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.

33

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.

66

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.

77

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.

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.

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

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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)

1111

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.

1212

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.

1313

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

1414

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.

1515

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

1616

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.

1717

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)

1818

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.

1919

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.

2020

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.

2121

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.

2222

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.

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