Hemostasis Symposium - Impact of Topical Hemostatic Agents

1. Hemostasis Symposium - Impact of Topical Hemostatic Agents Victor A. Ferraris, M.D., Ph.D. Tyler Gill Professor of Surgery University of Kentucky

2. Presenter Disclosure Information • Victor A. Ferraris, MD, PhD • AstraZeneca: Advisory board • Haemonetics: Advisory board • CMEology grant supported by Baxter Healthcare – CME event

3. Blood Transfusion in the Operating Room Is Bad! • Cardiac surgery • Thoracic operations • Vascular operations • Cancer procedures • General surgery

4. Transfusion and Serious Morbidity in 4445 Cardiac Surgical Patients • Serious morbidity and mortality increase with the amount transfused Ferraris VA, Ferraris SP. Int J Angiol. 2006;14:193-210.

5. ≥10,000 patients with normal HGB undergoing CPB. Relationships between maximum decrease in HGB (from baseline) and the incidence of mortality, renal failure, and stroke. Greater than 50% decrease in HGB was associated with a 50% chance of suffering adverse events. Anemia May Be as Bad as Transfusion! Transfusion, 2008;48:666-672 Karkouti, et al., Transfusion, 2008

6. Blood Transfusion in General Surgical Population Ferraris VA et al. Arch Surg. 2012;147:49-55.

7. Hospital Cost and Outcomes Ferraris VA et al. J ThoracCardiovasc Surg. 1998;115:593-602.

8. What Should We Do to Decrease Complications of Blood Transfusion? • Avoid transfusion! • Identify risk before operation • Intervene to limit bleeding and transfusion – especially in high-risk patients • Devices • Drugs • Process of care • Anemia may be as bad as transfusion!

9. What Works for Blood Conservation? • Multiple interventions are better than a few ‘favorite’ interventions • TQM approach – ‘Measurement and Management’ • ‘Outcome greater than sum of parts’ • Examples from cardiac operations • ANH, RAP, mini-circuits, biocompatible circuits, ultrafiltration, topical hemostatic agents, etc. have variable evidence but taken together they have synergistic effect. • What does not work – PEEP, chest tube reinfusion. Ferraris VA et al. Ann Thorac Surg. 2011;91:944-982.

10. Transfusion Profile • More than 50% do not get transfusion • Patients who receive > 10 units of blood are in 90th percentile • 10%-20% of patients consume 80% of blood products 4445 patients having cardiac procedures with CPB over 4 years Ferraris VA, Ferraris SP. Int J Angiol. 2006;14:193-210.

11. Why Topical Hemostats? • ‘Too numerous to count’ topical agents available. • Lack of high-quality data to guide usage. • Knowledge deficit – practitioners & administrators.

12. SABM to the Rescue! • SABM convened multidisciplinary panel • Physicians, Allied Health Professionals, Pharmacists, Administrators • Goals • Identify unmet needs related to topical agents. • Span knowledge gap in current use. • Offer clinicians guide for use of topical agents

13. Categories of Approved Topical Hemostatic Agents • Mechanical • Gelatin, collagen, cellulose, polysaccharide • Biologically active agents • Thrombin-based • Flowable • Collagen or gelatin plus thrombin • Sprayable • Fibrin sealant, synthetic sealant (CosealR), or animal protein hydrogel (BioGlueR)

14. In-depth Literature Search on Topical Hemostatic Agents

15. 59 Articles Reported Efficacy of Topical Agents • 30 articles – no agent comparator • 16 reports on efficacy of mechanical barrier hemostats compared to another mechanical agent. • 12 reports compared mechanical hemostats to another type of topical agent. • 9 reports compared topical agent to non-pharmacologic hemostat.

16. Efficacy Studies • 12 trials compared two topical agents. • 8 trials found no benefit of one agent versus comparator. • 3 of 8 trials compared bovine thrombin to recombinant thrombin. • 1 of 8 compared 2 formulations of the same agent.

