v.: 9/7/2007 ac submit1 statistical review of the observational studies of aprotinin safety part i:...
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v.: 9/7/2007 AC Submit 1
Statistical Review of the Observational Studies of Aprotinin Safety
Part I:Methods, Mangano and Karkouti Studies
CRDAC and DSaRM MeetingSeptember 12, 2007
Mark Levenson, Ph.D.Quantitative Safety & Pharmacoepidemiology Group
Office of Biostatistics
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Acknowledgements to Dr. Mangano and Dr. Karkouti
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Outline
1. Review Objectives
2. Statistical Methods
3. Mangano Review
4. Karkouti Review
5. Summary
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1. Review Objectives
1. To confirm the reported findings based on investigators’ methods
2. To evaluate the statistical robustness of the findings
– FDA analyzed the 3 studies• Same methods applied to all three studies• Robust • Diagnostics
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Outline
1. Review Objectives
2. Statistical Methods
3. Mangano Review
4. Karkouti Review
5. Summary
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Propensity Scores (PS)• Adjust for differences in baseline risk factors between
two treatment groups (Treatment A and Treatment B)
• Definition: Probability of assignment for a patient to Treatment A versus Treatment B based on measured risk factors
• Intuition: – Suppose Treatment A patient and Treatment B
patient have the same PS.– Comparisons between these two patients are fair
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Propensity Scores Practice
• Balance: similarity of distributions of a risk factor between treatment groups
• PS methods cannot account for unmeasured confounders
• The PS are estimated based on statistical modeling– Diagnostics important
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Propensity Scores Practice (Cont.)
• Estimating treatment effects using PS– Matching (Karkouti)– Stratification (FDA)– Multivariate regression (Mangano, i3)
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FDA Analysis Methods
• Pre-specified
• Propensity scores with stratification was used to adjust for baseline risk factors
• Medical, epidemiological, and statistical expertise was used to choose risk factors
• Diagnostics (analytical and graphical) were used to evaluate balance and explore findings
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Outline
1. Review Objectives
2. Statistical Methods
3. Mangano Review
4. Karkouti Review
5. Summary
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Mangano Study: Key Points
• Prospectively specified – Inclusion criteria– Outcome definitions– Subgroups– Analysis methods
• In-hospital outcomes (NEJM)• Long-term mortality follow-up outcomes (JAMA)• 7 of 69 centers did not participate in the long-
term follow-up
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Mangano Study: Key Points Analysis Methods
• Multivariate regression with and without propensity score as a covariate– Logistic for in-hospital outcomes– Cox PH for long-term mortality
• Propensity score for any active agent versus no agent for full analysis group
• No adjustment for geographical differences
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Mangano Study: Patients by Geographical Region and Treatment Group
Region
No Agent
N=1374
%
Aprotinin
N=1295
%
Amino-caproic
N=883
%
Tran-examic
N=822
%
Europe 57 69 0 49
North America
24 29 96 29
Other 19 1 4 22
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Mangano Study: Long-Term Follow-up
No AgentN=1374
%
AprotininN=1295
%
Completed 5-year follow-up or died
73 83
No post-hospital follow-up
10 1
Lost to follow-up in the post-hospital period
17 16
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Mangano Study: Demographic Factors
Characteristic No AgentN=1374
AprotininN=1295 P-Value
Age (mean ± sd) 63 ± 10 65 ± 9 <.001
Male (%) 81 79 0.135
African American or Hispanic (%) 4 4 0.542
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Mangano Study: Selected Baseline Risk Factors
Characteristic
No AgentN=1374
(%)
AprotininN=1295
(%) P-Value
Surgical: CABG + Other 11 19 <.001
