Transcript Guidelines: Blood Management in Heart Surgery

The Aprotinin Controversy: Oh
my –what next?
Bruce D. Spiess, MD, FAHA
Professor of Anesthesiology and Emergency Medicine
Director VCURES
Richmond, Virginia
Disclosures

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Bayer Pharmaceuticals
Synthetic Blood International
The Medicines Company
McSPI Hematology Sub-Group
Director (Past)
Some drug studies quoted were
done “off label”.
CPB: The Ultimate in “Biologic
Complexity”

The insult of CPB:

Heparin
Contact Activation
Heating



Leukocytes and Platelets

Complement System

Coagulation System

Kinin Generation

Fibrinolytic System

Protease Activated
Receptors
Kallikrein
HMWK
Factor XII
Bradykinin
Complement
Kallikrein
phagocytosis
inflammation
vasodilation
vascular permeability
t-PA release
Neutrophils
Plasminogen
inflammatory mediators
(IL-1, IL-6, elastase)
Plasmin
C4b2a
C3
C3a
C3b
VII
TF
C1
Contact Activation Build Slide
Complement
C5b
neutrophils
C5b67
Prekallikrein
XII
Heparin-Protamine Complex
Prorenin
XI
C5b-9
HMWK
Renin
XIIa
IX
pressor response
Plasminogen
XIa
X
enzymes
free radicals
aa metabolites
interleukins
IXa
Tissue
Factor
Complex
(TF:VIIa)
VIIIa
endothelium
Bradykinin
kinin generation
vasodilatation
vascular permeabilit
Xa
VIII
Va
V
Protein C
uPA
tPA
Prothrombin
Fibrin (m)
Fibrinogen
platelets
Fibrin (p)
XIIIa
Fibrin (cl)
XIII
coagulation
D-dimer
fibrinolysis
TFPI
activation
aggregation
consumption
5
Structure of Aprotinin
Lysine
Lysine
Data on File: Bayer Pharmaceuticals Corporation
Aprotinin
A Serine Protease Inhibitor
Binds with the human serine proteases:
Trypsin
Plasmin
Plasma kallikrein
Tissue kallikrein
Elastase
Urokinase
decreasing
affinity
Fritz H & Wunderer G, Drug Research, 1983;33(1):479-494
Mean Red Cell
Transfusion (Unit)
Aprotinin Dose-Response
Red Cell Transfusion
6
4
2
Cardiac Surgery
Placebo
200 mL prime
100ml Load + 100mL Prime + 25mL/hr
200ml Load + 200mL Prime + 50mL/hr
Orthopaedic Surgery
0
0
420 840 1260
Total Aprotinin Dose (mg)
Placebo
200 mL Load + 50 mL/hr
400 mL Load + 100 mL/hr
Royston Ann Thorac Surg 1998;65(4):S9-19
Samama et al Anesth Analg 2002;95:287-93
Aprotinin Use in AspirinPretreated Patients
Thoracic Drainage (ml)
Control
Total Units Transfused
Aprotinin (Blood Products)
9
3000
p = N/A
2000
p < .001
p < .001
50%
6
2766
78%
3
1000
1410
1393
4.1
3.5
0.8
352
0
8
n = 18 n = 26
Bidstrup
n = 25 n = 29
Murkin
0
n = 18 n = 26
Bidstrup
n = 25 n = 29
Murkin
Bidstrup et al. Perfusion 1990;5:77
Murkin et al. J Thorac Cardiovasc Surg 1994;107:554
Aprotinin in Primary CABG
Patients on Clopidogrel
Blood Loss (ml)
Blood Products Transfused
5
1200
p < .001
1000
800
600
1200
400
760
200
0
Units Transfused
1400
4
3
0.9
Platelets
RBC
1 Unit = 500 ml
platelets
2
2.8
1
0.1
1.2
n = 38
Control
n = 37
Aprotinin
0
n = 38
n = 37
Control
Aprotinin
van der Linden J et al. Circulation 2005;112:I276
p = .002
p = .02
Aprotinin
EfficacySafety-
>7400 articles
Is that enough?
Is a drug that decreases
bleeding pro-thrombotic?
Other Drugs-EACA, TA
Aprotinin for Off-Pump CABG

Poston RS et al. Aprotinin shows both hemostatic and antithrombotic effects during off-pump coronary artery
bypass grafting. AnnThorac Surg.2006;81:104-11.
Jeremiah Brown PhD
Many on the committee were conflicted
regarding aprotinin.
 Meta-analysis X 2
 NEJM 2006;354:1953-7.
 Circulation 2007;115:2801-13.

