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Statistical Review of the Observational Studies of Aprotinin Safety

Part II:The i3 Drug Safety Study

CRDAC and DSaRM MeetingSeptember 12, 2007

P. Chris Holland, M.S.Quantitative Safety and Pharmacoepidemiology Group

Office of Biostatistics

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Outline

• Objective• Background• Statistical Methods• Results

– Aprotinin vs. Aminocaproic Acid and Tranexamic Acid

• Comparisons between FDA and i3 results– Aprotinin vs. No Treatment

• Summary

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Objectives

• To examine the statistical robustness of the conclusions from the i3 Drug Safety study by implementing an alternative methodology

• To compare aprotinin patients to patients who receive no IV antifibrinolytic (AF) with respect to:– All-cause in-hospital mortality– Cardiovascular outcomes– Cerebrovascular outcomes– Renal outcomes

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Background

Preliminary Report Title: Mortality and Cardiovascular and Renal

Outcomes in Recipients of Aprotinin, Aminocaproic Acid and Tranexamic Acid

during CABG Surgery

Report on Computerized Inpatient Data from the Premier Perspective Comparative Database

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Sets of Analyses

Date NameAprotinin

N Comparison Group (N)9/06 Preliminary i3 Drug

Safety report29,358 Aminocaproic or

Tranexamic acid (37,077)

3/07-7/07

FDA analysis of preliminary report

data

29,358 Aminocaproic or Tranexamic acid (37,077)

8/07 FDA analysis of aprotinin vs. no treatment group

29,358 No treatment (51,588)

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Data Provided to and Analyzed by FDA

Data Set 2:69,176 patients

received no IV AF during CABG

Data Set 1:66,435 patients in the

preliminary study*

29,358 patients in aprotinin group

37,077 patients in other IV AF group

35,719 patientsin aminocaproic

acid group

1,358 patients in tranexamic

acid group

51,588 patients received no IV AF during or after CABG

17,588 patients received IV AFs after CABG

* Only includes patients who received a minimum sufficient dose of an IV AF agent

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Study Limitations• Accuracy of derivations for outcomes and covariates has

not been evaluated– For example, no medical chart review

• Unavailable Covariates– Creatinine levels, hemoglobin levels, platelet counts, use of

aspirin, use of heparin, use of antithrombotics, etc.• Outcome Definitions

– Not all outcomes are explicitly collected • (e.g., dialysis is a surrogate for renal failure)

– Heart failure and renal failure not evaluable on the day of CABG surgery

• Unable to determine whether they occur before or after CABG– Only in-hospital deaths are available

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Statistical Methods

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Statistical Methods• Propensity score (PS) methods were used for all FDA-

conducted statistical analyses• Subgroup and other sensitivity analyses were conducted

in order to assess the statistical robustness of the overall results– Sensitivity:

• Time adjusted rates (rates per patient weeks)• Analyses of patients with >1 and >3 hospital days prior to surgery• Analyses of patients in PS Deciles 1-9

– Subgroups:• Age (>65, <65)• Gender (Male, Female)• Race (White, Other)

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Propensity Score Analysis

• Stratified analysis:– Hospital characteristics that are predictive of aprotinin

use were chosen to create strata• Resulted in:

– 8 strata for aprotinin vs. other IV AFs– 4 strata for aprotinin vs. no treatment

– PS modeling performed within each strata • allows for better PS estimates• PS deciles constructed within each stratum

• Final estimates are weighted averages across strata (hospital characteristics and deciles)

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Patients Excluded for FDA Analysis• Patients with 0 days of

follow-up excluded from:– Heart failure outcome

analysis– Renal failure outcome

analysis

• Patients who met the criteria for pre-existing renal failure excluded from: – Renal failure outcome

analysis

ReasonAprotinin

n (%)

No Treatment

n (%)Other IV

AFs n (%)Death 231 (0.79) 159 (0.31) 115 (0.31)

Unknown 6 (0.02) 61 (0.12) 1 (0.00)

ReasonAprotinin

n (%)

No Treatment

n (%)Other IV

AFs n (%)Pre-existing renal failure

490 (1.67) 803 (1.56) 399 (1.08)

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Results

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Demographics

Characteristic

AprotininN=29,358

(%)

No Treatment N=51,588

(%)

