# Presentation: 660747

## Post-Marketing Safety Surveillance:

***Serine Protease Inhibitors & Anti-Fibrinolytics***

***Observational Study Paradigm***

**D. T. Mangano, Ph.D., M.D.**
**The Ischemia Research and Education Foundation (IREF)**
**The *****McSPI***** Research Group (*****McSPI*****)**

## Potential Conflict of Interest Declarations

**Potential Conflict of Interest Declarations**
**[www.iref.org]**

**JTCVS **
**[May 2007]**

**The Risk Associated with Aprotinin **
**in Cardiac Surgery**

**Mortality Associated with Aprotinin During**
** ****5 Years Following CABG Surgery**

**CABG Surgery Care Globalization: **
**The Impact of National Care on Fatal and Nonfatal Outcome**

**JAMA**
** ****[February 2007]**

**NEJM **
**[January 2006]**

## No Conflicts

| 
Investigator     Institution    Country | Conflict  | Years | Amount | Agency | Activity |
| --- | --- | --- | --- | --- | --- |
| 
Mangano             IREF               USA
Dietzel 
Miao
Tudor
Titov
  | 
NO
NO 
NO
NO
NO
 | 
-
-
-
-
-
- | 
-
-
-
-
-
- | 
-
-
-
-
-
- | 
None
None
None
None
None
 |

***No Conflicts***

**The Risk Associated with Aprotinin in Cardiac Surgery**

**NEJM ****[January 2006]**

## JAMA [February 2007]

| 
Investigator       Institution                            Country | Conflict  | Years | Amount | Agency | Activity |
| --- | --- | --- | --- | --- | --- |
| 
Mangano            IREF                                    USA
Dietzel 
Miao
Tudor
Titov
 | 
NO
NO 
NO
NO
NO
 | 
-
-
-
-
- | 
-
-
-
-
- | 
-
-
-
-
- | 
None
None
None
None
None
 |
| Vuylsteke          Papworth Hospital              UK | NO | - | - | - | None |
| Juneja               Escorts Heart Institute        India                   | NO | - | - | - | None |
| Filipescu           Institute of Cardiology        Romania | YES | 2002
 | $500
 | Bayer
 | Meeting  Fees |
| Hoeft                 Universitaet Bonn                Germany | NO | - | - | - | None |
| Fontes                Yale University                    USA | YES | 1994-99 | $4000 | Bayer | Honoraria  |
| Hillel                  Columbia University           USA | NO | - | - | - | None |
| Ott                     Ludwig-Maximill.Univer    Germany               | NO | - | - | - | None |
| Levin                 University of California      USA                          | NO
 | - | - | - | None |

**JAMA ****[February 2007]**

**Mortality Associated with Aprotinin During 5 Years Following CABG Surgery**

## JTCVS [May 2007]

| 
Investigator       Institution                            Country | Conflict  | Years | Amount | Agency | Activity |
| --- | --- | --- | --- | --- | --- |
| 
Mangano            IREF                                    USA
Tudor
 | 
NO
NO 
 | 
-
- | 
-
- | 
-
- | 
None
None
 |
| Ott                     Ludwig-Max University      Germany               | NO | - | - | - | None |
| Mazer               University of Toronto          Canada                  | YES | Current | tbd | Bayer | Consultant |
| Shore-               Montefiore Med Ctr             USA
Lesserson | YES | Current | tbd | Bayer | Consultant |
| Snyder-             University of Heidelberg    Germany     
Ramos | NO | - | - | - | None |
| Finegan             University of Alberta          Canada            | NO | - | - | - | None |
| Molne                Ludwig-MaxUniversity      Germany | NO | - | - | - | None |
| Hantler             Washington University       USA            | NO | - | - | - | None |
| Bottiger            University of Heidelberg     Germany

Latimer            Cambridge University         UK      

Browner            Cal-Pacific Med Ctr           USA

Levin                 University of California      USA
 | NO

NO

NO

NO | -

-

-

- | -

-

-

- | -

-

-

- | None

None

None

None |

**CABG Surgery Care Globalization: Impact of National Care on Outcome**

**JTCVS ****[May 2007]**

## Post-Marketing Safety Surveillance:

***Serine Protease Inhibitors & Anti-Fibrinolytics***

***Observational Study Paradigm***

**D. T. Mangano, Ph.D., M.D.**
**The Ischemia Research and Education Foundation (IREF)**
**The *****McSPI***** Research Group (*****McSPI*****)**

##                Aprotinin Early Development 

**	**
**          *********     *****Aprotinin Early Development**** **
***          **********      *****The Acute Graft Occlusion Issue**
**	**** *********    *****The Kidney Toxicity Issue**
***  *****	**** ********* ******    *****The Long-Term Mortality Issue**
**        *********  ******   *****Anticipated Questions / Responses**
**        **** *********    *****Impressions**

***Outline***

##                Aprotinin Early Development 

**	**
**          *********     *****Aprotinin Early Development**** **
***          **********      *****The Acute Graft Occlusion Issue**
**	**** *********    *****The Kidney Toxicity Issue**
***  *****	**** ********* ******    *****The Long-Term Mortality Issue**
**        *********  ******   *****Anticipated Questions / Responses**
**        **** *********    *****Impressions**

***Outline***

## 1959

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

***1959***

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**Trasylol****used in****patients**

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

_**Royston **_***[Lancet]***** ****22**** ****patients****Aprotinin**** ****[11]****Control [11]**

**Lancet 1987; 2:1289.**

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

_**Cosgrove**__***[***_***ATS]*****169**** ****patients****Aprotinin-h [57] Aprotinin-l [56] Control [56]**

**ATS 1992; 54:1031.**

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## FDA Approval

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** **
***Timeline***

***1993******12***

_**FDA **_**Approval**

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## QLimited Indication:CABG (+ CPB)   + ↑↑↑ Risk for Bleeding.

