pharmacologic blood conservation agents - casecag
TRANSCRIPT
Pharmacologic Blood Conservation Agents: Clinically Supportive Data & Recommended Practices
Edwin G. Avery, IV, M.D., C.P.I.Chief, Division of Cardiac Anesthesia
University Hospitals Case Medical CenterCase Western Reserve University School of Medicine
Cleveland, OH
http
://fin
earta
mer
ica.
com
/pro
duct
s/co
agul
atio
n-ab
stra
ct-a
lexa
nder
-but
ler-
gree
ting-
card
.htm
l
Disclosures:
Covidien: consultant, speaker’s bureau
Alere: funded research
The Medicines Company: funded research
Overview:
Un-conference format (discussion, ask questions, share experiences)
Blood conservation drugs…
Alternative blood conservation adjuncts
Coaguloapathic Hemorrhage meets…
What is the standard published purchase price of one unit of RBCs from the American Red Cross?
You won a gold watch!
Blood Conservation Drugs
Am
icar
TXA
Keyser Soze
Blood Conservation Drugs
Antifibrinolytics (Aminocaproic acid & Tranexamic acid)
Recombinant activated factor VII (NovoSeven®) Off-LABEL!
Desmopressin (DDAVP) Off-LABEL!
The usual suspects…
Blood Conservation Drugs: Antifibrinolytics
Old faithful…the lysine analogues
Antifibrinolytics (the lysine analogues)ε-Aminocaproic acid (ACA) is a syntheticmonoamino carboxylic acid derivative of the aminoacid lysine that is an indirect inhibitor of fibrinolysis;it is synthesized via a chemical process§
§ http://www.drugs.com/pro/amicar.htmlLast accessed 4.17.2012
Blood Conservation Drugs: AntifibrinolyticsClinically Supportive Data
ε-Aminocaproic acid (Amicar®, Xanodyne®) Tranexamic Acid (Cyklokapron®)
ACA & TXA work mainly by indirectly inhibiting fibrinolysis; they act as a lysine analogue and occupy lysine residue binding sites on plasminogen known to bind fibrin (a cofactor required for tissue plasminogen activator [TPA] to activate the plasminogen). With ACA/TXA occupying the fibrin binding sites on plasminogen (the inactive zymogenicform of plasmin) it cannot be readily converted to plasmin, the enzyme which is directly responsible for fibrinolysis§
ACA is also a very weak inhibitor of plasmin§
§http://www.drugbank.ca/drugs/DB00513Last accessed 4.17.2012
Blood Conservation Drugs: AntifibrinolyticsClinically Supportive Data
§ http://en.wikipedia.org/wiki/PlasminogenLast accessed 4.17.2012
Plasminogen
Fibrin
Lysine binding
site
Lysine binding residue
AA Aminocaproic acid
Plasmin
Fibrin
Plasminogen
TPA
TPA: tissue plasminogen activator
Fibrinolysis
Lysine residue
Plasminogen
Fibrin
Blood Conservation Drugs: Antifibrinolytics
Fibrin
Plasminogen
AX
Nor
mal
Clinically Supportive Data-Mechanism of Action
ACA & TXAACA/TXA administration is indicated to promote hemostasis when fibrinolysis is thought to be contributing to hemorrhage (e.g., cardiac and hepatic surgery, abruptio placentae, hepatic cirrhosis and carcinoma of various organs) §
§ http://www.drugs.com/pro/amicar.htmlLast accessed 4.17.2012
Blood Conservation Drugs: AntifibrinolyticsClinically Supportive Data
Blood Conservation Drugs: AntifibrinolyticsClinically Supportive Data - Primary Hyperfibrinolysis
http://www.google.com/url?sa=t&rct=j&q=&esrc=s&frm=1&source=web&cd=1&ved=0CCQQFjAA&url=http%3A%2F%2Fdiablovalleyperfusion.com%2Fmod%25206%2520fibrinolysis%2520core.ppt&ei=z9ONT43BBcfA0AHJ_J2oDw&usg=AFQjCNE-qmdy2ehP2tNeG8fYV55B3uy-AQ Last accessed 4.17.2012
Blood Conservation Drugs: AntifibrinolyticsClinically Supportive Data-Cardiac Surgery
The Lysine Analogues (ACA and TXA)The Good
↓Incidence of blood transfusion by 68% w/ACA M & 29% w/TXA M3
↓Magnitude of perioperative bleeding by 35% w/ACAM
Large RCT of high risk subjects examining effect of aprotinin, TXA and ACA did not reveal any significant safety concerns to be associated with lysine analogue use†