Other IV AFs N=37,077

(%)Race

White 78.2 75.8* 73.4*

Black 6.3 6.5 5.4*

Other 15.5 17.6* 21.2*

Mean Age (SD) 67 (11) 66 (11)* 65 (11)* Range 19-89 18-89 18-89

Male 70.8 69.8 71.5

Current/previous smoker 18.2 17.9 17.2

* p<0.001 compared to aprotinin

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Selected Baseline Risk Factors

Characteristic

AprotininN=29,358

(%)

No Treatment N=51,588

(%)

Other IV AFs

N=37,077(%)

Non-elective surgery 50.1 55.6* 52.8*

Re-do cardiac surgery 4.3 1.7* 1.6*

Additional cardiac surgery 26.2 13.6* 19.4*

Pre-existing renal failure 1.7 1.6 1.1*

Old myocardial infarction 14.9 14.9 13.7*

Old stroke 5.2 4.6* 4.4*

* p<0.001 compared to aprotinin

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Unadjusted Outcome Rates

OutcomeAprotininN=29,358

No Treatment N=51,588

Other IV AFs

N=37,077Death (all-cause in-hospital)

4.7% 2.6% 2.5%

Stroke (non- hemorrhagic)

2.1% 1.7% 1.6%

Acute Renal Failure 3.1% 1.8% 1.7%

Acute Heart Failure 13.9% 10.8% 12.1%

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Results

FDA Analysis of Aprotinin vs. Aminocaproic Acid and Tranexamic

Acid and Comparison with Preliminary Report Results

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Risk Ratios – All Outcomes

RR and 95% Confidence Interval

0.32 1 3.16

Heart Failure ( 29121 : 36961 )

Renal Failure ( 28639 : 36567 )

Stroke ( 29358 : 37077 )

Death ( 29358 : 37077 )

1.20 ( 1.14, 1.26)

1.82 ( 1.61, 2.06)

1.24 ( 1.07, 1.44)

1.54 ( 1.38, 1.73)

Outcome(Aprotinin N:Control N) RR (95% CI)

All Antifibrinolytic Patients(Aprotinin N=29358, Control N=37077)

NOTE: Values greater than 1 indicate greater risk for aprotinin patients

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Comparisons of Estimates forAprotinin vs. Other IV Antifibrinolytics

OutcomeUnadjustedRisk Ratio

i3 AnalysisOdds Ratio

FDARisk Ratio

Death 1.84 (1.69, 1.99) 1.68 (1.53, 1.84) 1.54 (1.38, 1.73)

Stroke 1.36 (1.22, 1.52) 1.20 (1.07, 1.35) 1.24 (1.07, 1.44)

Renal Failure 1.87 (1.68, 2.06) 1.70 (1.55, 1.86) 1.82 (1.61, 2.06)

Heart Failure 1.15 (1.10, 1.20) 1.08 (1.03, 1.14) 1.20 (1.14, 1.26)

• i3 analysis based on multivariate logistic regression results (OR used to estimate RR)• Crude and FDA analyses of renal failure excluded patients with pre-existing renal failure and with zero days of follow-up• Crude and FDA analyses of heart failure excluded patients with zero days of follow-up

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Results

FDA Analysis of Aprotinin vs. No Treatment

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Strata Sample Sizes

Strata AprotininNo

Treatment

Ratio(No Treatment/

Aprotinin)South, Teaching 9,811 17,936 1.83

South, non-Teaching 8,359 10,265 1.23

Non-South, Teaching 5,863 17,531 2.99

Non-South, non-Teaching 5,325 5,856 1.10

Total 29,358 51,588 1.76

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Propensity Score Estimation and Assessment of Overlap and Balance

• PS scores were estimated separately for each stratum– Patients were divided into PS deciles within

each stratum• Assessment of Overlap and Balance:

– PS overlap between treatment groups within each decile was good

– Analyses showed good balance between treatment groups with respect to most risk factors

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Good overlap between groups

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Selected Baseline Risk Factors Pre- and Post-Adjustment

Before PS Adjustment After PS Adjustment

Aprotinin%

No Treat.% P-Value

Aprotinin%

No Treat.% P-Value

Non-elective surgery 50.1 55.6 <0.001 53.8 53.7 0.871

Re-do cardiac surgery 4.3 1.7 <0.001 2.8 2.3 <0.001

Additional cardiac surgery

26.2 13.6 <0.001 18.9 18.1 <0.001

Pre-existing renal failure

1.7 1.6 0.219 1.5 1.6 0.831

Old myocardial infarction

14.9 14.9 0.945 14.9 15.0 0.536

Old Stroke 5.2 4.6 <0.001 5.0 5.0 0.777

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Risk Ratios – All Outcomes

RR and 95% Confidence Interval

0.32 1 3.16

Heart Failure ( 29121 : 51368 )

