Rosiglitazone Is Associated with Mortality in Chronic Hemodialysis Patients

Abstract

Recent studies have associated rosiglitazone, a thiazolidinedione drug, with adverse cardiovascular outcomes in the general population with diabetes. Using data from the Dialysis Outcomes and Practice Patterns Study in the United States, we examined cardiovascular hospitalization and mortality associated with prescription of rosiglitazone, compared with other oral hypoglycemic agents, among 2393 long-term hemodialysis patients who were followed for a median of 1.1 yr. We assessed mortality risk using Cox models in patient-level and dialysis facility-level analyses that used the facility proportion of patients on rosiglitazone as the predictor (instrumental variable approach) and adjusted the models for demographics, comorbid conditions, laboratory values, and achieved dialysis dosage. Compared with patients prescribed other oral hypoglycemic agents, patients prescribed rosiglitazone had significantly higher all-cause (hazard ratio [HR] 1.38; 95% confidence interval [CI] 1.05 to 1.82) and cardiovascular (HR 1.59; 95% CI 1.14 to 2.22) mortality, and their adjusted HR for hospitalization with myocardial infarction was 3.5-fold higher (P ϭ 0.02). We did not observe similar associations in a secondary analysis evaluating pioglitazone. By the instrumental variable approach, facilities with more than the median adjusted percentage (6.2%) of patients who had diabetes and were prescribed rosiglitazone had significantly higher all-cause mortality (HR 1.36; 95% CI 1.15 to 1.62) and cardiovascular mortality (HR 1.42; 95% CI 1.07 to 1.88) than facilities with less than the median expected percentage prescribed rosiglitazone. Our practice-based findings suggest significant associations of rosiglitazone use with higher cardiovascular and all-cause mortality among hemodialysis patients with diabetes. 20: 109420: -110120: , 200920: . doi: 10.1681 Thiazolidinedione (TZD) use is increasing in patients with diabetes. For example, its reported use rose from 7.2% in 1998 to 16.2% in 2001 in a population of Medicare patients who were hospitalized for diabetes 1 ; however, concern exists that the TZD rosiglitazone may increase the risk for adverse outcomes. A meta-analysis of 42 randomized, controlled trials comparing rosiglitazone with other oral hypoglycemic agents (OHAs), insulin, or placebo in the general population suggested a significantly higher risk for myocardial infarction (MI) and a borderline increased risk for death from cardiovascular causes. 2 Another meta-analysis of four randomized, controlled clinical trials demonstrated a 42% significantly increased risk for MI and a twofold significantly increased risk for congestive heart failure (CHF). 3 Whether rosiglitazone results in adverse clinical outcomes remains uncertain, given the limitations of meta-analysis design 2 and literature demonstrating rosiglitazone's favorable influence on glycemic control. 4,5 J Am Soc Nephrol

Instrumental Variable Analysis in Epidemiologic Studies: An Overview of the Estimation Methods

“…Also in case of these outcome variables, IV analysis has been applied with two-stage method. In that case, the second-stage model could be a Cox proportional hazards model [78][79][80]. However, Brookhart et al [3] stated that this approach for IV analysis is not motivated by a theoretical model and, therefore, parameters that are obtained from this approach may not be causally interpretable.…”

“…However, Brookhart et al [3] stated that this approach for IV analysis is not motivated by a theoretical model and, therefore, parameters that are obtained from this approach may not be causally interpretable. Examples of this approach are a study of the effect of rosiglitazone on (time to) cardiovascular hospitalization and all-cause mortality using facility-prescribing patterns as an IV [78], and a study of the effect of adjuvant chemotherapy on (time to) breast cancer recurrence using physician preference as an IV [79].…”

“…There is a rule of thumb that if the F-statistic value is greater than 10, the first assumption holds [13,96,97]. Other measures for the strength of the association between IVand exposure include the first-stage regression coefficient of the IV [50,98] or the R 2 of a linear first-stage model [15,78,83], the odds ratio [6,93], or pseudo-R-squared of the first-stage model [76]. When the correlation between IVand exposure is not strong enough, IVanalysis is likely to be biased (weak IV bias, which increases with the weakness of the IV).…”

Management of type 2 Diabetes in patients with Chronic Kidney Disease

“…Thiazoledinedione use has reduced nowadays with reports of cardiovascular mortality with rosiglitazone (14) and possibly bladder carcinoma with pioglitazone, although the latter is an unproven association (15). Both these drugs do not accumulate in patients with CKD, but they can cause edema and heart failure (16).…”

New Onset Diabetes After Solid Organ Transplantation

“…Table 3 summarizes the mechanisms of action and potential advantages and disadvantages of different classes of oral agents. It is noteworthy that the results of the Dialysis Outcomes and Practice Patterns Study (DOPPS) demonstrated that in long-term hemodialysis patients rosiglitazone was associated with a significantly higher all-cause (hazard ration 1.59) and cardiovascular mortality and a 3.5 fold increase of hospitalizations due to myocardial infarction (Ramirez et al, 2009). In contrast to the DOPPS study results, in an analysis of the national cohort study consisting of more than 5,000 dialysis patients with type 2 diabetes Brunelli et al observed a lower incidence of all-cause mortality in patients not on insulin vs. insulin requiring diabetic patients (Brunelli et al, 2009).…”