Surgical: Non-Elective 21 15 <.001
History of liver disease 8 12 <.001
History of renal disease 13 19 <.001
Previous sternotomy 3 13 <.001
Preop: Creatinine >1.3 mg/dL 14 15 0.338
Preop: Ejection fraction ≤ 44% 18 15 0.071
Preop: MI 15 16 0.863
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Mangano Study:Study Reported Findings and Methods
• Primary findings of NEJM and JAMA based on investigators’ methods reproduced
• Imbalances in baseline risk factors and geographical regions between aprotinin and no-agent groups after PS adjustment
• Lack of overlap in propensity score distributions between aprotinin and no-agent groups
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FDA Analysis Results
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Mangano Study: FDA AnalysisBaseline Risk Factors
Before and After PS Adjustment
Before PS Adjustment After PS Adjustment
NoAgent
%Aprotinin
% P-Value
NoAgent
%Aprotinin
% P-Value
Surgical: CABG + Other 11 19 <.001 15 16 0.543
Surgical: Non-Elective 21 15 <.001 18 19 0.651
History of liver disease 8 12 <.001 10 10 0.913
History of renal disease 13 19 <.001 16 16 0.849
Previous sternotomy 3 13 <.001 6 8 0.029
Preop: Elev. Creatinine 14 15 0.338 14 14 0.943
Preop: Eject. Fr. ≤ 44% 18 15 0.071 16 16 0.878
Preop: MI 15 16 0.863 15 15 0.745
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Mangano Study: FDA AnalysisIn-Hospital Outcome Adjusted Estimates
Aprotinin vs. No Agent*
OutcomeNo Agent
(%)Aprotinin
(%)
Risk RatioAprotinin/No Agent
(95% CI)
Renal Composite 4.8 7.8 1.63 (1.03, 2.60)
Renal Failure 2.5 5.1 2.05 (1.05, 3.99)
Renal Dysfunction 4.3 5.4 1.26 (0.76, 2.11)
Cardiovascular Composite 19.5 22.2 1.14 (0.94, 1.38)
Myocardial Infarction 14.8 16.4 1.10 (0.88, 1.39)
Congestive Heart Failure 8.4 8.8 1.05 (0.75, 1.47)
Stroke 2.0 2.8 1.36 (0.70, 2.64)
Death (in-hospital) 4.6 4.2 0.91 (0.54, 1.53)
*Analysis based on 1307 no agent patients and 1222 aprotinin patients
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Mangano Study: FDA AnalysisRenal Composite
0.0
00
.05
0.1
00
.15
0.2
00
.25
Propensity Score Strata
Re
na
l Co
mp
osi
te
1 2 3 4 5 6 7 8 9 10
No AgentAprotinin
205 187 164 160 134 130 105 104 72 4647 66 89 93 119 123 148 149 181 207
n=
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Mangano Study: FDA AnalysisLong-Term Mortality Adjusted Estimates
Aprotinin vs. No Agent*
OutcomeNo Agent
(%)Aprotinin
(%)
Risk RatioAprotinin/No Agent
(95% CI)
6 Weeks 5.2 4.8 0.93 (0.57, 1.51)
6 Months 6.4 7.0 1.10 (0.73, 1.68)
1 Year 7.1 8.2 1.16 (0.79, 1.71)
2 Years 8.4 10.7 1.27 (0.90, 1.79)
3 Years 9.7 13.0 1.34 (0.98, 1.83)
4 Years 11.4 15.9 1.39 (1.05, 1.84)
5 Years 14.3 18.1 1.26 (0.98, 1.62)
*Analysis based on 1307 no agent patients and 1222 aprotinin patients
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Mangano Study: FDA AnalysisLong-Term Mortality Adjusted Estimates
0.0
00
.05
0.1
00
.15
0.2
00
.25
Years
Mo
rta
lity
0 1 2 3 4 5
No AgentAprotinin
1164 1134 1096 1050 1007 909 881
1189 1144 1085 1015 954 888 849N Risk
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North American Subgroup
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Mangano Study: FDA Analysis by Region and Treatment Group
0.0
0.2
0.4
0.6
0.8
1.0
Pro
pe
nsi
ty S
core
No AgentAprotinin
Europe North America
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Mangano Study: FDA AnalysisNorth America
In-Hospital Outcome Adjusted EstimatesAprotinin vs. Aminocaproic*
OutcomeAmino.
(%)Aprotinin
(%)
Risk RatioAprotinin/Amino.
(95% CI)
Renal Composite 2.4 9.4 3.90 (1.98, 7.70)
Renal Failure 0.6 5.3 9.17 (3.10, 27.15)
Renal Dysfunction 2.0 6.7 3.39 (1.54, 7.44)
Cardiovascular Composite 17.7 22.5 1.28 (0.94, 1.74)
Myocardial Infarction 12.1 14.9 1.23 (0.83, 1.81)
Congestive Heart Failure 7.5 10.5 1.40 (0.84, 2.35)
Stroke 1.5 3.2 2.10 (0.76, 5.81)
Death (in-hospital) 2.1 4.7 2.21 (0.88, 5.52)
*Analysis based on 789 aminocaproic patients and 342 aprotinin patients
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Mangano Study: FDA AnalysisNorth America:
Long-Term Mortality Adjusted Estimates Aprotinin vs. Aminocaproic*
OutcomeAmino.
(%)Aprotinin
(%)
Risk RatioAprotinin/Amino.
