Transcript LOVE=INFLAMMATION - Blood CME Center

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
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
Coagulation
Cascade
Fibrinolytic
Cascade
Prothrombin
Plasminogen
–
APC
TAFIa
Thrombin
–
Plasmin
PC
TAFI
Thrombin
Thrombomodulin
Fibrinogen
Fibrin
FDPs
Antifibrinolytic
Agents
Tip the balance against fibrinolysis  More clot  Less bleeding
Adapted from Nesheim M. Chest. 2003;124:33S-39S.
3
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.
4
Lysine Analogues
• Block the lysinebinding 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 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.
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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
CPB=cardiopulmonary bypass.
Kikura M, et al. J Am Coll Surg. 2006;202:216-222.
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Blood Conservation Using Antifibrinolytics Trial (BART)
• 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
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.
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BART Trial (cont)
• 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)
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.
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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/06n0362/06N0362_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
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
Reprinted from Voils S. Pharmacotherapy.
2007;27:69S-84S.
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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)
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
Originally published in Gabay M. Am J Health-Syst Pharm. 2006;63:12441253. ©2006, American Society of Health-System Pharmacists, Inc.
All rights reserved. Reprinted with permission. (R0821)
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Indications
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.
Originally published in Gabay M. Am J Health-Syst Pharm. 2006;63:12441253. ©2006, American Society of Health-System Pharmacists, Inc.
All rights reserved. Reprinted with permission. (R0821)
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Indications (cont)
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;63:12441253. ©2006, American Society of Health-System Pharmacists, Inc.
All rights reserved. Reprinted with permission. (R0821)
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Considerations
• Efficacy: Few RCTsstudies have shown beneficial effects
in controlling capillary bleeding, achieving hemostasis in
vascular surgery, controlling bleeding from fistulapuncture 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_06Absorbable%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.
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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.
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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
TF=tissue factor.
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.
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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.
25
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.
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Thrombotic Adverse Events (cont)
•
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 rVIIatreated patients for thrombotic AEs—either on individual trial basis
or for combined trial populations (P=.57)
Levy JH, et al. Transfusion. 2006;46:919-933.
27
“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.
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Comparison of Available Randomized Patient
Data: Cardiac Surgery
4500
Enrolled
On-label
4000
Number of Patients
3500
3000
2500
2000
1500
1000
500
0
Aprotinin
BART
Factor VIIa
Silver DA, et al. Crit Care Med. 2007;35:1782-1783.
29
Current Ongoing Global Trials
Phase
Total
Enrollment
Expected
Completion
Phase 3
40
June 2008
??
??
December
2010
Randomized, DoubleBlind
(Subject, Caregiver,
Investigator) PlaceboControl, Parallel
Assignment,
Efficacy Study
Phase 3
52
December
2009
Randomized,
Controlled, OpenLabel, InvestigatorBlinded Pilot Study
Phase 2
30
January 2008
Trial Title
Study Design
"Salvage Use" of Recombinant
Activated Factor VII After
Inadequate Haemostatic
Response to Conventional
Therapy in Complex Cardiac
Surgery
Multicenter,
Treatment,
Randomized, DoubleBlind, PlaceboControl,
Parallel Assignment,
Safety/Efficacy Study
Evaluation of the Quality of the
NovoSeven (rVIIa) Treatment
Practice at Rigs hospital,
Copenhagen University Hospital
Natural History,
Longitudinal,
Defined Population,
Retrospective/
Prospective Study
Effect of Recombinant
Coagulation Factor VIIa on PeriOperative Blood Loss in Patients
Undergoing Major Burn Excision
and Grafting
Efficacy and Safety of Factor VIIa
(Eptacog Alfa) on Rebleeding
After Surgery for Spontaneous
Supratentorial Intracerebral
Hemorrhage
US National Institutes of Health. ClinicalTrials.gov. Available at:
www.clinicaltrials.gov. Accessed February 10, 2008.
30
Current Ongoing Global Trials (cont)
Phase
Total
Enrollment
Multicenter,
Treatment,
Randomized, DoubleBlind, PlaceboControl,
Parallel Assignment,
Safety/Efficacy Study
Phase 3
40
June 2008
Effect of Recombinant
Coagulation Factor VIIa on PeriOperative Blood Loss in Patients
Undergoing Major Burn Excision
and Grafting
Randomized, DoubleBlind
(Subject, Caregiver,
Investigator) PlaceboControl, 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, OpenLabel, InvestigatorBlinded Pilot Study
Phase 2
30
January 2008
Trial Title
Study Design
"Salvage Use" of Recombinant
Activated Factor VII After
Inadequate Haemostatic
Response to Conventional
Therapy in Complex Cardiac
Surgery
US National Institutes of Health. ClinicalTrials.gov. Available at:
www.clinicaltrials.gov. Accessed February 10, 2008.
Expected
Completion
31
Current Ongoing Global Trials (cont)
Trial Title
Study Design
Recombinant Human Activated
Factor VII as Salvage Therapy in
Women With Severe Postpartum
Hemorrhage
Randomized, OpenLabel, Active Control,
Parallel Assignment,
Safety/Efficacy Study
The Use of rVIIa in Trauma
Patients: A Multi-Center Case
Registry
Natural History,
Cross-Sectional,
Case Control,
Retrospective/
Prospective Study
Assessment of rVIIa in
Controlling Bleeding in Patients
With Severe Trauma Injuries
Treatment,
Randomized, DoubleBlind,
Placebo Control,
Parallel Assignment,
Safety/Efficacy Study
US National Institutes of Health. ClinicalTrials.gov. Available at:
www.clinicaltrials.gov. Accessed February 10, 2008.
Phase
Total
Enrollment
Expected
Completion
Phase 4
84
December
2009
??
1000
Not recruiting
yet
Phase 3
1502
Recruiting
32
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.
33
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
34