CRDAC & DSaRM Advisory Meeting CRDAC & DSaRM Advisory Meeting September 12, 2007September 12, 2007
Aprotinin Observational Studies
Advisory Committee Meeting - September 12, Advisory Committee Meeting - September 12, 20072007Rita Ouellet-Hellstrom, Ph.D., M.P.H.Rita Ouellet-Hellstrom, Ph.D., M.P.H.
FDA CDER Office of Surveillance and EpidemiologyFDA CDER Office of Surveillance and Epidemiology
Division of Drug Risk Evaluation (DDRE)Division of Drug Risk Evaluation (DDRE)
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Objectives
Safety concerns identified by observational studies (cardiovascular, cerebrovascular, renal events and in-hospital deaths)
Design, exposure & outcome definitions, potential bias, adjustment tools
Consistency of the published results Next step - Re-analysis or clinical trials
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Observational Studies &Clinical Trials
Clinical Trials Observational Studies
Design/Power
Efficacy (usually)Safety (sometimes)
Safety (maybe)
Size Small to moderate Moderate to large
Study Subjects
Select population, direct contact, informed consent
More representative of clinical practice
TreatmentCovariates
Randomly assigned for both known & unknown
Need statistical adjustment Known only or surrogate
Follow-up Limited, short-term Can be long-term
Cost Expensive(prospective data collection)
Relatively inexpensive(available data)
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Issues - Observational Studies
Study Design Types of procedures performed Population size Control or comparator group(s)
Exposure & outcome definitions
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
ProceduresStudy Procedures Comple
x(%)
Mangano et al1
Mortality2
Coronary Artery Bypass Grafting (CABG) withCardiopulmonary Bypass (CPB)
31.1
Karkouti et al3
Cardiac surgery withCardiopulmonary Bypass (CPB)
72.1
i3 – Premier4 Coronary Artery Bypass Grafting (CABG) withCardiopulmonary Bypass (CPB)
64.1
1 Mangano et al. NEJM; 354(4): 353-365 Jan 2006 2 Mangano et al. JAMA; 297(5):471-479, Feb 2007 3 Karkouti et al. Transfusion, 46:327-338 Mar 2006 4 Schneeweiss et al. Report from the Premier Perspective Comparative Database, Sep 2006
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Population - Size
Study Exposure NEJM 2006(N)
JAMA 2007(N)
JAMA 2007 (% )
Mangano et al
Aprotinin Aminocaproic acidTranexamic acid No-use (control)
1,295883822
1,374
1,277849512
1,238
98.696.162.390.1
Karkouti et al
AprotininTranexamic acid (control)
449 (586)449 (10,284)
i3 - Premier AprotininAminocaproic acidTranexamic acid
29,35835,7191,358
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Selected Hemostatic Agents; Premier Network of Hospitals, 2000 – 2006 by Quarter
Cardiovascular System
0
10,000
20,000
30,000
40,000
50,000
60,000
70,000
80,000
Nu
mb
er
AMINOCAP ACID APROTININ TRANEXAMIC ACID
CRDAC & DSaRM Advisory Meeting CRDAC & DSaRM Advisory Meeting September 12, 2007September 12, 2007
Definitions Exposure & Outcome
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Exposure
Study Exposure Comparator
Mangano et al Aprotinin Aminocaproic acid Tranexamic acid
No Treatment
Karkouti et al Aprotinin Tranexamic acid
i3 - Premier (interim report)
Aprotinin Aminocaproic acid Tranexamic acid
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Outcomes - During Hospital Stay
Cardiovascular Cerebral Renal Death
Mangano et al
Myocardial Infarction Heart failure
StrokeComa Encephalopathy
Dysfunction Failure
In-hospital5-yr long-term
Karkouti et al
Myocardial Infarction
Stroke DysfunctionFailure
In-hospital
I3 - Premier Heart FailureAcute Coronary
Revascularization
Stroke Failure In-hospital
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
CardiovascularMangano et al Myocardial
Infarction
New Q waves OR New persistent ST-segment OR T-wave changes
Heart Failure Cardiac output <2.0 L/min associated with Pulmonary artery occlusion pressure >18 mm Hg OR Central venous pressure >12 mm Hg, OR An S3 gallop, OR Rales
Karkouti et al Myocardial Infarction
New Q waves on post-operative EKG OR MB isoenzyme of creatinine kinase >50 U/L AND The CK-MB/CK ratio >5%, AND New EKG changes