17. Safety Data • 9 studies reported safety analysis but no comparator agent and no test of efficacy.

18. Outcome Measures for Topical Agents • Most common primary outcome measure was hemostasis within 10 minutes of application of test agent. • No indication of transfusion or bleeding outcomes in almost all studies.

19. Summary of Literature on Topical Hemostats – Uphill Battle! • Poor quality information • Not useful for guiding clinical practice. • No uniform outcome measure to judge efficacy. • Limited safety data.

20. Categories of Approved Topical Hemostatic Agents • Mechanical • Gelatin, collagen, cellulose, polysaccharide • Biologically active agents • Thrombin-based • Flowable • Collagen or gelatin plus thrombin • Topical fibrin sealants • Fibrin sealant, synthetic sealant (CosealR), or animal protein hydrogel (BioGlueR)

21. Mechanical Barrier Topical Agents • Form barrier to block blood flow and create thrombogenic surface. • Require intact coagulation system. • Main use is for minimal bleeding. • Four categories: • Porcine gelatin, bovine collagen, oxidized cellulose, and polysaccharide spheres. • Advantages: Low cost, easy to use, biodegradable. Shander, et al., 2013 (in press)

22. Mechanical Barrier Agents Pros & Cons • Pros • Safe • Low cost • Used by Military (Quick ClotR) & First Responders. • Cons • Animal based products can cause allergic reactions. • Expansion up to 200% can cause nerve damage in closed space. • Should be removed in controlled setting. • Use in hospital not controlled or recorded. Shander, et al., 2013 (in press)

23. Biologically Active Agents • Thrombin-containing products • Do not rely on patient’s intrinsic clotting system • Require intact fibrinogen. • Three types of thrombin • Bovine, pooled human, and recombinant. • Comparable efficacy. • Fibrin sealants contain thrombin and source of fibrin. Shander, et al., 2013 (in press)

24. Biologically Active Topical AgentsPros & Cons • Pros • Used in variety of ways – drip, spray, combined w/ absorbable hemostat. • Used in large raw surfaces (e.g. burns, adhesions, vascular grafts). • Cons • Bovine thrombin associated w/ immune coagulopathy. • Hypothetical risk of blood-borne pathogen transmission in pooled plasma thrombin. Shander, et al., 2013 (in press)

25. Flowable Topical Hemostatic Agents • Combine thrombin-containing substance w/ mechanical hemostat to form flowable paste. • Delivered by syringe as paste-like flowable mixture. Shander, et al., 2013 (in press)

26. Flowable Topical Agents • Pros • Conform to shape of irregular wounds. • Combine strengths of two types of topical agents (mechanical & biologically active) • Comparative trials favor flowable agent over static combo of gelatin sponge plus thrombin and over mechanical agents alone. • Cons • Increased cost. • Combine risks of two types of topical agents. • Only hard endpoint is time to hemostasis. • No control of use in most hospitals. Shander, et al., 2013 (in press)

27. Topical Fibrin Sealants • Combine high concentrations of human fibrinogen & thrombin at point-of-bleeding. • May also contain anti-fibrinolytic (e.g. aprotinin) to stabilize clot. • Comparative trial suggests superiority of topical fibrin sealant compared to other topical agents. • Only topical agent study with blood transfusion as an endpoint. Shander, et al., 2013 (in press)

28. Fibrin Sealant Topical AgentsPros & Cons • Pros • Hemostatic matrix may help wound healing. • Effective in patients w/ defects in clotting. • Most available trial evidence. • Cons • Costly • Theoretical risk of blood-borne pooled plasma infection. • Anaphylaxis from aprotinin. • Trials that show superiority are low quality. Shander, et al., 2013 (in press)

29. Relative Cost of Topical Agents

30. Choice of Topical Agent • Widespread practice variation. • Currently no agent of choice – lack of evidence. • Guidelines are vague • STS guidelines – “Topical hemostatic agents that employ localized compression or provide wound sealing may be considered to provide local hemostasis at anastomotic sites as part of a multi-modality blood management program. (Class IIb, Level C)” Ferraris VA et al. Ann Thorac Surg. 2011;91:944-982.

