postmarketing safety assessment: an observational paradigm fda 070912 1 post-marketing safety...

FDA 070912 1

Postmarketing Safety Assessment: An Observational Paradigm

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)

FDA 070912 2


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]

FDA 070912 3


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]

FDA 070912 4



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

FDA 070912 5



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 USALesserson

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 OutcomeJTCVS [May 2007]

FDA 070912 6


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)

FDA 070912 7


Aprotinin Early Development

The Acute Graft Occlusion Issue

The Kidney Toxicity Issue

The Long-Term Mortality Issue

Anticipated Questions / Responses

Impressions

Outline

FDA 070912 8


Aprotinin Early Development





Impressions

Outline

FDA 070912 9


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘94‘93

Aprotinin (Trasylol©)

Timeline

1959

‘59

Trasylolused inpatients

FDA 070912 10


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘94‘93


Timeline

Royston [Lancet]

22 patients

Aprotinin [11]Control [11]

Lancet 1987; 2:1289.

‘59

FDA 070912 11


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘94‘93


Timeline

Cosgrove[ATS]

169 patients

Aprotinin-h [57] Aprotinin-l [56]

Control [56]

ATS 1992; 54:1031.

‘59

FDA 070912 12


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘94‘93


Timeline

199312

FDA

Approval

‘59

FDA 070912 13


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘94‘93


Timeline

199312

FDA

Approval

‘59

Q

Limited Indication:

CABG (+ CPB) +

↑↑↑ Risk for Bleeding

.

FDA

Approval

FDA 070912 14


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06

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.

’11 ‘93‘59

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]

‘94


Timeline

‘94 ’08 ’11

FDA 070912 15


circa 1997………..

♦ Aprotinin Efficacy

All RCTs Substantial Blood-Sparing Effects

♦ Aprotinin Safety

Nearly All RCTs No Safety Concerns

FDA 070912 16


Aprotinin Early Development √





Impressions

Outline

FDA 070912 17


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘94‘93


Timeline

Cosgrove[ATS]

169 patients


Control [56]

ATS 1992; 54:1031.

‘59

FDA 070912 18



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 070912 19


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘94‘93


Timeline

Cosgrove[ATS]

169 patients


Control [56]

‘59

19943

FDA

Graft Thrombosis

ATS 1992; 54:1031.

FDA 070912 20


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


Timeline

FDA 070912 21


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘93 ‘94‘59


Timeline

Alderman[JTCVS ]

IMAGE

703 patients

Aprotinin [363]Control [340]

(‘93→’98)

JTCVS 1998; 116:716.

FDA 070912 22


Aprotinin (Trasylol©)TimelineJTCVS 1998; 116:716.

13 International sites

703 Primary CABG[A=363; P=340]

Angiography @ 11 days

FDA 070912 23


Aprotinin (Trasylol©)Timeline

Prespecified Endpoint:

Acute Vein Graft Occlusion

FDA 070912 24





Results:

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

FDA 070912 25





Inference:

Aprotinin ↑4,500 vein-graft occlusions / year

(per 100,000 administrations)

Results:


FDA 070912 26





Inference:

Aprotinin ↑4,500 vein-graft occlusions / year

(per 100,000 administrations)

Results:


“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.”

FDA 070912 27


No substantive change (i.e. no black-box warning)

IMAGE data / interpretation added to package insert

Mid 1998

Regulatory decision:

FDA 070912 28


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

FDA 070912 29


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘93 ‘94‘59


Timeline

19983

FDA Expanded

theIndication

FDA 070912 30


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘93 ‘94‘59


Timeline

19983

Aprotinin’s anti-inflammatory

properties

FDA Expanded

theIndication

FDA 070912 31


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘93 ‘94‘59


Timeline

19983

Aprotinin’s anti-inflammatory

properties

Expanded Indication:

All CABG (+ CPB)

+/- Risk for Bleeding

FDA Expanded

theIndication

FDA 070912 32


Anti-inflammatories proven unsafe in CABG:

Bextra [COX-2-] (JTCVS, 2003)

Pexelizumab [mca-C-5a-9] (JTCVS, 2004)

Cariporide [NH+EI] (unpub, 2005)

Parenthetically, our experience……….

