Effect of Rosiglitazone on the Risk of Myocardial Infarction And Death from Cardiovascular Causes Alternative Interpretations of the Evidence George A. Diamond, MD; Sanjay Kaul, MD Division of Cardiology Cedars-Sinai Medical Center Los Angeles, California No conflicts to disclose

The N E W E N G L A N D J O U R N A L of M E D I C I N E ESTABLISHED IN 1812 JUNE 14, 2007 VOL. 356 NO. 24 Effect of Rosiglitazone on the Risk of Myocardial Infarction And Death from Cardiovascular Causes Steven E. Nissen, M.D., and Kathy Wolski, M.P.H. Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death…that had borderline significance. CONCLUSIONS

Rosiglitazone Control No Event Rosiglitazone and Cardiovascular Events 27,833 Patients 158 Events 42 Trials 15, ,205 MI Myocardial Infarction 0.59% 0.55% Event Rate

Rosiglitazone and Cardiovascular Events Myocardial Infarction Rosiglitazone Control MI No Event Patients Zero event trials 4 4 EXCLUDED N=38

Rosiglitazone and Cardiovascular Events Cardiovascular Death No Event Death Rosiglitazone Control Patients N=23 Zero event trials EXCLUDED

Rosiglitazone and Cardiovascular Events Peto Meta-Analysis Odds Ratio 1 Myocardial Infarction Cardiovascular Death 1.43 ( ) p=0.03 N=38 Odds Ratio 1.64 ( ) p=0.06 N=23

Rosiglitazone and Cardiovascular Events Myocardial Infarction Rosiglitazone Control MI No Event Patients Zero event cells 6 20 INCLUDED

Rosiglitazone and Cardiovascular Events Cardiovascular Death No Event Death Rosiglitazone Control Patients Zero event cells 2 15 INCLUDED

Rosiglitazone and Cardiovascular Events Impact of Zero Events on Peto’s Odds Ratio ZeroO i -E i MIDeath Control  2015 Treatment  6 2

Rosiglitazone and Cardiovascular Events Cardiovascular Death No Event Death Rosiglitazone Control Patients

Rosiglitazone and Cardiovascular Events Continuity Correction Rosiglitazone Control k=1/2 k~1/N No Event Death Patients Sweeting et al, What to add to nothing? Stat Med 2006;23:

Rosiglitazone and Cardiovascular Events Meta-Analytic Sensitivity Peto ( - ) Inverse variance 1/N ( - ) Inverse variance 1/2 ( - ) Mantel-Haenszel 1/N ( - ) Mantel-Haenszel 1/2 ( - ) Mantel-Haenszel 1/N (+) Mantel-Haenszel 1/2 (+) Uniform Bayes 1/N (+) Uniform Bayes 1/2 (+) Myocardial Infarction Cardiovascular Death Odds Ratio *

Rosiglitazone and Cardiovascular Events Relative Risk Threshold Uncorrected Corrected Cardiovascular Death Magnitude of Harm Relative Risk Threshold Uncorrected Corrected Myocardial Infarction Probability of Harm

Rosiglitazone and Cardiovascular Events Limitations of the Published Meta-Analysis Not designed to assess outcomes No central adjudication of events No standardized definitions of events Limited sample size Short term duration No patient level data No sensitivity analysis No continuity correction

Rosiglitazone and Cardiovascular Events Key Questions Regarding the Published Meta-Analysis Rosiglitazone and Cardiovascular Events Key Questions Regarding the Published Meta-Analysis How robust is the meta-analysis? - Analytical methodology - Quality of the data What is the impact of heterogeneity on risk estimates? Are the risk estimates consistent with other studies?

Screened Phase 2, 3, 4 trials (N = 116) Rosiglitazone and Cardiovascular Events Flow Diagram of Inclusion/Exclusion Rosiglitazone and Cardiovascular Events Flow Diagram of Inclusion/Exclusion Retrieved for detailed evaluation (N = 48) Excluded on basis of: Lack of randomized comparator group <24 wks of drug exposure (N = 68) Included for meta-analysis (N = 42) Excluded on basis of: Lack of reported cardiovascular events (N = 6) Published literature Trial registries FDA summary report

Prespecified exclusion criteria Six trials omitted after taking a “peek” at outcomes (“no events”) Omission of these trials may potentially impact risk estimates Peer-reviewed data Included published (N=13) and unpublished (N=29) studies Uncertainty regarding quality due to lack of scientific peer review Patient-level data not available More robust time-to-event analysis not possible Endpoints None designed for CV endpoints; adjudication not standardized Potential for misclassification and ascertainment error Rosiglitazone and Cardiovascular Events Quality of Meta-Analysis Rosiglitazone and Cardiovascular Events Quality of Meta-Analysis

Pooling justified due to lack of statistical heterogeneity Cochran’s Q test of heterogeneity Limited ability to detect variability across studies with sparse data (low statistical power) Even if studies are statistically homogeneous there may be clinical heterogeneity in study design and population Rosiglitazone and Cardiovascular Events Is There Heterogeneity? Rosiglitazone and Cardiovascular Events Is There Heterogeneity?

