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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

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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

TheNEW ENGLAND

JOURNALofMEDICINE

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.

CONCLUSIONS

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.


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

Rosiglitazone and Cardiovascular Events

Myocardial Infarction

27,833 Patients

158 Events

42 Trials

15,470

12,205

No Event

86

72

MI

Rosiglitazone Control

0.59% 0.55% Event Rate


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

3000

2000

1000

0

Patients

No Event

N=38

MI

Rosiglitazone Control

Zero event trials 4 4 EXCLUDED

Rosiglitazone and Cardiovascular Events

Myocardial Infarction


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

3000

2000

1000

0

Patients

No Event

N=23

Death

Rosiglitazone Control

Zero event trials 19 19 EXCLUDED

Rosiglitazone and Cardiovascular Events

Cardiovascular Death


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

Rosiglitazone and Cardiovascular Events

Peto Meta-Analysis

Myocardial Infarction Cardiovascular Death

1

Odds Ratio

Odds Ratio

1.43 (1.03-1.98)

p=0.03

N=38

1.64 (0.98-2.14)

p=0.06

N=23


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

3000

2000

1000

0

Patients

No Event

MI

Rosiglitazone Control

Zero event cells 6 20 INCLUDED

Rosiglitazone and Cardiovascular Events

Myocardial Infarction


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

3000

2000

1000

0

Patients

No Event

Death

Rosiglitazone Control

Zero event cells 2 15 INCLUDED

Rosiglitazone and Cardiovascular Events

Cardiovascular Death


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

Rosiglitazone and Cardiovascular Events

Impact of Zero Events on Peto’s Odds Ratio


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

3000

2000

1000

0

Patients

No Event

Death

Rosiglitazone Control

Rosiglitazone and Cardiovascular Events

Cardiovascular Death


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

3000

2000

1000

0

Patients

No Event

Death

k=1/2

k~1/N

Rosiglitazone Control

Rosiglitazone and Cardiovascular Events

Continuity Correction

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


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

*

Rosiglitazone and Cardiovascular Events

Meta-Analytic Sensitivity

Myocardial Infarction Cardiovascular Death

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 (+)

0.5 1.0 1.5 2.0 2.5 3.0

0.5 1.0 1.5 2.0 2.5 3.0

Odds Ratio Odds Ratio


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

Rosiglitazone and Cardiovascular Events

Magnitude of Harm

Myocardial Infarction

Cardiovascular Death

Uncorrected

Uncorrected

Probability of Harm

Corrected

Corrected

Relative Risk Threshold

Relative Risk Threshold


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

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


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

Effect of Rosiglitazone on the Risk of Myocardial Infarction And Death from CardiovascularCausesAlternative Interpretations of the Evidence

Sanjay Kaul, MD; George A. Diamond, 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

Rosiglitazone and Cardiovascular Events

Key Questions Regarding the Published Meta-Analysis

  • Are the risk estimates robust?

  • Is there heterogeneity?

  • - What is the impact of continuity corrections on clinically relevant subgroups?

  • Are the risk estimates consistent with other studies?


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

Rosiglitazone and Cardiovascular Events

Is There Heterogeneity?

  • Pooling justified due to lack of statistical heterogeneity

  • Cochran’s Q test of heterogeneityLimited 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


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

Meta-analysis

N = 42

  • Without diabetes (N = 3)

  • Alzheimer's (N = 1)

  • Psoriasis (N = 2)

With Diabetes

N = 39

With contraindication

(CHF)N = 1

Without contraindication

N = 38

Rosiglitazone and Cardiovascular Events

Clinical Heterogeneity in Patient Populations


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

Meta-analysis

N = 42 trials

Small trials (N=77-1549)

Double-blind + open-label Follow-up (24-52 wks)

N = 40 trials

Large trials (N>4350)

Double-blind

Follow-up (3-5 yrs)

N = 2 trials

DREAM (N=5269)

Impaired glucose tolerance

ADOPT (N=4351)

Newly diagnosed DM (<3 yrs)