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

***1993******12***

_**FDA **_**Approval**

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_***Q***__***Limited Indication:***_***CABG (+ CPB)******   ****+**** ↑↑↑ Risk for Bleeding******.***

_**FDA **_**Approval**

## ‘99

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_**D’Ambra**__***[***_***JTCVS]***** ****222**** ****patients**** ****Aprotinin-l [70] Aprotinin-h [71] Control [71]**

**JTCVS 1994; 107:543.**
**Circulation 1995; 92:2236.**
**JTCVS***** *****1996; 112:1081.**

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_**Levy **__***[***_***Circ]*****287**** ****patients**** ****Aprotinin-h [73] Aprotinin-l [70] **** Aprotinin-p [72] Control [72]**

_**Lemmer **__***[***_***JTCVS]*****196**** ****patients**** ****Aprotinin-1 [74] Placebo-1 [67] **** Aprotinin-2 [23] Placebo-2 [32]**

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

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##                                         circa 1997...........

***    ******♦    ***_**Aprotinin Efficacy  **_
**	****	****       **_***All RCTs***_**         *****Substantial ******Blood-Sparing Effects***
***                ******	******	***
***    ******♦******    ***_**Aprotinin Safety      **_
***	******	******       ***_***Nearly All RCTs***_***      *****  *****No Safety Concerns    ***

##                Aprotinin Early Development  √

**	**
**          *********     *****Aprotinin Early Development**** ***** *****√**
***          **********      *****The Acute Graft Occlusion Issue**
**	**** *********    *****The Kidney Toxicity Issue**
***  *****	**** ********* ******    *****The Long-Term Mortality Issue**
**        *********  ******   *****Anticipated Questions / Responses**
**        **** *********    *****Impressions**

***Outline***

## ‘99

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

_**Cosgrove**__***[***_***ATS]*****169**** ****patients****Aprotinin-h [57] Aprotinin-l [56] Control [56]**

**ATS 1992; 54:1031.**

***‘******59***

## “Acute vein graft thrombosis was 

_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

**“****Acute vein graft thrombosis was **
**found in 6 of 12 vein grafts studied **
**at postmortem examination in **
**patients receiving aprotinin but **
**not in any of the five grafts in **
**patients receiving placebo.” **

## FDA Graft Thrombosis

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

_**Cosgrove**__***[***_***ATS]*****169**** ****patients****Aprotinin-h [57] Aprotinin-l [56] Control [56]**

***‘******59***

***1994******3***

_**FDA **_**Graft Thrombosis**

**ATS 1992; 54:1031.**

## FDA Review

_** **_
**1,267**** ****placebo-treated patients**
**   ****2,204 ****aprotinin-treated patients**
** **
_**Results**_**:****  ****A significant association between **
**aprotinin use and coronary graft closure **
**was found.***** **
**    ► ****Lead to ........**
- *http://www.fda.gov/cder/foi/nda/98/020304s004.htm

_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

## Alderman[JTCVS ] IMAGE 703 patientsAprotinin [363]Control [340](‘93→’98)

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** **
***Timeline***

_**Alderman**__***[***_***JTCVS ]***** ****IMAGE ****703**** ****patients****Aprotinin [363]****Control [340]****(‘93****→’98)**

**JTCVS***** *****1998; 116:716.**

##   13 International sites

_***Aprotinin***_*** *****(Trasylol****©****)**
***Timeline***

**JTCVS***** *****1998; 116:716.**

***  ******13 ******International sites***
***703 ******Primary CABG***
***[A=363; P=340]***
***Angiography @ 11 days***

##    Acute Vein Graft Occlusion 

_***Aprotinin***_*** *****(Trasylol****©****)**
***Timeline***

_**Prespecified Endpoint**_**: **
**   ****Acute Vein Graft Occlusion***** ***

## Aprotinin:  ↑41% Acute Graft Occlusion 

_***Aprotinin***_*** *****(Trasylol****©****)**
***Timeline***

_**Prespecified Endpoint**_**: **
**   ****Acute Vein Graft Occlusion***** ***

_**Results**_**:**
***Aprotinin:  *****↑****41% ****Acute Graft Occlusion **
**                                   ****[15.4% v   10.9%]***** ***

##   Aprotinin        ↑4,500 vein-graft occlusions / year

_***Aprotinin***_*** *****(Trasylol****©****)**
***Timeline***

_**Prespecified Endpoint**_**: **
**   ****Acute Vein Graft Occlusion***** ***

_**Inference:**_
***  ******Aprotinin*****        ****↑****4,500 vein-graft occlusions ****/ year**
**                                         *****(per 100,000 administrations) ***
***                                             ***

_**Results**_**:**
***Aprotinin:  *****↑****41% ****Acute Graft Occlusion **
**	****                 ****[15.4% v   10.9%]***** ***

##   Aprotinin        ↑4,500 vein-graft occlusions / year

_***Aprotinin***_*** *****(Trasylol****©****)**
***Timeline***

_**Prespecified Endpoint**_**: **
**   ****Acute Vein Graft Occlusion***** ***

_**Inference:**_
***  ******Aprotinin*****        ****↑****4,500 vein-graft occlusions ****/ year**
**                                         *****(per 100,000 administrations) ***
***                                             ***

_**Results**_**:**
***Aprotinin:  *****↑****41% ****Acute Graft Occlusion **
**	****                 ****[15.4% v   10.9%]***** ***

***“******Conclusions:  In this study the probability of early vein ***
***occlusion was increased by aprotinin, but this outcome ***
***was promoted by multiple risk factors for graft occlusion.” ***

