1. CRDAC & DSaRM Advisory Meeting September 12, 2007 Aprotinin Observational Studies Advisory Committee Meeting - September 12, 2007 Rita Ouellet-Hellstrom, Ph.D., M.P.H. FDA CDER Office of Surveillance and Epidemiology Division of Drug Risk Evaluation (DDRE)

2. CRDAC & DSaRM Advisory Committee September 12, 2007 2 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

3. CRDAC & DSaRM Advisory Committee September 12, 2007 3 Observational Studies & Clinical Trials Clinical TrialsObservational Studies Design/PowerEfficacy (usually) Safety (sometimes) Safety (maybe) SizeSmall to moderateModerate to large Study Subjects Select population, direct contact, informed consent More representative of clinical practice Treatment Covariates Randomly assigned for both known & unknown Need statistical adjustment Known only or surrogate Follow-upLimited, short-termCan be long-term CostExpensive (prospective data collection) Relatively inexpensive (available data)

4. CRDAC & DSaRM Advisory Committee September 12, 2007 4 Issues - Observational Studies Study Design Types of procedures performed Population size Control or comparator group(s) Exposure & outcome definitions

5. CRDAC & DSaRM Advisory Committee September 12, 2007 5 Procedures StudyProceduresComplex (%) Mangano et al 1 Mortality 2 Coronary Artery Bypass Grafting (CABG) with Cardiopulmonary Bypass (CPB) 31.1 Karkouti et al 3 Cardiac surgery with Cardiopulmonary Bypass (CPB) 72.1 i3 – Premier 4 Coronary Artery Bypass Grafting (CABG) with Cardiopulmonary 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

6. CRDAC & DSaRM Advisory Committee September 12, 2007 6 Population - Size StudyExposureNEJM 2006 (N) JAMA 2007 (N) JAMA 2007 (% ) Mangano et alAprotinin Aminocaproic acid Tranexamic acid No-use (control) 1,295 883 822 1,374 1,277 849 512 1,238 98.6 96.1 62.3 90.1 Karkouti et alAprotinin Tranexamic acid (control) 449 (586) 449 (10,284) i3 - PremierAprotinin Aminocaproic acid Tranexamic acid 29,358 35,719 1,358

7. CRDAC & DSaRM Advisory Committee September 12, 2007 7 Selected Hemostatic Agents; Premier Network of Hospitals, 2000 – 2006 by Quarter Cardiovascular System

8. CRDAC & DSaRM Advisory Meeting September 12, 2007 Definitions Exposure & Outcome

9. CRDAC & DSaRM Advisory Committee September 12, 2007 9 Exposure StudyExposureComparator Mangano et alAprotinin Aminocaproic acid Tranexamic acid No Treatment Karkouti et alAprotininTranexamic acid i3 - Premier (interim report) AprotininAminocaproic acid Tranexamic acid

10. CRDAC & DSaRM Advisory Committee September 12, 2007 10 Outcomes - During Hospital Stay CardiovascularCerebralRenalDeath Mangano et alMyocardial Infarction Heart failure Stroke Coma Encephalopathy Dysfunction Failure In-hospital 5-yr long-term Karkouti et alMyocardial InfarctionStrokeDysfunction Failure In-hospital I3 - PremierHeart Failure Acute Coronary Revascularization StrokeFailureIn-hospital

11. CRDAC & DSaRM Advisory Committee September 12, 2007 11 Cardiovascular Mangano et alMyocardial 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 alMyocardial 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-PremierAcute 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

12. CRDAC & DSaRM Advisory Committee September 12, 2007 12 Cerebrovascular Mangano et alComposite & separate Clinically diagnosed stroke, encephalopathy, AND coma Karkouti et alStroke Any new persistent post-operative neurologic deficit i3-PremierStroke Codes for post-operative stroke, ischemic stroke (no TIA), OR Charge codes for stroke diagnostics & therapeutics Excludes codes for hemorrhagic stroke

13. CRDAC & DSaRM Advisory Committee September 12, 2007 13 Renal ManganoDysfunction 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 KarkoutiDysfunction A >50% ↑ in creatinine during 1 st 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-PremierAcute Failure Codes for hemo- or peritoneal dialysis or hemofiltration

14. CRDAC & DSaRM Advisory Committee September 12, 2007 14 Death ManganoIn-hospital No other information specified Long-term Death, all cause over 5 years (62 of 69 centers) (from interviews & death registries) KarkoutiIn-hospital No other information specified i3-PremierIn-hospital Codes from UB-29 forms with discharge status 20-29 and 40-42