Rosiglitazone and Cardiovascular Events

Clinical Heterogeneity in Trial Design


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

Meta-analysis

N = 42 trials

RSG vs placebo

N = 10 trials

RSG vs standard Rx

N = 32 trials

  • Add-on RSG vs placebo to

  • Run-in Rx (N = 28)

  • Metformin (N = 10)

  • Sulfonylurea (N = 12)

  • Insulin (N = 5)

  • Usual care (N = 1)

  • Head-to-head monotherapy (N = 4)

  • RSG vs Sulfonylurea (N = 3)

  • RSG vs Metformin/Sulfonylurea (N = 1)

Rosiglitazone and Cardiovascular Events

Clinical Heterogeneity in Treatment Groups


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

Rosiglitazone and Cardiovascular Events

Is There Heterogeneity?

Absence of statistical heterogeneity does not imply absence of clinical heterogeneity


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

Uncorrected (Peto)

Corrected (MH/CC)

1.45 (0.88-2.39)

Small trials combined

(N=16391)

1.16 (0.76-1.78)

DREAM (N=5269)

ADOPT (N=4351)

1.43 (1.03-1.98)

1.28 (0.95-1.72)

Overall pooled data

(N=26011)

0

1

2

3

4

0

1

2

3

4

Odds ratio

Odds ratio

Rosiglitazone and Cardiovascular Events

Meta-Analytic Subgroups

Myocardial Infarction


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

Uncorrected (Peto)

Corrected (MH/CC)

Small trials combined

(N=10825)

1.51 (0.82-2.78)

2.40 (1.17-4.91)

DREAM (N=5269)

ADOPT (N=4351)

1.33 (0.83-2.13)

1.64 (0.98-2.74)

Overall pooled data

(N=20445)

0

1

2

3

4

5

0

1

2

3

4

5

Odds ratio

Odds ratio

Rosiglitazone and Cardiovascular Events

Meta-Analytic Subgroups

Cardiovascular Death


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

Corrected (MH/CC)

Uncorrected (Peto)

1.25

1.37

Diabetes (-CHF) (N=38)

2.69

Other diseases (N=4)

1.90

RSG vs placebo (N=10)

1.31

1.52

RSG vs antidiabetic Rx (N=32)

1.27

1.40

RSG + SULF vs SULF (N=12)

1.23

1.11

RSG + MET vs MET (N=10)

1.49

1.05

3.49

2.77

RSG + INS vs INS (N=5)

0 1 2 3 4 5

0 1 2 3 4 5

Odds Ratio

Odds Ratio

Rosiglitazone and Cardiovascular Events

Meta-Analytic Subgroups

MyocardialInfarction


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

Corrected (MH/CC)

Uncorrected (Peto)

Diabetes (-CHF) (N=38)

1.34

1.58

Other diseases (N=4)

1.31

2.10

RSG vs placebo (N=10)

1.24

1.50

1.42

RSG vs antidiabetic Rx (N=32)

1.79

1.67

RSG + SULF vs SULF (N=12)

2.43

RSG + MET vs MET (N=10)

1.34

1.75

1.92

RSG + INS vs INS (N=5)

5.37

0 2 4 6 8 10

0 2 4 6 8 10

Odds Ratio

Odds Ratio

Rosiglitazone and Cardiovascular Events

Meta-Analytic Subgroups

Cardiovascular Death


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

Rosiglitazone and Cardiovascular Events

Are the Risk Estimates Consistent?

MyocardialInfarction/Ischemia

GSK ICT analysis

(N=42 trials)

RECORD (N=4407)

Balanced Cohort Study

(N=33363)

0

1

2

3

Rate ratio

Nonsignificantly increased odds ratio

Cochrane Review (N=18 trials)


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

Rosiglitazone and Cardiovascular Events

Conclusions

  • Sensitive to meta-analytic method

  • Sensitive to continuity correction

  • Sensitive to subgroup analysis

  • If present, magnitude of harm is small

We need more data!


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