## Regulatory decision:

***                         ******IMAGE data / interpretation added to package insert***

***      ******Mid 1998***

***Regulatory decision:***

***In late 1998, in an unrelated action......***

## FDA Expanded theIndication

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

***1998******3***

_**FDA **_**Expanded the****Indication**

## Aprotinin’s anti-inflammatory properties

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

***1998******3***

***Aprotinin’s ******anti-inflammatory properties***

_**FDA **_**Expanded the****Indication**

## Aprotinin’s anti-inflammatory properties

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

***1998******3***

***Aprotinin’s ******anti-inflammatory properties***

_***Expanded Indication:***_***All ******CABG (+ CPB)******  ****** ****+/-**  ****Risk for Bleeding***

_**FDA **_**Expanded the****Indication**

##    Parenthetically, our experience..........

**Bextra**** ****[COX-2****-****]**** ****(JTCVS, 2003)**
**Pexelizumab**** ****[mca-C****-****5a-9****]**** ****(JTCVS, 2004)**
**Cariporide**** ****[NH****+****EI]**** ****(unpub, 2005)**

***      ***
***   ******Parenthetically, our experience..........***

***   ******Net effect: 1998 to 2005........***

##                Rapid Growth:  1998 - 2005

_***2005***_***:     ******350,000 patients received Aprotinin***
_***2006***_*** ******[January]:    ******Projection > 700,000 patients***

##                Aprotinin Early Development  √

**	**
**          *********     *****Aprotinin Early Development**** ***** *****√**
***          **********      *****The Acute Graft Occlusion Issue ***** *****√**
**	**** *********    *****The Kidney Toxicity Issue ***** *****√**
***  *****	**** ********* ******    *****The Long-Term Mortality Issue ***** *****√**
**        *********  ******   *****Anticipated Questions / Responses ***** *****√**
**        **** *********    *****Impressions ***** *****√**

***Outline***

## ‘99

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

_**IREF/McSPI**__***[***_***NEJM]*****4,374 ****patients****Aprotinin [1,277]  ****EACA [883]  ****TEA [822]  ****Control [1,238]****  **

**N Engl J Med 2006; 354:353.**

## Renal Events Among the 4,374 Study Patients

**Results: *****Safety***

**N Engl J Med 2006; 354:353.**

**2.41**** ****[1.49-3.90] (P<0.001)**

## Results: Safety

**Results: *****Safety***

**N Engl J Med 2006; 354:353.**

**Aprotinin: Dose-Response**

**3.79**** ****[1.41-10.18] (P=0.0018)**

## Results: Safety

**Results: *****Safety***

**N Engl J Med 2006; 354:353.**

**Other Events Among the 4,374 Study Patients**

**1.39**** ****[1.13-1.72] (P=0.002)**

## ↑                    ↑

**N Engl J Med 2006; 354:353.**

**Results: *****Efficacy***

**EACA [24h] =****	****     719 ml****  ±  578 **
**TEA ****[24h] =***** *****	****     676 ml****  ±  741**
_**Aprotinin [24h] =   **__*** ***__**753 ml**__**  ±  660 **_
**Control [24h] =***** *****	****      827 ml****  ±  573**

**EACA/TEA [24h]**** =  ****692**** ml****  ±  659**
**Aprotinin [24h]**** = ****   *****  *****753**** ml****  ±  660 **
* ***Control [24h] =  ****  ****    ****827 ml*** ***±  573**

**↑                    ↑**

## FDAAdvisory Committee

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

_**IREF/McSPI**__***[***_***NEJM]*****4,374 ****patients****Aprotinin [1,277]  ****EACA [883]  ****TEA [822]  ****Control [1,238]****  **

_**FDA**_**Advisory ****Committee**

***2006******2c***

**N Engl J Med 2006; 354:353.**** **

## NO  ∆

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

_**IREF/McSPI**__***[***_***NEJM]*****4,374 ****patients****Aprotinin [1,277]  ****EACA [883]  ****TEA [822]  ****Control [1,238]****  **

_**FDA**_**Advisory ****Committee**

***2006******2c***

**N Engl J Med 2006; 354:353.**** **

**NO  ****∆**

## FDAAdvisory Committee

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

_**IREF/McSPI**__***[***_***NEJM]*****4,374 ****patients****Aprotinin [1,277]  ****EACA [883]  ****TEA [822]  ****Control [1,238]****  **

_**FDA**_**Advisory ****Committee**

***2006******2c***

_**Other Data**_
**67,000**** ****patients**
**Aprotinin [30,000]****Control [37,000]**

**N Engl J Med 2006; 354:353.**** **
**NYT 2006; Sept. 30:p1.**

## Slide 44

##        ‘In a highly unusual move, the food and drug agency released 

_**67,000 Patients**_
**30,000 Aprotinin**
**37,000 Placebo**

**       ****‘****In a highly unusual move, the food and drug agency released **
**       ****a public advisory saying it had learned of the study’s existence**
**	****	****only on Wednesday. **
**        ****Preliminary results of the study demonstrate “that use of **
**       ****Trasylol may increase the chance for death, serious kidney***** ***
**	****    ****damage, congestive heart failure and strokes,” the advisory **
**        ****said.’**

##        Preliminary results of the study demonstrate “that use of 

_**67,000 Patients**_
**30,000 Aprotinin**
**37,000 Placebo**

**       ****Preliminary results of the study demonstrate “that use of **
**        ****Trasylol may increase the chance for death, serious kidney***** ***
**	****    ****damage, congestive heart failure and strokes,” the advisory **
**        ****said.’**

##        Preliminary results of the study demonstrate “that use of 

_**67,000 Patients**_
**30,000 Aprotinin**
**37,000 Placebo**

**       ****Preliminary results of the study demonstrate “that use of **
**        ****Trasylol may increase the chance for death, serious kidney***** ***
**	****    ****damage, congestive heart failure and strokes,” the advisory **
**        ****said.’**