i3-Premier Acute Coronary Revascularization
Codes for thrombolysis, percutaneous transluminal coronary angioplasty (PTCA), OR Codes for redo CABG
Heart Failure Codes for use of dobutamine OR Codes for left ventricular assist device
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Cerebrovascular
Mangano et al
Composite & separate
Clinically diagnosed stroke, encephalopathy, AND coma
Karkouti et al
Stroke Any new persistent post-operative neurologic deficit
i3-Premier Stroke Codes for post-operative stroke, ischemic stroke (no TIA), OR
Charge codes for stroke diagnostics & therapeutics
Excludes codes for hemorrhagic stroke
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
RenalMangano Dysfunctio
n
Post-operative serum creatinine 177 + μmol/L AND
↑ of 62 μmol/L from baseline
Acute Failure
Renal dysfunction requiring dialysis OR In-hospital death with autopsy evidence of
acute renal failure
Karkouti Dysfunction
A >50% ↑ in creatinine during 1st pre-op week to >100 μmol/L in women & >110 μmol/L in men OR
New requirement for dialysis support
Acute Failure
New requirement for dialysis support
i3-Premier
Acute Failure
Codes for hemo- or peritoneal dialysis or hemofiltration
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Death
Mangano In-hospital No other information specified
Long-term Death, all cause over 5 years (62 of 69 centers)(from interviews & death registries)
Karkouti In-hospital No other information specified
i3-Premier
In-hospital Codes from UB-29 forms with discharge status 20-29 and 40-42
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Percent Lost-to-Follow-upby Treatment Group
0
5
10
15
20
25
30
35
No use Aprotinin Aminocaproic Acid Tranexamic Acid
% Deceased % Lost-to-Follow-up
Mangano et al. JAMA; 297(5):471-479, Feb 2007
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Confounders & Bias Utilization codes Imbalance of baseline characteristics
across treatment groups Channeling bias Geographical, institutional, and
provider clustering Time-to-event analyses Comprehensive follow-up
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Utilization CodesIdentify Outcomes & Confounders
Myocardial Infarction Sensitivity - 67% Specificity - 100%
Thrombolysis in ischemic stroke Sensitivity - 55% Specificity - 98%
Non-specific codes for heart failure, renal dysfunction
McAlpine R et al. Pharmacoepidemiol & Drug Safety, 7:311-318, 1998Qureshi AI et al. J Clin Epidemiology, 59:856-858, 2006
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Renal Failure Covariates - i3 Premier
Odds Ratioadjusted
95% CI
Aprotinin 1.7 1.6 - 1.9
Diabetes 2.6 2.3 - 2.9
Liver Disease 7.5 6.2 - 9.0
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Adjustment Tools Multivariate Modeling
Logistic regression (all) Proportional hazard regression (time) Conditional logistic regression (matching)
Matching/Stratifying
Propensity Scores Design Analysis
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Observation Time - Hospital Stay
Short-term Longer hospital stays
Increase the probability of having an outcome observed
Early discharge to other facilities Missing observations
Average length of stay specified by Karkouti 8 days for each treatment group & a range of 6-13
days for aprotinin & 6-12 days for tranexamic acid Long-term
Lost-to-follow-up Competing co-morbidities
CRDAC & DSaRM Advisory Meeting CRDAC & DSaRM Advisory Meeting September 12, 2007September 12, 2007
Results
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Cardiovascular
Study Group Risk Ratioadjusted
95% CI / p value
Mangano et al
PrimaryComplex
1.41.1
1.1 - 1.90.8 - 1.6
Karkouti et al
Matched 1.5 p = 0.7
I3- Premier ACRHF
1.31.1
1.1 - 1.81.0 - 1.1
ACR = Acute Coronary Revascularization; HF = Heart Failure
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Cerebrovascular
Study Group Risk Ratio
adjusted
95% CI / p value
Mangano et al
PrimaryComplex
2.21.3
1.1 - 4.10.7 - 2.4
Karkouti et al
Matched 1.0 p = 0.7
I3 Premier All patients2+ hospital days pre-CABG
1.21.2
1.1 - 1.41.1 - 1.4
* CVE = cerebrovascular event defined as stroke, encephalopathy, or coma.
