Are Anti- Fibrinolytic Drugs the Magic Bullets for Perioperative Hemostasis? Daniela Filipescu, MD. PhD. Assoc. Prof. of Anesthesia & Intensive Care Carol Davila University Emergency Institute of Cardiovascular Diseases Department of Cardiac Anesthesia & Intensive Care Bucharest, 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 Serine protease inhibitor from bovine pancreas In-vivo inhibition of serine proteases by Aprotinin prevents plasmin-mediated fibrinolysis preserves platelet function and number inhibits contact activation inhibits complement activation anti-inflammatory and anti-oxidant effects McEvoy MD, et al. Anesth Analg 2007;105:949-962
Mode of action of lysine analogues Mannucci P, Levi M. NEJM 2007;356:2301-2311
Aprotinin Saga 2008 1959 1993 1998 2006-2007 59 60-87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 Launched in Germany Royston [Lancet] 22 patients Aprotinin [11] Control [11] FDA Approval Limited indication Expanded indication Aprotinin s anti-inflammatory properties Mangano D [NEJM] [JAMA] Karkouti K [Transfusion] BART [NEJM]
RCT Multicenter Blinded High-risk cardiac surgery 2331 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 EFFICACYof therapy comes from randomized trials - Caveat: Low quality RCTs may overestimate benefits of therapy Best evidence on HARMof 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;5:174 Ray & Stein. NEJM 2008;358:2398
Life without aprotinin Retrospective analysis 7988 pts Cardiac surgery 2003-2007 Aprotinin-free blood saving program Specific hemostasis/coagulation management protocol Ranucci M et al. Acta Scand 2009;53:573
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
Lysine Aprotinin: analogues: Key Key limitations 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
Heterogeneity of dosing Tranexamic 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 10 mg/kg 1 mg/kg/h 1000 mg 400 mg/h 500 mg/cpb 30 mg/kg 16 mg/kg/h 2 mg/kg/cpb Renal failure moderate: 2.5 mg/kg/h severe: 1.25 mg/kg/h Renal dysfunction moderate: 200 mg/h severe: 100 mg/h 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 30 mg/kg + 16 mg/kg/h + 2 mg/kg prime 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 Dowd NP et al. Anesthesiology 2002;97:390
Overdosing - EACA Dose: Induction 100 mg/kg + 30 mg/kg/h + 5 g prime Plasma concentrations Greilich PE et al. Anesth Analg 2009;109:15
Efficacy of anti-fibrinolytic drugs 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
Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion 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% Henry DA, et al. Cochrane Database of Systematic Reviews 2011
Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion 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 However, any small advantage needs to be moderated by possible publication bias and uncertainty over the Aprotinin appeared more effective in reducing the comparative need for RBC dose-response transfusion (10%) relationship. Aprotinin reduced the need for re-operation due to bleeding by 54%. A similar trend was seen with EACA but not TXA Henry DA, et al. Cochrane Database of Systematic Reviews 2011
More heparin needed on CPB?! 45% 45% 30% 19% 15% 0% Aprotinin TXA 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
Antifibrinolytics in patients on aspirin 24-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
ATACAS 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 Myles PS, et al. Am Heart J 2008:224
Eur J Anesthesiol 2011:57-62 aspirin & clopidogrel aspirin & 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
Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion Adverse outcome 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). Henry DA, et al. Cochrane Database of Systematic Reviews 2011
Meta-analysis comparing mortality between aprotinin and TXA or EACA Ferraris VA, et al. Ann Thorac Surg 2011;91:944-982
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
Aprotinin TXA Karkouti K, et al. Anesth Analg 2010;110:21
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 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 Sander M, et al. Critical Care 2010;14:R148
Adverse outcome 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* Sander M, et al. Critical Care 2010;14:R148
Incidence: 3.8% vs. 1.3%
Seizures -mechanisms 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
Incidence of seizures Dose-dependency 16 Without TXA 14 12 15,4 Children Adult 4 g 10 Dose 67 mg/kg 8 6 4 2 0,4 3,5 4,6 4,8 Dose 109 mg/kg 0 SEIZURES (%) 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 look at the Big Picture!
TXA & EACA are efficacious, however 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
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
Figure Tissue injury and fibrinolysis Jerrold H Levy. The Lancet 2010;376:3-4
TXA for every patient? Do not extrapolate
Which patients could benefit from antifibrinolytics? 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
Factors influencing clinical phenotype in the perioperative period Jochen D. Muehlschlegel and Simon C. Body Am. J. Hematol. 2008; 83:732 737
Nadia 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
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 tailormade for individuals and adapted to each person s own genetic makeup
Units of RBC
24 h bloodloss (ml) n=269
Markers of fibrinolysis taken from the circuit and the wound during cardiac surgery Chung JH, et al. Circulation 1996;93:2014 Tabuchi N, et al. J Thorac Cardiovasc Surg 1993;106:828 Edmunds LH. Ann Thorac Surg 2010;89:324
Timing Thrombosis Research, Vol 73, No6, pp. 419-430, 1994
Figure 1 Mortality due to bleeding by subgroups The CRASH-2 collaborators The Lancet 2011;377:1096-1101
Overdosing - EACA Plasma concentrations 100 mg/kg + 30 mg/kg + 5 g prime Greilich PE et al. Anesth Analg 2009;109:15 Yurka HG, et al. AnesthAnalg 2011;111:180