31. Problems with Topical Hemostats • True scope of practice is unclear. • No regulation within hospitals – not treated like a drug or device. • No rationale use of topical products • Products not matched to type of hemorrhage. • Knowledge base of practitioners is incomplete. • Safety concerns are uncertain • Safety data not recorded or even recognized. • Use of topical agents is not patient focused • Most patients don’t even know that they received these agents.

32. Solutions • More comparative efficacy trials • Track bleeding outcomes and other patient outcomes. • Better efficacy outcomes – bleeding control w/in 5-10 minutes may not be meaningful. • Better tracking of topical products within hospitals. • Patient involvement – consent process. • Safety trials – Phase IV information.

33. Specific Recommendations for Improvement • Treat topical agents like any other drug or device • Topical agents stored, handled, and processed using institution-specific policies, similar to drug delivery. • Track use of topical agents in a practical, searchable and retrievable manner • Patient and clinician education necessary • No real informed consent with use of topical agents. • Need for clinically relevant studies with appropriate endpoints. • Safety data needs to be recorded. Shander, et al. 2013 (submitted)

34. Rational Approach to Topical Hemostats Shander, et al. 2013 (submitted)

35. Predictors of Postoperative Bleeding and Blood Transfusion 2011 STS Guidelines • Advanced age • RBC volume • Small body size or preop anemia • Drugs • Anti-platelet or anti-coagulant drugs • Co-morbidities • Emergent operations • Complex operations Ferraris VA et al. Ann Thorac Surg. 2011;91:944-982.

36. Topical Hemostatic Agents – 2011 (Class IIb, Level C) Anastomotic sealants Anti-fibrinolytic solutions Aprotinin based topical solutions Lysine analog solutions. • Cellulose & Collagen • Fibrin sealants (e.g. TissealR) • Thrombin/gelfoam • Synthetic • Cyanoacrylate • Polyethylene glycol • Albumin/gluteraldehyde • Chitin & polysachharides. Topical hemostatic agents that employ localized compression or provide wound sealing may be considered to provide local hemostasis at anastomotic sites as part of a multi-modality blood management program. (Class IIb, Level C)” Ferraris VA et al. Ann Thorac Surg. 2011;91:944-982.

37. Preserving RBC Volume • RBC Volume • HCT *Blood volume • Measure of amount of blood patient can afford to lose. • Perioperative EPO. • Mini-circuits. • Ultrafiltration. • Pump salvage (centrifugation). • Microplegia. • Retrograde autologous priming (RAP).

38. How Do You Measure Quality in Blood Management? • Five Domains in Cardiac Surgery • Preoperative medical care • Operative care • Perfusion interventions • Hemostatic drugs • Outcome measures

39. Performance Measure -Preoperative Medical Care • Multidisciplinary protocols • Treat preoperative anemia (EPO/Fe) • Continue aspirin • Stop P2Y12 inhibitors • Use point-of-care tests

40. Performance Measure - Operative Care • Choice of operation • Minimally invasive procedures • Preserving RBC volume • Blood salvage, perfusion interventions when appropriate (mini-circuits, microplegia, ultrafiltration, biocompatible circuits, etc.) • Intraoperative drugs • Anti-fibrinolytic drugs • Topical hemostatic agents

41. Performance Measure - Blood Conservation Outcomes • Any intraoperative blood transfusion • Any non-PRBC transfusion (platelets, FFP, Cryo) • Unusual blood derivitives (rFVIIa, Factor IX, etc.) • Reoperation for bleeding • Any transfusion within 72 hours of operation

42. What Do You Think? • Are these reasonable measures of performance? • Would you like to be rated on these measures?

43. Conclusions • Topical agents are part of multi-modality approach to bleeding. • More rigorous approach to use of topical agents is necessary. • Specific knowledge of mode of action, cost, and complications is sub-optimal. • Treat topical agents like any other drug or device. • Use of topical agents is a reasonable quality metric.

44. Questions?