Post on 17-Jan-2016
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
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
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
FDA 070912 5
Postmarketing Safety Assessment: An Observational Paradigm
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 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
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 7
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
Aprotinin Early Development
The Acute Graft Occlusion Issue
The Kidney Toxicity Issue
The Long-Term Mortality Issue
Anticipated Questions / Responses
Impressions
Outline
FDA 070912 9
Postmarketing Safety Assessment: An Observational Paradigm
‘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
Postmarketing Safety Assessment: An Observational Paradigm
‘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
Royston [Lancet]
22 patients
Aprotinin [11]Control [11]
Lancet 1987; 2:1289.
‘59
FDA 070912 11
Postmarketing Safety Assessment: An Observational Paradigm
‘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
Cosgrove[ATS]
169 patients
Aprotinin-h [57] Aprotinin-l [56]
Control [56]
ATS 1992; 54:1031.
‘59
FDA 070912 12
Postmarketing Safety Assessment: An Observational Paradigm
‘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
199312
FDA
Approval
‘59
FDA 070912 13
Postmarketing Safety Assessment: An Observational Paradigm
‘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
199312
FDA
Approval
‘59
Q
Limited Indication:
CABG (+ CPB) +
↑↑↑ Risk for Bleeding
.
FDA
Approval
FDA 070912 14
Postmarketing Safety Assessment: An Observational Paradigm
‘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
Aprotinin (Trasylol©)
Timeline
‘94 ’08 ’11
FDA 070912 15
Postmarketing Safety Assessment: An Observational Paradigm
circa 1997………..
♦ Aprotinin Efficacy
All RCTs Substantial Blood-Sparing Effects
♦ Aprotinin Safety
Nearly All RCTs No Safety Concerns
FDA 070912 16
Postmarketing Safety Assessment: An Observational Paradigm
Aprotinin Early Development √
The Acute Graft Occlusion Issue
The Kidney Toxicity Issue
The Long-Term Mortality Issue
Anticipated Questions / Responses
Impressions
Outline
FDA 070912 17
Postmarketing Safety Assessment: An Observational Paradigm
‘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
Cosgrove[ATS]
169 patients
Aprotinin-h [57] Aprotinin-l [56]
Control [56]
ATS 1992; 54:1031.
‘59
FDA 070912 18
Postmarketing Safety Assessment: An Observational Paradigm
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 070912 19
Postmarketing Safety Assessment: An Observational Paradigm
‘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
Cosgrove[ATS]
169 patients
Aprotinin-h [57] Aprotinin-l [56]
Control [56]
‘59
19943
FDA
Graft Thrombosis
ATS 1992; 54:1031.
FDA 070912 20
Postmarketing Safety Assessment: An Observational Paradigm
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
FDA 070912 21
Postmarketing Safety Assessment: An Observational Paradigm
‘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
Aprotinin (Trasylol©)
Timeline
Alderman[JTCVS ]
IMAGE
703 patients
Aprotinin [363]Control [340]
(‘93→’98)
JTCVS 1998; 116:716.
FDA 070912 22
Postmarketing Safety Assessment: An Observational Paradigm
Aprotinin (Trasylol©)TimelineJTCVS 1998; 116:716.
13 International sites
703 Primary CABG[A=363; P=340]
Angiography @ 11 days
FDA 070912 23
Postmarketing Safety Assessment: An Observational Paradigm
Aprotinin (Trasylol©)Timeline
Prespecified Endpoint:
Acute Vein Graft Occlusion
FDA 070912 24
Postmarketing Safety Assessment: An Observational Paradigm
Aprotinin (Trasylol©)Timeline
Prespecified Endpoint:
Acute Vein Graft Occlusion
Results:
Aprotinin: ↑41% Acute Graft Occlusion [15.4% v 10.9%]
FDA 070912 25
Postmarketing Safety Assessment: An Observational Paradigm
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%]
FDA 070912 26
Postmarketing Safety Assessment: An Observational Paradigm
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.”
FDA 070912 27
Postmarketing Safety Assessment: An Observational Paradigm
No substantive change (i.e. no black-box warning)
IMAGE data / interpretation added to package insert
Mid 1998
Regulatory decision:
FDA 070912 28
Postmarketing Safety Assessment: An Observational Paradigm
In late 1998, in an unrelated action..….
FDA 070912 29
Postmarketing Safety Assessment: An Observational Paradigm
‘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
Aprotinin (Trasylol©)
Timeline
19983
FDA Expanded
theIndication
FDA 070912 30
Postmarketing Safety Assessment: An Observational Paradigm
‘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
Aprotinin (Trasylol©)
Timeline
19983
Aprotinin’s anti-inflammatory
properties
FDA Expanded
theIndication
FDA 070912 31
Postmarketing Safety Assessment: An Observational Paradigm
‘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
Aprotinin (Trasylol©)
Timeline
19983
Aprotinin’s anti-inflammatory
properties
Expanded Indication:
All CABG (+ CPB)
+/- Risk for Bleeding
FDA Expanded
theIndication
FDA 070912 32
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
Net effect: 1998 to 2005……..
