History of Aprotinin

A Naturally Occurring Proteolytic Enzyme Inhibitor

n

Discovered independently in the 1930s Kraut et al isolated a kallikrein inhibitor from bovine lung Kunitz and Northrop described a bovine pancreatic trypsin inhibitor Launched as Trasylol in Germany in 1959

P1

Aprotinin
A Naturally Occurring Serine Protease Inhibitor
n n n n n n

Consists of 58 amino acid residues Single-chain polypeptide: 6512 daltons Cross-linked by 3 disulfide bridges Reactive bond site is lysine-15-alanine-16 Forms reversible stoichiometric complexes Reacts with serine site of enzyme

P2

Structure of Aprotinin

P3

Aprotinin
A Serine Protease Inhibitor Binds with the human serine proteases:
n n n n n n n

Trypsin Plasmin Plasma kallikrein Tissue kallikrein Elastase Urokinase Thrombin

decreasing affinity

P4

Serine Protease Enzyme Systems

The Potential Inhibitory Role of Aprotinin
n n n n n n

Kallikrein-kininogen-kinin Complement Coagulation Fibrinolysis Renin-angiotensin Leukocyte elastase

P5

Aprotinin
Pharmacokinetic Properties
n n n n n n n n

Inactive via oral route Rapid distribution into total extravascular space Following redistribution, plasma half-life 150 min Filtered by glomeruli and reabsorbed by proximal tubules Less than 10% excreted as unchanged drug Slowly degraded by lysosomal enzymes Terminal elimination phase half-life 10 h Does not cross the blood-brain barrier
P6

Fibrinolysis
Circulating in Blood

t-PA Plasminogen Lysine Fibrin Plasmin

F1

t-PA

Role of 2 Plasmin Inhibitor

2-antiplasmin
0.01 sec Free Plasmin

> 5 min

F2

Pharmacologic Inhibition of Fibrinolysis

Lysine Antifibrinolytics Serine Protease Inhibitors

X
F3

Aprotinin
Approved Indication
Trasylol is indicated for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass in the course of coronary artery bypass graft (CABG) surgery Please note important boxed warning and other safety information

C1

Aprotinin Warning Information

Anaphylactic or anaphylactoid reactions are possible when Trasylol is administered. Hypersensitivity reactions are rare in patients with no prior exposure to aprotinin. The risk of anaphylaxis is increased in patients who are reexposed to aprotinin-containing products. The benefit of Trasylol to patients undergoing primary CABG surgery should be weighed against the risk of anaphylaxis should a second exposure be required.
C2

Aprotinin in Repeat Cardiac Surgery

2000

First Use of the High-Dose Regimen

1509

P < .001
41 units in 11/11 patients

Blood Loss (mL)

1000

286
0

5 units in 5/11 patients

Placebo

Aprotinin
C3

Royston et al Lancet 1987 Dec 5;2:1289-1291

High-Dose Aprotinin
Original Administration Regimen
Test Dose 1 mL Loading Pump-Prime Dose Dose 200 mL 200 mL

Bypass Period

Operation Period

50 mL / h

Constant Infusion
C4

Royston et al Lancet 1987 Dec 5;2:1289-91

Aprotinin Dosing and Administration

Test Dose Loading Dose Pump-Prime Dose Constant-Infusion Dose

Regimen B (Plasmin Inhibiting)

1 mL 1.4 mg, or 10,000 KIU KIU/h 100 mL 140 mg, or 1.0 million KIU 100 mL 140 mg, or 1.0 million KIU 25 mL/h 35 mg/hr, or 250,000

C5

Aprotinin Dosing and Administration

Test Dose Loading Dose Pump-Prime Dose Constant-Infusion Dose

Regimen A (Kallikrein Inhibiting)

1 mL mL/h (1.4 mg, or mg/h, or 10,000 KIU) KIU/h) (280 mg, or 2.0 million KIU) 280 mg, or 2.0 million KIU) (70 500,000
C6

200 mL

200 mL

50

Dosing and Aprotinin Administration

Test Dose n All patients should first receive a test dose. Administer intravenously at least 10 minutes before loading dose. Loading Dose n After induction of anesthesia but prior to sternotomy, give intravenously to patient in supine position. Administer slowly over 20-30 minutes

C7

Dosing and Aprotinin Administration

Pump-prime Dose n Add to priming fluid of cardiopulmonary bypass circuit, by replacement of an aliquot of priming fluid, prior to institution of cardiopulmonary bypass. Constant Infusion Dose n Administer when loading dose is complete. Continue until surgery is complete and patient leaves operating room.

