Aprotinin Observational Studies

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CRDAC & DSaRM Advisory Meeting CRDAC & DSaRM Advisory Meeting September 12, 2007September 12, 2007

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 EpidemiologyDivision of Drug Risk Evaluation (DDRE)Division of Drug Risk Evaluation (DDRE)

2CRDAC & 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

Observational Studies &Clinical Trials

Clinical Trials Observational Studies

Design/Power

Efficacy (usually)Safety (sometimes)

Safety (maybe)

Size Small to moderate Moderate to largeStudy 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-termCost Expensive

(prospective data collection)

Relatively inexpensive(available data)

Issues - Observational Studies Study Design

Types of procedures performed Population size Control or comparator group(s)

Exposure & outcome definitions

ProceduresStudy Procedures Comple

Mangano et al1Mortality2

Coronary Artery Bypass Grafting (CABG) withCardiopulmonary Bypass (CPB)

Karkouti et al3

Cardiac surgery withCardiopulmonary Bypass (CPB)

i3 – Premier4 Coronary Artery Bypass Grafting (CABG) withCardiopulmonary Bypass (CPB)

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

Population - SizeStudy Exposure NEJM

2006(N)

JAMA 2007(N)

JAMA 2007 (% )

Mangano et al

Aprotinin Aminocaproic acidTranexamic acid No-use (control)

1,295883822

1,277849512

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

Selected Hemostatic Agents; Premier Network of Hospitals, 2000 – 2006 by Quarter

Cardiovascular System

10,000

20,000

30,000

40,000

50,000

60,000

70,000

80,000

AMINOCAP ACID APROTININ TRANEXAMIC ACID

Definitions Exposure & Outcome

ExposureStudy Exposure ComparatorMangano et al Aprotinin

Aminocaproic acid Tranexamic acid

No Treatment

Karkouti et al Aprotinin Tranexamic acid

i3 - Premier (interim report)

Aprotinin Aminocaproic acid Tranexamic acid

Outcomes - During Hospital Stay

Cardiovascular Cerebral Renal DeathMangano 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

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

CerebrovascularMangano 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

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 failureKarkouti Dysfunctio

n 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 supportAcute Failure

New requirement for dialysis support

i3-Premier

Acute Failure

Codes for hemo- or peritoneal dialysis or hemofiltration

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

Percent Lost-to-Follow-upby Treatment Group

101520253035

No use Aprotinin Aminocaproic Acid Tranexamic Acid

% Deceased % Lost-to-Follow-upMangano et al. JAMA; 297(5):471-479, Feb 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

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

Renal Failure Covariates - i3 Premier

Odds Ratioadjusted

95% CI

Aprotinin 1.7 1.6 - 1.9

Diabetes 2.6 2.3 - 2.9Liver Disease 7.5 6.2 - 9.0

Adjustment Tools Multivariate Modeling

Logistic regression (all) Proportional hazard regression (time) Conditional logistic regression (matching)

Matching/Stratifying Propensity Scores

Design Analysis

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

Results

CardiovascularStudy Group Risk Ratio

adjusted95% 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

CerebrovascularStudy Group Risk

Ratioadjusted

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.

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

1.71.7

1.6 - 1.91.6 - 1.9

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

1.71.7

1.5 - 1.81.5 - 1.8

Clinical Trials (US)Treatment-Emergent Events

89-004Redo CABG

89-005Valve

Replacement/Repair

89-006Primary & Redo CABG

Aprotinin

Placebo (56)

Aprotinin(71)

Placebo(71)

Aprotinin

Placebo(108)

% % Risk Rati

oMI 22.0 12.5 1.8 5.6 4.2 1.3 9.3 6.5 1.4Other 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 1.2Death 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

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

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

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

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.

Aprotinin Observational Studies

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