# Presentation: 313543

## 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)*

## 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 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-up | Limited, short-term | Can be long-term |
| Cost | 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

## Procedures

| Study | Procedures | Complex(%) |
| --- | --- | --- |
| Mangano et al1
Mortality2 | Coronary Artery Bypass Grafting (CABG) with
Cardiopulmonary Bypass (CPB) | 31.1
 |
| Karkouti et al3 | Cardiac surgery with
Cardiopulmonary Bypass (CPB) | 72.1 |
| i3 – Premier4 | 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  |  |  |

## Population - Size

| Study | Exposure | NEJM 2006(N) | JAMA 2007(N) | 	JAMA 2007 (% ) |
| --- | --- | --- | --- | --- |
| Mangano et al | Aprotinin 
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 al | Aprotinin
Tranexamic acid (control) | 449 	(586)
449 	(10,284) |  |  |
| i3 - Premier  | Aprotinin
Aminocaproic acid
Tranexamic acid | 	29,358
	35,719
	1,358 |  |  |

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

## Definitions Exposure & Outcome

## 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 |

## Outcomes - During Hospital Stay

|  | Cardiovascular | Cerebral | Renal | Death |
| --- | --- | --- | --- | --- |
| Mangano et al | Myocardial Infarction Heart failure | StrokeComa Encephalopathy | Dysfunction  Failure | In-hospital
5-yr long-term |
| Karkouti et al
 | Myocardial Infarction | Stroke | DysfunctionFailure | In-hospital |
| I3 - Premier | Heart Failure
Acute Coronary Revascularization | Stroke | Failure | In-hospital |

## Cardiovascular

| Mangano 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 |

## 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 |

## Renal

| Mangano | Dysfunction | 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 |

## 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 |

## Percent Lost-to-Follow-upby Treatment Group

*Mangano 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 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*

## Renal Failure Covariates - i3 Premier 

|  | Odds Ratioadjusted | 95% CI |
| --- | --- | --- |
| Aprotinin | 1.7 | 1.6 - 1.9 |
|  |  |  |
| Diabetes | 2.6 | 2.3 - 2.9 |
| Liver 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

## Cardiovascular

| Study | Group | Risk Ratio
adjusted | 95% CI / 
p value |
| --- | --- | --- | --- |
| Mangano et al | Primary
Complex | 1.4
1.1 | 1.1 - 1.9
0.8 - 1.6 |
| Karkouti et al | Matched | 1.5 | p = 0.7 |
| I3- Premier
 | ACR
HF | 1.3
1.1 | 1.1 - 1.8
1.0 - 1.1 |
| ACR = Acute Coronary Revascularization; HF = Heart Failure |  |  |  |

## Cerebrovascular

| Study | Group | Risk Ratio
adjusted | 95% CI / 
p value |
| --- | --- | --- | --- |
| Mangano et al | Primary
Complex | 2.2
1.3 | 1.1 - 4.1
0.7 - 2.4 |
| Karkouti et al | Matched | 1.0 | p = 0.7 |
| I3 Premier
 | All patients
2+ hospital days pre-CABG | 1.2
1.2 | 1.1 - 1.4
1.1 - 1.4 |
| * CVE = cerebrovascular event defined as stroke, encephalopathy, or coma. |  |  |  |

## Renal

| Study | Group | Risk Ratio 
adjusted | 95% CI / 
p value |
| --- | --- | --- | --- |
| Mangano et al | Primary: dysfunction or failure
Complex: dysfunction or failure | 2.3
2.6 | 1.3 - 4.3
1.4 - 5.0 |
| Karkouti et al | Dysfunction - 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 Premier
 | All patients
2+ hospital days pre-CABG | 1.7
1.7 | 1.6 - 1.9
1.6 - 1.9 |

## Death

| Study | Group | Risk Ratio
adjusted | 95% CI / 
p value |
| --- | --- | --- | --- |
| Mangano et al | Primary
Complex | 1.6
0.9 | 0.8 - 3.3
0.4 - 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 patients
2+ hospital days pre-CABG | 1.7
1.7 | 1.5 - 1.8
1.5 - 1.8 |

## 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 | % | % | Risk Ratio | % | % | Risk Ratio |
| 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 |  |  |  |  |  |  |  |  |  |

## 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

## Acknowledgements

| OSE | 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. |