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