The
Download
1 / 27

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 - PowerPoint PPT Presentation


  • 74 Views
  • Uploaded on

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

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about ' 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' - tauret


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript

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.


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


3000

2000

1000

0

Patients

No Event

N=38

MI

Rosiglitazone Control

Zero event trials 4 4 EXCLUDED

Rosiglitazone and Cardiovascular Events

Myocardial Infarction


3000

2000

1000

0

Patients

No Event

N=23

Death

Rosiglitazone Control

Zero event trials 19 19 EXCLUDED

Rosiglitazone and Cardiovascular Events

Cardiovascular Death


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


3000

2000

1000

0

Patients

No Event

MI

Rosiglitazone Control

Zero event cells 6 20 INCLUDED

Rosiglitazone and Cardiovascular Events

Myocardial Infarction


3000

2000

1000

0

Patients

No Event

Death

Rosiglitazone Control

Zero event cells 2 15 INCLUDED

Rosiglitazone and Cardiovascular Events

Cardiovascular Death


Rosiglitazone and Cardiovascular Events

Impact of Zero Events on Peto’s Odds Ratio


3000

2000

1000

0

Patients

No Event

Death

Rosiglitazone Control

Rosiglitazone and Cardiovascular Events

Cardiovascular Death


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.


*

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


Rosiglitazone and Cardiovascular Events

Magnitude of Harm

Myocardial Infarction

Cardiovascular Death

Uncorrected

Uncorrected

Probability of Harm

Corrected

Corrected

Relative Risk Threshold

Relative Risk Threshold


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


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


Rosiglitazone and Cardiovascular Events And Death from Cardiovascular

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?


Rosiglitazone and Cardiovascular Events And Death from Cardiovascular

Is There Heterogeneity?

  • 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


Meta-analysis And Death from Cardiovascular

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


Meta-analysis And Death from Cardiovascular

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


Meta-analysis And Death from Cardiovascular

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


Rosiglitazone and Cardiovascular Events And Death from Cardiovascular

Is There Heterogeneity?

Absence of statistical heterogeneity does not imply absence of clinical heterogeneity


Uncorrected (Peto) And Death from Cardiovascular

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


Uncorrected (Peto) And Death from Cardiovascular

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


Corrected (MH/CC) And Death from Cardiovascular

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


Corrected (MH/CC) And Death from Cardiovascular

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


Rosiglitazone and Cardiovascular Events And Death from Cardiovascular

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)


Rosiglitazone and Cardiovascular Events And Death from Cardiovascular

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!


ad