FDA 070912 33


Net effect: 1998 to 2005……..

FDA 070912 34


Rapid Growth: 1998 - 2005

2005: 350,000 patients received Aprotinin

2006 [January]: Projection > 700,000 patients

FDA 070912 35



The Acute Graft Occlusion Issue √

The Kidney Toxicity Issue √

The Long-Term Mortality Issue √

Anticipated Questions / Responses √

Impressions √

Outline

FDA 070912 36


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘93 ‘94‘59


Timeline

IREF/McSPI[NEJM]

4,374 patients

Aprotinin [1,277] EACA [883] TEA [822]

Control [1,238]

N Engl J Med 2006; 354:353.

FDA 070912 37


Renal Events Among the 4,374 Study Patients

Results: Safety

N Engl J Med 2006; 354:353.

2

1

33

1

33

1

4

65

8

0

2

4

6

8

Renal Dysfunction(<0.0001)

Renal Dialysis (<0.0001)

Renal Composite(<0.0001)

Ou

tco

me

Inci

den

ce (

%)

Control EACA TEA Aprotinin

d

2.41 [1.49-3.90] (P<0.001)

FDA 070912 38


Results: Safety

N Engl J Med 2006; 354:353.

Aprotinin: Dose-Response

2.41.2

2.7

5.7

3.7

7.1

12.1

6.1

18.2

0

5

10

15

20




Ou

tco

me

In

cid

en

ce

(%

) Control Aprotinin-low dose Aprotinin-high dose

3.79 [1.41-10.18] (P=0.0018)

FDA 070912 39


Results: Safety

N Engl J Med 2006; 354:353.

Other Events Among the 4,374 Study Patients

2 3

16

19

2 3

16

20

24

17

21

46

22

29

0

10

20

30

Death (0.004)

Neurologic (<0.0001)

Cardiovascular(<0.0001)

Composite (<0.0001)

Ou

tco

me

Inci

den

ce (

%)

Control EACA TEA Aprotinin 1.39 [1.13-1.72] (P=0.002)

FDA 070912 40


Blood-Sparing Effectiveness: EACA/TEA versus Aprotinin

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

44

10

58 55

1714

46

13

67 65

28

18

0

25

50

75

100

Blood Loss (0.2259)

CTO (0.0015)

T-any (<0.0001)

T-rbc (<0.0001)

T-ffp (<0.0001)

T-plt (<0.0001)

Hemorrhage Variable [24 hours]

Inci

den

ce (

%)

EACA/TEA Aprotinin EACA/TEA [24h] = 692 ml ± 659

Aprotinin [24h] = 753 ml ± 660

Control [24h] = 827 ml ± 573

↑ ↑

FDA 070912 41


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘93 ‘94‘59


Timeline

IREF/McSPI[NEJM]

4,374 patients


Control [1,238]

FDAAdvisory

Committee

20062c

N Engl J Med 2006; 354:353.

FDA 070912 42


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘93 ‘94‘59


Timeline

IREF/McSPI[NEJM]

4,374 patients


Control [1,238]

FDAAdvisory

Committee

20062c

N Engl J Med 2006; 354:353.

NO ∆

FDA 070912 43


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘93 ‘94‘59


Timeline

IREF/McSPI[NEJM]

4,374 patients


Control [1,238]

FDAAdvisory

Committee

20062c

Other Data67,000 patients

Aprotinin [30,000]Control [37,000]N Engl J Med 2006; 354:353.

NYT 2006; Sept. 30:p1.

FDA 070912 44


FDA 070912 45


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.’

