Pharmacologic Blood Conservation Agents: Clinically Supportive Data & Recommended Practices

Transcription

1 Pharmacologic Blood Conservation Agents: Clinically Supportive Data & Recommended Practices Edwin G. Avery, IV, M.D., C.P.I. Chief, Division of Cardiac Anesthesia Chairman, Transfusion Committee University Hospitals Case Medical Center Case Western Reserve University School of Medicine Cleveland, OH

2 Disclosures: Covidien: funded research, consultant, speaker s bureau CSL Behring: funded research

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6 Learning Objectives: Gain practical knowledge of the basic clinical use of blood conservation agents and familiarize oneself with the literature that supports their use Gain practical knowledge of alternative blood conservation agents and familiarize oneself with the developing off label clinical use strategies of these adjuncts

7 Blood conservation drugs Antifibrinolytics Desmopressin Overview: Alternative blood conservation adjuncts Fibrinogen Concentrate Prothrombin Complex Concentrates Recombinant Activated Factor VII

8 Blood Conservation Drugs

9 Blood Conservation Drugs: Antifibrinolytics Old faithful the lysine analogues

10 Blood Conservation Drugs: Antifibrinolytics Clinically Supportive Data Antifibrinolytics (the lysine analogues) -Aminocaproic acid (ACA) is a synthetic monoamino carboxylic acid derivative of the amino acid lysine that is an indirect inhibitor of fibrinolysis; it is synthesized via a chemical process It s chemical composition and size make it unlikely to induce an allergic reaction & it s inexpensive (~$3/5 g vial ACA) Last accessed

11 Blood Conservation Drugs: Antifibrinolytics Clinically Supportive Data -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 zymogenic form 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 Last accessed

12 Blood Conservation Drugs: Antifibrinolytics Pharmacologic bleeding prophylaxis Avery EG, Klick JC. AABB Intraoperative Patent Blood Management 2014 (In Press)

13 Blood Conservation Drugs: Antifibrinolytics Pharmacologic bleeding prophylaxis Avery EG, Klick JC. AABB Intraoperative Patent Blood Management 2014 (In Press)

14 Blood Conservation Drugs: Antifibrinolytics Clinically Supportive Data ACA & TXA ACA/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) Last accessed

15 Blood Conservation Drugs: Antifibrinolytics Clinically Supportive Data - Primary Hyperfibrinolysis Treat 1º fibrinolysis w/aca/txa Treat 2º fibrinolysis w/anticoagulation, not ACA/TXA valleyperfusion.com%2fmod%25206%2520fibrinolysis%2520core.ppt&ei=z9ont43bbcfa0ahj_j2odw&usg=afqjcneqmdy2ehp2tneg8fyv55b3uy-aq Last accessed

16 Blood Conservation Drugs: Antifibrinolytics Clinically 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/aca M 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 Bad No significant effect of ACA on reduced transfusion in a meta-analyses M2 TXA /ACA use not associated with incidence of surgical re-exploration All 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) M 1999 Ann Thorac Surg 68; (meta-analysis) M Anesth Analg 85; (meta-analysis) M Cochrane Database Syst Rev CD (meta-analysis) 2008 NEJM 358(22); (RCT, n=2331) Manji RA, et al Can J Anesth JCTVA 25(1):20-5 (retrospective, n=604)

17 Blood Conservation Drugs: Antifibrinolytics Clinically Supportive Data-Hepatic Surgery The Lysine Analogs (ACA and TXA) The Good Magnitude of TEG assessed fibrinolysis w/aca in Orthotopic liver transplant surgery Transfusion free hepatic tumor resection surgery has been described with TXA Inexpensive at ~$3/5 g vial ACA Semi-inexpensive at ~$30/1 g vial TXA The Bad Few data support the use of antifibrinolytics in hepatic surgery No published dosing recommendations exist in the peer reviewed literature 1987 Anesth 66; Ann Surg 243(2);173-80

18 Blood Conservation Drugs: Antifibrinolytics Recommended Treatment Dosing Regimens -Aminocaproic acid and Tranexamic acid Dosing regimens vary significantly across clinical venues Cardiac 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 Anesth 66; Ann Surg 243(2);173-80

19 Blood Conservation Drugs: Antifibrinolytics Recommended Treatment -Aminocaproic acid and Tranexamic acid Prophylactic antifibrinolytic therapy is often indicated in surgical procedures in which fibrinolysis is common (e.g., cardiac surgery, hepatic surgery, trauma surgery) Class I recommendation Level of Evidence A Antifibrinolytic therapy is never 100% routine as individuals with known thrombophilias or hypercoagulable states may be at risk for thrombotic complications if treated with these agents Renal 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 2011 Ann Thorac Surg;91:

