1. Hemostasis for the Surgeon: Treatment Practices Peter K. Smith, MD Professor and Chief Division of Cardiovascular and Thoracic Surgery Duke University Medical Center Durham, North Carolina

2. 22 Prohemostatic Agents Antifibrinolytics  Lysine analogues  Aprotinin Topical hemostatics Desmopressin (DDAVP) Recombinant activated factor VIIa (rVIIa) Levi M. Minerva Anestesiol. 2004;70:267-271.

3. 33 Fibrinolysis Antifibrinolytic Agents Tip the balance against fibrinolysis  More clot  Less bleeding ProthrombinPlasminogen ThrombinPlasmin APCTAFIa TAFIPC Fibrinogen Fibrin FDPs –– Adapted from Nesheim M. Chest. 2003;124:33S-39S. Fibrinolytic Cascade Coagulation Cascade Thrombin Thrombomodulin

4. 44 Antifibrinolytics As implied by the name, these agents enhance hemostasis when fibrinolysis contributes to bleeding Lysine analogues  ε-aminocaproic acid (EACA)  Tranexamic acid (TXA) Aprotinin: Approved by FDA to reduce blood loss and transfusion in coronary artery bypass graft surgery (CABG) but marketing suspended 11/5/07 1. Levi M. Minerva Anestesiol. 2004;70:267-271. 2. US Food and Drug Administration. Available at: http://www.fda.gov/CDER/DRUG/infopage/ aprotinin/default.htm. Accessed May 7, 2008.

5. 55 Lysine Analogues Block the lysine- binding sites on plasminogen, inhibiting the formation of plasmin TXA is 6-10 times more potent than EACA Mannucci PM, et al. N Engl J Med. 2007;356:2301-2311.

6. 66 Lysine Analogues (cont) Lysine analogues 1-3 : EACA and TXA  Indicated for enhancing hemostasis when fibrinolysis contributes to bleeding  Both competitively inhibit plasmin binding to fibrin  Widely used in cardiac surgery, but data supporting safety and efficacy are limited  EACA associated with increased incidence of certain neurologic deficits; concerns about rhabdomyolysis and renal dysfunction 1. Mannucci PM, et al. N Engl J Med 2007;356:2301-2311. 2. Levy JH. Am J Health-Syst Pharm. 2005;62(suppl 4):S15-S19. 3. Adams GL, et al. Hematol Oncol Clin North Am. 2007;21:13-24.

7. 77 Lysine Analogues: EACA and TXA Trial data have limitations 1,2  Often only small numbers of patients studied  Variable design  ?Treatment criteria  ?Factor reduction  Most data are for TXA, not EACA  TXA doses range from 2 g to 25 g  Most EACA/TXA studies in lower-risk patients Meta-analyses need to be cautiously interpreted EACA removed from many European markets 3  ?Safety data 1.Mannucci PM, et al. N Engl J Med 2007;356:2301-2311. 2.Levi M. Minerva Anestesiol. 2004;70:267-271. 3.European Medicines Agency. Available at: http://www.emea.europa.eu/pdfs/human/press/pr/Aprotinin_Q&A.pdf. Accessed May 13, 2008.

8. 88 EACA: Study Findings A study by Kikura and colleagues evaluated the efficacy of EACA Study design:  Double-blind, placebo-controlled, randomized trial  100 patients randomized to receive EACA (100 mg/kg before incision, 1 g/h infusion until chest closure, 10 g in CPB circuit) or placebo Postoperative thoracic-drainage volume (P=.003)  EACA—649±261 mL  Placebo—940±626 mL No significant between-group differences in:  Need for RBC transfusion (P=.62) EACA—24% Placebo—18%  Units of donor RBCs transfused (P=.29) EACA—2.2±0.8 U Placebo—1.9±0.8 U EACA did not reduce risk of RBC transfusion compared with placebo (OR: 1.2; 95% CI: 0.4 to 3.2; P=.63) EACA reduced postoperative thoracic-drainage volume by 30% but did not reduce need for allogeneic therapy Kikura M, et al. J Am Coll Surg. 2006;202:216-222. CPB=cardiopulmonary bypass.

