disease at baseline. Can the authors provide an adjusted survival time analysis for combined deaths from causes other than cardiovascular disease and suggest why there was an excess of such deaths in their study? Presumably, this outcome is not “consistent with the treatment effect.”
2 ReferencesJames E. East, M.R.C.P.
St. Mark's Hospital, Harrow HA1 3UJ, United Kingdom
jameseast6@yahoo.com 1
Shepherd J ,Blauw DJ ,Murphy MB , et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;360:1623-1630
CrossRef | Web of Science | Medline2
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group
CrossRef | Web of Science
To the Editor:
The SPARCL investigators report that statin therapy was associated with a reduction in coronary events among patients with stroke or transient ischemic attack (TIA) and no known coronary disease. They therefore suggest considering stroke a “coronary heart disease risk equivalent.” Risk equivalency, however, implies a high absolute risk of a major coronary event (>20% over a period of 10 years).1 Stroke in most patients — those without carotid artery disease — is not currently considered to be a coronary risk equivalent.1 The 5.1% risk of a major coronary event over a 5-year period in the placebo group in the SPARCL study also falls short of risk equivalency. With stroke included in the composite end point of a major cardiovascular event, however, the risk (17.2% over 5 years) would easily surpass 20% over 10 years. This finding is consistent with population-based data showing that patients with stroke are more likely to have recurrent strokes than coronary events.2 SPARCL and earlier studies,3 moreover, show that statins reduce the risk of stroke among patients with a history of either stroke or cardiac disease. One might therefore prefer the term “coronary and stroke risk equivalent,” which would emphasize the reduction in both stroke and coronary outcomes in both patient groups.
Mitchell S.V. Elkind, M.D.
Columbia University, New York, NY 10032
mse13@columbia.edu Dr. Elkind reports receiving speaking fees from BMS-Sanofi Partnership and Boehringer Ingelheim and research support from BMS-Sanofi Partnership and diaDexus and having served as an expert witness for Merck.
3 References1
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
CrossRef | Web of Science2
Dhamoon MS ,Sciacca RR ,Rundek T ,Sacco RL ,Elkind MSV . Recurrent stroke and cardiac risks after first ischemic stroke: the Northern Manhattan Study. Neurology 2006;66:641-646
CrossRef | Web of Science | Medline3
Collins R ,Armitage J ,Parish S ,Sleight P ,Peto R . Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet 2004;363:757-767
CrossRef | Web of Science | Medline
To the Editor:
Amarenco and colleagues report that, as compared with placebo, the use of 80 mg of atorvastatin per day in patients who had a stroke or TIA resulted in a 2.2% absolute risk reduction in the occurrence of a fatal or nonfatal stroke. Apart from the event rates, it would have been useful to compare the disability resulting from a nonfatal stroke among the patients in the two groups by means of a valid stroke-outcome tool. An assessment of the effect of 80 mg of atorvastatin per day on the disability caused by a future stroke would have implications for the treatment and long-term outcome of these patients.
Nasim A. Khan, M.D.
Shah Associates, Hollywood, MD 20636To the Editor:
Translating trial results into clinical practice is often difficult, and application of the SPARCL results may be very hard. Physicians treating a patient with recent stroke but without known coronary heart disease may have difficulty prescribing a presumably lifelong drug such as high-dose atorvastatin, which may have harmful side effects. According to the SPARCL investigators, atorvastatin reduces the risk of nonfatal stroke from 11.8% to 10.4% over a period of 5 years, but it does so without improving survival.
Therefore, we do not think there is a dangerous underuse of statins among such patients, as suggested by Kent in the accompanying editorial. Finally, it is disturbing that the editorial on the trial, which was supported by a pharmaceutical company, was written by someone declaring a conflict of interest involving the same company.
Luca Mascitelli, M.D.
Comando Brigata alpina Julia, 33100 Udine, Italy
lumasci@libero.it Francesca Pezzetta, M.D.
Ospedale di S. Vito al Tagliamento, 33078 S. Vito al Tagliamento, ItalyAuthor/Editor Response
Cohen points out that in the SPARCL trial, as in other statin trials, liver enzyme elevations occurred more frequently in patients who received statins than in patients who received placebo. It is difficult to compare liver enzyme levels among patients in the SPARCL trial with those among patients in previous trials, since many trials included run-in periods to establish tolerability or patients had previously used statins, probably reducing the observed incidence of abnormalities. The liver enzyme elevations in the SPARCL trial were consistent with known elevations as detailed in the product label.