20 Blood Conservation Drugs: Antifibrinolytics Pharmacologic bleeding prophylaxis Intravenous vs. Topical Video provided by the courtesy of Brian Hamlin, MD

21 Blood Conservation Drugs: Antifibrinolytics Pharmacologic bleeding prophylaxis Ann Thorac Surg 2011;91:

22 Blood Conservation Drugs: Antifibrinolytics Pharmacologic bleeding prophylaxis Intravenous Orthopedics Courtesy of Dr. Raymond Graber, Chief, Orthopedic Anesthesia

23 Blood Conservation Drugs: Antifibrinolytics Pharmacologic bleeding prophylaxis Topical Orthopedics Konig G, Hamlin B, Waters JH. Topical Tranexamic Acid Reduces Blood Loss and Transfusion Rates in Total Hip and Knee Arthroplasty. J Arthroplasty 2013;28: Wong J, Abrishami A, El Beheir HE, et al. Topical Application of Tranexamic Acid Reduces Postoperative Blood Loss in Total Knee Arthroplasty. J Bone Joint Surg 2010;92-A(15):

24 Avery EG, Klick JC. AABB Intraoperative Patent Blood Management 2014 (In Press) Blood Conservation Drugs: Antifibrinolytics Pharmacologic bleeding prophylaxis Pediatric Surgery

25 Blood Conservation Drugs: DDAVP

26 Blood Conservation Drugs: DDAVP Clinically Supportive Data 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) It has a number of U.S. FDA labeled indications that relate to the treatment of some patients with hemophilia A, those with a certain type of von Willebrand disease, those with central diabetes insipidus, individuals with certain symptoms of head trauma, or surgery of the pituitary gland. etingmaterials/pediatricadvisorycommittee/ucm pdf 2011 Ann Thorac Surg;91:

27 Blood Conservation Drugs: DDAVP Clinically Supportive Data Desmopressin (DDAVP), Stimulates the release of factor VIII precursors, von Willebrand factor and tissue type plasminogen activator from vascular endothelium Has the potential to improve platelet function through its pharmacodynamics in certain clinical scenarios Its use to promote blood conservation through its effect on platelet function is OFF-LABEL 2011 Ann Thorac Surg;91: Klick JC. Avery EG. Anesthesiology 2 nd ed. 2012; Chap 16;

28 Blood Conservation Drugs: DDAVP Clinically Supportive Data Cardiac Surgery Desmopressin (DDAVP) OFF-LABEL 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, 2011 Ann Thorac Surg;91: Lancet 354; Anesth 77;38-46

29 Blood Conservation Drugs: DDAVP Clinically Supportive Data Cardiac Surgery Desmopressin (DDAVP) OFF-LABEL Has been demonstrated to be effective in improving platelet function in patients with uremia induced platelet dysfunction as well as in those with laboratory testing (e.g., platelet aggregometry, TEG/ROTEM) based evidence of platelet dysfunction Ann Thorac Surg;91:

30 Blood Conservation Drugs: DDAVP Recommended Practice Cardiac Surgery Desmopressin (DDAVP) Dose at 0.3 g/kg (slow IV infusion to avoid BP) Redose at hr intervals or greater More effective in the setting of lab/poct based demonstration of platelet dysfunction (e.g., TEG, ROTEM, PFA-100) Not recommended for routine use Tip: Round to a multiple of 4 µgs as this is how it is supplied & it is a semi-costly agent. (~$8/4 µg vial ) Avery EG, Klick JC. AABB Intraoperative Patent Blood Management 2014 (In Press) 2011 Ann Thorac Surg;91: Klick JC. Avery EG. Anesthesiology 2 nd ed. 2012; Chap 16;

31 Alternative Blood Conservation Drugs

32 Alternative Blood Conservation Drugs: Factor I

33 Alternative Blood Conservation Drugs: Factor I Fibrinogen Concentrate Factor I Fibrinogen concentrate (RIASTAP ) Indicated in treatment of afibrinogenemia Fibrinogen is the precursor to fibrin which serves as the proteinaceous scaffolding of a blood clot and promotes platelet aggregation Recent appreciation has been made of the potential contributions of fibrinogen in the treatment of severe hemorrhage, Note: Acquisition cost of 1 g vial Factor I is ~$950 Avery EG, Klick JC. AABB Intraoperative Patent Blood Management 2014 (In Press) 2009 Expert Opin Biol Ther. 9: Anes Analg;114: Klick JC. Avery EG. Anesthesiology 2 nd ed. 2012; Chap 16;