C7

Aprotinin Use in Primary CABG Operations

6 5
Units Transfused

Cryo 0.9 1.9 0.7 2.1 Platelets RBC

P < .001
Thoracic Drainage (mL)

1600 1200

1503

FFP

P < .001
855 800 400 0
Placebo Aprotinin

4 3 2 1 0

0.8

0.3 1.1
Aprotinin

P = .044 P = .002 P = .025

Placebo

Lemmer et al J Thorac Cardiovasc Surg 1994;107:543-553

C8

Aprotinin Use in CABG Reoperations

Total Thoracic-Drainage Volume (mL)
2000 1500 1000 500 0 1979

P = 0.037
1225

2000 1500 1000 500 0

1700

P < .001
900

Placebo

Aprotinin

Placebo

Aprotinin

Lemmer et al J Thorac Cardiovasc Surg 1994;107:543-53

Levy et al Circulation 1995;92:2236-44

C9

Aprotinin Use in CABG Reoperations

Donor-Blood-Product Requirements
15
No. Units Transfused

P < .001

15
11.9

P < .001
10.3

10 5 1.6 0 RBC FFP Plt Cryo Total

10

5 2.2 0 RBC FFP Plt Cryo Total

Lemmer et al J Thorac Cardiovasc Surg 1994;107:543-53

Levy et al Circulation 1995;92:2236-44

C10

Aprotinin Use in CABG Reoperations

Patients Requiring Donor Red Blood Cells (%)

80 60 40 20 0

75% 54%
P =.007

72% 30%
P = .001

Placebo Ap rotinin

Levy

Lemmer
C11

Levy et al Circulation 1995;92:2236-44 Lemmer et al J Thorac Cardiovasc Surg 1994;107:543-53

Results of Differing Dose Regimens

Thoracic Drainage (mL) Platelets Placebo 5.414.6 Half Dose 3.315.4 Full Dose 1.66.3
Cosgrove et al Ann Thorac Surg 1992;54:1031-38
C12

Units Given RBC 4.16.2

1,121683

8661636

4.811.8

720753

2.14.2

Comparative Dose Trial in Repeat CABG Surgery

Thoracic Drainage (mL)
1500 1000 500 0
Placebo n = 157 Prime only n = 159

Total Units Transfused

5 4 4.1

1286 899 811 786

3 2 1 0
Low Dose n = 168 High Dose n = 160

1.7 1.6 1.5

Lemmer et al Ann Thorac Surg 1996;62:1659-68

C13

Comparative Dose Trial in Repeat CABG Surgery

Thoracic Drainage (mL)
2000 1700 1420 1000 1040 900
12 10 8 6 4 2

Total Units Transfused

10.3

5.1 3.4 2.2

0
Placebo Prime only

0
Low Dose High Dose

Levy et al Circulation 1995;92:2236-44

C14

Aprotinin Dose vs Thoracic Drainage Rate

Thoracic Drainage Rate mL/hr 90 80 70 60 50 40 30 0 250 500 750 1000 Total Dose of Aprotinin (mg)
C15

y = -0.058x + 89.440 r2 = 0.999

Royston D. In: Machiraju VR, ed. Redo Cardiac Surgery in Adults. New York: CME Network, 1998:10-22.

Aprotinin Dose vs Hemostatic Factors Given

8 Hemostatic Factors Given (Units) 6 4 2 0 0 250 500 750 1000 Total Dose of Aprotinin (mg)
C16

r y = -2.940LOG(x) + 9.8022= 1.000

Royston D. In: Machiraju VR, ed. Redo Cardiac Surgery in Adults. New York: CME Network, 1998:10-22.