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
RenalStudy Group Risk
Ratio adjusted
95% CI / p value
Mangano et al
Primary: dysfunction or failureComplex: dysfunction or failure
2.32.6
1.3 - 4.31.4 - 5.0
Karkouti et al
Dysfunction - All patientsFailure - All patients
1.41.8
p = 0.01p = 0.08
Dysfunction - Normal pre-opFailure - Normal pre-op
1.41.5
p = 0.09p = 0.30
Dysfunction - Abnormal pre-opFailure - Abnormal pre-op
1.72.2
p = 0.03p = 0.10
I3 Premier All patients2+ hospital days pre-CABG
1.71.7
1.6 - 1.91.6 - 1.9
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
DeathStudy Group Risk
Ratioadjusted
95% CI / p value
Mangano et al
PrimaryComplex
1.60.9
0.8 - 3.30.4 - 1.7
All (in-hospital + long term)
1.4 1.1 - 1.7
Karkouti et al
Matched 1.0 p = 0.7
I3 Premier All patients2+ hospital days pre-CABG
1.71.7
1.5 - 1.81.5 - 1.8
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Clinical Trials (US)Treatment-Emergent Events
89-004Redo CABG
89-005Valve
Replacement/Repair
89-006Primary & Redo CABG
Aprotinin
(59)
Placebo (56)
Aprotinin(71)
Placebo(71)
Aprotinin
(108)
Placebo(108)
% % Risk Rati
o
% % Risk Rati
o
% % Risk Rati
o
MI 22.0 12.5 1.8 5.6 4.2 1.3 9.3 6.5 1.4
Other Heart†
5.1 0.0 ~ *11.3 *2.8 4.0 23.1 14.8 1.6
Renal 16.9 7.1 2.4 *8.5 *0.0 ~ 5.6 4.6 1.2
Death 6.8 7.1 0.9 4.2 0.0 ~ 5.6 3.7 1.5† 89-004 = Ventricular tachycardia; 89-005 = Heart Failure including congestive; 89-006 = Atrial Fibrillation* Statistically significant difference
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Re-analysis Can:
Reproduce study results Standardize analytical approaches Assess comparability of risk across
treatment groups Perform time-to-event analyses Compare aprotinin treatment with
no treatment
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Re-analysis Cannot: Re-define outcome & exposure
criteria Provide missing information
On patients from excluded centers Patients lost-to-follow-up Uncollected data identifying co-
morbidity & competing risks in long-term follow-up
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
Summary - Observational Studies
Different designs & outcome definitions Some studies with large number of patients Others with access to medical records & some with
direct patient contact Consistency of results for renal events Suggestive but inconclusive results on in-hospital
deaths, cardiovascular & cerebrovascular events Re-analysis provides some answers but final results
may have to await a large study powered to assess safety & death
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CRDAC & DSaRM Advisory Committee CRDAC & DSaRM Advisory Committee September 12, 2007September 12, 2007
AcknowledgementsOSE Gerald DalPan, M.D, M.H.S.
Mark Avigan, M.D., C.M.
Allen Brinker, M.D., M.S.
Susan Lu, R.Ph.
Laura Governale, Pharm.D., M.B.A.
Joyce Weaver, Pharm.D.
DMIHP George Shashaty, M.D.
R. Dwaine Rieves, M.D.
OB/QSPG George Rochester, Ph.D.
Mark Levenson, Ph.D.
Chris Holland, M.S.
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