Renal Failure ( 28639 : 50576 )

Stroke ( 29358 : 51588 )

Death ( 29358 : 51588 )

1.17 ( 1.13, 1.22)

1.50 ( 1.36, 1.67)

1.12 ( 1.00, 1.25)

1.55 ( 1.43, 1.68)

Outcome(Aprotinin N:Control N) RR (95% CI)

Aprotinin and No Treatment Patients(Aprotinin N=29358, Control N=51588)

NOTE: Values greater than 1 indicate greater risk for aprotinin patients

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Risk Differences – All Outcomes

Risk Difference per 100 Patients

-4 -2 0 2 4

Heart Failure ( 29121 : 51368 )

Renal Failure ( 28639 : 50576 )

Stroke ( 29358 : 51588 )

Death ( 29358 : 51588 )

2.06 ( 1.53, 2.60)

1.04 ( 0.78, 1.30)

0.22 ( 0.00, 0.45)

1.65 ( 1.34, 1.96)

Outcome (N) RD (95% CI)

Aprotinin and No Treatment Patients(Aprotinin N=29358, Control N=51588)

NOTE: Values greater than 0 indicate greater risk for aprotinin patients

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Risk Ratios – Death

RR and 95% Confidence Interval

0.1 0.32 1 3.16 10

Overall ( 29358 : 51588 )

Non-South, Non-Teaching ( 5325 : 5856 )

Non-South, Teaching ( 5863 : 17531 )

South, Non-Teaching ( 8359 : 10265 )

South, Teaching ( 9811 : 17936 )

1.55 ( 1.43, 1.68)

1.43 ( 1.13, 1.81)

1.84 ( 1.56, 2.18)

1.53 ( 1.30, 1.80)

1.47 ( 1.29, 1.68)

Strata(Aprotinin N : Control N) RR (95% CI)

Aprotinin and No Treatment Patients Outcome= Death

NOTE: Values greater than 1 indicate greater risk for aprotinin patients

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Risk Ratios – Renal Failure

RR and 95% Confidence Interval

0.1 0.32 1 3.16 10

Overall ( 28639 : 50576 )

Non-South, Non-Teaching ( 5241 : 5708 )

Non-South, Teaching ( 5688 : 17211 )

South, Non-Teaching ( 8139 : 10116 )

South, Teaching ( 9571 : 17541 )

1.50 ( 1.36, 1.67)

1.31 ( 1.00, 1.71)

1.69 ( 1.38, 2.08)

1.67 ( 1.36, 2.06)

1.39 ( 1.18, 1.64)

Strata(Aprotinin N : Control N) RR (95% CI)

Aprotinin and No Treatment Patients Outcome= Renal Failure

NOTE: Values greater than 1 indicate greater risk for aprotinin patients

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Sensitivity Analyses – Risk Ratios

OutcomeAll

Patients

>1 Pre-surgery

Days

>3 Pre-surgery

DaysDeciles 1-9 Only

Events per Patient-weeks

Death 1.55 (1.43, 1.68)

1.64 (1.48, 1.81)

1.62 (1.42, 1.84)

1.64 (1.51, 1.79)

1.54 (1.41, 1.68)

Stroke 1.12(1.00, 1.25)

1.12 (0.97, 1.29)

1.08 (0.90, 1.29)

1.19 (1.06, 1.33)

1.12 (1.00, 1.25)

Renal Failure

1.50(1.36, 1.67)

1.53 (1.33, 1.75)

1.41 (1.19, 1.66)

1.58 (1.42, 1.76)

1.48 (1.33, 1.64)

Heart Failure

1.17 (1.13, 1.22)

1.10 (1.01, 1.19)

1.19 (1.10, 1.28)

1.11 (1.02, 1.22)

1.01 (0.92, 1.12)

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Summary

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Summary• Compared to other IV antifibrinolytics and no treatment,

aprotinin is associated with increased risks of:– Death– Renal failure– Heart failure– Stroke

• Study limitations:– Unavailable confounders for which adjustments could not have

been made– Accuracy of the derivations for covariates and outcomes has not

been evaluated– No medical chart review

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Acknowledgements

Mark Levenson, Rita Ouellet-Hellstrom, Allen Brinker, George Shashaty, Tiffany Brown, Dwaine Rieves, Kathy Robie-Suh, Karen Weiss, Gerald Dal Pan