Aprotinin Use in Repeat CABG Operations

12 10
Total Units Transfused

Cryo 0.9
5

Platelets FFP RBC

Total Thoracic Drainage Volume (mL)

1200 1103

P < .001

8 6 4 2 0

960

1.3

0.5
1.3
0.3

3.7

0.1
0.9
0.2

2.2

1.6

800
Regimen B Regimen A
C17

Placebo Regimen B Regimen A

Product Information 11/98

Aprotinin Use in Primary CABG Operations

4.5 4 3.5
Total Units Transfused

Cryo 0.5 1.3 0.6 0.1 0.3 0.2 1 0 0.3 0.2 0.9 Platelets FFP RBC
Total Thoracic Drainage Volume (mL)

800

792

P < .001
705

3 2.5 2 1.5 1 0.5 0

1.7

400
Placebo Aprotinin
C18

Placebo Regimen B Regimen A

Product Information 11/98

Selected Cost Factors Related to CABG

n n n n n n n n n n

Drug Monitoring Blood products Single donor platelets Blood product -associated complications Operating room times - surgical/anesthetic Re-exploration Myocardial infarction Stroke Length of stay - ICU/hospital

$1

Selected Cost Factors Related to CABG

n n n

Drug Monitoring Blood products ($60-$100/unit) Single donor platelets ($250-$500/unit) Blood product associated complications

Operating room times _ surgical costs ($5-$15/min) _ anesthetic costs Re-exploration ($3,000-$20,000) Myocardial infarction Stroke _ in hospital ($10,000-$30,000) _ out of hospital ($100,000$250,000) LOS- ICU/Hospital ($800-$2,500/day)
$2

n n n

Cardiac Surgery Impairs Hemostasis

Inhibition of Hemostasis n hypothermia n hemodilution n heparin / protamine n preoperative drug therapies Extrinsic Pathway Activation n pericardial shed blood n reperfusion of heart and lungs n local thrombin generation Contact Activation of Factor XII

I1

Contact Activation - The Role of Kallikrein

Negative Charged Surface
XII HK FXIIa PKK FXIIa
Kallikrein

XII HK PKK FXIIa XII HK FXI FXIIa XIa

Bradykinin

Kallikrein

I2

Thrombin Generation

Factor XII Factor XIIa

Kinin Generation Angiotensin System Complement System Prekallikrein

HMW-Kininogen Bradykinin Prorenin Renin Factor XII Factor XI

Kallikrein
Factor XIIa

C1 _ C1
Plasminogen

Factor XIa

Coagulation System Fibrinolytic System

Plasmin

I3

The Insult of Cardiopulmonary Bypass

Contact of Blood with the Foreign Surface of the Bypass Circuit May Activate:
n n n n n

White cells and platelets Complement System Coagulation System Kinin Generation Fibrinolytic System

I4

Contact Activation of Blood Proteins

Blood/Surface Interaction
Intrinsic Pathway Heparin Clotting Platelets Plasmin Kallikrein

Serine Protease Inhibitors Fibrinolysis Kinins Complement

White Cells

Cytokines/Adhesion Molecules

Systemic Inflammatory Response

I5

Neutrophil Adhesion Processes

Endothelial Cells

Circulating Neutrophil (1000m/s)

CD11b/CD18 Rolling Neutrophil (30m/s) Adherent CD11a/CD18 L-Selectin

Penetrating

Degranulating I6

Systemic Inflammatory Response to CPB

n

The systemic response to bypass is a result of the interrelated activation of: Hemostasis Fibrinolysis Cellular and humoral inflammatory systems Aprotinins action to inhibit serine proteases (e.g., kallikrein, plasmin) attenuates: Inflammatory responses Fibrinolysis Thrombin generation

I7

Anti-inflammatory Action of Aprotinin

Aprotinin inhibits pro-inflammatory cytokine release and maintains glycoprotein homeostasis
n

Platelets - reduces glycoprotein loss (e.g., GpIb, GpIIb/IIIa) Granulocytes - prevents the expression of pro-inflammatory adhesive glycoproteins (e.g., CD11b)

