ROSIGLITAZONE AND CARDIOVASCULAR OUTCOMES Table3.(Continued.) Study Rosiglitazone Group Control Group Death from ad a number number AVA10019 394 124 0 0 DREAM 2635 12 2634 10 ADOPT 1456 27 2895 Total 39 cardiovascular cause sure of such patients to rosiglitazone is wide spread.the oublic health imnact ofan increase in fined according to the comparator drug.Similar cardiovascular risk could be substantial if our results were obtained when the analysis exclud- data are borne out by further analysis and the ed trials with an active comparator group.The results of larger controlled trials. rogeneity for myocardia Although we did not have access to the on an om carc A mated odds ratios in all cases were greater than for both of these end points suggests that ob- 1.0,suggesting that observed adverse effects dur-served adverse effects associated with rosiglita ing rosiglitazone treatment were not unique to zone were probably not due to chance alone any specific comp rator regimen This meta-anal ded a group of trials tha on (2 405 ar milar to the W2s11895%CL,0.89to1.55:P=0.24 sis.Thus,in susceptible patients rosiglitaz therapy may be capable of provoking myocardial DIscussion infarction or death from cardiovascular causes after relatively short-term exposure.In contrast ong-term therapies that improve diovascula er an tcomes,suc as stat and anti se in the risk of r and Notably the estimates fo the odds ratios for with an increase in the risk of death from cardio mvocardial infarction and death from cardiovas vascular causes that was of borderline signifi- cular causes appear elevated for rosiglitazone in suggests that the increased risk as erapies (Table 5). cated with s not a func The r app. rent increas protecti dial i arctio cess to trialt esults fr ain.One es not on patient-level source data furthermore be the adverse effect of the drug on serum lipids results are based on a relatively small number o The FDA-approved rosiglitazone product label ting in odds ratios that reports a mean increase in low-density lipopro tein f o%am None hel ,0U ngs are we mg da with diah es ies and lipid-l ng trials l ervat els of N ENGLJ MED 356:24 WWW.NEJM.ORG JUNE 14,200 2467 The New England Journal of Medicine Rosiglitazone and Cardiovascular Outcomes n engl j med 356;24 www.nejm.org june 14, 2007 2467 farction and death from cardiovascular causes associated with rosiglitazone for subgroups de￾fined according to the comparator drug. Similar results were obtained when the analysis exclud￾ed trials with an active comparator group. The heterogeneity P values were 0.53 for myocardial infarction and 0.68 for death from cardiovascu￾lar causes across subgroups. As compared with placebo or other antidiabetic regimens, the esti￾mated odds ratios in all cases were greater than 1.0, suggesting that observed adverse effects dur￾ing rosiglitazone treatment were not unique to any specific comparator regimen. In an analysis that was not prespecified, we also studied the effects of rosiglitazone on death from any cause. The odds ratio for death from any cause was 1.18 (95% CI, 0.89 to 1.55; P=0.24). Discussion Our data show that, as compared with placebo or with other antidiabetic regimens, treatment with rosig­litazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardio￾vascular causes that was of borderline signifi￾cance. The similar odds ratio for comparison with placebo suggests that the increased risk as￾sociated with rosiglitazone was not a function of the protective effects of active comparator drugs. However, these findings are based on limited ac￾cess to trial results from publicly available sourc￾es, not on patient-level source data. Furthermore, results are based on a relatively small number of events, resulting in odds ratios that could be af￾fected by small changes in the classification of events. Nonetheless, our findings are worrisome because of the high incidence of cardiovascular events in patients with diabetes.4 Because expo￾sure of such patients to rosiglitazone is wide￾spread, the public health impact of an increase in cardiovascular risk could be substantial if our data are borne out by further analysis and the results of larger controlled trials. Although we did not have access to the source data to construct a composite outcome that in￾cluded myocardial infarction or death from car￾diovascular causes, the increase in the odds ratios for both of these end points suggests that ob￾served adverse effects associated with rosiglita￾zone were probably not due to chance alone. This meta-analysis included a group of trials that were of relatively short duration (24 to 52 weeks). The odds ratio for these shorter-term trials was similar to the overall results of the meta-analy￾sis. Thus, in susceptible patients, rosiglitazone therapy may be capable of provoking myocardial infarction or death from cardiovascular causes after relatively short-term exposure. In contrast, long-term therapies that improve cardiovascular outcomes, such as statins and antihypertensive drugs, often take several years to provide benefits. Notably, the estimates for the odds ratios for myocardial infarction and death from cardiovas￾cular causes appear elevated for rosiglitazone in comparison with placebo or other commonly pre￾scribed antidiabetic therapies (Table 5). The mechanism for the apparent increase in myocardial infarction and death from cardiovas￾cular causes associated with rosiglitazone remains uncertain. One potential contributing factor may be the adverse effect of the drug on serum lipids. The FDA-approved rosiglitazone product label reports a mean increase in low-density lipopro￾tein (LDL) cholesterol of 18.6% among patients treated for 26 weeks with an 8-mg daily dose, as compared with placebo.25 In observational stud￾ies and lipid-lowering trials, elevated levels of Table 3. (Continued.) Study Rosiglitazone Group Control Group No. of Patients Myocardial Infarction Death from Cardiovascular Cause No. of Patients Myocardial Infarction Death from Cardiovascular Cause number number AVA100193 394 1 1 124 0 0 DREAM 2635 15 12 2634 9 10 ADOPT 1456 27 2 2895 41 5 Total 86 39 72 22 The New England Journal of Medicine Downloaded from nejm.org on February 5, 2016. For personal use only. No other uses without permission. Copyright © 2007 Massachusetts Medical Society. All rights reserved