Letter by Simard et al Regarding Article, “Sulfonylurea Use Before Stroke Does Not Influence Outcome”
To the Editor:
Favilla and colleagues1 address the use of sulfonylureas in diabetic patients with stroke. The article deals with 2 important interrelated questions: first, a “safety question”—does prior use of sulfonylureas worsen stroke presentation or outcome? Second, an “efficacy question”—does prior use plus continued use of sulfonylureas during hospitalization for stroke favorably influence outcome? Given extensive preclinical evidence for the beneficial role of sulfonylureas in rodent models of stroke, and 2 prior retrospective analyses suggesting beneficial effects in patients with stroke when sulfonylureas are continued during hospitalization, it is important to assess the negative results from Favilla et al as it relates to the “efficacy question.” Important methodological considerations raise serious concerns about their conclusions.
The “efficacy question” was studied previously by comparing diabetics who were on and continued on a sulfonylurea during hospitalization with diabetics not on a sulfonylurea.2,3 In both studies, patients in the sulfonylurea group were more likely to enjoy significant neurological improvement at discharge compared with patients not on sulfonylurea. In the Kunte et al2 study, patients with nonlacunar strokes were more likely to benefit than those with lacunar strokes.
In the Favilla et al study, the “efficacy question” was examined by comparing diabetics who were on and continued on a sulfonylurea during hospitalization with diabetics who were on but stopped sulfonylurea after admission. Their analysis of this question is covered in 1 brief paragraph. Because information on daily in-hospital medications may not be available for all patients in the Virtual International Stroke Trials Archive (VISTA) database, we do not know how many of the “control subjects” were also on sulfonylurea. Most glaring, baseline characteristics of the 2 groups are not provided, making it impossible to independently verify that the groups were appropriately balanced in terms of the key variables at admission that affect outcome, including those in the VISTA database and those such as stroke subtype criteria that are not included in VISTA. Also, it is conceivable that the heterogeneity and disparity in size of the “control” group gave rise to such a large variance in outcome that a meaningful comparison between the 2 groups was not possible, even if corrective measures were applied.
The SUR1-regulated NC(Ca-ATP) channel, the target of sulfonylureas in cerebral ischemia, is not normally expressed but is transcriptionally upregulated ≥3 hours after an ischemic insult and remains upregulated for several days. If the target molecule is not present, the drug will not be beneficial, but when the target does appear, adequate, sustained drug levels are required to block it for the entire time that it is present.
Serious omissions in the Favilla analysis reflect the fact that the VISTA database lacks critical information. We appreciate the authors acknowledging the limitations of the VISTA data set, but in the specific case of sulfonylureas in ischemic stroke, the limitations outweigh its ability to generate meaningful conclusions. The absence of critical data cannot be used to condone unjustifiable conclusions that are unjustifiable precisely because of the absence of those data. The Favilla analysis is not sufficiently rigorous on the “efficacy question,” and the message conveyed is misleading. Moreover, that message is made egregiously worse by the running title of the article: “Sulfonylureas Do Not Influence Stroke Outcome,” which is not validated in a scientific manner.
The important question of the use of sulfonylurea use after stroke will require a prospective clinical trial of sulfonylurea in nondiabetics with stroke.
J. Marc Simard, MD, PhD
University of Maryland School of Medicine
Thomas A. Kent, MD
Baylor College of Medicine
Hagen Kunte, MD
Klinik und Poliklinik für Neurologie
Sources of Funding
J.M.S. is supported by National Institutes of Health grants (HL082517, NS061808, NS060801).
J.M.S. holds a patent (7,285,574) and is on the scientific advisory board and holds shares in Remedy Pharmaceuticals.
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- © 2011 American Heart Association, Inc.
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