Response to Letter by Squizzato et al
We would like to thank Dr Squizzato and colleagues for their interest in our article.1 In their letter the authors state that our article contains some “methodological limitations that do not allow to confirm the results of the SPARCL study and do not help physicians to identify patients who could most benefit from statin therapy.”
First, the purpose of our study was not to identify patients who could benefit most from statin therapy, but to investigate the effect of statin treatment on the occurrence of ischemic and hemorrhagic strokes in patients with a history of cerebrovascular disease. Our systematic review clearly shows that in patients with a history of cerebrovascular disease statins decrease the risk of future strokes, but that this beneficial effect is relatively small as a result of an associated increased risk of hemorrhagic stroke.
Second, Dr Squizzato and colleagues put forward that a possible limitation of our study is that some included trials did not specify the type of previous stroke. However, this is not a limitation for our main analysis on overall stroke risk, because the SPARCL study also included all types of stroke (ischemic stroke, transient ischemic attack, or hemorrhagic stroke) as an entry event. Moreover, the SPARCL study was only powered to detect a decreased risk of future stroke in patients with all different kinds of cerebrovascular disease histories.2 In other words, even SPARCL was not powered to identify patients with specific subtypes of stroke who could benefit most from statin therapy.
We agree with the authors that 3 trials (LIPID, CARE, and HPS) unfortunately do not provide detailed baseline characteristics of (sub)groups of patients randomized to statin treatment and placebo. However, because all trials included in our systematic review are large randomized placebo-controlled trials, differences in baseline characteristics between groups are unlikely. Moreover, because the results of these studies are in agreement with the SPARCL study, it is unlikely that major differences in baseline characteristics have occurred.
Finally, the authors state that the use of relative risks is not applicable in randomized controlled trials with long-term follow-up, and that hazard ratios should be used instead. In our opinion, time-to-event was not of special interest. Our focus was on the total prevention of stroke during follow-up as a result of statin treatment. Therefore, we decided not to use survival type data, but to extract data on number of patients with events during follow-up as described in tables in the included articles and to use relative risks estimates.
We conclude that the results of our systematic review are of interest to physicians who treat stroke patients. We agree with Dr Squizzato and coauthors that future studies should investigate the effect of statins in different subtypes of stroke, with a special interest in the risk of hemorrhagic stroke. Subgroup analyses of SPARCL recently showed that there is a statistically significant increased risk of hemorrhagic stroke not only in patients with a history of hemorrhagic stroke, but also in patients with lacunar stroke (small vessel disease).3 Especially in patients with these stroke subtypes, it should therefore be investigated whether the increased hemorrhagic stroke risk outweighs the decreased risk on ischemic stroke, as measured on disability and mortality outcome scales.
Vergouwen MDI, De Haan RJ, Vermeulen M, Roos YBWEM. Statin treatment and the occurence of hemorrhagic stroke in patients with a history of cerebrovascular disease. Stroke. 2008; 39: 497–502.
Amarenco P, Bogousslavsky J, Callahan AS, Goldstein L, Hennerici M, Sillesen H, Welch MA, Zivin J; SPARCL Investigators. Design and baseline characteristics of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) study. Cerebrovasc Dis. 2003; 16: 389–395.
Goldstein LB, Amarenco P, Szarek M, Callahan A, Hennerici M, Sillesen H, Zivin JA, Welch KM; SPARCL Investigators. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study. Neurology. 2008; in press.