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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