9. 99 Blood Conservation Using Antifibrinolytics Trial (BART) Fergusson DA, et al. N Engl J Med. 2008;358:2319-2331; Hebert PC, et al. Available at: http://www.ohri.ca/programs/clinical_epidemiology/thrombosis_group/studies/BART.asp. Accessed May 8, 2008. Design: Multicenter, triple-blind RCT  Compared aprotinin, TXA, and epsilon-EACA Population: 2330 high-risk cardiac surgical patients Intervention:  Aprotinin 2 million KIU bolus + 2 million KIU pump prime + 2 million KIU infusion on CPB  TXA 30 mg/kg loading dose + 2 mg/kg pump prime + 16 mg/kg/hr on CPB  Epsilon-EACA 10 g loading dose + 2 g/hr on CPB

10. 10 BART Trial (cont) Fergusson DA, et al. N Engl J Med. 2008;358:2319-2331; Hebert PC, et al. Available at: http://www.ohri.ca/programs/clinical_epidemiology/thrombosis_group/studies/BART.asp. Accessed May 8, 2008; US Food and Drug Administration. Available at http://www.fda.gov/Cder/drug/early_comm/aprotinin.htm. Accessed May 8, 2008. Primary outcome  Massive post-op bleeding Secondary outcomes  In-hospital death  Death from any cause at 30 days  Life-threatening or serious adverse clinical events Trial terminated prematurely  Enhanced relative risk (RR) of mortality for aprotinin compared to drug B (RR 1.5; P=.06) and drug C (RR 1.5; P=.08)

11. 11 Aprotinin A small protein isolated from bovine lung 1 A non-specific serine protease inhibitor  inhibits trypsin, plasmin, plasma/tissue kallikrein, etc 1,2 Inhibits contact phase activation of coagulation that both initiates coagulation and promotes fibrinolysis 2 In CPB, it reduces derangements in coagulation/fibrinolysis caused by negatively charged surface of CPB circuit 2 Indirectly preserves platelet function in extracorporeal circulation 1 Marketing suspended on 11/5/07 following FDA Advisory 2/8/06 3 Available for “on-label” investigational use with IRB approval, see Bayer Web site BART trial publication 5/08 4 1. Levi M. Minerva Anestesiol. 2004;70:267-271; 2. Mannucci PM, et al. N Engl J Med. 2007;356:2301-2311; 3. US Food and Drug Administration. Available at: http://www.fda.gov/CDER/DRUG/infopage/aprotinin/default.htm. Accessed May 7, 2008; 4. Fergusson DA, et al. N Engl J Med. 2008;358:2319-2331.

12. 12 Topical Hemostatic Agents Identified by FDA as “a device intended to produce hemostasis by accelerating the clotting process of blood” 1 Used to augment hemostasis in surgery/trauma Available in a variety of forms (solutions, gels, granules, sprays) and used in conjunction with collagen, gelatin, cellulose matrices Local thrombin and fibrinogen levels determine the rate of clot formation at wound site Classification:  Tissue/fibrin sealants (contain thrombin, fibrin, ? aprotinin, etc)  Absorbable hemostatic agents (contain matrices)  Combination products (contain both groups above) Efficacy: Few RCTs 1 Safety: Associated with numerous adverse events 2 1. Lawson JH, et al. Available at: www. fda.gov/ohrms/dockets/dockets/06n0362/06N- 0362_ECI-Attach-1.pdf. Accessed February 20, 2008. 2. Gabay M. Am J Health-Syst Pharm. 2006;63:1244-1253.

13. 13 Some Topical Hemostatic Agents Reprinted from Voils S. Pharmacotherapy. 2007;27:69S-84S. Sealants and Combination Products: AgentTopical Application InstructionsMajor Drawbacks or Comments Bovine thrombinDry, spray, or mixed with isotonic saline applied to bleeding or oozing surfaces; may also be used with absorbable gelatin sponge or with FloSeal  NT Prion disease transmission; autoantibodies may develop to impurities, potentially resulting in coagulopathy Recombinant human thrombin Released in 2008; similar to bovine thrombin Potentially less immunogenic than bovine thrombin FloSeal  Hemostatic Matrix: bovine gelatin granules and human thrombin After reconstituting thrombin and mixing with gelatin granules, applied to bleeding wound and conforms to its shape Infectious disease transmission similar to that with other human blood products; bovine sensitization Virally inactivated aprotinin-free fibrin sealant (Crosseal  ): thrombin and fibrinogen (human) Stored frozen, then thawed and sprayed Contains no animal protein and is virally inactivated and highly purified; safety concerns minimized

14. 14 Some Topical Hemostatic Agents (cont) AgentTopical Application InstructionsMajor Drawbacks or Comments CoStasis  : microfibrillar collagen-fibrin (bovine) Reconstituted mixture forms gel matrix Similar to other bovine preparations CoSeal  Surgical Sealant: 2 synthetic polyethylene glycols Reconstituted mixture forms a hydrogel that is applied to bleeding or oozing surfaces; forms mechanical seal Swells up to 4 times its volume; may cause compression of anatomic structures Aprotinin and TXASolutions containing 1 MU of aprotinin or 2.5 g of TXA in 250 mL of saline poured into pericardial cavity during CPB Single study with minimal effectiveness of aprotinin; TXA was less effective in reducing blood product usage Chitosan hemostatic bandage Bandage that binds electrostatically to red blood cells; considered a device; used in combat Floats off wound in severe hemorrhage ZeolitePowder applied to wounded tissue; considered a device; used in combat Local hyperthermia-induced tissue damage Reprinted from Voils S. Pharmacotherapy. 2007;27:69S-84S.