##        Preliminary results of the study demonstrate “that use of 

_**67,000 Patients**_
**30,000 Aprotinin**
**37,000 Placebo**

**       ****Preliminary results of the study demonstrate “that use of **
**        ****Trasylol may increase the chance for death, serious kidney***** ***
**	****    ****damage, congestive heart failure and strokes,” the advisory **
**        ****said.’**

##        Preliminary results of the study demonstrate “that use of 

_**67,000 Patients**_
**30,000 Aprotinin**
**37,000 Placebo**

**       ****Preliminary results of the study demonstrate “that use of **
**        ****Trasylol may increase the chance for death, serious kidney***** ***
**	****    ****damage, congestive heart failure and strokes,” the advisory **
**        ****said.’**

##        Preliminary results of the study demonstrate “that use of 

_**67,000 Patients**_
**30,000 Aprotinin**
**37,000 Placebo**

**       ****Preliminary results of the study demonstrate “that use of **
**        ****Trasylol may increase the chance for death, serious kidney***** ***
**	****    ****damage, congestive heart failure and strokes,” the advisory **
**        ****said.’**

## ‘99

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

_**Karkouti**__***[***_***Transfusion ]*****898**** ****patients****Aprotinin [449]  ****TEA [449]****  **

_**Ad**__***[***_***Circ]***

_**Brown**__***[***_***Nejm]***

_**IREF/McSPI**__***[***_***NEJM]*****4,374 ****patients****Aprotinin [1,277]  ****EACA [883]  ****TEA [822]  ****Control [1,238]****  **

***]****** ***_**Other Data**_
_***[***_***NYT***
**67,000**** ****patients**
**Aprotinin [30,000]****Control [37,000]**

**N Engl J Med 2006; 354:353.**** **
**N Engl J Med 2006; 354:2954 ****Transfusion 2006; 46:327.**
**Circulation 2006; 114:II 476.**
**NYT 2006; Sept. 30:p1.**

## > 80,000 patients 

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

_**Karkouti**__***[***_***Transfusion ]*****898**** ****patients****Aprotinin [449]  ****TEA [449]****  **

_**Ad**__***[***_***Circ]***

_**Brown**__***[***_***Nejm]***

_**IREF/McSPI**__***[***_***NEJM]*****4,374 ****patients****Aprotinin [1,277]  ****EACA [883]  ****TEA [822]  ****Control [1,238]****  **

***]****** ***_**Other Data**_
_***[***_***NYT***
**67,000**** ****patients**
**Aprotinin [30,000]****Control [37,000]**

**> ****80,000 ****patients**_*** ***_
**↑**** ****Renal Risk**** [40% to 150%]**

**N Engl J Med 2006; 354:353.**** **
**N Engl J Med 2006; 354:2954 ****Transfusion 2006; 46:327.**
**Circulation 2006; 114:II 476.**
**NYT 2006; Sept. 30:p1.**

## Thus, in 2006 Aprotinin Safety was challenged:

***Kidney Toxicity***

## 	Approval of Aprotinin

- 	**Approval of Aprotinin**
- 	**News 12/30/1993**
- 	P93-48					**Food and Drug Administration**
- 	**FOR IMMEDIATE RELEASE**			Susan M. Cruzan (301) 443-3285
- 	The Food and Drug Administration today announced approval of aprotinin, a drug that can reduce the need for 	blood transfusions in patients undergoing heart bypass surgery.  In 1991, 265,000 coronary bypass graft 	operations were performed to replace diseased blood vessels.  Excessive bleeding is a frequent complication of 	this surgery.
- 	Two placebo controlled clinical trials conducted in the United States demonstrated that aprotinin effectively 	reduced blood loss and decreased the need for transfusions.  In one study, 42 percent of patients treated with 	aprotinin needed at least one unit of blood, compared to 77 percent who did not receive the drug.  The second 	study showed similar results.
- 	Aprotinin was studied for use mainly in heart surgery because the circulation of the blood outside the body in 	this surgery 	increases the likelihood of excessive bleeding during and after surgery.  Its use should be reserved 	for high risk patients, however, because severe allergic reactions can result from using it more than once in a 	patient.  Kidney toxicity was also a problem in some patients in the trials.
- 	"Aprotinin can reduce the risks of bypass surgery for some patients," said FDA Commissioner David A. Kessler, 	M.D. "Fewer transfusions mean a much lower risk of infection or possible adverse reactions to the blood."
- 	Aprotinin will be most useful in patients at high risk of bleeding—particularly patients with clotting defects, for 	example. The drug may also be used in patients with rare blood types or in other cases when access to blood is 	limited.
- 	Miles Inc. of West Haven, Conn., will market aprotinin under the name Trasylol Injection.  The company has 	agreed to conduct further studies to evaluate the drug in other types of surgery associated with a high risk of 	bleeding, such as organ transplants and aortic reconstruction.