FDA 070912 46


67,000 Patients

30,000 Aprotinin

37,000 Placebo



FDA 070912 47


67,000 Patients

30,000 Aprotinin

37,000 Placebo



2

1

33

1

33

1

4

65

8

0

2

4

6

8




Ou

tco

me In

cid

en

ce (

%)


d

FDA 070912 48


67,000 Patients

30,000 Aprotinin

37,000 Placebo



2 3

16

19

2 3

16

20

24

17

21

46

22

29

0

10

20

30

Death (0.004)



Composite (<0.0001)

Ou

tco

me I

ncid

en

ce (

%)


FDA 070912 49


67,000 Patients

30,000 Aprotinin

37,000 Placebo



2 3

16

19

2 3

16

20

24

17

21

46

22

29

0

10

20

30

Death (0.004)



Composite (<0.0001)

Ou

tco

me I

ncid

en

ce (

%)


FDA 070912 50


67,000 Patients

30,000 Aprotinin

37,000 Placebo



2 3

16

19

2 3

16

20

24

17

21

46

22

29

0

10

20

30

Death (0.004)



Composite (<0.0001)

Ou

tco

me I

ncid

en

ce (

%)


FDA 070912 51


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘93 ‘94‘59


Timeline

Karkouti[Transfusion ]

898 patients

Aprotinin [449] TEA [449] Ad

[Circ]

Brown[Nejm]

IREF/McSPI[NEJM]

4,374 patients


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.

FDA 070912 52


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘93 ‘94‘59


Timeline


898 patients

Aprotinin [449] TEA [449] Ad

[Circ]

Brown[Nejm]

IREF/McSPI[NEJM]

4,374 patients


Control [1,238]

]

Other Data[NYT

67,000 patients


> 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.

FDA 070912 53


Thus, in 2006 Aprotinin Safety was challenged:

Kidney Toxicity

FDA 070912 54


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.

FDA 070912 55


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.”

FDA 070912 56


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

Kidney Toxicity[validating the 1993 FDA concern]

FDA 070912 57


2007

FDA 070912 58







Impressions √

Outline

FDA 070912 59


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘93 ‘94‘59


Timeline

JAMA 2007; 297:471.

IREF/McSPI[JAMA]

3,876 patients

Aprotinin [1,295]

EACA [849]

TEA [512]

Control [1,374]

FDA 070912 60


Cumulative Mortality Curves Compared Among Study Groups

JAMA 2007; 297:471.

0

5

10

15

20

Time Following Surgery

Mo

rtal

ity,

%

ControlAminocaproic acidTranexamic acidAprotinin

0 1year 2year 3year 4year 5year

All Patients

No. at Risk Aprotinin 1286 1121 1042 971 911 845 Tranexamic Acid 821 465 441 406 393 377 Aminocaproic Acid 873 796 774 753 726 698 Control 1365 1118 1077 1027 985 879

FDA 070912 61


Cumulative Mortality Curves Compared Among Study Groups

JAMA 2007; 297:471.

0

5

10

15

20

Tim e Following Surgery

Mor

talit

y, %

ControlA minocaproic ac idTranexamic ac idA protinin

0 1year 2year 3year 4year 5year

Patients Without In-Hospital Death

FDA 070912 62


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

FDA 070912 63


Thus, in 2007 Aprotinin Safety was challenged:

Long-Term Mortality

FDA 070912 64







Impressions √

Outline

FDA 070912 65


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

FDA 070912 66


NEJM/JAMA Studies





Prior Studies:




FDA 070912 67


NEJM/JAMA Studies:





Prior Studies:




FDA 070912 68


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

FDA 070912 69


↑ ↑

3 2

4 45 5 5

4 4

2

46

4 4

67

9 9 910

11 12 12 13

34

333 3

43

3

14

88

0

5

10

15

20

All Chol UA/MI HTN C|P Women Age Em-UrS CS DM Vasc Ds LVD

Risk Group

Inci

denc

e of

Ren

al E

vent

(%)

Control Aminocaproic/Tranexamic acid Aprotinin

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

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

FDA 070912 70


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.