The BadNo significant effect of ACA on reduced transfusion in a meta-analysesM2
TXA /ACA use not associated with ↓incidence of surgical re-explorationAll of the performed studies appear inhomogeneous and thus may not be appropriate for meta-analysis M
Recent evidence suggests that the use of TXA has a significant association with ↑postoperative seizure risk (OR 7.4; P<.001)§,‡
↑Incidence of renal insufficiency with ACA v TXA (30% v 20%; P=0.005)‡
M1999 Ann Thorac Surg 68;1321-5 (meta-analysis)M21997 Anesth Analg 85;1258-67 (meta-analysis) M32001 Cochrane Database Syst Rev CD001886 (meta-analysis) †2008 NEJM 358(22);2319-31 (RCT, n=2331)
§Manji RA, et al. 2011 Can J Anesth.‡2011 JCTVA 25(1):20-5 (retrospective, n=604)
Blood Conservation Drugs: AntifibrinolyticsClinically Supportive Data-Hepatic Surgery
The Lysine Analogs (ACA and TXA)
The Good↓Magnitude of TEG assessed fibrinolysisw/ACA in Orthotopic liver transplant surgery†Transfusion free hepatic tumor resection surgery has been described with TXA‡
The BadFew data support the use of antifibrinolytics in hepatic surgery No published dosing recommendations exist in the peer reviewed literature
†1987 Anesth 66; 766-73‡2006 Ann Surg 243(2);173-80
ε-Aminocaproic acid and Tranexamic acidProphylactic antifibrinolytic therapy is often indicated in surgical procedures in which fibrinolysis is common (e.g., cardiac surgery)§
Class I recommendation – Level of Evidence AAntifibrinolytic therapy is never 100% routine as individuals with known thrombophilias or hypercoagulable states may be at ↑risk for thrombotic complications if treated with these agentsRenal dosage adjustment is needed in patients with compromised renal function†Alternatively, rescue lysine analog administration† can be executed with the knowledge that there is little data supporting this approach
§ 2007 Ann Thor Surg 83;S27-86
Blood Conservation Drugs: AntifibrinolyticsRecommended Treatment
† http://www.casecag.com/Amicar_Clin_Prot_12-05-2010.pdf
ε-Aminocaproic acid and Tranexamic acidDosing regimens vary significantly across clinical venuesCardiac surgical regimens tend to be much higher than those in orthopedic or hepatic surgery§,†,‡
No specific society generated dosing guidelines exist for either of the lysine analogs
§http://www.casecag.com/Amicar_Clin_Prot_12-05-2010.pdf†1987 Anesth 66; 766-73‡2006 Ann Surg 243(2);173-80
Blood Conservation Drugs: AntifibrinolyticsRecommended Treatment – Dosing Regimens
†2012 Canad J Anesth 59(1);6-13§ 2007 Ann Thorac Surg;83: S27-86
http
://w
ww.
case
cag.
com
/clin
ical
%20
prot
ocol
s%20
inde
x%20
page
.htm
l
Blood Conservation Drugs: AntifibrinolyticsRecommended Treatment – Dosing Regimens
Antifibrinolytics (pre-CPB vs. Rescue)ε-Aminocaproic acid§
Tranexamic acid (↑seizure risk OR 7.4, P<0.001)-consider waiting on extubation as propofol gtt likely mitigates seizure occurrence†
www.casecag.com
What is the standard published purchase price of one unit of fresh frozen plasma from the American Red
Cross?
You won a new car!
Blood Conservation Drugs: NovoSeven
Blood Conservation Drugs: NovoSeven
Recombinant activated factor VII (Novo Seven®)
A recombinant protein derived from baby hamster kidney cells that is similar to human factor VIIa but in fact no human serum or proteins are used in the production or formulation of this product §
Clinically Supportive Data
§NovoSeven Package Insert (09-2009)
Blood Conservation Drugs: NovoSeven
rVIIaIt works by activating the extrinsic coagulation pathway which occurs when rVIIa combines with Tissue Factor to activate factor X→Xa and IX→IXa which ultimately results in thrombin generation and clotting at the site of vessel injury§
Clinically Supportive Data
§NovoSeven Package Insert (09-2009)
http
://w
ww.