FDA 070912 34
Postmarketing Safety Assessment: An Observational Paradigm
Rapid Growth: 1998 - 2005
2005: 350,000 patients received Aprotinin
2006 [January]: Projection > 700,000 patients
FDA 070912 35
Postmarketing Safety Assessment: An Observational Paradigm
Aprotinin Early Development √
The Acute Graft Occlusion Issue √
The Kidney Toxicity Issue √
The Long-Term Mortality Issue √
Anticipated Questions / Responses √
Impressions √
Outline
FDA 070912 36
Postmarketing Safety Assessment: An Observational Paradigm
‘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
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.
FDA 070912 37
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
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
Renal Dysfunction(<0.0001)
Renal Dialysis (<0.0001)
Renal Composite(<0.0001)
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
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
‘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
Aprotinin (Trasylol©)
Timeline
IREF/McSPI[NEJM]
4,374 patients
Aprotinin [1,277] EACA [883] TEA [822]
Control [1,238]
FDAAdvisory
Committee
20062c
N Engl J Med 2006; 354:353.
FDA 070912 42
Postmarketing Safety Assessment: An Observational Paradigm
‘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
Aprotinin (Trasylol©)
Timeline
IREF/McSPI[NEJM]
4,374 patients
Aprotinin [1,277] EACA [883] TEA [822]
Control [1,238]
FDAAdvisory
Committee
20062c
N Engl J Med 2006; 354:353.
NO ∆
FDA 070912 43
Postmarketing Safety Assessment: An Observational Paradigm
‘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
Aprotinin (Trasylol©)
Timeline
IREF/McSPI[NEJM]
4,374 patients
Aprotinin [1,277] EACA [883] TEA [822]
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
Postmarketing Safety Assessment: An Observational Paradigm
FDA 070912 45
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
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.’
FDA 070912 47
Postmarketing Safety Assessment: An Observational Paradigm
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.’
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 In
cid
en
ce (
%)
Control EACA TEA Aprotinin
d
FDA 070912 48
Postmarketing Safety Assessment: An Observational Paradigm
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.’
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 I
ncid
en
ce (
%)
Control EACA TEA Aprotinin
FDA 070912 49
Postmarketing Safety Assessment: An Observational Paradigm
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.’
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 I
ncid
en
ce (
%)
Control EACA TEA Aprotinin
FDA 070912 50
Postmarketing Safety Assessment: An Observational Paradigm
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.’
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 I
ncid
en
ce (
%)
Control EACA TEA Aprotinin
FDA 070912 51
Postmarketing Safety Assessment: An Observational Paradigm
‘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
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.
FDA 070912 52
Postmarketing Safety Assessment: An Observational Paradigm
‘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
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.
FDA 070912 53
Postmarketing Safety Assessment: An Observational Paradigm
Thus, in 2006 Aprotinin Safety was challenged:
Kidney Toxicity
FDA 070912 54
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
In effect, in 2006 Aprotinin Safety was re-challenged:
Kidney Toxicity[validating the 1993 FDA concern]
FDA 070912 57
Postmarketing Safety Assessment: An Observational Paradigm
2007
FDA 070912 58
Postmarketing Safety Assessment: An Observational Paradigm
Aprotinin Early Development √
The Acute Graft Occlusion Issue √
The Kidney Toxicity Issue √
The Long-Term Mortality Issue √
Anticipated Questions / Responses √
Impressions √
Outline
FDA 070912 59
Postmarketing Safety Assessment: An Observational Paradigm
‘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
Aprotinin (Trasylol©)
Timeline
JAMA 2007; 297:471.
IREF/McSPI[JAMA]
3,876 patients
Aprotinin [1,295]
EACA [849]
TEA [512]
Control [1,374]
FDA 070912 60
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
Thus, in 2007 Aprotinin Safety was challenged:
Long-Term Mortality
FDA 070912 64
Postmarketing Safety Assessment: An Observational Paradigm
Aprotinin Early Development √
The Acute Graft Occlusion Issue √
The Kidney Toxicity Issue √
The Long-Term Mortality Issue √
Anticipated Questions / Responses √
Impressions √
Outline
FDA 070912 65
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
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 67
Postmarketing Safety Assessment: An Observational Paradigm
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 68
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
↑ ↑
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
Postmarketing Safety Assessment: An Observational Paradigm
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
FDA 070912 71
Postmarketing Safety Assessment: An Observational Paradigm
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
(%)
In-Hospital Renal Events
FDA 070912 72
Postmarketing Safety Assessment: An Observational Paradigm
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
(%)
Control Aminocaproic/Tranexamic acid Aprotinin
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
Postmarketing Safety Assessment: An Observational Paradigm
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
(%)
Control Aminocaproic/Tranexamic acid Aprotinin
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
Postmarketing Safety Assessment: An Observational Paradigm
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 75
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
May 2007
FDA 070912 77
Postmarketing Safety Assessment: An Observational Paradigm
‘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
Aprotinin (Trasylol©)
Timeline
JAMA 2007; 297:471.