FDA 070912 71


Comparisons Among High Risk Patients: Blood Loss

N Engl J Med 2006; 354:353.

1 1

54

2

44 455

6

12

333

8

0

5

10

15

0 - 430 431 - 615 620 - 890 892 - 17428

Blood Loss in Quartiles (ml)

Inci

den

ce o

f R

enal

Eve

nt

(%)


FDA 070912 72


Long-Term 5-Year Mortality

JAMA 2007; 297:471.

Long-term Mortality by Patient Disease

9 811 10 8 9

13 12 14

19 2017

12 1013 14 14

9

19 1917 18 1922 23 23

27 28 2932

16161614

25

14

0

10

20

30

40

All Chol UA/MI HTN Women Em-UrS C|P Age DM LVD CS Vasc Ds

Risk Group

5-Yea

r Mor

tality

(%)


P<0.001 P=0.001 P<0.001 P<0.001 P=0.001 P<0.001 P=0.021 P<0.001 P<0.001 P=0.008 P<0.001 P=0.002

Comparisons Among High Risk Patients: Disease Markers

FDA 070912 73


11

20 22 23 23

14

2421 22 23

30 32 32

25

34

0

10

20

30

40

CC STS Euro1 Euro2 VA

Risk Group

5-Year

Mort

ality

(%)


P<0.001 P=0.012 P=0.002 P=0.004 P=0.002

B

JAMA 2007; 297:471.

Long-Term 5-Year Mortality

Comparisons Among High Risk Patients: Risk Index

FDA 070912 74


NEJM/JAMA Studies:





Prior Studies:




FDA 070912 75


N Engl J Med 2006; 354:353.

Results: Renal SafetyBy-Region

Renal Composite By-Region

2.7

3.6

2.53

43.5

7.4

9.6

8.0

0

2

4

6

8

10

All patients (<0.0001)

US Patients (<0.0001)

Non-US Patients (<0.0001)

Inci

denc

e (%

)

Control EACA/TEA Aprotinin

FDA 070912 76


May 2007

FDA 070912 77


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘93 ‘94‘59


Timeline

JAMA 2007; 297:471.

IREF/McSPI[JAMA]

2,960 patients

UK [619]

Canada [444]

USA [1263]

Germany [634]

FDA 070912 78


FDA 070912 79


Several Factors Explaining Country Differences for Early Composite Outcome

FDA 070912 80


NEJM/JAMA Studies:





Prior Studies:




FDA 070912 81


Impact of MI / CHF Definition on Findings

Results: Safety

5.7

8.5

5.6

3.8 3.4

16.4

9.3

11.7

8.8

6.85.4

12.1

0

5

10

15

20

MI [nejm] (0.0010)

MI [ecg] (0.0002)

MI [crf] (0.0035)

CHF [nejm] (0.0008)

CHF [hemo] (0.0003)

CHF [iabp] (0.0075)

Out

com

e In

cide

nce

(%)

EACA/TEA AprotininCHFMI

N Engl J Med 2006; 354:353.

FDA 070912 82


NEJM/JAMA Studies:





Prior Studies:




FDA 070912 83


Kidney Toxicity

Kidney Toxicity

The 45 aprotinin surgery trials: review suggests a number of renal “safety

signals," including aprotinin-associated:

(1) α1-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

FDA 070912 84


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘93 ‘94‘59

“Spurious”


898 patients

Aprotinin [449] TEA [449]

Ad[Circ]

Brown[Nejm]

IREF/McSPI[NEJM]

4,374 patients


Control [1,238]

]

Other Data[NYT

67,000 patients


> 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” 67,000N 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

FDA 070912 85


“Increases in postoperative creatinine were found in some RCTs

.…however, such changes are transient & without consequence.”