(95% CI)
6 Weeks 2.4 4.7 1.91 (0.82, 4.47)
6 Months 3.5 7.3 2.11 (1.04, 4.28)
1 Year 5.1 9.9 1.96 (1.10, 3.47)
2 Years 7.3 13.7 1.89 (1.19, 3.00)
3 Years 10.0 18.4 1.84 (1.23, 2.73)
4 Years 15.1 21.9 1.45 (1.03, 2.04)
5 Years 19.8 24.6 1.24 (0.92, 1.67)
*Analysis based on 789 aminocaproic patients and 342 aprotinin patients
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Mangano Study: Review Summary
• Renal outcomes (particularly renal failure) effect in a range of patients and in North American region subgroup
• Effects for cardiovascular, cerebrovascular, and in-hospital death outcomes not statistically demonstrated
• Long-term mortality effects in a range of patients and in North American region subgroup
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Outline
1. Statistical Review Objectives
2. Statistical Methods
3. Mangano Review
4. Karkouti Review
5. Summary
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Karkouti Study: Key Points
• Retrospective study of 5 years of patient data from a single center
• Patient population: Cardiac surgery (CABG and non-CABG) with cardio-pulmonary bypass
• Aprotinin used for high risk patients, tranexamic acid used for other patients
• Used propensity scores with 1-1 matching– 449 of 586 aprotinin patients matched
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Karkouti Study: Demographic Factors
Characteristic
TranexamicAcid
N=10251AprotininN=586 P-Value
Age (mean ± sd) 63 ± 12 55 ± 17 <.001
Male (%) 75 65 <.001
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Karkouti Study: Selected Baseline Risk Factors
Characteristic
TranexamicAcid
N=10251(%)
AprotininN=586
(%) P-Value
Surgical: Not CABG only 33 89 <.001
Surgical: Non-Elective 8 19 <.001
Previous sternotomy 5 61 <.001
Preop: Creatinine abnormal 19 26 <.001
Preop: Ejection fraction <40% 20 23 0.148
Preop: MI 17 7 <.001
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Karkouti Study: Study Reported Findings and Methods
• Primary findings using investigators’ methods reproduced
• Observed risk factors balanced with propensity score matching approach
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Karkouti Study: FDA Analysis
• A subgroup of patients with overlap in propensity scores was defined to enable treatment comparison
• Subgroup contained – 553/586 (94%) of the aprotinin patients– 3759/10251 (37%) of tranexamic patients
• Baseline risk factors more similar between treatment groups in subgroup than full group
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Karkouti: FDA AnalysisAnalysis Subgroup, Baseline Risk Factors
Before and After PS Adjustment
Before PS Adjustment After PS Adjustment
Tran.%
Aprotinin% P-Value
Tran.%
Aprotinin% P-Value
Surgical: Not CABG only 83 92 <.001 83 83 0.873
Surgical: Non-Elective 16 18 0.137 16 19 0.366
Previous sternotomy 14 64 <.001 19 22 0.126
Preop: Elev. Creatinine 3 5 0.010 3 3 0.950
Preop: Eject. Fr. <40% 21 22 0.426 21 19 0.693
Preop: MI 11 7 0.003 10 16 0.036
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Karkouti Study: FDA AnalysisTreatment Effect Estimates
Aprotinin vs. Tranexamic Acid*
Outcome
FDA AnalysisRisk Ratio
Aprotinin/Tran.
Matched-PairOdds Ratio
Aprotinin/Tran.
Renal dysfunction 1.53 (1.11, 2.12)
Renal failure 1.38 (0.86, 2.23) 1.85 (0.94, 3.63)
Myocardial Infarction 1.42 (0.71, 2.83) 1.22 (0.51, 2.95)
Stroke 1.72 (0.93, 3.19) 1.15 (0.55, 2.43)
Death (in-hospital) 1.18 (0.79, 1.76) 0.90 (0.54, 1.51)
*Analysis based on 3759 tran. patients and 553 aprotinin patients
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Karkouti Study: FDA AnalysisRenal Failure
0.0
00
.05
0.1
00
.15
0.2
00
.25
Propensity Score Strata
Po
st-O
pe
rativ
e R
en
al F
ailu
re
1 2 3 4 5
Tran. AcidAprotinin
852 838 821 768 48010 25 41 95 382
n=
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Karkouti Study: Review Summary
• Renal dysfunction effect statistically significant
• Some evidence for renal failure effect
• Effects for myocardial infarction, stroke, and in-hospital death outcomes not statistically demonstrated
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Outline
1. Review Objectives
2. Statistical Methods
3. Mangano Review
4. Karkouti Review
5. Summary
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Summary
• Evidence for renal effect, including renal failure consistent
• Effects for cardiovascular, cerebrovascular, and in-hospital death outcomes not statistically demonstrated
• Evidence for long-term mortality effect • Potential for unadjusted confounders
between the treatment groups which may bias the treatment effect estimates