15. CRDAC & DSaRM Advisory Committee September 12, 2007 15 Percent Lost-to-Follow-up by Treatment Group Mangano et al. JAMA; 297(5):471-479, Feb 2007

16. CRDAC & DSaRM Advisory Committee September 12, 2007 16 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

17. CRDAC & DSaRM Advisory Committee September 12, 2007 17 Utilization Codes Identify 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, 1998 Qureshi AI et al. J Clin Epidemiology, 59:856-858, 2006

18. CRDAC & DSaRM Advisory Committee September 12, 2007 18 Renal Failure Covariates - i3 Premier Odds Ratio adjusted 95% CI Aprotinin1.71.6 - 1.9 Diabetes2.62.3 - 2.9 Liver Disease7.56.2 - 9.0

19. CRDAC & DSaRM Advisory Committee September 12, 2007 19 Adjustment Tools Multivariate Modeling Logistic regression (all) Proportional hazard regression (time) Conditional logistic regression (matching) Matching/Stratifying Propensity Scores Design Analysis

20. CRDAC & DSaRM Advisory Committee September 12, 2007 20 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

21. CRDAC & DSaRM Advisory Meeting September 12, 2007 Results

22. CRDAC & DSaRM Advisory Committee September 12, 2007 22 Cardiovascular StudyGroupRisk Ratio adjusted 95% CI / p value Mangano et alPrimary Complex 1.4 1.1 1.1 - 1.9 0.8 - 1.6 Karkouti et alMatched1.5p = 0.7 I3- PremierACR HF 1.3 1.1 1.1 - 1.8 1.0 - 1.1 ACR = Acute Coronary Revascularization; HF = Heart Failure

23. CRDAC & DSaRM Advisory Committee September 12, 2007 23 Cerebrovascular StudyGroupRisk Ratio adjusted 95% CI / p value Mangano et alPrimary Complex 2.2 1.3 1.1 - 4.1 0.7 - 2.4 Karkouti et alMatched1.0p = 0.7 I3 PremierAll patients 2+ hospital days pre-CABG 1.2 1.1 - 1.4 * CVE = cerebrovascular event defined as stroke, encephalopathy, or coma.

24. CRDAC & DSaRM Advisory Committee September 12, 2007 24 Renal StudyGroupRisk Ratio adjusted 95% CI / p value Mangano et alPrimary: dysfunction or failure Complex: dysfunction or failure 2.3 2.6 1.3 - 4.3 1.4 - 5.0 Karkouti et alDysfunction - All patients Failure - All patients 1.4 1.8 p = 0.01 p = 0.08 Dysfunction - Normal pre-op Failure - Normal pre-op 1.4 1.5 p = 0.09 p = 0.30 Dysfunction - Abnormal pre-op Failure - Abnormal pre-op 1.7 2.2 p = 0.03 p = 0.10 I3 PremierAll patients 2+ hospital days pre-CABG 1.7 1.6 - 1.9

25. CRDAC & DSaRM Advisory Committee September 12, 2007 25 Death StudyGroupRisk Ratio adjusted 95% CI / p value Mangano et alPrimary Complex 1.6 0.9 0.8 - 3.3 0.4 - 1.7 All (in-hospital + long term) 1.41.1 - 1.7 Karkouti et alMatched1.0p = 0.7 I3 PremierAll patients 2+ hospital days pre-CABG 1.7 1.5 - 1.8

26. CRDAC & DSaRM Advisory Committee September 12, 2007 26 Clinical Trials (US) Treatment-Emergent Events 89-004 Redo CABG 89-005 Valve Replacement/Repair 89-006 Primary & Redo CABG Aprotinin (59) Placebo (56) Aprotinin (71) Placebo (71) Aprotinin (108) Placebo (108) %Risk Ratio % % MI22.012.51.85.64.21.39.36.51.4 Other Heart † 5.10.0~*11.3*2.84.023.114.81.6 Renal16.97.12.4*8.5*0.0~5.64.61.2 Death6.87.10.94.20.0~5.63.71.5 † 89-004 = Ventricular tachycardia; 89-005 = Heart Failure including congestive; 89-006 = Atrial Fibrillation * Statistically significant difference

27. CRDAC & DSaRM Advisory Committee September 12, 2007 27 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

28. CRDAC & DSaRM Advisory Committee September 12, 2007 28 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

29. CRDAC & DSaRM Advisory Committee September 12, 2007 29 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

30. CRDAC & DSaRM Advisory Committee September 12, 2007 30 Acknowledgements OSEGerald 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. DMIHPGeorge Shashaty, M.D. R. Dwaine Rieves, M.D. OB/QSPGGeorge Rochester, Ph.D. Mark Levenson, Ph.D. Chris Holland, M.S.