34 Alternative Blood Conservation Drugs: Factor I Fibrinogen Concentrate Factor I Fibrinogen concentrate is derived from human plasma and is heat treated before it is processed into a lyophilized cake that is reconstituted with sterile water just prior to use; allergic reactions or infectious complications are not of significant concern but are theoretically possible. Fibrinogen rich cryoprecipitate takes approximately 45 minutes to thaw/prepare for use and must be used within 4 hours of thawing. In contrast, fibrinogen concentrate has a shelf life of 30 months when stored at a temperature of 2 to 25 C in its original carton that protects it from light exposure. The dosing of fibrinogen concentrate can be targeted to a goal fibrinogen level based on the patient s measured blood concentration or it can be dosed empirically. Avery EG, Klick JC. AABB Intraoperative Patent Blood Management 2014 (In Press) 2009 Expert Opin Biol Ther. 9: Anes Analg;114: Klick JC. Avery EG. Anesthesiology 2 nd ed. 2012; Chap 16;

35 Alternative Blood Conservation Drugs: Factor I Fibrinogen Concentrate Factor I The process of reconstituting and solubilizing this biologic will take a variable amount of time depending on what temperature the product and the sterile water are at the time it is prepared; if the product is prepared immediately after taken from a 6 C storage environment, it can take up to 20 minutes to fully go into solution. Room temperature vials of fibrinogen concentrate will solubilize in approximately five minutes. The vials should not be vigorously shaken, as this activity could denature the protein. Gentle swirling of the vials allows the biologic to solubilize more rapidly. Wrapping the fibrinogen and sterile water vials in a warm blanket prior to reconstituting them favors more rapid preparation. More intense application of heat than a warm blanket should be strictly avoided as the heat can denature the protein rendering it inactive Expert Opin Biol Ther. 9: Anes Analg;114: Klick JC. Avery EG. Anesthesiology 2 nd ed. 2012; Chap 16;

36 Alternative Blood Conservation Drugs: Factor I Recommended Practices Fibrinogen concentrate OFF LABEL - formulaic based on target fibrinogen concentration and known fibrinogen level; slow IV infusion ~10 minutes; 1 vial 5 pack of cryoprecipitate for fibrinogen content PI_NZ-DS_3.00,0.pdf Levy JH, Szlam F, Tanaka KA, et al. Fibrinogen and Hemostasis: A Primary Hemostatic Target for the Management of Acquired Bleeding. Anes Analg 2012;114:

37 Alternative Blood Conservation Drugs: PCCs

38 Alternative Blood Conservation Drugs: PCCs Prothrombin Complex Concentrates PCCs are available as either 3 factor or 4 factor preparations. The 3 factor PCCs contain variable amounts of factors II, VII, IX and X and were developed as a treatment for factor IX deficiency (that is, Christmas disease or hemophilia B). There is very little factor VII in these 3 factor preparations and thus they are considered unbalanced. The potency of the various U.S. Food and Drug Administration-cleared 3 factor PCCs is assessed based on the amount of factor IX that they contain. The 4 factor PCC (KCentra ) was recently cleared by the U.S. Food and Drug Administration for the reversal of warfarin and is different from the 3 factor PCCs in that it has a more balanced content of the vitamin K dependent factors, which include factors II, VII, IX, X, protein C and S, antithrombin III and a small amount of heparin. Klick JC. Avery EG. Anesthesiology 2 nd ed. 2012; Chap 16;

39 Alternative Blood Conservation Drugs: PCCs Prothrombin Complex Concentrates The potency of the various U.S. Food and Drug Administration-cleared 3 factor PCCs is assessed based on the amount of factor IX that they contain. The 4 factor PCC was recently cleared by the U.S. Food and Drug Administration for the reversal of warfarin and is different from the 3 factor PCCs in that it has a more balanced content of the vitamin K dependent factors, which include factors II, VII, IX, X, protein C and S, antithrombin III and a small amount of heparin. Klick JC. Avery EG. Anesthesiology 2 nd ed. 2012; Chap 16;

40 Intraoperative Transfusion Strategies Pharmacologic Transfusion Adjuncts 3 Factor PCCs Konyne & Profilnine (not recommended unless balanced 4 factor PCC not available) OFF LABEL - dose at IU Factor IX for intractable hemorrhage not responsive to treatment with allogeneic hemostatic products slow IV push 4 Factor PCCs OFF LABEL IU Factor IX activity for intractable hemorrhage not responsive to treatment with allogeneic hemostatic products slow IV push Gorlinger K, Dirkmann D, Hanke AA, et al. First-line Therapy with Coagulation Factor Concentrates Combined with Point-of-care Coagulation Testing is Associated With Decrease Allogeneic Blood Transfusion in Cardiovascular Surgery: A Retrospective, Single-center Cohort Study. Anesthesiology 2011;155(6):