Adverse outcomes by antifibrinolytic agents: head-to-head comparison
Brown, J. R. et al. Circulation 2007;115:2801-2813
Copyright ©2007 American Heart Association
Renal failure and dysfunction by antifibrinolytic agent compared with placebo
Brown, J. R. et al. Circulation 2007;115:2801-2813
Copyright ©2007 American Heart Association
Anti-Fibrinolytics
Mangano DT, Tudor JC, Dietzel C. The risk associated with aprotinin in
cardiac surgery. N Engl J Med 2006; 354 :353-65.
The “First” Article

4373 patients, observational,
retrospective analysis of data
base
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Increased renal failure,
adverse cardiac outcomes,
increased stroke or
encephelopathy!
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Do you believe the
data/analysis/statistics?
Channeling?
Does this trump everything???
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Mangano DT, Tudor IC, Dietzel CT and McSPI
Investigators. The risk associated with aprotinin in
cardiac surgery. NEJM 2006;354:353-365.
The “Other Article”
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449 propensity matched patients for aprotinin v. TA out of a data base of 10,870 (TA
for the rest).

Adverse events rates were comparable in the two groups, except for renal
dysfunction (defined as a greater than 50% increase in creatinine
concentration during the first postoperative week to >100 µmol/L in women
and >110 µmol/L in men or a new requirement for dialysis support), which
occurred in 24 percent (107/449) of aprotinin patients and 17 percent
(75/449) of tranexamic acid patients (p = 0.01).
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Keyvan Karkouti, W. Scott Beattie, Kathleen M. Dattilo, Stuart A. McCluskey, Mohammed
Ghannam, Ahmed Hamdy, Duminda N. Wijeysundera, Ludwik Fedorko, Terrence M. Yau (2006) A
propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk
cardiac surgery
Transfusion 46 (3) , 327–338
Channeling
Physicians pick the drug that fits the risks
of the patient.
 Those with more risk received aprotinin
(67 covariates positive).

 Can
statistics (multivariate/propensity) smooth all
these biases out and reverse the
effects of channeling?
FDA Cardio-Renal Meeting # 1
Karkhouti and Mangango Presented
 FDA votes: Restrict aprotinin to bypass
available only due to anaphylaxis.
 No change in warnings and no change in
marketing.
 Bayer complimented for transparency and
suggested that there should be expanded
indications.

Out of Left field!
I3- “Study” revealed 3 weeks after the first
FDA meeting.
 What was the I3 “study”?
 Why was it not revealed –public
comment?
 What is the real truth?
 Bad-Bad PR!

Paper # 2
A Lot has Happened: Since we last
spoke!
Mangano Publications: JAMA, NEJM
 I3 (unpublished but reported to FDA)
 FDA-Cardio-Renal Advisory Committee
Meeting
 STS/SCA- Guidelines
 Furnary, et al. paper
 Other-published work coming out daily

What are your “Facts”?
What have you heard?
What is the truth!
 I3 study supported and proved the McSPI
data regarding mortality and renal failure?
 FDA reviewed McSPI’s data and noted it
was the right analysis?
 BART Study found significant more
mortality with aprotinin?
 The FDA forced the Bayer to withdraw
aprotinin from the market?
 Aprotinin is no longer on the market?
The Truth
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I3 was discredited as being highly confounded. Robust (
a lot of patients but Medicare and billing database)
FDA supported some of McSPI’s data but had major
questions about some analysis.
BART was stopped by the DSMB due to a nonsignificant (0.06) but strong trend towards more mortality
with aprotinin. There was a problem with sever
hemorrhage leading to mortality. No final word yet!
Bayer, notified the FDA of a hold on marketing of
aprotinin.
Aprotinin is still produced, available but not actively
marketed.
FDA Meeting

www.FDA.gov
(aprotinin, slides are
available and you can
(soon) get full
transcript of meeting)see for yourself.
FDA Cardio Renal Meeting-9-12-07
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Should aprotinin stay on the market:
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Should there be a label change to reflect
data from the retrospective studies:
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17 yes, 1 abstain, 1 no
16 no, 1 abstain
Should Bayer do a new (contemporary)
study of aprotinin?
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17 yes, 0 no, 0 abstain
Did he get all the confounders
correct?
That is the big question is it not?
 Karkhouti did! As he added in each
potential confounder the odds ratio for
aprotinin decreased.
 His conclusion to the FDA was that only
renal dysfunction existed as a real finding.
 A partial retraction of his original paper?

