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
Dec 16, 2015
Hemostasis for the Surgeon:Treatment Practices
Peter K. Smith, MDProfessor and ChiefDivision of Cardiovascular and Thoracic SurgeryDuke University Medical CenterDurham, North Carolina
22
Prohemostatic Agents
• Antifibrinolytics
Lysine analogues
Aprotinin
• Topical hemostatics
• Desmopressin (DDAVP)
• Recombinant activated factor VIIa (rVIIa)
Levi M. Minerva Anestesiol. 2004;70:267-271.
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Fibrinolysis
Antifibrinolytic Agents
Tip the balance against fibrinolysis More clot Less bleeding
Prothrombin Plasminogen
Thrombin Plasmin
APC TAFIa
TAFIPC
Fibrinogen Fibrin FDPs
– –
Adapted from Nesheim M. Chest. 2003;124:33S-39S.
FibrinolyticCascade
CoagulationCascade
ThrombinThrombomodulin
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.
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.
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Lysine Analogues (cont)
• Lysine analogues1-3: 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.
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Lysine Analogues: EACA and TXA
• Trial data have limitations1,2
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 markets3
?Safety data1. 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.
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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.
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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
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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)
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Aprotinin
• A small protein isolated from bovine lung1 • A non-specific serine protease inhibitor
inhibits trypsin, plasmin, plasma/tissue kallikrein, etc1,2
• Inhibits contact phase activation of coagulation that both initiates coagulation and promotes fibrinolysis2
• In CPB, it reduces derangements in coagulation/fibrinolysis caused by negatively charged surface of CPB circuit2
• Indirectly preserves platelet function in extracorporeal circulation1
• Marketing suspended on 11/5/07 following FDA Advisory 2/8/063
• Available for “on-label” investigational use with IRB approval, see Bayer Web site
• BART trial publication 5/084
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.
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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 RCTs1
• Safety: Associated with numerous adverse events2
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.
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Some Topical Hemostatic Agents
Reprinted from Voils S. Pharmacotherapy. 2007;27:69S-84S.
Sealants and Combination Products:
Agent Topical Application Instructions Major Drawbacks or Comments
Bovine thrombin Dry, 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
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Some Topical Hemostatic Agents (cont)
Agent Topical Application Instructions Major 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 TXA Solutions 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
Zeolite Powder applied to wounded tissue; considered a device; used in combat
Local hyperthermia-induced tissue damage
Reprinted from Voils S. Pharmacotherapy. 2007;27:69S-84S.
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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 Hemostatic Composition Approval 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 sponge September 30, 1999
Avitene (Davol) Bovine collagen August 26, 1976 (as a drug)October 24, 1980 (as a device)
Instat (J&J/Gateway) Bovine collagen October 10, 1985
Helistat (Integra LifeSciences) Bovine collagen November 8, 1985
Helitene (Integra LifeSciences) Bovine collagen November 8, 1985
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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 Agent Labeled 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.
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Hemostatic Agent Labeled 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)
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Considerations
• Efficacy: Few RCTsstudies 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.
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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.
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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.
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Desmopressin
• Originally developed and licensed for the treatment of inherited
defects of hemostasis1,2
• Several reviews suggest its effect is too small to influence the
need for transfusion and reoperation1,2
• Most evidence of efficacy is in mild hemophilia A and
von Willebrand’s disease1,2
• Not indicated for use in cardiac surgery patients1,2
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.
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Desmopressin and Surgical Bleeding in Patients With Inherited Coagulation Disorders
• Study data limitations1-3
Small numbers of patients
Mostly retrospective analyses
Multimodal approaches
• Antifibrinolytics used concomitantly with other
factor concentrates2
• Bleeding depends on types of surgical procedure1
Superficial vs major
Vascular, cardiac, neurosurgical
• Monitoring of effects is limited—especially with platelet
function tests1
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.
2323
Recombinant Factor VIIa
• Vitamin K-dependent glycoprotein structurally similar to human plasma-derived FVIIa1
• Approved in United States for treatment of bleeding
in patients with hemophilia A or B with inhibitors to FVIII
or FIX1
• Multiple reports of off-label use in cardiac surgery,
trauma, liver transplantation to secure hemostasis2
• Promotes hemostasis by activating the coagulation
cascade1
• Believed to cause local thrombin generation and platelet
recruitment at sites of vascular and microvascular injury2
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.
2424
Recombinant Factor VIIa (cont)
• A central factor in coagulation1
• A trypsin-like serine protease
(characterized by a serine residue
in the active side of the enzyme)2
• Initiates coagulation in a complex with TF2
• Once bound to TF, it is activated (rVIIa) by
different proteases2
• Produced in liver3
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.
2525
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.
2626
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.
2727
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)
2828
“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-traumarelated (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
Comparison of Available Randomized Patient Data: Cardiac Surgery
0
500
1000
1500
2000
2500
3000
3500
4000
4500
Aprotinin BART Factor VIIa
Nu
mb
er o
f P
atie
nts
Enrolled
On-label
Silver DA, et al. Crit Care Med. 2007;35:1782-1783.
3030
Trial Title Study Design Phase
Total Enrollmen
tExpected
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 3 40 June 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 3 52 December 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 2 30 January 2008
US National Institutes of Health. ClinicalTrials.gov. Available at: www.clinicaltrials.gov. Accessed February 10, 2008.
Current Ongoing Global Trials
3131
Trial Title Study Design Phase
Total Enrollmen
tExpected
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 3 40 June 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 3 52 December 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 2 30 January 2008
Current Ongoing Global Trials (cont)
US National Institutes of Health. ClinicalTrials.gov. Available at: www.clinicaltrials.gov. Accessed February 10, 2008.
3232
Trial Title Study Design PhaseTotal
EnrollmentExpected
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 4 84 December 2009
The Use of rVIIa in Trauma Patients: A Multi-Center Case Registry
Natural History, Cross-Sectional, Case Control, Retrospective/Prospective Study
?? 1000 Not 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 3 1502 Recruiting
US National Institutes of Health. ClinicalTrials.gov. Available at: www.clinicaltrials.gov. Accessed February 10, 2008.
Current Ongoing Global Trials (cont)
3333
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.
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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