41 Alternative Blood Conservation Drugs: rviia

42 Alternative Blood Conservation Drugs: rviia Clinically Supportive Data Recombinant activated factor VII (Novo Seven ) A recombinant protein derived from baby hamster kidney cell cultures 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 NovoSeven Package Insert ( )

43 Alternative Blood Conservation Drugs: rviia rviia It 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 ( )

44 Alternative Blood Conservation Drugs: rviia Clinically Supportive Data Recombinant activated factor VII Recombinant activated factor VII has been cleared by the U.S. Food and Drug Administration for the prevention and treatment of bleeding episodes in select clinical settings that include the following: perioperative use in individuals with hemophilia A or B with inhibitors, in acquired hemophilia, and for congenital factor VII deficiency.

45 Alternative Blood Conservation Drugs: rviia Clinically Supportive Data Recombinant activated factor VII use 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 Costly at $1,800.00/mg

46 Alternative Blood Conservation Drugs: rviia Pharmacologic Transfusion Adjuncts Recombinant activated Factor VII OFF LABEL Thromboembolic complications Ponschab M, Landoni G, Biondi-Zoccai G, et al. Recombinant Activated Factor VII Increases Stroke in Cardiac Surgery: A Meta- Analysis. J Cardiothorac Vasc Anesth 2011;25:

47 Alternative Blood Conservation Drugs: rviia Clinically Supportive Data Recombinant activated factor VII 2011 J Cardiothorac Vasc Anes 25(5): Circulation 120; Ann Thor Surg 83;S27-86 J Trauma 2005;59:8-18 Ann Emerg Med 2009;54: Neurocirugia (Asturias, Spain). 22(3):209-23, 2011 Jun. J Obstet Gynaecol Res. 37(7):901-7, 2011 Jul

48 Alternative Blood Conservation Drugs: rviia Clinically 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 ( )]; P=0.03 M Perioperative thrombotic events (7.5% v 5.6%); [OR 1.84( )]; P=0.14 M Pilot dose escalating study stopped early at recommendation of DSMB and 140 μg/kg dose not tested Few studies M 2011 J Cardiothorac Vasc Anes 25(5): (6 trials/2 RPCT; n=470) 2009 Circulation 120;21-7 (pilot P-II ICU only, n=172)

49 Alternative Blood Conservation Drugs: rviia Clinically 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 Bad No difference in death rate between rviia and placebo treated subjects J Trauma 2005;59:8-18 (RPCT; n=301)

50 Alternative Blood Conservation Drugs: rviia Clinically Supportive Data-Neurosurgery The Good Crickets chirping The Bad Systematic 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 Neurocirugia (Astur). 22(3):209-23, 2011 Jun

51 Alternative Blood Conservation Drugs: rviia Clinically Supportive Data - Post-partum hemorrhage The Good 75% incidence (6/8) of good bleeding control ( hemorrhage within 15 minutes of dosing) No serious adverse events were observed The authors suggest that based on their results rviia should be considered prior to hysterectomy in this clinical setting The Bad Limited 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 ( 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

52 Alternative Blood Conservation Drugs: rviia Recommended Practices rviia is a largely nonvalidated OFF-LABEL treatment that presently should be considered a ***Salvage Therapy*** in severely hemorrhaging patients regardless of the clinical venue.

53 Alternative Blood Conservation Drugs: rviia Pharmacologic Transfusion Adjuncts Recombinant activated Factor VII OFF LABEL 35 to 90 µg/kg slow IV push (start with low dose at 35 µg/kg to test response), re-dosing may be required within 4-6 hrs thromboembolic complications are well documented with this agent thus it is appropriate to consider administration after hemostatic allogeneic blood components have failed to control bleeding (after 2 rounds of products) J Trauma 2005;59:8-18. J Cardiothorac Vasc Anesth 2011;25: J Obstet Gynaecol 2011;37(7): Neurocirugia (Astur). 2011; 22(3): Avery EG, Klick JC. AABB Intraoperative Patent Blood Management 2014 (In Press)

54 Alternative Blood Conservation Drugs: rviia Recommended Practices 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 or massive transfusion protocol (MTP) based 1:1:1 resuscitation 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 35 μg/kg is recommended with the option to repeat the dose at 45 μg/kg one hour later+ if bleeding is responsive to this treatment, but persistent It may he helpful to use point-of-care and/or central lab testing to assess the effect of initial treatment

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