15. 15 Some Topical Hemostatic Agents (cont) Originally published in Gabay M. Am J Health-Syst Pharm. 2006;63:1244- 1253. ©2006, American Society of Health-System Pharmacists, Inc. All rights reserved. Reprinted with permission. (R0821) Cellulose-, Collagen-, and Gelatin-Based Topical HemostaticCompositionApproval Date Surgicel  (J&J) Regenerated oxidized cellulose October 14, 1960 Gelfoam  (Pfizer)Porcine gelatin molded into a sponge Available 1945; approved July 8, 1983 Surgifoam (J&J) Porcine gelatin spongeSeptember 30, 1999 Avitene  (Davol)Bovine collagenAugust 26, 1976 (as a drug) October 24, 1980 (as a device) Instat (J&J/Gateway) Bovine collagenOctober 10, 1985 Helistat  (Integra LifeSciences)Bovine collagenNovember 8, 1985 Helitene  (Integra LifeSciences)Bovine collagenNovember 8, 1985

16. 16 Indications Originally published in Gabay M. Am J Health-Syst Pharm. 2006;63:1244- 1253. ©2006, American Society of Health-System Pharmacists, Inc. All rights reserved. Reprinted with permission. (R0821) Hemostatic AgentLabeled Indication(s) Surgicel  For use in surgical procedures when conventional methods of hemostasis, such as pressure and ligature, are ineffective; for endoscopic procedures, may be used by cutting to size. Gelfoam  For use in surgical procedures, including those that may result in calcellous bone bleeding, when conventional methods of hemostasis are ineffective or impractical. Surgifoam For use in surgical procedures, except urologic and ophthalmic procedures, when conventional methods of hemostasis are ineffective or impractical. Avitene  For use in surgical procedures when conventional methods of hemostasis are ineffective or impractical. Instat For use in surgical procedures, except ophthalmic procedures, when conventional methods of hemostasis are ineffective or impractical; for endoscopic procedures, may be used by cutting to size. Helistat  For use in surgical procedures, except urologic and ophthalmic procedures, when conventional methods of hemostasis are ineffective or impractical.

17. 17 Hemostatic AgentLabeled Indication(s) Helitene  For use in surgical procedures, except urologic and ophthalmic procedures, when conventional methods of hemostasis are ineffective or impractical. CoStasis  For use in surgical procedures, except neurologic, ophthalmic, and urologic procedures, when conventional methods of hemostasis are ineffective or impractical. FloSeal  For use in surgical procedures, except ophthalmic procedures, when conventional methods of hemostasis are ineffective or impractical. Thrombin-JMI  For use as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules are accessible; may be used in combination with absorbable gelatin sponge for hemostasis; may be used in conjunction with any other device that has been approved by FDA with a specified dosage of topical thrombin. Originally published in Gabay M. Am J Health-Syst Pharm. 2006;63:1244- 1253. ©2006, American Society of Health-System Pharmacists, Inc. All rights reserved. Reprinted with permission. (R0821) Indications (cont)

18. 18 Considerations Efficacy: Few RCTsstudies have shown beneficial effects in controlling capillary bleeding, achieving hemostasis in vascular surgery, controlling bleeding from fistula- puncture site in hemodialysis, etc Cost: No published study of cost-effectiveness Safety Gabay M. Am J Health-Syst Pharm. 2006;63:1244-1253.

19. 19 Adverse Events Device failure (continued bleeding observed) Device deployment failure Infection Granuloma Abscess Foreign body reaction Allergic reaction Interference with wound healing Respiratory difficulty Bowel obstruction Hematoma Intermittent ischemia Stroke Tissue necrosis Erythema Edema US Food and Drug Administration. Available at: www.fda.gov/ohrms/dockets/ac/02/briefing/3876b1_06- Absorbable%20Hemostatic%20Agent%20Reclass%20Memo.doc. Accessed May 9, 2008.