## “Kidney Toxicity was also a problem in some patients in the trials.”

- 	**Approval of Aprotinin**
- 	**News 12/30/1993**
- 	P93-48					**Food and Drug Administration**
- 	**FOR IMMEDIATE RELEASE**			Susan M. Cruzan (301) 443-3285
- 	The Food and Drug Administration today announced approval of aprotinin, a drug that can reduce the need for 	blood transfusions in patients undergoing heart bypass surgery.  In 1991, 265,000 coronary bypass graft 	operations were performed to replace diseased blood vessels.  Excessive bleeding is a frequent complication of 	this surgery.
- 	Two placebo controlled clinical trials conducted in the United States demonstrated that aprotinin effectively 	reduced blood loss and decreased the need for transfusions.  In one study, 42 percent of patients treated with 	aprotinin needed at least one unit of blood, compared to 77 percent who did not receive the drug.  The second 	study showed similar results.
- 	Aprotinin was studied for use mainly in heart surgery because the circulation of the blood outside the body in 	this surgery 	increases the likelihood of excessive bleeding during and after surgery.  Its use should be reserved 	for high risk patients, however, because severe allergic reactions can result from using it more than once in a 	patient.  Kidney toxicity was also a problem in some patients in the trials.
- 	"Aprotinin can reduce the risks of bypass surgery for some patients," said FDA Commissioner David A. Kessler, 	M.D. "Fewer transfusions mean a much lower risk of infection or possible adverse reactions to the blood."
- 	Aprotinin will be most useful in patients at high risk of bleeding—particularly patients with clotting defects, for 	example. The drug may also be used in patients with rare blood types or in other cases when access to blood is 	limited.
- 	Miles Inc. of West Haven, Conn., will market aprotinin under the name Trasylol Injection.  The company has 	agreed to conduct further studies to evaluate the drug in other types of surgery associated with a high risk of 	bleeding, such as organ transplants and aortic reconstruction.

**“****Kidney Toxicity was also a problem in some patients in the trials.”**

## In effect, in 2006 Aprotinin Safety was re-challenged:

***Kidney Toxicity***
***[validating the 1993 FDA concern] ***
*** ***

## 2007

##                Aprotinin Early Development  √

**	**
**          *********     *****Aprotinin Early Development**** ***** *****√**
***          **********      *****The Acute Graft Occlusion Issue ***** *****√**
**	**** *********    *****The Kidney Toxicity Issue ***** *****√**
***  *****	**** ********* ******    *****The Long-Term Mortality Issue ***** *****√**
**        *********  ******   *****Anticipated Questions / Responses ***** *****√**
**        **** *********    *****Impressions ***** *****√**

***Outline***

## ‘99

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

**JAMA 2007; 297:471.**

_**IREF/McSPI**__***[***_***JAMA]*****3,876 ****patients****Aprotinin**** [1,295]****  ****EACA**** ****[849****] ****TEA**** ****[512]****  ****Control**** ****[1,374]****  **

## Cumulative Mortality Curves Compared Among Study Groups

**JAMA 2007; 297:471.**

## Cumulative Mortality Curves Compared Among Study Groups

**JAMA 2007; 297:471.**

## Pre-existing Disease Differences

**Cox Proportional Hazard Survival Analyses with Propensity Adjustment**

|  | Analysis in Presence of Covariates without Propensity Adjustment |  | Analysis in Presence of Covariates with Propensity Adjustment |  |
| --- | --- | --- | --- | --- |
| Risk Factor | Hazard Ratio (95% CI) | P Value | Hazard Ratio (95% CI) | P Value |
| Aprotinin vs. control | 1.48 (1.19 – 1.85) | <.001 | 1.37 (1.09 – 1.73) | .008 |
| Aminocaproic acid vs. control | 1.03 (0.80 – 1.33) | .810 | 0.89 (0.68 – 1.17) | .395 |
| Tranexamic acid vs. control | 1.07 (0.80 – 1.45) | .641 | 1.04 (0.77 – 1.41) | .789 |
| Propensity score, deciles |            ― | ― | 1.06 (1.02 – 1.10) | .001 |
| Complex vs. primary surgery | 1.59 (1.32 – 1.90) | <.001 | 1.52 (1.25 – 1.83) | <.001 |
| Age / 10 years or > 60 years | 1.52 (1.37 – 1.69) | <.001 | 1.49 (1.34 – 1.66) | <.001 |
| History: CHF (hospitalization) | 1.61 (1.29 – 2.01) | <.001 | 1.64 (1.31 – 2.06) | <.001 |
| History: multiple MI | 1.27 (1.01 – 1.61) | .045 | 1.25 (0.98 – 1.59) | .069 |
| History: valve disease [surgery] | 1.39 (1.07 – 1.80) | .014 | 1.32 (1.01 – 1.72) | .043 |
| History: diabetes mellitus | 1.40 (1.17 – 1.67) | <.001 | 1.36 (1.13 – 1.64) | .001 |
| History: syncope  | 1.41 (1.08 – 1.84) | .011 | 1.41 (1.08 – 1.85) | .012 |
| History: peripheral vascular dis. | 1.46 (1.20 – 1.76) | <.001 | 1.46 (1.20 – 1.77) | <.001 |
| Preop: Creatinine >1.3 mg/dl | 1.77 (1.46 – 2.15) | <.001 | 1.75 (1.44 – 2.13) | <.001 |
| Preop: Stroke | 1.26 (1.06 – 1.50) | .010 | 1.26 (1.05 – 1.50) | .012 |
| Preop: CHF | 1.27 (1.05 – 1.53) | .013 | 1.29 (1.06 – 1.56) | .010 |
| Preop: MI | 2.02 (1.33 – 3.06) | .001 | 1.82 (1.16 – 2.85) | .009 |

## Thus, in 2007 Aprotinin Safety was challenged:

***  ******Long-Term Mortality***

##                Aprotinin Early Development  √

**	**
**          *********     *****Aprotinin Early Development**** ***** *****√**
***          **********      *****The Acute Graft Occlusion Issue ***** *****√**
**	**** *********    *****The Kidney Toxicity Issue ***** *****√**
***  *****	**** ********* ******    *****The Long-Term Mortality Issue ***** *****√**
**        *********  ******   *****Anticipated Questions / Responses**** ***** *****√**
**        **** *********    *****Impressions ***** *****√**

***Outline***

##          1.   Pre-existing disease:  Aprotinin  patients were sicker.

**  **_**NEJM/JAMA Studies**_**:**
**         ****1.****   **_**Pre-existing disease**_**:  *****Aprotinin  patients were sicker.***
**          ****2.****    **_**US versus non-US**_**:   *****Significant differences exist.***
**          ****3.****   **_**MI / CHF Definitions**_**:  *****Robustness of findings over a range of definitions.***
**          ****4.****   **_**Renal Findings**_**:   *****‘Tansient’, ‘Inconsequential’.***
**   **_**Prior Studies**_**:**
***           *****5.***** *****  **_**RCTs**_**:   *****RCTs are the ‘Gold Standard’ & the RCTs clearly prove Safety.***
**           ****6.****    **_**Meta-analyses**_**: *****“ Reliable”***

