Rosiglitazone evaluated for cardiovascular outcomes: An interim analysis of the RECORD trial
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Rosiglitazone Evaluated for Cardiovascular Outcomes: An Interim Analysis of the RECORD Trial Home PD, Pocock SJ, Beck-Nielsen H, et al.: Rosiglitazone evaluated for cardiac outcomes--an interim analysis. N Engl J Med 2007, 357:28–38. Rating: •• Of major importance. Introduction: Rosiglitazone (Avandia, GlaxoSmithKline, Philadelphia, PA) is a peroxisome proliferator activator- H receptor agonist that improves insulin sensitivity and lowers blood sugar. A recent meta-analysis of rosiglitazone showed that it is associated with a significant increased risk of myocardial infarction and a borderline significant increased risk of death from cardiovascular disease [1]. This prompted investigators of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial to conduct an unplanned interim analysis of the trial. Their findings are the focus of this report. Aims: RECORD is a noninferiority study designed to compare cardiovascular outcomes in patients treated with rosiglitazone plus metformin or sulfonylurea (rosiglitazone group) with outcomes in the metformin plus sulfonylurea (control) group. Methods: This study is a randomized, multicenter, openlabel noninferiority trial. The interim analysis included 4447 patients with type 2 diabetes mellitus, including 2220 patients in the rosiglitazone group and 2227 in the control group. The target hemoglobin A1c level was 7% or less. The starting dose of rosiglitazone was 4 mg/d. The starting doses of metformin and sulfonylurea were determined according to practice. If the hemoglobin A1c level exceeded 7% after 8 weeks of treatment, the drug doses were increased to a maximum of 8 mg of rosiglitazone, 2550 mg of metformin, 15 mg of glyburide, 240 mg of gliclazide, and 4 mg of glimepiride. If the hemoglobin A1c exceeded 8.5% while patients were receiving the maximum tolerated dose, a third agent was added for patients in the rosiglitazone group or insulin was initiated for patients in the control group. If patients receiving triple therapy in the rosiglitazone group had hemoglobin A1c levels of more than 8.5%, insulin was started and rosiglitazone was stopped. Results: The initial study design was for 6 years. At the time of the interim analysis, the mean follow-up was 3.75
years. Therefore, the interim analysis had limited statistical power to detect treatment differences. A total of 217 patients in the rosiglitazone group and 202 patients in the control group had the adjudicated primary end point (HR, 1.08; 95% CI, 0.89–1.31). The primary end point was hospitalization for cardiovascular events (acute myocardial infarction, congestive heart failure, stroke, unstable angina, transient ischemic attack, unexplained cardiovascular revascularization, amputation of extremities, or any other definite cardiovascular events) or death from cardiovascular causes (heart failure, acute myocardial infarction, sudden death, and death caused by acute vascular events including stroke). After the inclusion of end points pending adjudication, the HR was 1.11
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