20. 20 Adverse Events (cont) In 2004, FDA issued a notification on possible development of paralysis following use of absorbable hemostatic agents If agent used and left on or near a bony or neural space, when wetted, the material swelled and exerted pressure on neural structures, resulting in pain, numbness, or paralysis Recommendations:  Read labels carefully  If used on or near bony/neural spaces, use the minimum amount necessary to achieve hemostasis and remove as much of the agent as possible after hemostasis is achieved US Food and Drug Administration. Available at: http://www.fda.gov/cdrh/safety/040204-hemostatics.html. Accessed May 9, 2008.

21. 21 Desmopressin Originally developed and licensed for the treatment of inherited defects of hemostasis 1,2 Several reviews suggest its effect is too small to influence the need for transfusion and reoperation 1,2 Most evidence of efficacy is in mild hemophilia A and von Willebrand’s disease 1,2 Not indicated for use in cardiac surgery patients 1,2  Meta-analysis in cardiac patients: 2-fold increase in MI, a small decrease in perioperative blood loss, and no added benefits on clinical outcomes 1. Mannucci PM, et al. N Engl J Med. 2007;356:2301-2311. 2. Levy JH. Am J Health-Syst Pharm. 2005; 62(suppl 4):S15-S19.

22. 22 Desmopressin and Surgical Bleeding in Patients With Inherited Coagulation Disorders Study data limitations 1-3  Small numbers of patients  Mostly retrospective analyses  Multimodal approaches Antifibrinolytics used concomitantly with other factor concentrates 2 Bleeding depends on types of surgical procedure 1  Superficial vs major  Vascular, cardiac, neurosurgical Monitoring of effects is limited—especially with platelet function tests 1 1.Mannucci PM, et al. N Engl J Med. 2007;356:2301-2311. 2.Berntorp E. Haemophilia. 2006;12:62-66. 3. Levy JH. Am J Health-Syst Pharm. 2005; 62(suppl 4):S15-S19.

23. 23 Recombinant Factor VIIa Vitamin K-dependent glycoprotein structurally similar to human plasma-derived FVIIa 1 Approved in United States for treatment of bleeding in patients with hemophilia A or B with inhibitors to FVIII or FIX 1 Multiple reports of off-label use in cardiac surgery, trauma, liver transplantation to secure hemostasis 2 Promotes hemostasis by activating the coagulation cascade 1 Believed to cause local thrombin generation and platelet recruitment at sites of vascular and microvascular injury 2 1. Levy JH. Am J Health-Syst Pharm. 2005; 62(suppl 4):S15-S19. 2. Mannucci PM, et al. N Engl J Med. 2007;356:2301-2311.

24. 24 Recombinant Factor VIIa (cont) A central factor in coagulation 1 A trypsin-like serine protease (characterized by a serine residue in the active side of the enzyme) 2 Initiates coagulation in a complex with TF 2 Once bound to TF, it is activated (rVIIa) by different proteases 2 Produced in liver 3 1.Levy JH. Am J Health-Syst Pharm. 2005; 62(suppl 4):S15-S19. 2.Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64. 3.Levy JH. Transfusion. 2006; 46:919-933. TF=tissue factor.

25. 25 Mechanism of Action Remember the mechanism… FIXa and FVIIIa aid FVIIa in activating X If FIXa or FVIIIa is missing (or inhibited), rFVIIa can replace their function by converting more FX to FXa Mannucci PM, et al. N Engl J Med. 2007;356:2301-2311.

26. 26 Thrombotic Adverse Events From March 1999 to December 2004, 431 adverse events (AEs) were reported to the FDA  185 (43%) were thrombotic AEs In 36 (72%) of 50 reported deaths, thrombotic AE was probable cause 73 TBEs (52%) occurred within 24 hours of rVIIa therapy Concomitant use of other hemostatic agents was noted in 64 cases (38%) O’Connell KA, et al. JAMA. 2006;295:293-298.

27. 27 Thrombotic Adverse Events (cont) Levy JH, et al. Transfusion. 2006;46:919-933. Critical safety data obtained from 13 pharmaceutical-sponsored clinical trials of rVIIa  Patients with coagulopathy due to: Anticoagulant therapy Cirrhosis Severe traumatic injury Thrombotic AEs reported  Placebo: 5.3% (23/430)  Active treatment: 6.0% (45/748) No significant differences between placebo-treated and rVIIa- treated patients for thrombotic AEs—either on individual trial basis or for combined trial populations (P=.57)

28. 28 “Off-label” Uses of rVIIa Increasingly being considered for:  Reversal of oral anticoagulation  Reversal of heparin, lepirudin, and fondaparinux  Thrombocytopenia and thrombocytopathy  Bleeding with impaired liver function  Gastrointestinal bleeding  Trauma  Surgery: Non-traumarelated (hepatic resection, prostatectomy, cardiac, spinal) These off-label uses are mostly based on anecdotal case reports  Need better evidence Franchini M. Thromb Haemost. 2005;93:1027-1035.

