Effect of Rosiglitazone on the Risk of Myocardial Infarction And Death from Cardiovascular Causes...

The N E W E N G L A N DJ 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 InfarctionAnd 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

0

3 0 0 0

0

3 000

0

3 0 0 0

Rosiglitazone Control

No Event

Rosiglitazone and Cardiovascular Events

27,833 Patients 158 Events42 Trials

15,470

86 72

12,205

MI

Myocardial Infarction

0.59% 0.55% Event Rate

Rosiglitazone and Cardiovascular EventsMyocardial Infarction

3000

2000

1000

0

0

3 000

3 -D C o lu mn 1

3 -D C o lu mn 1

0

3 0 0 0

3 -D C o lu mn 1

Rosiglitazone Control

MI

No Event

Pat

ient

s

0

3 0 0 0

3 -D C o lu mn 1

Zero event trials 4 4 EXCLUDED

N=38

Rosiglitazone and Cardiovascular EventsCardiovascular Death

3000

2000

1000

0

0

3 000

3 -D C o lu mn 1

0

3 000

1

3 -D C o lu mn 1

0

3 0 0 0

3 -D C o lu mn 1

No Event

Death

Rosiglitazone Control

Pat

ient

s

N=23

Zero event trials 19 19 EXCLUDED

Rosiglitazone and Cardiovascular EventsPeto Meta-Analysis

0.0001 0.01 1 100 10000 0.001 0.1 10 1000

Odds Ratio

1

Myocardial Infarction Cardiovascular Death

1.43 (1.03-1.98)p=0.03N=38

Odds Ratio 1.64 (0.98-2.14)

p=0.06N=23

Rosiglitazone and Cardiovascular EventsMyocardial Infarction

3000

2000

1000

0

0

3 000

3 -D C o lu mn 1

3 -D C o lu mn 1

0

3 0 0 0

3 -D C o lu mn 1

Rosiglitazone Control

MI

No Event

Pat

ient

s

0

3 0 0 0

3 -D C o lu mn 1

Zero event cells 6 20 INCLUDED

Rosiglitazone and Cardiovascular EventsCardiovascular Death

3000

2000

1000

0

0

3 000

3 -D C o lu mn 1

0

3 000

1

3 -D C o lu mn 1

0

3 0 0 0

3 -D C o lu mn 1

No Event

Death

Rosiglitazone Control

Pat

ient

s

Zero event cells 2 15 INCLUDED

Rosiglitazone and Cardiovascular EventsImpact of Zero Events on Peto’s Odds Ratio

k

i

k

iiiiPeto VEOOR

1 1

/)(exp

Zero Oi-Ei MI DeathControl 20 15

Treatment 6 2

Rosiglitazone and Cardiovascular EventsCardiovascular Death

3000

2000

1000

0

0

3 000

3 -D C o lu mn 1

0

3 000

1

3 -D C o lu mn 1

No Event

Death

Rosiglitazone Control

Pat

ient

s

0

3 0 0 0

3 -D C o lu mn 1

Rosiglitazone and Cardiovascular EventsContinuity Correction

3000

2000

1000

0

0

3 000

3 -D C o lu mn 1

0

3 000

1

3 -D C o lu mn 1

Rosiglitazone Control

k=1/2k~1/N

No Event

Death

Pat

ient

s

0

3 000

3 -D C o lu mn 1

Sweeting et al, What to add to nothing? Stat Med 2006;23:1351-75.

Rosiglitazone and Cardiovascular EventsMeta-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 Odds Ratio0.5 1.0 1.5 2.0 2.5 3.0 0.5 1.0 1.5 2.0 2.5 3.0

*

Rosiglitazone and Cardiovascular Events

Relative Risk Threshold

Uncorrected

Corrected

Cardiovascular Death

Magnitude of Harm

0 .0

0 .2

0 .4

0 .6

0 .8

1 .0

1 1 0 1 0 0

Relative Risk Threshold

Uncorrected

Corrected

Myocardial Infarction

Prob

abili

ty o

f Har

m

Rosiglitazone and Cardiovascular EventsLimitations 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

• 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

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) studiesUncertainty regarding quality due to lack of scientific peer review

• Patient-level data not availableMore 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

• 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?

Without diabetes (N = 3)• Alzheimer's (N = 1)• Psoriasis (N = 2)

Meta-analysisN = 42

With contraindication (CHF)N = 1

Without contraindication

N = 38

With DiabetesN = 39

Rosiglitazone and Cardiovascular Events

Clinical Heterogeneity in Patient Populations

Small trials (N=77-1549)Double-blind + open-label

Follow-up (24-52 wks)N = 40 trials

Meta-analysisN = 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

RSG vs placeboN = 10 trials

Meta-analysisN = 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 RxN = 32 trials

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?

Myocardial Infarction

Overall pooled data (N=26011)

ADOPT (N=4351)

DREAM (N=5269)

Small trials combined(N=16391)

0 1 2 3 4Odds ratio

Uncorrected (Peto)

1.45 (0.88-2.39)

1.43 (1.03-1.98)

0 1 2 3 4Odds ratio

Corrected (MH/CC)

1.16 (0.76-1.78)

1.28 (0.95-1.72)

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 ratio0 1 2 3 4 5

Uncorrected (Peto)

2.40 (1.17-4.91)

1.64 (0.98-2.74)

Odds ratio0 1 2 3 4 5

Corrected (MH/CC)

1.51 (0.82-2.78)

1.33 (0.83-2.13)

Rosiglitazone and Cardiovascular Events

Meta-Analytic Subgroups

Myocardial Infarction

Rosiglitazone and Cardiovascular Events

Meta-Analytic SubgroupsUncorrected (Peto)

Odds Ratio 0 1 2 3 4 5

1.37

1.52

1.40

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)

1.23

1.49

2.69

3.49

Other diseases (N=4)

RSG + INS vs INS (N=5)

Corrected (MH/CC)

0 1 2 3 4 5

Odds Ratio

1.25

1.31

1.27

1.11

1.05

1.90

2.77

Rosiglitazone and Cardiovascular Events

Meta-Analytic SubgroupsCardiovascular Death

0 2 4 6 8 10

Corrected (MH/CC)

Odds Ratio

1.34

1.24

1.42

1.67

1.34

1.31

1.92

0 2 4 6 8 10

Uncorrected (Peto)

Odds Ratio

1.58

1.50

1.79

2.43

1.75

2.10

5.37

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?

0 1 2 3

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

IHDCVD/MI/Stroke

MICV death

MI

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