“Inconsequential”

FDA 070912 86


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 MortalityAll Patients


FDA 070912 87


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


Postoperative Creatinine & LT Mortality

FDA 070912 88


NEJM/JAMA Studies:





Prior Studies:




FDA 070912 89


NEJM/JAMA Studies:





Prior Studies:




FDA 070912 90


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘94‘93


Timeline

199312

FDA

Approval

‘59

“Kidney toxicity was also a problem in some patients in

the trials.”

FDA 070912 91


‘99 ’00 ’01 ’02 ’03 ’04 ’05 ’07 ’08 ’60 -’87 ‘88 ‘89 ‘90 ‘91 ‘96 ‘97 ’09 ’10 ‘92 ‘95 ‘98 ’06 ’11 ‘94‘93


Timeline

199312

FDA

Approval

‘59

“Kidney toxicity was also a problem in some patients in

the trials.”

“All demonstrate safety.”

FDA 070912 92


Power vs Sample Size[35 RCTs]

0%

20%

40%

60%

80%

100%

0 200 400 600 800 1000

Sample Size (# patients)

Po

we

rEfficacy--Transfusion

FDA 070912 93



0%

20%

40%

60%

80%

100%

0 200 400 600 800 1000


Po

we

rEfficacy--Transfusion

Effective

FDA 070912 94



0%

20%

40%

60%

80%

100%

0 200 400 600 800 1000


Po

we

rSafety--Renal Injury

FDA 070912 95



0%

20%

40%

60%

80%

100%

0 200 400 600 800 1000


Po

we


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

FDA 070912 96



0%

20%

40%

60%

80%

100%

0 200 400 600 800 1000


Po

we


18/35 RCTs: Did not assess Renal Injury

FDA 070912 97



0%

20%

40%

60%

80%

100%

0 200 400 600 800 1000


Po

we


“Not significant”,therefore “Safe”

FDA 070912 98



0%

20%

40%

60%

80%

100%

0 200 400 600 800 1000


Po

wer

Death

MI

Dialysis

Stroke

‘Safe’

FDA 070912 99



0%

20%

40%

60%

80%

100%

0 100 200 300 400 500 600 700 800 900 1000


Po

wer

Death

MI

Dialysis

Stroke

Xfus


‘Safe’ & Effective

FDA 070912 100


NEJM/JAMA Studies:





Prior Studies:




FDA 070912 101


‘Reliable’: Heterogeneity

Patients Excluded by-Disease (n=4390)

126 126244

9801071

1371

1727

326

515

0

500

1000

1500

2000

MI Stroke Kidneyds

UA CHF DM ↓Hct ↑Cr Hemat.ds

# Pa

tient

s

[ N = 4390]

FDA 070912 102



Patients Excluded by Preop Therapy (n=4390)

51 58128

220274

463

870 881

993

213

0

250

500

750

1000

# Pa

tient

s

[ N = 4390]

FDA 070912 103



Current Surgery I/E (n=4390)

26592436

2833

17311954

1557

3673

717

0

1000

2000

3000

4000

5000

ElectiveSurgery

PrimarySurgery

Otherprocedures

Vesselrestriction

# P

ati

en

ts

NoYes

b

[ N = 4390]

FDA 070912 104


35 RCTs: Frequency of Unmeasured / Unreported Outcomes

29%

55%

64%

76%

53% 53%

30%

58%

0%

25%

50%

75%

100%

MI CHF AF Stroke Enceph RenalDys

RenalFail

Death

% R

CT

with

Mis

sing

Dat

a h


FDA 070912 105


NEJM/JAMA Studies:





Prior Studies:




FDA 070912 106







Impressions √

Outline

FDA 070912 107


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.

FDA 070912 108


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.

FDA 070912 109


Thank you.

postmarketing safety assessment: an observational paradigm fda 070912 1 post-marketing safety...

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