29. 29 Comparison of Available Randomized Patient Data: Cardiac Surgery Silver DA, et al. Crit Care Med. 2007;35:1782-1783.

30. 30 Trial TitleStudy DesignPhase Total Enrollment Expected Completion "Salvage Use" of Recombinant Activated Factor VII After Inadequate Haemostatic Response to Conventional Therapy in Complex Cardiac Surgery Multicenter, Treatment, Randomized, Double- Blind, Placebo- Control, Parallel Assignment, Safety/Efficacy Study Phase 340June 2008 Evaluation of the Quality of the NovoSeven (rVIIa) Treatment Practice at Rigs hospital, Copenhagen University Hospital Natural History, Longitudinal, Defined Population, Retrospective/ Prospective Study ?? December 2010 Effect of Recombinant Coagulation Factor VIIa on Peri- Operative Blood Loss in Patients Undergoing Major Burn Excision and Grafting Randomized, Double- Blind (Subject, Caregiver, Investigator) Placebo- Control, Parallel Assignment, Efficacy Study Phase 352December 2009 Efficacy and Safety of Factor VIIa (Eptacog Alfa) on Rebleeding After Surgery for Spontaneous Supratentorial Intracerebral Hemorrhage Randomized, Controlled, Open- Label, Investigator- Blinded Pilot Study Phase 230January 2008 US National Institutes of Health. ClinicalTrials.gov. Available at: www.clinicaltrials.gov. Accessed February 10, 2008. Current Ongoing Global Trials

31. 31 Trial TitleStudy DesignPhase Total Enrollment Expected Completion "Salvage Use" of Recombinant Activated Factor VII After Inadequate Haemostatic Response to Conventional Therapy in Complex Cardiac Surgery Multicenter, Treatment, Randomized, Double- Blind, Placebo- Control, Parallel Assignment, Safety/Efficacy Study Phase 340June 2008 Effect of Recombinant Coagulation Factor VIIa on Peri- Operative Blood Loss in Patients Undergoing Major Burn Excision and Grafting Randomized, Double- Blind (Subject, Caregiver, Investigator) Placebo- Control, Parallel Assignment, Efficacy Study Phase 352December 2009 Efficacy and Safety of Factor VIIa on Rebleeding After Surgery for Spontaneous Intracerebral Hemorrhage (ICH) (PRE-SICH) Randomized, Controlled, Open- Label, Investigator- Blinded Pilot Study Phase 230January 2008 Current Ongoing Global Trials (cont) US National Institutes of Health. ClinicalTrials.gov. Available at: www.clinicaltrials.gov. Accessed February 10, 2008.

32. 32 Trial TitleStudy DesignPhase Total Enrollment Expected Completion Recombinant Human Activated Factor VII as Salvage Therapy in Women With Severe Postpartum Hemorrhage Randomized, Open- Label, Active Control, Parallel Assignment, Safety/Efficacy Study Phase 484December 2009 The Use of rVIIa in Trauma Patients: A Multi-Center Case Registry Natural History, Cross-Sectional, Case Control, Retrospective/ Prospective Study ??1000Not recruiting yet Assessment of rVIIa in Controlling Bleeding in Patients With Severe Trauma Injuries Treatment, Randomized, Double- Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study Phase 31502Recruiting US National Institutes of Health. ClinicalTrials.gov. Available at: www.clinicaltrials.gov. Accessed February 10, 2008. Current Ongoing Global Trials (cont)

33. 33 The Role of Recombinant Factor VIIa in On-pump Cardiac Surgery: Proceedings of the Canadian Consensus Conference Panel recommendation against prophylactic or routine use of rVIIa Weak recommendation for use of rVIIa as rescue therapy for blood loss refractory to standard hemostasis Tx  1-2 doses of 35-70 µg/kg Karkouti K, et al. Can J Anesth. 2007;54:573-582.

34. 34 Final Thoughts Prohemostatic agents fall into multiple categories Significant surgical bleeding with fibrinolysis can be controlled using antifibrinolytic agents Topical hemostatic agents play an important role in the management of significant surgical bleeding Recombinant factor VIIa is an intriguing, potential new agent, the role of which will be better defined for different types of surgery when results of multiple RCTs are published in near future