porto
la.c
om/g
raph
ics/
Coa
gula
tion-
Cas
cade
.jpg
Blood Conservation Drugs: NovoSevenClinically Supportive Data
Recombinant activated factor VIIOff-labeluse for refractory life threatening bleeding (unrelated to factor VII, VIII, or IX deficiency)Has been observed to be an effective blood conservation adjunct in a number of trials in various clinical settings (few exist in cardiac surgery)Does appear to have some safety issues associated with its use
Blood Conservation Drugs: NovoSevenClinically Supportive Data
Recombinant activated factor VII
J Obstet Gynaecol Res. 37(7):901-7, 2011 Jul
Neurocirugia (Asturias, Spain). 22(3):209-23, 2011 Jun.
J Trauma 2005;59:8-18Ann Emerg Med 2009;54:737-44
2011 J Cardiothorac Vasc Anes 25(5): 804-102009 Circulation 120;21-72007 Ann Thor Surg 83;S27-86
Blood Conservation Drugs: NovoSevenClinically Supportive Data-Cardiac Surgery
Recombinant activated factor VII
The Good↓Incidence of reoperation for bleeding (P=0.03)† and NS(13% v 42%)M
↓Transfusion requirement (P=0.01)†
↓Rate of mediastinal drainage (24 mLs/° v 51 mLs/°); P=0.018†
No difference in the death rate M
The Bad↑Incidence of critical SAEs (NS)†
↑Incidence stroke (4.7% v 0.9%); [OR 3.69 (1.1-12.38)]; P=0.03M
↑Perioperative thrombotic events (7.5% v 5.6%); [OR 1.84(0.82-4.89)]; P=0.14M
Pilot dose escalating study stopped early at recommendation of DSMB and 140 μg/kg dose not testedFew studies
M2011 J Cardiothorac Vasc Anes 25(5): 804-10 (6 trials/2 RPCT; n=470)†2009 Circulation 120;21-7 (pilot P-II ICU only, n=172)
Blood Conservation Drugs: NovoSevenClinically Supportive Data-Trauma/ER
The Good↓Incidence of RBC transfusion by 2.6 units in rVIIa treated blunt trauma (BT) subjects (P=0.02)†
↓Incidence of RBC transfusion by 1.0 unit in rVIIa treated penetrating trauma (PT)subjects (NS)†
↓Need for massive transfusion (>20 units) in BT 14% v 33% (P=0.03)†
↓Need for massive transfusion (>20 units) in PT 7% v 19% (NS)†
Trend towards ↓mortality and critical complications
The BadNo difference in death rate between rVIIa and placebo treated subjects
†J Trauma 2005;59:8-18 (RPCT; n=301)
Blood Conservation Drugs: NovoSevenClinically Supportive Data-Neurosurgery
† Neurocirugia (Astur). 22(3):209-23, 2011 Jun
The Good The BadSystematic administration of rVIIa is not recommended for spontaneous intracranial hemorrhage†
Limited data consisting of retrospective studies and case reports provide minimal support to the practice of treating other neurosurgical bleeds with rVIIa†Crickets chirping…
Blood Conservation Drugs: NovoSevenClinically Supportive Data - Post-partum hemorrhage
The Good75% incidence (6/8) of good bleeding control (↓hemorrhage within 15 minutes of dosing)No serious adverse events were observedThe authors suggest that based on their results rVIIa should be considered prior to hysterectomy in this clinical setting
The BadLimited data consisting of a single retrospective case series (n=8) study which provides minimal support to the practice of treating other post-partum hemorrhage with rVIIa†
No consistent dose regimen (55-105 μg/kg) examined thus no single treatment dose can be recommended based upon this work
† J Obstet Gynaecol Res. 37(7):901-7, 2011 Jul
rVIIa is a largely nonvalidated OFF-LABELtreatment that presently should be considered a