At the end of the day!
I3 –incomplete data set from a “billing
registry”, no independent inspection (cross
check) of original data, lacking many
standard confounders.
 McSPI articles-tremendously confounded
and inconclusive-what you look at is what
you get!
 “If there is smoke is there fire?”
 Is it all due to transfusion?

Other papers by Mangano and McSPI that relate
to aprotinin, renal dysfunction, and Tx.

Moehnle P et al. Morbid risks of unnecessary red blood cell transfusion in stable
coronary artery bypass graft patients. Blood (American Society of Hematology
Abstracts) 2005; 106; abstract 427.
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Snyder-Ramos S et al. On going variability in transfusion practices in cardiac
surgery despite established guidelines. Blood (American Society of Hematology
Abstracts) 2005; 106:abstract 947.

Kullier A et al. Impact of preoperative anemia on outcome in patients undergoing
coronary artery bypass graft surgery. Circulation 2007; 116:471-479.

Aronson S et al. Risk index for perioperative renal dysfunction/failure:
critical dependence on pulse pressure hypertension. Circulation
2007;115: 733-42.

Ott E et al. Coronary artery bypass graft surgery--care globalization: the
impact of national care on fatal and nonfatal outcome. J Thorac
Cardiovasc Surg 2007; 133: 1242-51.
Ott E et al. Coronary artery bypass graft surgery--care globalization: the
impact of national care on fatal and nonfatal outcome. J Thorac
Cardiovasc Surg 2007; 133: 1242-51.
Dramatic differences in aprotinin use:
Germany 69%, Canada 5.7%
 Dramatic differences in FFP usage: 10.6%
Germany, 1.4% Canada
 Dramatic differences in renal
dysfunction/failure: More patients dialyzed
in Germany than had renal dysfunction???
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What about Transfusion
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Is transfusion an outcome or a risk, both?
In the year after McSPI’s first article there was a
14.7% sudden unprecedented increase in
transfusion for heart surgery from the STS
database.
Prior three years transfusion was stable even
though patient acuity had risen.
No data yet for transfusion or mortality after the
BART DSMB action.
What is the definition of human
experimentation?
Niv Ad Propensity Matched
Survival
Propensity Matched for Aprotinin (yes/no)
Percent survival
100
75
No Aprotinin
Aprotinin
p<0.014
50
No. of Patients at Risk of Dying
25
Year
0
1
2
3
4
5
No Aprotinin
554
541
539
536
527
432
Aprotinin
554
533
525
516
507
269
0
0
1
2
3
4
Survival Time
5
6
7
Niv Ad, Survival with and without
Tx. added into the analysis!
Propensity Matched for Aprotinin Use (yes/no)
100
100
80
80
Aprotinin No, BP No
Aprotinin No, BP Yes
Aprotinin Yes, BP No
Aprotinin Yes, BP Yes
60
40
20
Percent survival
Percent survival
All Patients
Aprotinin No, BP No
Aprotinin No, BP Yes
Aprotinin Yes, BP No
Aprotinin Yes, BP Yes
60
40
20
0
0
0
1
2
3
4
Survival Time
5
6
7
0
1
2
3
4
Survival Time
5
6
7
The Right Analysis?
It is all about what you include!
Furnary Analysis 3-Ways!
Tx. Causes Renal Failure!
The Latest
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8548 Pts at Munich Heart Center
Various dosages of aprotinin
Renal failure (dialysis)
Renal dysfunction (increased creatinine)
No evidence of increased renal failure or
dysfunction even with increased dosing,
Risk factors (patient and operative) were related
to outcome.
Dietrich W, Busley R, Boulesteix A-L. Effects of aprotinin dosage on
renal function. Anesthesiology; 2008:189-98.
Brand New!
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9875 pts retrospective observational study
Renal dysfunction without ACE OR 1.81(95% CI 0.794.13 p=0.16)
Renal dysfunction with ACE on bypass 1.73 (0.56-5.32,
p=0.34)
848 pts off pump with ACE 2.87 (1.25-6.58,p=0.013)
“ Our results have shown that aprotinin seems to be safe
during on-pump cardiac surgery.”
Mouton R et al. effect of aprotinin on renal dysfunction in
patients undergoing on-pump and off-pump cardiac
surgery: a retrospective observational study. Lancet
2008;371:475-482.
The Duke Paper
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10,275 pts over 10 years (1996-2005)
1343 (13.2%) aprotinin
6776 (66.8%) EACA
2029 (20.0%) no Rx.
Creatinine Increase p<0.001
Dialysis: P=0.56
Mortality: 1.32 (95% CI 1.12-1.55) placebo
 1.27 (95% CI 1.10-1.46) EACA
JCTVS March 2008