I8

Antiinflammatory Actions of Aprotinin

Suppression of ProInflammatory Cytokine Release
40 Plasma Levels of TNF-1 (pg.ml ) Control Ste roids 30 Aprotinin 20 10 0 Base line 50 min CPB 30 min post CPB
*

Hill et al J Thorac Cardiovasc Surg 1995;110:1658-62

I9

The ACT and Aprotinin

In vivo Action
1000
Control Aprotinin

In vitro Action
1200 800 400 0

750
Seconds

500 250 0
Pre Bypass 10 On 40 On Post Bypass

Seconds

Control

Heparin Heparin/ Aprotinin

Royston D J Cardiothorac Anesth 1989;3:80

Royston D In: Pifarre R, ed. 1993

H1

Monitoring Anticoagulation With Aprotinin

n n n n

Maintain celite-based ACT values at 750 seconds OR Maintain kaolin-based ACT values at 480 seconds OR Give additional heparin in a fixed-dosage regimen OR Use heparin/protamine tritration, a monitoring test that does not rely on contact activation

H2

DHCA and Heparinization Management

Appropriate heparinization schedules must be used to ensure anticoagulation throughout the bypass procedure
n

Activated clotting time (ACT) should be maintained at more than 1000 seconds during the procedure To achieve this may require a larger loading dose of heparin and an additional bolus of heparin prior to initiation of circulatory arrest

H3

Aprotinin and Heparin Inhibition

XIIa
Contact Pathway

XIa IXa

Extrinsic Pathway

Xa
Inhibited by aprotinin Inhibited by AT III/heparin

TF:VIIa

IIa
H4

Royston J Cardiothorac Vasc Anesth 1992;6:76-100

Coagulation Monitoring With Aprotinin

Activated Clotting Time (ACT)
n n

Celite 750 seconds Kaolin 480 seconds

Independent of the effects of hemodilution and/or hypothermia (Difficult to quantify during CPB)

Trasylol Prescribing Information, Bayer Corporation

H5

Limitations of ACT in Heparin Monitoring

7 6 5 4 3 2 1 0 -60 -30 0
Hct (%/10) Temp (C/10) N = 32
HC ACT (sec/100) HT ACT (sec/100)

Xa HC (U/mL) WB HC (U/mL)

30 60 90 120 150 CPB Time (min)

H6

Despotis et al J Thorac Cardiovasc Surg 1994;108:1076-82

Coagulation Monitoring With Aprotinin

Fixed Heparin Dosing
n n

Loading dose + pump prime = at least 350 IU/kg Additional heparin should be given based on: _ Patient weight _ Length of CPB Heparin elimination _ e.g. 1/3 initial dose in U/kg every 45 min

Trasylol Prescribing Information, Bayer Corporation

H7

Coagulation Monitoring With Aprotinin

Heparin-Protamine Titration
n

A heparin dose response, assessed by protamine titration, should be performed prior to aprotinin administration to determine heparin loading dose Maintain heparin levels during CPB at least above 2.7U/mL Maintenance of patient-specific pre-CPB reference (whole blood heparin concentration associated with kaolin ACT of approximately 480 seconds)

n n

Trasylol Prescribing Information, Bayer Corporation

H8

Coagulation Monitoring With Aprotinin

Heparin Reversal With Protamine

Amount of protamine administered based on the amount of heparin given (e.g. 0.5-0.7 mg protamine:mg total heparin*) , not the ACT value

* Despotis et al J Thorac Cardiovasc Surg 1995;110:46-54 Trasylol Prescribing Information, Bayer Corporation

H9

Aprotinin Risk/Benefit Issues

n n n n n n n n

Hypersensitivity Mortality Myocardial Infarction Graft Patency Use with Hypothermic Circulatory Arrest Renal Function Stroke Miscellaneous Adverse Events

S1

Incidence of Hypersensitivity Reactions

Including mild skin rash, bronchospasm, and anaphylaxis
Incidence No prior exposure * <0.1% Reexposure within six months ** 5.0% Reexposure after six months ** 0.9% * Bayer Corporation, Data on File ** Dietrich et al Ann Thorac Surg 1998;65:S60-4