** ****6 Anticipated Questions & Responses***** ***

##          1.   Pre-existing disease:  Aprotinin  patients were sicker.

**  **_**NEJM/JAMA Studies**_
**         ****1.****   **_**Pre-existing disease**_**:  *****Aprotinin  patients were sicker.***
**          ****2.****    **_**US versus non-US**_**:   *****Significant differences exist.***
**          ****3.****   **_**MI / CHF Definitions**_**:  *****Robustness of findings over a range of definitions.***
**          ****4.****   **_**Renal Findings**_**:   *****‘Tansient’, ‘Inconsequential’.***
**   **_**Prior Studies**_**:**
***           *****5.***** *****  **_**RCTs**_**:   *****RCTs are the ‘Gold Standard’ & the RCTs clearly prove Safety.***
**           ****6.****    **_**Meta-analyses**_**: *****“ Reliable”***

** ****6 Anticipated Questions & Responses***** ***

##          1.   Pre-existing disease:  Aprotinin  patients were sicker.

**  **_**NEJM/JAMA Studies**_**:**
**         ****1.****   **_**Pre-existing disease**_**:  *****Aprotinin  patients were sicker.***
**          ****2.****    **_**US versus non-US**_**:   *****Significant differences exist.***
**          ****3.****   **_**MI / CHF Definitions**_**:  *****Robustness of findings over a range of definitions.***
**          ****4.****   **_**Renal Findings**_**:   *****‘Tansient’, ‘Inconsequential’.***
**   **_**Prior Studies**_**:**
***           *****5.***** *****  **_**RCTs**_**:   *****RCTs are the ‘Gold Standard’ & the RCTs clearly prove Safety.***
**           ****6.****    **_**Meta-analyses**_**: *****“ Reliable”***

** ****6 Anticipated Questions & Responses***** ***

## Pre-existing Disease:  Aprotinin patients were sicker.

_**Pre-existing Disease**_**:****  **_***Aprotinin patients were sicker.***_
**     ****1.  Covariate-adjusted Point Estimates**** ****√**
***     *****2.  Dose-response Validation**** ****√**
** ****     **
**     ****3.  Multivariable Logistic Regression Adjustment**** ****√**
**     ****4.  Cox Proportional Hazard Survival Analyses**** ****&**** Propensity Adjustment**** ****√**
**     ****5.  Average-of-Covariates Adjusted Survival**** ****√**
**     ****6.*****  *****Examples – Comparisons among high-risk patients****:  **
***                                            ******(1) In-hospital Renal Events      ***
***                                            ******(2) Long-term 5–year Mortality***

##  ↑                                      ↑

** ↑                                      ↑**

**High-Risk Subgroups **

**P<0.001    P<0.001       P<0.001     P<0.001       P=0.006     P<0.001     P<0.001        P<0.001      P<0.001     P<0.001      P<0.001      P<0.001**

**↑                   ↑                             ↑**

**N Engl J Med 2006; 354:353.**** **

***In-Hospital Renal Events***

**Comparisons Among High Risk Patients:  Disease Markers**

## ↑              ↑                 ↑                 ↑                ↑

**Comparisons Among High Risk Patients:  Risk Index**

**High-Risk Subgroups **
***[defined by risk index] ***

**bP=0.002                      P<0.001                        P<0.001                      P<0.001                        P<0.001**

**↑              ↑                 ↑                 ****↑                ↑**

**N Engl J Med 2006; 354:353.**** **

***In-Hospital Renal Events***

## Comparisons Among High Risk Patients:  Blood Loss

**N Engl J Med 2006; 354:353.**** **

***In-Hospital Renal Events***

## Comparisons Among High Risk Patients:  Disease Markers

**JAMA 2007; 297:471.**

**Long-term Mortality by Patient Disease**

**Comparisons Among High Risk Patients:  Disease Markers**

## Comparisons Among High Risk Patients:  Risk Index

**JAMA 2007; 297:471.**

***Long-Term 5-Year Mortality***

**Comparisons Among High Risk Patients:  Risk Index**

##          1.   Pre-existing disease:  Aprotinin  patients were sicker.

**  **_**NEJM/JAMA Studies**_**:**
**         ****1.****   **_**Pre-existing disease**_**:  *****Aprotinin  patients were sicker.***
**          ****2.****    **_**US versus non-US**_**:   *****Significant differences exist.***
**          ****3.****   **_**MI / CHF Definitions**_**:  *****Robustness of findings over a range of definitions.***
**          ****4.****   **_**Renal Findings**_**:   *****‘Tansient’, ‘Inconsequential’.***
**   **_**Prior Studies**_**:**
***           *****5.***** *****  **_**RCTs**_**:   *****RCTs are the ‘Gold Standard’ & the RCTs clearly prove Safety.***
**           ****6.****    **_**Meta-analyses**_**: *****“ Reliable”***

** ****6 Anticipated Questions & Responses***** ***

## Results: Renal Safety

**N Engl J Med 2006; 354:353.**

**Results: *****Renal Safety***
***By-Region***

**Renal Composite By-Region**

## May 2007

## ‘99

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

**JAMA 2007; 297:471.**

_**IREF/McSPI**__***[***_***JAMA]*****2,960 ****patients****UK**** [619]****  ****Canada**** ****[444****] ****USA**** ****[1263]****  ****Germany**** ****[634]****  **

