NEW ENGLAND
JOURNAL of MEDICINE
The
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
No Event
MI
15,470
86
12,205
72
Rosiglitazone
Control
0.59%
0.55%
Event Rate
Rosiglitazone and Cardiovascular Events
Myocardial Infarction
Patients
3000
2000
1000
0
No Event
MI
Zero event trials
N=38
Rosiglitazone
Control
4
4
EXCLUDED
Rosiglitazone and Cardiovascular Events
Cardiovascular Death
Patients
3000
2000
1000
0
No Event
Death
Zero event trials
N=23
Rosiglitazone
Control
19
19
EXCLUDED
Rosiglitazone and Cardiovascular Events
Peto Meta-Analysis
Myocardial Infarction
0.0001
0.01
1
100
10000
Cardiovascular Death
0.001
0.1
1
10
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
1000
Rosiglitazone and Cardiovascular Events
Myocardial Infarction
Patients
3000
2000
1000
0
No Event
MI
Zero event cells
Rosiglitazone
Control
6
20
INCLUDED
Rosiglitazone and Cardiovascular Events
Cardiovascular Death
Patients
3000
2000
1000
0
No Event
Death
Zero event cells
Rosiglitazone
Control
2
15
INCLUDED
Rosiglitazone and Cardiovascular Events
Impact of Zero Events on Peto’s Odds Ratio


 exp  (Oi  Ei ) / Vi 
i 1
 i 1

k
ORPeto
k
Zero
Oi-Ei
MI
Death
Control
Treatment


20
6
15
2
Rosiglitazone and Cardiovascular Events
Cardiovascular Death
Patients
3000
2000
1000
0
No Event
Death
Rosiglitazone
Control
Rosiglitazone and Cardiovascular Events
Continuity Correction
Patients
3000
2000
1000
0
No Event
Death
k=1/2
k~1/N
Rosiglitazone
Control
Sweeting et al, What to add to nothing? Stat Med 2006;23:1351-75.
Rosiglitazone and Cardiovascular Events
Meta-Analytic Sensitivity
Myocardial Infarction
Peto ( - )
Cardiovascular Death
*
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
Odds Ratio
3.0
0.5
1.0
1.5
2.0
2.5
Odds Ratio
3.0
Rosiglitazone and Cardiovascular Events
Magnitude of Harm
Myocardial Infarction
1.0
Probability of Harm
1.0
Cardiovascular Death
Uncorrected
Uncorrected
0.8
0.8
0.6
0.6
0.4
0.4
Corrected
0.2
0.2
0.0
0.0
1
10
Relative Risk Threshold
100
Corrected
1
10
Relative Risk Threshold
100
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
• 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?
Rosiglitazone and Cardiovascular Events
Flow Diagram of Inclusion/Exclusion
Screened Phase 2, 3, 4 trials
(N = 116)
Published literature
Excluded on basis of:
Trial registries
Lack of randomized comparator group
FDA summary report
<24 wks of drug exposure
(N = 68)
Retrieved for detailed evaluation
(N = 48)
Excluded on basis of:
Lack of reported cardiovascular events
(N = 6)
Included for meta-analysis
(N = 42)
Rosiglitazone and Cardiovascular Events
Quality of Meta-Analysis
•
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
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
Rosiglitazone and Cardiovascular Events
Clinical Heterogeneity in Patient Populations
Meta-analysis
N = 42
Without diabetes (N = 3)
• Alzheimer's (N = 1)
• Psoriasis (N = 2)
With contraindication
(CHF)
N=1
With Diabetes
N = 39
Without
contraindication
N = 38
Rosiglitazone and Cardiovascular Events
Clinical Heterogeneity in Trial Design
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 Treatment Groups
Meta-analysis
N = 42 trials
RSG vs placebo
RSG vs standard Rx
N = 10 trials
N = 32 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)
Rosiglitazone and Cardiovascular Events
Is There Heterogeneity?
Absence of statistical heterogeneity does
not imply absence of clinical heterogeneity
Rosiglitazone and Cardiovascular Events
Meta-Analytic Subgroups
Myocardial Infarction
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)
Overall pooled data
(N=26011)
1.43 (1.03-1.98)
0
1
2
Odds ratio
3
4 0
1.28 (0.95-1.72)
1
2
Odds ratio
3
4
Rosiglitazone and Cardiovascular Events
Meta-Analytic Subgroups
Cardiovascular Death
Uncorrected (Peto)
Small trials combined
(N=10825)
Corrected (MH/CC)
1.51 (0.82-2.78)
2.40 (1.17-4.91)
DREAM (N=5269)
ADOPT (N=4351)
Overall pooled data
(N=20445)
1.33 (0.83-2.13)
1.64 (0.98-2.74)
0
1
2
3
Odds ratio
4
5 0
1
2
3
Odds ratio
4
5
Rosiglitazone and Cardiovascular Events
Meta-Analytic Subgroups
Myocardial Infarction
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)
1.52
1.31
RSG vs antidiabetic Rx (N=32)
1.40
1.27
RSG + SULF vs SULF (N=12)
1.23
1.11
RSG + MET vs MET (N=10)
1.49
1.05
3.49
RSG + INS vs INS (N=5)
0
1
2
3
Odds Ratio
4
5
2.77
0
1
2
3
Odds Ratio
4
5
Rosiglitazone and Cardiovascular Events
Meta-Analytic Subgroups
Cardiovascular Death
Uncorrected (Peto)
Corrected (MH/CC)
1.58
1.34
Diabetes (-CHF) (N=38)
Other diseases (N=4)
1.31
2.10
RSG vs placebo (N=10)
1.50
1.24
RSG vs antidiabetic Rx (N=32)
1.79
1.42
RSG + SULF vs SULF (N=12)
2.43
1.67
RSG + MET vs MET (N=10)
1.75
1.34
RSG + INS vs INS (N=5)
1.92
5.37
0
2
4
6
Odds Ratio
8
10
0
2
4
6
Odds Ratio
8
10
Rosiglitazone and Cardiovascular Events
Are the Risk Estimates Consistent?
GSK ICT analysis
(N=42 trials)
IHD
CVD/MI/Stroke
FDA (N=42 trials)
IHD
CVD/MI/Stroke
MI
CV death
RECORD (N=4407)
Cochrane Review
(N=18 trials)
Balanced Cohort Study
(N=33363)
MI
MI
0
1
2
Odds or hazard ratio
3
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!