S2

Epidemiology of Serious Hypersensitivity Reactions

n n

Treated patients Known prior exposure Major hypersensitivity

> 3000 200 1

Ceriani et al J CardiothoracVasc Anesth 1995;9:477

S3

Hypersensitivity Reactions to Aprotinin

90 % of Patients 70 50 30 10 0 Adverse Event No Event 200d 1y 2y 3y Time After Sensitization 19 y

Dietrich et al J Ann Thorac Surg 1998;65:S60-64

S4

Testing for Hypersensitivity

n n n n

All patients should first receive a test dose of Trasylol to assess the potential for allergic reactions The 1 mL test dose should be administered intravenously at least 10 minutes before the loading dose Even after the uneventful administration of the test dose, the full therapeutic dose may cause anaphylaxis If this happens, the infusion should be stopped immediately and emergency treatment for anaphylaxis should be applied

Trasylol Prescribing Information, Bayer Corporation

S5

Management Recommendations
Patients With Prior Exposure
n n

Have standard emergency treatments for hypersensitivity or anaphylactic reactions readily available in the operating room Administration of the test dose and loading dose should only be done when the conditions for rapid cannulation (if necessary) are present Delay the addition of Trasylol into the pump-prime solution until after the loading dose has been safely administered Additionally, administration of H1 and H2 blockers 15 minutes before the test dose may be considered
Trasylol Prescribing Information, Bayer Corporation
S6

n n

Aprotinin-Drug Interactions
n

Blocks the anti-hypertensive action of Captopril Inhibits action of thrombolytic agents in vitro and in animal studies Interferes with assays used to assess adequate heparinization during CPB

S7

Mortality Rates
Primary CABG Surgery
10
Mortality (%)

8 6 4 2 0 2
High Dose

2
Low Dose

Pump Prime

Placebo

Lemmer et al Ann Thorac Surg 1996;62:1659-68

S8

Diagnosis of Myocardial Infarction

Based on Evaluation by a Blinded Core Laboratory

n n n n

Electrocardiogram Creatine kinase and CK-MB SGOT Lactic dehydrogenase

S9

Definition of Myocardial Infarction

Definite MI n Defined by a definite new Q wave on the EKG, or CK-MB levels _120 U/L at 6, 12, and 18 h postop Definite or Probable MI n Based on any or all of the information, including but not limited to enzyme values Definite, Probable, or Possible MI n Based on any and all information No MI
S10

Incidence of Myocardial Infarction

20
Incidence (%)

Primary CABG Surgery

P= 0.045 16 13 P=NS 13 10 7
Half Dose

Possible MI Probable MI Definite MI

15 10 P=NS 5 9 4 0
Placebo

P=NS 11 8 6
Full Dose

5
Pump Prime

Lemmer et al Ann Thorac Surg 1996;62:1659-68

S11

Incidence of Myocardial Infarction Repeat CABG Surgery

50
Incidence (%)

Repeat CABG Surgery

40 30 20 10 12 0
Placebo

Possible MI

31 29

32 30 24 9
Pump Prime

32 29 12
Full Dose

Probable MI Definite MI

15
Half Dose

Levy et al Circulation 1995;92:2236-44

S12

Incidence of Myocardial Infarction

Effect of Aprotinin Dosing Regimens
25 Incidence (%) 20 15 10 5 0 Possible MI Probable MI

15 14 6

17 15 6

15 14 6

17 15 7.5 13 10.5 4.5 13 9.5 10

Definite MI

Pump Half Full PlaceboPrime Placebo Dose Placebo Dose

Smith PK and Muhlbaier LH Ann Thorac Surg 1996;62:1575-7

S13

Graft Patency Rates

Placebo
Analysis by Graft
Bidstrup 1993 MRI Havel 1994 Angio Lemmer 1994 CT Kalangos 1994 Angio Lass 1995 Angio
Occluded Total

