Are Anti - Fibrinolytic Drugs the Magic Bullets for ... · • TXA 15 mg/kg x 2 • 6 weeks follow...

Are AntiAre Anti--Fibrinolytic Drugs Fibrinolytic Drugs the Magic Bullets the Magic Bullets for Perioperative for Perioperative

Hemostasis?Hemostasis?

Daniela Filipescu, MD. PhD.Assoc. Prof. of Anesthesia & Intensive Care

Carol Davila University Emergency Institute of Cardiovascular Diseases

Department of Cardiac Anesthesia & Intensive CareBucharest, Romania

Disclosure

Competing conflicts of interest

– Grants and speaker fees from Bayer, Novo Nordisk,

Pfizer and Sanofi

– Member of Multicenter Studies of Perioperative

Ischemia (McSPI) Research Group

Anti-fibrinolytic drugs

• Serine protease- inhibitors

Aprotinin

• Lysine analogues

Tranexamic acid

Epsilon aminocaproic acid

The ideal hemostatic agent

• Will clot inappropriate bleeding

• Will not clot normal vessels

• Favorable pharmacokinetics

• Easy to store and use

• Monitored by a validated laboratory assay

• Inexpensive

• No side effects

Aprotinin

√√√√ prevents plasmin-mediated fibrinolysis

√√√√ preserves platelet functionand number

√√√√ inhibits contact activation

√√√√ inhibits complementactivation

√√√√ anti-inflammatory andanti-oxidant effects

McEvoy MD, et al. Anesth Analg 2007;105:949-962

In-vivo inhibition of serine proteases by Aprotinin

Serine protease inhibitor from bovine pancreas

Mode of action of lysine analogues

Mannucci P, Levi M. NEJM 2007;356:2301-2311

‘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

1959

‘59

Royston [Lancet]

22 patientsAprotinin [11]Control [11]

Launched in Germany

1993

Limited indication

FDA

Approval

1998

Aprotinin’s

anti-inflammatory

properties

Expanded

indication

Mangano D[NEJM][JAMA]

Karkouti K

[Transfusion]

2006-2007

Aprotinin Saga

BART[NEJM]

2008

RCT MulticenterBlinded High-risk cardiac surgery2331 patients

Fergusson DA, et al. NEJM 2008;358:2319

Why do the BART findings differ from

those of meta-analyses of previous trials?

Previous meta-analyses did not detect an increased

risk of death for aprotinin because of:

• pooling data from many small trials that were not designed to study mortality

• the high proportion of data from trials with low or moderate quality

• the inclusion of a mixture of both high-risk and low-risk patients

• the frequent failure to ascertain the deaths of patients after hospital discharge

Ray WA, Stein CM. NEJM 2008;358:2398

RCTs vs. observational studies

• Best evidence on EFFICACY of therapy comes from randomized trials

- Caveat: Low quality RCTs may overestimate benefits of therapy

• Best evidence on HARM of therapy will often come from large, properly analyzed nonrandomized trials

- Caveat: Observational study must be of high quality

Large sample size

Proper adjustment for baseline differences to reduce

confounding by indication

Transparent

Sponsor-Independent

Vandenbroucke SA. CMAJ 2006;5:174Ray & Stein. NEJM 2008;358:2398

Life without aprotinin

Ranucci M et al. Acta Scand 2009;53:573

Retrospective analysis7988 ptsCardiac surgery2003-2007Aprotinin-free blood saving programSpecific hemostasis/coagulation management protocol

What have we learned from the

aprotinin saga?

1. Avoid redundancy of efficacy trials in drugs evaluation

2. Necessity of head to head comparisons

3. Safety studies after regulatory approval of a drug are

urgently needed

4. Safety concerns have to be taken seriously

5. Use of mortality as an end-point

Aprotinin: Key limitations

• Multiple dosage regimens

• Undefined pharmacokinetics

• Variable plasma levels

• Absence of direct monitoring of in vivo activity

• Undefined end-point in determination of the adequacy of therapy

• Undefined timing of discontinuation of therapy

Lysine analogues: Key limitations

Heterogeneity of dosingTranexamic acid

Pharmacokinetic

Fiechtner

Anesth Analg 2001

Dose/reponse

Horrow

Anesth 1995

Casati JTCS 2000

BART

NEJM 2008

Target: 20 μg/ml

5.4 mg/kg

5 mg/kg/h

20 mg/L CPB

Renal failure

moderate: 2.5 mg/kg/h

severe: 1.25 mg/kg/h

10 mg/kg

1 mg/kg/h

1000 mg

400 mg/h

500 mg/CPB

Renal dysfunction

moderate: 200 mg/h

severe: 100 mg/h

30 mg/kg

16 mg/kg/h

2 mg/kg/CPB

Bolus before induction: 1-10 g or 2.5-100 mg/kg

CPB: 0.5-2.5 g (2 mg/kg)

Infusion: 0.5-10 g or 0.2-1 g/h (0.25-16 mg/kg/h)