## Slide 78

## Several Factors Explaining Country Differences for Early Composite Outcome

**Several Factors Explaining Country Differences for Early Composite Outcome**

##          1.   Pre-existing disease:  Aprotinin  patients were sicker.

**  **_**NEJM/JAMA Studies**_**:**
**         ****1.****   **_**Pre-existing disease**_**:  *****Aprotinin  patients were sicker.***
**          ****2.****    **_**US versus non-US**_**:   *****Significant differences exist.***
**          ****3.****   **_**MI / CHF Definitions**_**:  *****Robustness of findings over a range of definitions.***
**          ****4.****   **_**Renal Findings**_**:   *****‘Tansient’, ‘Inconsequential’.***
**   **_**Prior Studies**_**:**
***           *****5.***** *****  **_**RCTs**_**:   *****RCTs are the ‘Gold Standard’ & the RCTs clearly prove Safety.***
**           ****6.****    **_**Meta-analyses**_**: *****“ Reliable”***

** ****6 Anticipated Questions & Responses***** ***

## Impact of MI / CHF Definition on Findings

**Results: *****Safety***

**CHF**

**MI**

**N Engl J Med 2006; 354:353.**** **

##          1.   Pre-existing disease:  Aprotinin  patients were sicker.

**  **_**NEJM/JAMA Studies**_**:**
**         ****1.****   **_**Pre-existing disease**_**:  *****Aprotinin  patients were sicker.***
**          ****2.****    **_**US versus non-US**_**:   *****Significant differences exist.***
**          ****3.****   **_**MI / CHF Definitions**_**:  *****Robustness of findings over a range of definitions******.***
**          ****4.****   **_**Renal Findings**_**:   *****‘Tansient’, ‘Inconsequential’.***
**   **_**Prior Studies**_**:**
***           *****5.***** *****  **_**RCTs**_**:   *****RCTs are the ‘Gold Standard’ & the RCTs clearly prove Safety.***
**           ****6.****    **_**Meta-analyses**_**: *****“ Reliable”***

** ****6 Anticipated Questions & Responses***** ***

## “Spurious”

_**Kidney Toxicity**_
****** ****The 45 aprotinin surgery trials:***** *****review suggests a number of renal “safety signals," including aprotinin-associated: **
**           ****(1) α****1****-microglobulin production;****8**** **
**           ****(2) deposition of protein bands within tubule cells accompanied by marked proteinurea;****8**** **
**           ****(3) dose-dependent increases in postoperative creatinine;****5, 9**** **
**           ****(4) renal dysfunction;****9**** and **
**           ****(5) platelet-fibrin thrombotic occlusions of the renal arterioles post-mortem.****7**

***“******Spurious”***

**Prior Findings**

## “Spurious”

***‘******99***

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***’******60****** -******’******87***

***‘******88***

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***‘******96***

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***“******Spurious”***

_**Karkouti**__***[***_***Transfusion ]*****898**** ****patients****Aprotinin [449]  ****TEA [449]****  **

_**Ad**__***[***_***Circ]***

_**Brown**__***[***_***Nejm]***

_**IREF/McSPI**__***[***_***NEJM]*****4,374 ****patients****Aprotinin [1,277]  ****EACA [883]  ****TEA [822]  ****Control [1,238]****  **

***]****** ***_**Other Data**_
_***[***_***NYT***
**67,000**** ****patients**
**Aprotinin [30,000]****Control [37,000]**

**>**** 80,000**** ****patients**

**2.52**** [1.66-3.82]**

**2.21**** [1.25-3.88]**

**1.47**** [1.12-1.94]**

**1.43**** [1.03-1.97]**

**4,374**

**8,018**

**998**

**898**

**“****serious kidney damage” **

**67,000**

**N Engl J Med 2006; 354:353.**** **
**N Engl J Med 2006; 354:2954 ****Transfusion 2006; 46:327.**
**Circulation 2006; 114:II 476.**
**NYT 2006; Sept. 30:p1.**

**Recent Findings**

## “Inconsequential”

** ****“****Increases in  postoperative creatinine were found in some RCTs**
**        ****....however, such changes are transient & without consequence.”**

***“******Inconsequential”***

## “Inconsequential”

***                             ******P<0.0001***

***                             ******	******	***_****__** **__**Cr > 0.5 mg/dl**_

_****__** **__**Cr > 0.5 mg/dl & Post Cr > 2.0**_

_****__** **__**Cr > 2.0 mg/dl**_

***                             ******P<0.0001***

***                             ******P<0.0001***

**Postoperative Creatinine & ****LT Mortality**

**All Patients**

***“******Inconsequential”***

## “Inconsequential”

**Patients Surviving Index Hospitalization **

***                             ******	******	***_****__** **__**Cr > 0.5 mg/dl**_

_****__** **__**Cr > 0.5 mg/dl & Post Cr > 2.0**_

_****__** **__**Cr > 2.0 mg/dl**_

***                             ******P<0.0001***

***                             ******P<0.0001***

***                             ******P<0.0001***

***“******Inconsequential”***

**Postoperative Creatinine & ****LT Mortality**

##          1.   Pre-existing disease:  Aprotinin  patients were sicker.

**  **_**NEJM/JAMA Studies**_**:**
**         ****1.****   **_**Pre-existing disease**_**:  *****Aprotinin  patients were sicker.***
**          ****2.****    **_**US versus non-US**_**:   *****Significant differences exist.***
**          ****3.****   **_**MI / CHF Definitions**_**:  *****Robustness of findings over a range of definitions.***
**          ****4.****   **_**Renal Findings**_**:   *****‘Tansient’, ‘Inconsequential’.***
**   **_**Prior Studies**_**:**
***           *****5.***** *****  **_**RCTs**_**:   *****RCTs are the ‘Gold Standard’ & the RCTs clearly prove Safety.***
**           ****6.****    **_**Meta-analyses**_**: *****“ Reliable”***