IREF/McSPI[JAMA]
2,960 patients
UK [619]
Canada [444]
USA [1263]
Germany [634]
FDA 070912 78
Postmarketing Safety Assessment: An Observational Paradigm
FDA 070912 79
Postmarketing Safety Assessment: An Observational Paradigm
Several Factors Explaining Country Differences for Early Composite Outcome
FDA 070912 80
Postmarketing Safety Assessment: An Observational Paradigm
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 81
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
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 83
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
‘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”
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” 67,000N 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
Postmarketing Safety Assessment: An Observational Paradigm
“Increases in postoperative creatinine were found in some RCTs
.…however, such changes are transient & without consequence.”
“Inconsequential”
FDA 070912 86
Postmarketing Safety Assessment: An Observational Paradigm
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
“Inconsequential”
FDA 070912 87
Postmarketing Safety Assessment: An Observational Paradigm
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
FDA 070912 88
Postmarketing Safety Assessment: An Observational Paradigm
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 89
Postmarketing Safety Assessment: An Observational Paradigm
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 90
Postmarketing Safety Assessment: An Observational Paradigm
‘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
199312
FDA
Approval
‘59
“Kidney toxicity was also a problem in some patients in
the trials.”
FDA 070912 91
Postmarketing Safety Assessment: An Observational Paradigm
‘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
199312
FDA
Approval
‘59
“Kidney toxicity was also a problem in some patients in
the trials.”
“All demonstrate safety.”
FDA 070912 92
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
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
Effective
FDA 070912 94
Postmarketing Safety Assessment: An Observational Paradigm
Power vs Sample Size[35 RCTs]
0%
20%
40%
60%
80%
100%
0 200 400 600 800 1000
Sample Size (# patients)
Po
we
rSafety--Renal Injury
FDA 070912 95
Postmarketing Safety Assessment: An Observational Paradigm
Power vs Sample Size[35 RCTs]
0%
20%
40%
60%
80%
100%
0 200 400 600 800 1000
Sample Size (# patients)
Po
we
rSafety--Renal Injury
Generally Small Studies:# Pts (avg) = 63 A / 48 C [54/28]
FDA 070912 96
Postmarketing Safety Assessment: An Observational Paradigm
Power vs Sample Size[35 RCTs]
0%
20%
40%
60%
80%
100%
0 200 400 600 800 1000
Sample Size (# patients)
Po
we
rSafety--Renal Injury
18/35 RCTs: Did not assess Renal Injury
FDA 070912 97
Postmarketing Safety Assessment: An Observational Paradigm
Power vs Sample Size[35 RCTs]
0%
20%
40%
60%
80%
100%
0 200 400 600 800 1000
Sample Size (# patients)
Po
we
rSafety--Renal Injury
“Not significant”,therefore “Safe”
FDA 070912 98
Postmarketing Safety Assessment: An Observational Paradigm
Power vs Sample Size[35 RCTs]
0%
20%
40%
60%
80%
100%
0 200 400 600 800 1000
Sample Size (# patients)
Po
wer
Death
MI
Dialysis
Stroke
‘Safe’
FDA 070912 99
Postmarketing Safety Assessment: An Observational Paradigm
Power vs Sample Size[35 RCTs]
0%
20%
40%
60%
80%
100%
0 100 200 300 400 500 600 700 800 900 1000
Sample Size (# patients)
Po
wer
Death
MI
Dialysis
Stroke
Xfus
Sample Size (# patients)
‘Safe’ & Effective
FDA 070912 100
Postmarketing Safety Assessment: An Observational Paradigm
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 101
Postmarketing Safety Assessment: An Observational Paradigm
‘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
Postmarketing Safety Assessment: An Observational Paradigm
‘Reliable’: Heterogeneity
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
Postmarketing Safety Assessment: An Observational Paradigm
‘Reliable’: Heterogeneity
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
Postmarketing Safety Assessment: An Observational Paradigm
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
‘Reliable’: Heterogeneity
FDA 070912 105
Postmarketing Safety Assessment: An Observational Paradigm
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 106
Postmarketing Safety Assessment: An Observational Paradigm
Aprotinin Early Development √
The Acute Graft Occlusion Issue √
The Kidney Toxicity Issue √
The Long-Term Mortality Issue √
Anticipated Questions / Responses √
Impressions √
Outline
FDA 070912 107
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
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
Postmarketing Safety Assessment: An Observational Paradigm
Thank you.