Dose-dependent effects

Sukeik M at al. Journal of Bone and Joint Surgery 2011: 39-46

Overdosing !!! - TXA

Dowd NP et al. Anesthesiology 2002;97:390

12.5 mg/kg + 6.5 mg/kg/h + 1 mg/kg prime

8 mg/kg + 4 mg/kg/h + 0.6 mg/kg prime

30 mg/kg + 16 mg/kg/h + 2 mg/kg prime

Overdosing - EACA

Greilich PE et al. Anesth Analg 2009;109:15

Dose:

Induction 100 mg/kg

+ 30 mg/kg/h

+ 5 g prime

Plasma concentrations

• 252 RCTs

• Over 25,000 participants

• Type of surgery

Cardiac 173

Orthopedic 53

Liver 14

Vascular 5

Thoracic 4

Henry DA, et al. Cochrane Database of Systematic Reviews 2011

Efficacy of anti-fibrinolytic drugs

All types of surgery

• Compared to control TXA significantly reduced the need for allogeneic blood transfusion by a relative 39%

Cardiac surgery 32%, orthopedic surgery 51%, liver surgery no reduced risk

• Compared to control EACA significantly reduced the need for allogeneic blood transfusion by a relative 19%

Anti-fibrinolytic use for minimising

perioperative allogeneic blood transfusion

Henry DA, et al. Cochrane Database of Systematic Reviews 2011

• Data from the head-to-head trials suggest an advantage of aprotinin over the lysine analogues TXA and EACA in terms of reducing perioperative blood loss, but the differences were small

• Aprotinin appeared more effective in reducing the need for RBC transfusion (10%)

• Aprotinin reduced the need for re-operation due to bleeding by 54%. A similar trend was seen with EACA but not TXA

Anti-fibrinolytic use for minimising

perioperative allogeneic blood transfusion

Henry DA, et al. Cochrane Database of Systematic Reviews 2011

However, any small advantage needs to be moderated by possible publication bias and uncertainty over the comparative dose-response relationship.

Dietrich W, et al. Anesth Analg 2008;107:1469-78

Andreasen JJ, Nielsen C. Eur J Cardiohorac Surg 2004;311

Maddali MM, et al. Asian Cardiovasc Thorac Ann 2007;313

More heparin needed on CPB ?!

19%

45%

0%

15%

30%

45%

Aprotinin TXA

Antifibrinolytics in patients on aspirin24-hour chest-tube drainage

McIlroy D R et al. Br. J. Anaesth. 2009;102:168-178

Antifibrinolytics in patients on aspirin

Proportion of patients receiving blood products

McIlroy D R et al. Br. J. Anaesth. 2009;102:168-178

Antifibrinolytics in patients on aspirin

Re-exploration

McIlroy D R et al. Br. J. Anaesth. 2009;102:168-178

Aspirin and Tranexamic Acid for Coronary

Artery Surgery

• A collaborative randomized controlled trial being conducted

by the ANZCA Trials Group and the Australian NHMRC Centre

of Clinical Research Excellence in Therapeutics

ATACAS

Myles PS, et al. Am Heart J 2008:224

Eur J Anesthesiol 2011:57-62

aspirin & clopidogrelaspirin & clopidogrel

Safety of lysine analogues

• Mortality

• Thromboembolic complications

• Adverse effects

Effect on thrombus formation

M.Sperzel and J. Huetter. J Thromb Haemost 2007;5:2113-8

• The lysine analogues appear to be free of serious adverse effects (myocardial infarction, renal dysfunction, stroke, deep venous thrombosis).

• When aprotinin was compared directly with either, or both, of the two lysine analogues it resulted in a significant increase in the risk of death (RR 1.39, 95% CI 1.02, 1.89).

Anti-fibrinolytic use for minimising

perioperative allogeneic blood transfusion

Adverse outcome

Henry DA, et al. Cochrane Database of Systematic Reviews 2011

Ferraris VA, et al. Ann Thorac Surg 2011;91:944-982

Meta-analysis comparing mortality between aprotinin and TXA or EACA

• Retrospective single-center cohort study

• Study period: 2000-2008

• 15365 pts. (1017 aprotinin, 14358 TXA)

• Aprotinin tends to have a better risk benefit profile

than tranexamic acid in high-risk, but not low- to moderate-risk patients

Aprotinin use in high-risk cases may be therefore warranted

Karkouti K, et al. Anesth Analg 2010;110:21

Karkouti K, et al. Anesth Analg 2010;110:21

Aprotinin

TXA

Vascular and death event in hip

fracture

• 110 pts. operated in less than 48 hours after injury

• TXA 15 mg/kg x 2

• 6 weeks follow up

• No symptomatic venous thrombosis or pulmonary embolism

• A non-significant but three fold increased risk of vascular events with the use of TXA when compared with placebo

1 asymptomatic proximal DVT, 4 asymptomatic distal DVTs,

3 acute coronary syndromes , 1 stroke, 1 death.