Aprotinin
Occluded Total

4 2 8 1 13

138 40 163 139 102

5 2 14 2 13

131 39 176 142 124

Dobkowski et al Drug Safety 1998;18:21-41

S14

Mortality Rates
Randomized Placebo Controlled Trials (2512 patients)

High Dose (%)

Low Dose (%)

Placebo (%)

Cosgrove Lemmer Murkin Levy DAmbra Lemmer Alderman

1992 1994 1994 1995 1996 1996 1998

7 6 6 7 4 2 1

9 11 3 2 -

7 4 0 7 0 3 2
S15

Factors Affecting Graft Patency

Quality of Artery n If > 2mm = occlusions in 17.6% n If < 2mm = occlusions in 42.3% Technique of Anastomosis of Distal End n Single anastomosis failure in 9.2% n Sequential anastomosis failure in 4.3% Surgical Center n Failure rate between centers showed a range of 7.1% to 57.1%
Refers to valve replacement (All NDA studies summarized-these data in Product Information)

Ollivier Arch Mal Cur 1991;84:537-42

S16

US Multicenter Vein Graft-Occlusion Study

Primary CABG Surgery 164 Patients at 5 Centers Evaluated by Ultrafast CT Scans Aprotinin
By Patient 13/83 15.7% NS 14/176 8.0% NS

Placebo P
7/81 8.6% 8/163 4.9%

By Graft

Lemmer et al J Thorac Cardiovasc Surg 1994;107:543-53

S17

US Multicenter Vein Graft-Occlusion Study

Single-Center Analysis
Aprotinin Occluded grafts Poor target vessel 5/43 (11.6%) 8/43 Placebo 0/38 (0%) 0/38

No differences between treatment groups in the incidence of perioperative MI assessed by enzymes or electrophysiology
Laub et al Chest 1994,106: 1370-75

S18

US Multicenter Vein Graft-Occlusion Study

Centers By Patient Aprotinin (11.8%) Placebo (10.8%) By Graft Aprotinin (6.8%) Placebo (6.4%) All 1 Center 4 13/83 7/81 5/16 0/16 8/67 7/65

14/176 8/163

5/43 0/38

9/133 8/125

Lemmer et al J Thorac Cardiovasc Surg 1994;107:543-53 Laub et al Chest 1994, 106: 1370-75

S19

International Multicenter Aprotinin Graft Patency Experience (IMAGE)

Study Sites n 10 US; 2 Israel; 1 Denmark Patient Population n 870 primary CABG patients randomized to receive placebo or full-dose aprotinin Study Evaluations n Graft patency n Incidence of myocardial infarction n Mortality n Blood loss and transfusion requirements

Alderman et al J Thorac Cardiovasc Surg 1998;116:716-30

S20

IMAGE
796 (91%) 703 (81%) Patients assessable for blood loss/usage Patients assessable by angiography for saphenous vein-graft patency (at mean of 10.8 days postop)

831 (95%) Patients assessable for MI by ECG and cardiac enzyme evaluation

S21

IMAGE Study
Blood Loss and Blood Product Replacement
Drainage and Transfusion Thoracic Drainage (mL) 1500 Units Transfused Patients Requiring Any Blood Product 4 3 1168 500 664 0 Placebo Aprotinin
Alderman et al J Thorac Cardiovasc Surg 1998;116:716-30
S22

P <.001 P <.001

Placebo 58%

Aprotinin

1000

2 1 0

P <0.0001

40%

IMAGE Study
Internal Thoracic Artery Graft Occlusion
Aprotinin No Aprotinin P Value Patients Assessed % with Occluded Grafts 326 1.8 304 1.00 .32

Alderman et al J Thorac Cardiovasc Surg 1998;116:716-30

S23

IMAGE Study
Saphenous Vein Graft Occlusion and Clinical Events
Overall Vein Graft Closure Rates All Centers (n = 703) % Aprotinin Placebo 15.4 10.9 US Centers (n = 381) % 9.4 9.5 Incidence of MI All Centers (n = 703) % 2.9 3.8 Incidence of Death All Centers (n = 703) % 1.4 1.6