** ****6 Anticipated Questions & Responses***** ***

##          1.   Pre-existing disease:  Aprotinin  patients were sicker.

**  **_**NEJM/JAMA Studies**_**:**
**         ****1.****   **_**Pre-existing disease**_**:  *****Aprotinin  patients were sicker.***
**          ****2.****    **_**US versus non-US**_**:   *****Significant differences exist.***
**          ****3.****   **_**MI / CHF Definitions**_**:  *****Robustness of findings over a range of definitions.***
**          ****4.****   **_**Renal Findings**_**:   *****‘Tansient’, ‘Inconsequential’.***
**   **_**Prior Studies**_**:**
***           *****5.***** *****  **_**RCTs**_**:   *****RCTs are the ‘Gold Standard’ & the RCTs clearly prove Safety.***
**           ****6.****    **_**Meta-analyses**_**: *****“ Reliable”***

** ****6 Anticipated Questions & Responses***** ***

## “Kidney toxicity was also a problem in some patients in the trials.”

***‘******99***

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***‘******90***

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***‘******92***

***‘******95***

***‘******98***

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***‘******94***

***‘******93***

_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

***1993******12***

_**FDA **_**Approval**

***‘******59***

**“****Kidney toxicity was also a problem in some patients in the trials.”**

## “All demonstrate safety.” 

***‘******99***

***’******00******  ***

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***’******02******  ***

***’******03  ***

***’******04 ****** ***

***’******05******  ***

***’******07******  ***

***’******08******  ***

***’******60****** -******’******87***

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***‘******90***

***‘******91***

***‘******96***

***‘******97***

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_***Aprotinin***_*** *****(Trasylol****©****)**
** **
***Timeline***

***1993******12***

_**FDA **_**Approval**

***‘******59***

**“****Kidney toxicity was also a problem in some patients in the trials.”**

**“****All demonstrate safety.”***** ***

## Slide 92

##  Effective

*** ******Effective***

## Slide 94

## Generally Small Studies:# Pts (avg) = 63 A / 48 C [54/28]  

**Generally Small Studies:****# Pts ****(avg)**** = 63 A / 48 C***** ******[54/28]******  ***

## 18/35 RCTs: Did not assess Renal Injury  

**18/35 RCTs: ****Did not assess Renal Injury*****  ***

## therefore “Safe”

**“****Not significant”,**
**therefore “*****Safe*****”**

## ‘Safe’

***‘******Safe’***

## ‘Safe’ & Effective

***‘******Safe’****** *****&**** Effective**

##          1.   Pre-existing disease:  Aprotinin  patients were sicker.

**  **_**NEJM/JAMA Studies**_**:**
**         ****1.****   **_**Pre-existing disease**_**:  *****Aprotinin  patients were sicker.***
**          ****2.****    **_**US versus non-US**_**:   *****Significant differences exist.***
**          ****3.****   **_**MI / CHF Definitions**_**:  *****Robustness of findings over a range of definitions.***
**          ****4.****   **_**Renal Findings**_**:   *****‘Tansient’, ‘Inconsequential’.***
**   **_**Prior Studies**_**:**
***           *****5.***** *****  **_**RCTs**_**:   *****RCTs are the ‘Gold Standard’ & the RCTs clearly prove Safety.***
**           ****6.****    **_**Meta-analyses**_**: *****“ Reliable”***

** ****6 Anticipated Questions & Responses***** ***

## ‘Reliable’:  Heterogeneity

** ****[ N = 4390]**

## ‘Reliable’:  Heterogeneity

** ****[ N = 4390]**

## ‘Reliable’:  Heterogeneity

** ****[ N = 4390]**

## ‘Reliable’:  Heterogeneity

***‘******Reliable’:  Heterogeneity***

##          1.   Pre-existing disease:  Aprotinin  patients were sicker.

**  **_**NEJM/JAMA Studies**_**:**
**         ****1.****   **_**Pre-existing disease**_**:  *****Aprotinin  patients were sicker.***
**          ****2.****    **_**US versus non-US**_**:   *****Significant differences exist.***
**          ****3.****   **_**MI / CHF Definitions**_**:  *****Robustness of findings over a range of definitions.***
**          ****4.****   **_**Renal Findings**_**:   *****‘Tansient’, ‘Inconsequential’.***
**   **_**Prior Studies**_**:**
***           *****5.***** *****  **_**RCTs**_**:   *****RCTs are the ‘Gold Standard’ & the RCTs clearly prove Safety.***
**           ****6.****    **_**Meta-analyses**_**: *****“ Reliable”***

** ****6 Anticipated Questions & Responses***** ***

##                Aprotinin Early Development  √

**	**
**          *********     *****Aprotinin Early Development**** ***** *****√**
***          **********      *****The Acute Graft Occlusion Issue ***** *****√**
**	**** *********    *****The Kidney Toxicity Issue ***** *****√**
***  *****	**** ********* ******    *****The Long-Term Mortality Issue ***** *****√**
**        *********  ******   *****Anticipated Questions / Responses ***** *****√**
**        **** *********    *****Impressions**** ***** *****√**

***Outline***

## Impressions

_**Impressions**_
**The association of aprotinin with acute renal injury**
**and with long-term mortality, **
**indicates that continued use is not prudent****©****......**
**...****..particularly given that there exist**
**far-safer, equally effective, ****and less-expensive generic medications****: **
**aminocaproic acid and tranexamic acid. **

## Impressions

_**Impressions**_
**The association of aprotinin with acute renal injury**
**and with long-term mortality, **
**indicates that continued use is not prudent****©****...........**
**..........particularly given that there exist**
**far-safer, equally effective, ****and less-expensive generic medications****: **
**aminocaproic acid and tranexamic acid. **

## Thank you.