Adverse outcome

Sander M, et al. Critical Care 2010;14:R148

All patients Aprotinin

N=557

Tranexamic acid

N=336

Renal failure 8.5 13.7*

Late ischemic stroke 3.4* 0.9

Late neurologic disability 5.8 2.4

Convulsive seizures 0.9 2.7

Hospital stay 17 18.9

Mortality 6.9 8.7

Open heart Aprotinin

N=215

Tranexamic acid

N=105

Renal failure 11.2 20.0*

Myocardial infarction 0 1.9*

Late ischemic stroke 4.2 1

Late neurologic disability 7 1

Convulsive seizures 1.9 6.7*

Hospital stay 20.8 23.6

Mortality 7.5 16.2*

Adverse outcome

Sander M, et al. Critical Care 2010;14:R148

Incidence: 3.8% vs. 1.3%Incidence: 3.8% vs. 1.3%

• Blockade of GABA-mediated inhibition in the CNS

• Experimental epileptogenic effect when applied topically to the cortex, intrathecally and iv.

Iplikcioglu AC, et al. Surg Neurol 2003;59:10

Furtmuller R, et al. J Pharmacol ExpTer 2002;301:168-173

De Leede-van der Maarl MG, et al. J Neurol 1999: 843

Seizures - mechanisms

Incidence of seizuresDose-dependency

0,4

3,54,6 4,8

15,4

0

2

4

6

8

10

12

14

16

SEIZURES (%)

Without TXA

Children

Adult 4 g

Dose 67 mg/kg

Dose 109 mg/kg

Martin K, et al. Anesth Analg 2008:1783

Breuer T, et al. Eur J Cardiothorac Surg 2009:167

Jerath A, et al. Can J Anesth 2009;56:abstract S7

Tranexamic or EACA acid?

• 604 open heart surgery patients

• Equipotent doses

• Higher blood loss with EACA

• Trends of increased re-operation rate

• No difference in transfusion

• Higher incidence of new onset seizures in the TXA group

7.6 % vs. 3.3 %

• Increased rate of renal dysfunction in the EACA group

30 % vs. 20 %

Temporally and regionally heterogeneity in plasmin activity - EACA

Reust DL et al. Ann Thorac Sug 2010;89:1538

Stand back and lookat the Big Picture !

• There are not enough safety data on the use of

TXA and EACA

• Potential harms of inhibiting endogenous

fibrinolytic system have not been systematically

reviewed

TXA & EACA are efficacious,

however…

Antifibrinolytics in trauma

• CRASH-2 trial (Lancet 2010: 376:23-32)

• RCT of 20,211 adult trauma patients in 274 hospitals in 40 countries

• Inclusion criteria: clinically significant hemorrhage

• Randomized to receive placebo or

– TXA 1 g over 10 min then infusion 1 g over 8h

– Treatment initiated within 8 hours of injury

– Staff blinded to treatment arm

• Results:

– Blood transfusion rate not different (50.4% vs 51.3%)

n= 20 211

FigureTissue injury and

fibrinolysis

Jerrold H Levy. The Lancet 2010;376:3-4

TXA for every patient?

Do not extrapolate

PAI- 1 is a natural antifibrinolytic

• 5G carriers showed greater tendency to post-CPB

chest tube blood loss.

• 5G homozygotes, not receiving TXA, showed

significantly more postoperative bleeding than

patients with other PAI-1 genotypes.

• 5G homozygotes who received TXA showed the

greatest blood-sparing benefit.

Iribarren JL, et al. Anesthesiology 2008;108:59-602

Duggan E, et al. Anesth Analg 2007;104:1343-1347

Which patients could benefit

from antifibrinolytics ?

Jochen D. Muehlschlegel and Simon C. Body Am. J. Hematol. 2008; 83:732–737

Factors influencing clinical

phenotype in the perioperative period

Nadia Comaneci 1976: First Perfect Score of 10 In OlympicsNadia Comaneci 1976: First Perfect Score of 10 In Olympics

Hemostasis is like a balance beam performance

Both efficacy and safety of drugs affecting hemostasis are important, and if you fail to balance efficacy and safety, the patient may get hurt

Hemostasis is like a balance beam performance

Both efficacy and safety of drugs affecting hemostasis are important, and if you fail to balance efficacy and safety, the patient may get hurt

We must move forward and

focus our attention on ways to

limit blood loss and transfusion

that are safe and effective for

patients undergoing surgery

Revision of protocols may be

more important than the choice

of a pro-hemostatic drug

Drugs might one day be tailor-

made for individuals and

adapted to each person’s own

genetic makeup

Units of RBC

24 h bloodloss (ml)

n=269

Chung JH, et al. Circulation 1996;93:2014Tabuchi N, et al. J Thorac Cardiovasc Surg 1993;106:828

Edmunds LH. Ann Thorac Surg 2010;89:324

Markers of fibrinolysis taken from the circuit and the wound during cardiac surgery

Thrombosis Research, Vol 73, No6, pp. 419-430, 1994

Timing

Figure 1

Mortality due to bleeding by subgroups

The CRASH-2 collaborators The Lancet 2011;377:1096-1101

Overdosing - EACA

Greilich PE et al. Anesth Analg 2009;109:15

Plasma concentrations

100 mg/kg + 30 mg/kg + 5 g prime

Yurka HG, et al. AnesthAnalg 2011;111:180