Without diabetes ( N = 3) Alzheimer's (N = 1) Psoriasis (N = 2) Meta-analysis N = 42 With contraindication (CHF) N = 1 Without contraindication N = 38 With Diabetes N = 39 Rosiglitazone and Cardiovascular Events Clinical Heterogeneity in Patient Populations Rosiglitazone and Cardiovascular Events Clinical Heterogeneity in Patient Populations

Small trials (N= ) Double-blind + open-label Follow-up (24-52 wks) N = 40 trials Meta-analysis N = 42 trials DREAM (N=5269) Impaired glucose tolerance ADOPT (N=4351) Newly diagnosed DM (<3 yrs) Large trials (N>4350) Double-blind Follow-up (3-5 yrs) N = 2 trials Rosiglitazone and Cardiovascular Events Clinical Heterogeneity in Trial Design Rosiglitazone and Cardiovascular Events Clinical Heterogeneity in Trial Design

RSG vs placebo N = 10 trials Meta-analysis N = 42 trials Head-to-head monotherapy (N = 4) RSG vs Sulfonylurea (N = 3) RSG vs Metformin/Sulfonylurea (N = 1) Add-on RSG vs placebo to Run-in Rx (N = 28) Metformin (N = 10) Sulfonylurea (N = 12) Insulin (N = 5) Usual care (N = 1) RSG vs standard Rx N = 32 trials Rosiglitazone and Cardiovascular Events Clinical Heterogeneity in Treatment Groups Rosiglitazone and Cardiovascular Events Clinical Heterogeneity in Treatment Groups

Absence of statistical heterogeneity does not imply absence of clinical heterogeneity Rosiglitazone and Cardiovascular Events Is There Heterogeneity? Rosiglitazone and Cardiovascular Events Is There Heterogeneity?

Myocardial Infarction Overall pooled data (N=26011) ADOPT (N=4351) DREAM (N=5269) Small trials combined (N=16391) Odds ratio Uncorrected (Peto) 1.45 ( ) 1.43 ( ) Odds ratio Corrected (MH/CC) 1.16 ( ) 1.28 ( ) Rosiglitazone and Cardiovascular Events Meta-Analytic Subgroups Rosiglitazone and Cardiovascular Events Meta-Analytic Subgroups

Cardiovascular Death Overall pooled data (N=20445) ADOPT (N=4351) DREAM (N=5269) Small trials combined (N=10825) Odds ratio Uncorrected (Peto) 2.40 ( ) 1.64 ( ) Odds ratio Corrected (MH/CC) 1.51 ( ) 1.33 ( ) Rosiglitazone and Cardiovascular Events Meta-Analytic Subgroups Rosiglitazone and Cardiovascular Events Meta-Analytic Subgroups

Myocardial Infarction Rosiglitazone and Cardiovascular Events Meta-Analytic Subgroups Rosiglitazone and Cardiovascular Events Meta-Analytic Subgroups Uncorrected (Peto) Odds Ratio Diabetes (-CHF) (N=38) RSG vs placebo (N=10) RSG vs antidiabetic Rx (N=32) RSG + SULF vs SULF (N=12) RSG + MET vs MET (N=10) Other diseases (N=4) RSG + INS vs INS (N=5) Corrected (MH/CC) Odds Ratio

Rosiglitazone and Cardiovascular Events Meta-Analytic Subgroups Rosiglitazone and Cardiovascular Events Meta-Analytic Subgroups Cardiovascular Death Corrected (MH/CC) Odds Ratio Uncorrected (Peto) Odds Ratio Diabetes (-CHF) (N=38) RSG vs placebo (N=10) RSG vs antidiabetic Rx (N=32) RSG + SULF vs SULF (N=12) RSG + MET vs MET (N=10) Other diseases (N=4) RSG + INS vs INS (N=5)

Rosiglitazone and Cardiovascular Events Are the Risk Estimates Consistent? Rosiglitazone and Cardiovascular Events Are the Risk Estimates Consistent? 0123 FDA (N=42 trials) IHD Balanced Cohort Study (N=33363) GSK ICT analysis (N=42 trials) Cochrane Review (N=18 trials) RECORD (N=4407) CVD/MI/Stroke IHD CVD/MI/Stroke MI CV death MI Odds or hazard ratio

Sensitive to meta-analytic method Sensitive to continuity correction Sensitive to subgroup analysis If present, magnitude of harm is small We need more data! Rosiglitazone and Cardiovascular Events Conclusions Rosiglitazone and Cardiovascular Events Conclusions