Alderman et al J Thorac Cardiovasc Surg 1998;116:716-30

S24

IMAGE Study
30
Patients with Occluded SVG (%)

Placebo
P = .03

Aprotinin
P = .01

23

20 10.9

15.4
9.5

P = .72

10

9.4

12.4

All Centers

US Centers

Non US Centers
S25

Alderman et al J Thorac Cardiovasc Surg 1998;116:716-30

IMAGE Study
Adverse Outcome Death Myocardial Infarction Definite Def+probable Def+prob+possible Placebo 1.6% (6/434) 3.8% (16/421) 9.1% (38/418) 12.0% (50/418) Aprotinin 1.4% (5/436) 2.9% (12/410) 8.6% (35/407) 12.3% (50/408)

Alderman et al J Thorac Cardiovasc Surg 1998;116:716-30

S26

IMAGE Study
Occluded SVG and Myocardial Infarction Placebo
Angio + MI assessment Occluded SVG Occluded SVG + MI 328 11% (36/328) 31% (11/36)

Aprotinin
340 16% (54/340) 20% (11/54)

Alderman et al J Thorac Cardiovasc Surg 1998;116:716-30

S27

Aprotinin Effects on Renal Function

n n

Transient and reversible effects May relate to: > Accumulation of drug in renal brush border > Inhibition of serine proteases associated with renal function u kallikrein u renin > Interaction with drug therapies u angiotensin-converting enzyme inhibitors

S28

Renal Function
Creatinine Clearance Fractional Na+ Excretion

150 133
(mL/min)

6
122 110
(%)

Aprotinin Placebo

125 100 75
Placebo

4 2 0 OP

ICU Day 1
S29

Half-dose Full-dose Aprotinin

Cosgrove et al Ann Thorac Surg 1992;54:1031

Blauhut et al J Thorac Cardiovasc Surg 1991;101:958

Renal Dysfunction
Peak Increase in Serum Creatinine (mg/dL)
Value

Aprotinin n = 108 _0.5 - <1.0 mg/dL _1.0 - < 1.5 mg/dL _1.5 - < 2.0 mg/dL _ 2.0 mg/dL 13 3 1 3 20 1

Placebo n = 108 9 2 2 0 13 1

P 0.37 1.00 1.00 0.25 0.19 1.00

Total Dialysis

Lemmer et al Ann Thorac Surg 1995;59:132-136

S30

Renal Dysfunction
Postoperative Mean Serum Creatinine Level (mg/dL)
Intensive Care Preop 1.15 1.16 1.07 Unit 0.94 0.99 1 1.16 1.18 Postoperative Day 2 1.21 1.13 3 1.24 1.09 4 1.30 1.09 7 1.28* 1.10

Treatment Follow-up Group Visit Aprotinin 1.06 Placebo

* P = 0.047
Lemmer et al Ann Thorac Surg 1995;59:132-136
S31

Cerebrovascular Accident
8
Incidence of Events (%)

7 6 5 4 3 2 1 0

n = 496

n = 636

n = 1721

P = 0.059 P = 0.027

Placebo

Pump Prime

Placebo

Half Dose

Placebo

Full Dose
S32

Smith PK and Muhlbaier LH. Ann Thorac Surg 1996;62:1575-7

Neurologic Deficit (Stroke)

Incidence of Stroke Events in Repeat CABG Surgery
% Placebo 7 Aprotinin 1 0 0 Number of Patients 5 / 72 Pump Prime Low Dose High Dose 1 / 72 0 / 70 0 / 73

P = 0.01
Levy et al Circulation 1995;92:2236 -44

S33

Adverse Events
EVENT
Thrombosis Shock Cerebrovascular accident Thrombophlebitis Lung edema Pulmonary embolus Kidney failure Acute kidney failure Kidney tubular necrosis
Percentage of Patients Treated With Aprotinin n = 2002 Percentage of Patients Treated With Placebo n = 1084

1.0 0.7 0.7 0.2 1.3 0.3 1.0 0.5 0.8

0.6 0.4 2.1 0.5 1.5 0.6 0.6 0.6 0.4

Data from Trasylol Package Insert

S34