***Salvage Therapy***in severely hemorrhaging patients regardless of the clinical venue.
Recommended PracticesBlood Conservation Drugs: NovoSeven
No published guidelines exist to direct dosing therapy with this agent in the U.S.In all but the most dire clinical circumstances physicians should first administer algorithm guided hemostatic blood products prior to treatment with rVIIa rVIIa Doses of 40 μg/kg to 90 μg/kg have undergone limited investigation in cardiac surgery and safety issues have been noted to be associated with its use; thus, a starting dose of 40 μg/kg is recommended with the option to repeat the dose at 40-50 μg/kg one hour later+ if bleeding is responsive to this treatment, but persistentIt may he helpful to use point-of-care and/or central lab testing to assess the effect of initial treatment
Recommended PracticesBlood Conservation Drugs: NovoSeven
Clinical Case
Clinical Case 64 YOM w/severe AI secondary to paravalvular leak
of bioprostheticAV, 2v CAD, ↓LVEF, mild pulmonary HTN, DM type II, HTN, ↑cholesterolemia
Redo-sternotomy, CABG x2 and AVR (Edwards Perimount® bovine pericardial 23
mm) AXC 2:44
Noted tear in left pulmonary artery, re-AXC 1:03Repair pulmonary artery
Off CPB 6:43
Clinical Case
Left heart failure/cardiogenic shock→ Inotropes + IABP
Δ 20 min→Right heart failure/cardiogenic shock
Off CPB 7:46 total
Back on CPB, RVAD (Abiomed AB5000)
Clinical Case The surgical team assesses the bleeding as severe following protamine
administration of 0.7 mg per 100 IU Heparin. Next steps…?
Clinical Case
Clinical Case – TEG #1 FFP
Clinical Case – TEG #1 Heparinase
Clinical Case – TEG #1 Heparinase
4710.3
s/p 70% Protamine3 doses Plts4 units FFP1150mg RIASTAP2 RBC
4.9Heparinase
Clinical Case – TEG #2 Heparinase
s/p 50 mg Protamine2 doses Plts (total 5)
2 units FFP (total 6)
1150mg RIASTAP (total 2300)
2 RBC (total 4)
11.8 4.7 38 56.7Heparinase
Clinical Case – TEG #3 Heparinases/p 50 mg ProtaminerVIIa 35 μg/kg3 units FFP (total 9)
1150mg RIASTAP (total 3450)
7.1 2.8 54.4 63.1Heparinase
Clinical Case
Clinical CaseHemostasis achieved
Massive inflammatory tissue injury including lung injury (TRALI) with copious edema and blood from ETT for 3-4 hours
Oxygenation OK with recruitment maneuvers every 5-10 minutes but PaCO2 > 120 mmHg & pH 6.5
Bleeding restarted, loss of vascular tone, worsening left heart failure all unresponsive to medications and finally death
What is the standard published purchase price of one single donor unit of platelets from the American Red
Cross?
You won a new house!
Blood Conservation Drugs: DDAVP
§2007 Ann Thorac Surg;83: S27-86
Blood Conservation Drugs: DDAVPClinically Supportive Data
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM215090.pdf
Desmopressin (DDAVP) [1-deamino-8-d-arginine vasopressin]†DDAVP is a chemically synthesized derivative of human antidiuretic hormone (ADH) (a.k.a. 8-arginine vasopressin)Indicated as antidiuretic replacement therapy for central diabetes insipidis and for management of temporary polyuriaand polydipsia associated with head trauma or surgery in the pituitary region
Desmopressin (DDAVP)§,†
Stimulates the release of factor VIII precursors, von Willebrand factor and tissue type plasminogen activator from vascular endotheliumHas the potential to improve platelet function through its pharmacodynamics in certain clinical scenariosIts use to promote blood conservation through its effect on platelet function is OFF-LABEL
†Klick JC. Avery EG. Anesthesiology 2nd ed. 2012; Chap 16; 196-217
Blood Conservation Drugs: DDAVPClinically Supportive Data
§2007 Ann Thorac Surg;83: S27-86
Desmopressin (DDAVP)Has been well tested as a blood conservation adjunct in a number of cardiac surgical trials
Class IIb recommendation – Level of Evidence B§
It does not reduce bleeding after cardiac surgery when administered prophylactically
Class III recommendation – Level of Evidence A§
Patients with lab-based testing proven platelet defects have been observed to benefit from DDAVP in this setting†, ‡
†1999 Lancet 354;106-10‡1992 Anesth 77;38-46
§2007 Ann Thorac Surg;83: S27-86
Blood Conservation Drugs: DDAVPClinically Supportive Data – Cardiac Surgery
Desmopressin (DDAVP)Has been demonstrated to be effective in improving platelet function in patients with uremia induced platelet dysfunction as well as in those with Type I von Willebrand’s disease§
§2007 Ann Thorac Surg;83: S27-86
Blood Conservation Drugs: DDAVPClinically Supportive Data – Cardiac Surgery
Desmopressin (DDAVP)Dose at 0.3 μg/kg (slow IV infusion to avoid ↓BP)§
Not recommended for routine use
†Klick JC. Avery EG. Anesthesiology 2nd ed. 2012; Chap 16; 196-217
§2007 Ann Thorac Surg;83: S27-86
Blood Conservation Drugs: DDAVPRecommended Practice – Cardiac Surgery
What is the standard published purchase price of one unit of cryoprecipitate from the American Red Cross?