Risk factors for ischemic and hemorrhagic stroke overlap, and many patients surviving brain hemorrhage remain at profound risk for major ischemic vascular events. Also, distinguishing hemorrhagic conversion from primary hemorrhage is often difficult. Since in both instances patients might benefit from atorvastatin, patients with brain hemorrhage were not excluded from the SPARCL trial (and accounted for 2% of the study population). Secondary analyses have been conducted to address the implications of statin therapy for patients who had hemorrhagic stroke during the trial. A preliminary exploratory analysis1 suggests that brain hemorrhage is not related to a major lowering of low-density lipoprotein cholesterol levels.
As East states, SPARCL did not have the statistical power to evaluate the effect of atorvastatin on mortality. There was no significant difference in death rates between patients who were randomly assigned to receive active treatment and those who were assigned to receive placebo. A trend toward a reduction in deaths from cardiovascular disease (78 vs. 98, P=0.11) was noted in the treatment group, with an increase in deaths from causes other than cardiovascular disease (138 vs. 113, P=0.102; adjusted hazard ratio, 1.20 [95% confidence interval, 0.91 to 1.57; P=0.196]). The incidence of death from cancer was nearly identical in the two groups (P=0.80). Other deaths from noncardiovascular causes (81 vs. 60) included death from infection, accidental or violent death, and unclassified death — an imbalance that seems best explained by chance.
We accept Elkind's caution in proposing stroke alone as a coronary risk equivalent, and we appreciate his suggestion that stroke may be the risk equivalent of a major cardiovascular event — a composite end point that includes stroke. Additional analyses to determine the specific risks of coronary heart disease and cardiovascular events for patients in the SPARCL study are under way.
Khan's hope for a disability analysis was anticipated. Briefly, 474 patients in the intention-to-treat population had an ischemic stroke during the trial, and severity data were available for these patients. In an exploratory analysis with the use of the modified Rankin scale 90 days after the event, the severity of stroke among patients who had received the assigned study drug within 1 month of the event was significantly reduced in the 175 patients receiving atorvastatin, as compared with the 222 patients receiving placebo (P=0.01 by the Cochran–Mantel–Haenszel test). Among the 76 patients who had not received the study drug for more than 1 month before the stroke, the severity of the stroke did not differ significantly between the 34 patients who received atorvastatin and the 42 patients who received placebo (P=0.2).2
We do not share Mascitelli's and Pezzetta's pessimism, and we strongly believe that the SPARCL trial showed the benefits of atorvastatin at a dose of 80 mg per day for secondary stroke prevention.
2 ReferencesK.M.A. Welch, M.B., Ch.B.
Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064
michael.welch@rosalindfranklin. edu for the SPARCL Investigators
1
The SPARCL Investigators. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study. Presented at the World Congress of Cardiology, Barcelona, September 2–6, 2006.
2
Goldstein LB, SPARCL Investigators
Web of Science
Author/Editor Response
Mascitelli and Pezzetta are unimpressed by the benefits of atorvastatin reported in the SPARCL trial. A modest effect size, however, is typical of most preventive therapies, so it is hard to understand how forgoing treatments with incremental benefits of this magnitude as a class would help patients. An answer to the question of whether the benefits of atorvastatin can be captured by treating a smaller group of patients at high risk for stroke and with the potential to receive a large benefit from treatment, rather than the relatively less selected group enrolled in SPARCL, must await substudies, which I hope will be forthcoming. The gross undertreatment reported by Ovbiagele et al.1 referred to patients with higher vascular risk meeting Adult Treatment Panel II criteria of the National Cholesterol Education Program. For these patients, treatment should not be controversial (even if only for cardioprotection).
Regarding my research funding, I had received an open, nationally competitive “Scholars” grant in clinical epidemiology funded by Pfizer, which was unrelated to any Pfizer product and expired in June 2005. Awardees were selected by an independent academic advisory committee.
1 ReferencesDavid Kent, M.D.
Tufts–New England Medical Center, Boston, MA 021111
Ovbiagele B ,Saver JL ,Bang H , et al. Statin treatment and adherence to national cholesterol guidelines after ischemic stroke. Neurology 2006;66:1164-1170
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
JB Warren. (2008) Cholesterol—When Is Lower Better?. Clinical Pharmacology & Therapeutics 83:5, 777-780
CrossRef2
Luis Castilla Guerra, María del Carmen Fernández Moreno, José Manuel López Chozas, María Dolores Jiménez Hernández. (2008) Statins in stroke prevention: What an internist should know. European Journal of Internal Medicine 19:1, 8-14
CrossRef