“These , Gentlemen are the opinions upon which
I base my facts!” -Sir Winston Churchill

Editorial by DeAnda- “In the face of conflicting
“facts” and numerous opinions, it appears that
the best course of action remains to adhere to
individual responsibilities.” JCTVS
2008;135:492-4

Pagano et al. Bleeding in cardiac surgery: The
use of aprotinin does not affect survival. JCTVS
2008;135:495-502 7836 patients over 9 years.
JCTVS March 2008

Westaby S. Aprotinin: twenty-five years of claim
and counterclaim. JCTVS;2008:135:487-91.

Koster A et al. High dose aprotinin effectively
reduces blood loss during on-pump coronary
artery bypass grafting with bivalirudin
anticoagulation. JCTVS 2008;135:685-7.

Iwata Y et al. Aprotinin confers neuroprotection
by reducing excitotoxic cell death. JCTVS
2008;135:573-8.
Meta-analysis & Observational
Cochrane
Sedrakyan
Mangano
Death
MI/Cardiovascular
Renal
Cerebrovascular
0.1
1
10
Odds Ratio
Renal Injury, Hemodilution and
Transfusion
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Retrospective 1760 Pts
Single center
31% female
CABG with CPB
Major Outcome: Delta Creatinine
Renal Injury= Delta Creatinine >50%
Acute Renal Failure=100% increase in Creatinine and >
2.1mg/dl.
Anemia associated with renal failure
Habib R et al. Role of Hemodilutional Anemia and Transfusion during Cardiopulmonary Bypass in
Renal Injury After Coronary Revascularization: Implications on Operative Outcome. Critical Care
Medicine 2005;33:1749-56.
Propensity Analysis: Tx and Cr
Change
% Change Cr.
 %Cr-Clearance
 Renal Injury
 ARF
 LOS


0.0029
0.0043
0.0030
0.0010
0.0027
Habib R et al. Role of Hemodilutional Anemia and Transfusion
during Cardiopulmonary Bypass in Renal Injury After Coronary
Revascularization: Implications on Operative Outcome. Critical Care
Medicine 2005;33:1749-56.
Editorial
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Spiess BD. Choose One: Damned if you
do/Damned if you don’t. Critical Care Medicine
2005 (in press).
Both Low Hct and Tx are implicated in adverse
events.
Tx makes it worse, not better.
Blood Conservation is the Answer!
Habib R et al. Role of Hemodilutional Anemia and Transfusion during
Cardiopulmonary Bypass in Renal Injury After Coronary Revascularization:
Implications on Operative Outcome. Critical Care Medicine 2005;33:1871-4.
What About BART?
Not published yet!
 Mortality data is being adjudicated!

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But, don’t judge until it is published!
Evidence Based


“… the science of medicine becomes a
structured and organized way of using
probability…to best benefit the patient
and the community.”
Jenicek M. Foundations of evidence-based medicine. New York: Parthenon Pub.
Group. 2002.
Conclusions
What is the significance of “transient” creatinine changes?
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Should we wait for BART?
Will Bart answer everything?
What if Bart does not answer anything?
How much to blame are we all?
How do you assure drug safety?
Do we determine medical care by “60 Minutes”, threat of
medical legal action?
What is the sociology of this “research”?
Do you feel like betting on this one?
How are you going to bet on this
one? What are we teaching our
kids (students, public, patients)?