# Presentation: 680876

## Outcomes Using Aprotinin Therapy

- Linda Shore-Lesserson, M.D.
- Associate Professor
- Department of Anesthesiology
- Montefiore Medical Center
- Bronx, New York

- Randomized Trials vs. Observational Studies

## Disclosure

- Worked with aprotinin since 1993 (compassionate use protocol)
- Clinical research- Bayer support
- Consultant- TMC, Abbott, AZ, Bayer
- Speakers Bureau- TMC, Abbott, Bayer, ARC
- McSPI member
- PI for McSPI project on antifibrinolytic Rx

## Major Points

- Cardiac surgery becoming  complex
- Preponderance of RCTs show reduced blood loss and transfusion and reops
- STS/SCA Guidelines
- Clinical experience agrees with RCT
- Observational studies cannot control for ALL confounders, esp if unmeasured or unknown.

## Meta-Analysis

- Randomized trials, double blind CABG
- 72 trials by Med Search
- 35 trials (n=3887) listed adverse events
- 29 used full dose aprotinin

- Sedrakyan et al: JTCVS 2004;128:442-8

## Events/Number

**Transfusion****    793/1966    936/1464**
**Mortality        ****53/2149     39/1630**
**MI                   ****96/2024     77/1531**

**Renal Failure    ****26/1755   16/1248**
**Stroke                ****19/1714   28/1262**
**A Fib     ****              320/1408   263/1052**

- Sedrakyan et al: JTCVS 2004;128:442-8

## Rise of Catheter Based Therapies

## Meta-Analysis in CPB

- Medline and Cochrane database
- 1999-2004
- Clopidogrel within 7days vs. control
- Blood loss, transfusions, AE’s, vent time, LOS, death, reops
- (n=4002), n=605 clop, n=3397 control

- Purkayastha S: Heart 2006;92:531-532

## Clopidogrel Group

-  Blood loss
-  Transfusion requirements
-  AE’s
-  LOS
-  Re-exploration
-  Ventilator time

- Purkayastha S: Heart 2006;92:531-532

## Meta-Analysis in CPB

- Purkayastha S: Heart 2006;92:531-532

|  | WMD/OR | Heterog | p |
| --- | --- | --- | --- |
| CTD (ml) | 323ml [137-510] | Y | <0.01 |
| Tx req (U) | 1.36U [0.8-1.92] | Y | <0.01 |
| Tx risk (%) | 4.9 [2.79-8.59] | Y | <0.01 |
| Reop (%) | 6.76 [3.37-13.56] | N | <0.01 |
| LOS (d) | 1.18d [0.24-2.12] | Y | 0.01 |

## Blood Loss in CABG

**n=73, p<0.001**

- Van der Linden: Circulation 2005;112:I276-80

## Transfusion in CABG

**P<0.04**

- Van der Linden: Circulation 2005;112:I276-80

## CABG After ACS

- ACS- unstable angina or NSTEMI
- CABG performed after at least 5 days
- Randomization (n=49)
- Continue clop and ASA, HD aprotinin (mean drug Rx time 17d)
- D/C drugs 5d prior, heparin IV until 30mins

- Akowuah et al: Ann Thorac Surg 2005;80:149-52

## Bleeding and Transfusion

- Akowuah et al: Ann Thorac Surg 2005;80:149-52

|  | Aprotinin + Clop | Heparin  Rx  no Clop | p |
| --- | --- | --- | --- |
| 8H CTD (ml) | 265±169 | 385±273 | 0.036 |
| Total CTD (ml) | 447±287 | 702±495 | 0.004 |
| CT time (hr) | 19.6±6.8 | 22.8±7.7 | 0.004 |
| RBC (U) | 0.32±1.2 | 1.0±1.7 | 0.03 |

## Clinicians Do Not “Agree” With Findings of this Observational Study

- Unusual circumstances of authorship given the history of McSPI

## Slide 15

## Slide 16

## Slide 17

## Slide 18

## CABG-Surgery in Europe and North America: Timelines and Outcomes

- Ott E, Moehnle P, Tudor C, Hsu PH, Mangano DT

*Anesthesiology 2003;99:A254*
*(Submitted, in revision, JTCVS)*

## Ott E et al: Anesthesiology 2003;99:A254

| 
Outcome % | UK
(n = 619) | Canada
(n = 444) | USA
(n = 1,283) | Germany
(n = 8 34) | p value  |
| --- | --- | --- | --- | --- | --- |
| In-hospital Mortality | 1.5‡ | 2.0 | 2.7 | 3.8 | 0.034 |
| Cardiac morbidity | 9.2‡ | 12.4 | 13.6 | 18.5 | < 0.001 |
| Morbidity and/or mortality* | 12.4‡ | 15.5 | 18.0 | 23.9 | < 0.001 |
| Aprotinin  (%) | 23.1 | 5.7 † | 19.5 | 69.3 ‡ | <0.001 |
| FFP in OR  (%) | 2.4 †
 | 1.4 †
 | 8.4
 | 10.6
 | <0.001 |

## Slide 21

## Renal Composite Outcomes

- Mangano DT et al: NEJM 2006;34:353-65

| Risk Factor | OR | OR p propensity | P value |
| --- | --- | --- | --- |
| Aprotinin | 2.52 | 2.41[1.49-3.90] | <0.001 |
| Hx renal dz | 2.5 | 2.53[1.70-3.75] | <0.001 |
| Creat > 1.3 | 2.71 | 3.12[2.11-4.60] | <0.001 |
| CHF adm | 2.33 | 2.64[1.84-3.80] | <0.001 |
| FFP admin | 2.51 | 2.40[1.58-3.66] | <0.001 |
| Hx liver dz | 0.35 | 0.28[0.13-0.61] | <0.001 |

## Slide 23

## Summary

- Cardiac surgery has become increasingly complex.
- Hemostasis improved by aprotinin
- RCT’s and clinical impression of clinicians support that end-organ outcomes are either unchanged or *improved* with aprotinin.

## Summary

- Observational study captures that aprotinin is selected in higher risk patients.  (Mangano 2006)
- There is a true “association” of morbid outcomes with aprotinin because they are co-linear.
- Even the best propensity matching cannot control for this selection bias.

## Conclusion

- Covariates not evaluated (or not published) in the NEJM study:
- Country, FFP use, CPB time, aspirin use
- Covariates not measured in NEJM 2006
- Surgeon expertise, regional techniques
- To suggest cause and effect (ischemic events) from observational data is irresponsible
- To suggest use of cheaper alternatives unstudied and not labelled for this use is irresponsible