You won a Gulfstream-6 jet!
Alternative Blood Conservation Drugs
Fibrinogen concentrate (Riastap®) Off-LABEL!
Prothrombin complex concentrates (Konyne®, Profilnine or Beriplex®) Off-LABEL!
TMCO-2010 NOT FDA APPROVED
Whole blood?
Alternative Blood Conservation Drugs
Treatment of Cardiac Surgical Bleeding
Fibrinogen concentrate (RIASTAP) λIndicated in treatment of afibrinogenemiaFibrinogen is the precursor to fibrin which serves as the proteinaceousscaffolding of a blood clot and promotes platelet aggregationRecent appreciation has been made of the potential contributions of fibrinogen in the treatment of severe hemorrhage§, †
Pharmacologic Adjuncts
†Klick JC. Avery EG. Anesthesiology 2nd ed. 2012; Chap 16; 196-217§2012 Anes Analg;114: 261-274λ2009 Expert Opin Biol Ther. 9:1325-1333.
Treatment of Cardiac Surgical Bleeding
Prothrombin complex concentrates (PCCs)Originally intended as a treatment for Hemophilia B (Christmas disease)Contains Factors II, VII, IX, and X (in varying amounts depending on manufacturer)†
Has been described as a rescue bleeding agent in cardiac surgery§ and is a standard rescue therapy in some large academic medical centersLimited safety data available at present – not for routine use
Pharmacologic Adjuncts
†Klick JC. Avery EG. Anesthesiology 2nd ed. 2012; Chap 16; 196-217
§2008 Crit Care 12;R1052010 Vox Sang. 99(3):251-602006 Crit Care Resusc. 8(2):141-5
Alternative Drug Adjuncts-TMCO-2010
Drug Size (Daltons) Ki for Plasmin (M) Ki for Plasma Kallikrein (M)
ε−aminocaproicacid
131 0.32 None
tranexamic acid 157 0.016 None
aprotinin 6,512 (58AA) 4.2 x 10-9 38 x 10-9
ecallantide 7,054(60AA) 1.4 x 10-7 25 x 10-12
TMCO-2010 700 2.2 x 10-9 0.019 x 10-9
Textilinin-1 6,700(59AA) NA NA
J Ane
sth
2010
;24:
96-1
06 &
Ane
sth
2009
;110
:123
-30
TMCO-2010
TMCO-2010†
Aprotinin
Whole blood from (n = 10) healthy volunteers was tested.
TranexamicAcid
Plasmin
Ki= 2 nM
Ki= 4 nM
Ki= 0.016 M
Plasma Kallikrein
Ki= 0.019 nM
Ki= 38 nM
Factor Xa
Ki= 45 nM
Ki=55,600 nM
Factor XIa
Ki= 18 nM
Ki= 1840 nM
N/A N/A N/A
Anes 2009;110:123
Preclinical/comparative studies data: TMCO-2010
Alternative Drug Adjuncts-TMCO-2010
Alternative Drug Adjuncts-TMCO-2010
TMCO-2010 has potential to fill the void left when aprotinin was pulled from the US market for a number of reasons:
It is small enough that allergic reactions will not be likelyIt is as powerful if not more so than aprotinin as a plasma kallikreininhibitor as well as a direct plasmin inhibitorCurrently a phase II study is ongoing in the EU and the US which will provide further insight into the potential for this drug to serve as a blood conservation agent for cardiac surgical patients at risk for hemorrhage
Alternative Drug Adjuncts-Whole Blood
Acute Normovolemic Hemodilution
Baseline (sec): 136
On CPB: 619
Post-protamine: 193
Final ACT: 141
Alternative Drug Adjuncts-Whole Blood
Alternative Drug Adjuncts-Whole Blood
Rewarming on CPB after deep hypothermic circulatory arrest (AVR + Hemiarch)
Alternative Drug Adjuncts-Whole Blood
Post 1 unit of whole blood (~400 mLs)
