Warfarin Reversal with Prothrombin Complex Concentrates and Challenges of the New Oral Anticoagulants.

(1)

Warfarin Reversal with

Prothrombin Complex

Concentrates and Challenges of

the New Oral Anticoagulants.

Irene Sadek

Medical Director

Blood Transfusion Services Capital Health

(2)

Overview

• Plasma products and transfusion guidelines

• Prothrombin Concentrate Products Effectivness

• National and Provincial PCC guidelines

▫ INR level >1.7

▫ Dosing recommendations

• CDHA utilization of PCC

(3)

Plasma products

• Apheresis Fresh frozen Plasma - collected by

apheresis and frozen within 8 hours, 500 ml and 250 ml

• BC frozen plasma- whole blood derived and frozen within 24 hours .

• Fresh frozen plasma – whole blood derived and frozen within 8 hours

• Frozen plasma - whole blood derived and frozen within 24 hours .

(4)

FFP vs BC FP Protein Function

(ABO matched, n=20)

0.50 - 1.50 U 0.188

0.87 0.142

1.03

Factor IX

0.50 - 1.50 U 0.250

0.91

0.315 1.26

Factor VIII

0.50 - 1.50 U 0.207

0.90 0.230

1.09

Factor VII

0.50 - 1.50 U 0.192

1.06

0.189 1.15

Factor V

0.50 - 1.50 U 0.123

0.95 0.137

1.12

Factor II

0.50 - 1.50 U 0.151

0.94 0.161

1.11

Factor XI

0.50 - 1.50 U 0.164 1.07 0.164 1.24 Factor X NL Range Std Dev Mean Std Dev Mean

FP produced from BC 20-24 hrs after

collection FFP produced within 8

hours of collection

4

(5)

FFP vs BC FP Protein Function

(ABO matched, n=20)

--- 0.084 0.96 0.084 1.01 Alpha 2 Antiplasmin >0.50 U 0.377 1.13 0.405 1.24 Von Willebrand >0.65 U 0.180 1.03 0.472 1.15 Protein S

2.00 - 5.00 g/L

1.945 3.92 0.481 3.01 Fibrinogen >0.70 U 0.122 1.05 0.223 1.19 Protein C >0.75 U 0.053 1.01 0.078 0.97 Antithrombin NL Range Std Dev Mean Std Dev Mean

Produced from BC 20-24 hrs after collection FFP Produced within

8 hours of collection

5

(6)

Plasma transfusion guidelines

• Indications for frozen plasma (FP/FFP):

1. Bleeding or prior to an invasive or operative procedure in patients with an

INR > 1.7. The dose of plasma must be sufficient to raise coagulation factors to adequate levels (10-15 mL/kg of plasma is the recommended dose, but more may be required if the patient is actively bleeding or a consumptive process is ongoing).

• Of note 1: Prothrombin complex concentrate (PCC) products (Octaplex or Beriplex) are recommended for patients on warfarin with an elevated INR (>1.7) who are bleeding or are going for an invasive or operative procedure within 6 hours.

• Of note 2: Protamine sulfate is the treatment for prolonged aPTT from heparin (if the patient is bleeding or will be undergoing an invasive or operative procedure).

• Of note 3: In patients with advanced liver disease, plasma infusions should be considered prior to considering massive amounts of red blood cell transfusions in bleeding patients if INR > 1.7. Prophylactic plasma transfusion is not indicated for certain invasive procedures (e.g., transjugular liver biopsy, paracentesis, thoracentesis) in patients with Liver disease if their INR is 2.0 or less.

(7)

Plasma transfusion guidelines

• Of note 1: Prothrombin complex concentrate

(PCC) products (Octaplex or Beriplex) are

recommended for patients on warfarin with an

elevated INR (>1.7) who are bleeding or are

going for an invasive or operative procedure

within 6 hours.

(8)

Prothrombin complex concentrates

• Human plasma derived products and

• Solvent/detergent treatment and/or

nanofiltration for viral, bacterial and parasite

inactivation and removal.

• Contain the procoagulant Vitamin K dependent

factors – II, VII, IX and X

(9)

(10)

(11)

(12)

RECOMMENDATIONS FOR USE OF PROTHROMBIN

COMPLEX CONCENTRATES IN CANADA (National Advisory Committee on blood and blood products June 2011)

• Recommended in:

▫ Reversal of warfarin therapy or vitamin K

deficiency in patients exhibiting major bleeding manifestations.

▫ Reversal of warfarin therapy or vitamin K

deficiency in patients requiring urgent(< 6 hours)

surgical procedures.

• Contraindicated in:

▫ Patients with a history of Heparin Induced Thrombocytopenia

(13)

• Recommended in:

Reversal of warfarin therapy or vitamin K

deficiency in patients exhibiting major bleeding manifestations.

Reversal of warfarin therapy or vitamin K

deficiency in patients requiring urgent(< 6 hours) surgical procedures.

• Contraindicated in:

Patients with a history of Heparin Induced Thrombocytopenia

(14)

(15)

Beriplex P/N Phase I PK Study: Demonstrated rapid

and sustained increases in coagulation factors

i.v., intravenous; PCC, prothrombin complex concentrate Ostermann et al. Thromb Haemost 2007; 98: 790–7

Time 144 96 72 48 24 18 12 6 2 60 30 10 5 Pre

Minutes: Post-Infusion Hours: Post-Infusion

100 200 300 50 100 150 200 200 200 150 100 50 250 150 100 FVII (% ) FII (% ) FIX (% ) FX (%) i.v. PCC 15

(16)

Beriplex P/N Phase I PK Study: Demonstrated rapid

and sustained increases in thromboinhibitors

144 96 72 48 24 18 12 6 2 60 30 10 5 Pre

Minutes Hours

Time 100 150 200 100 200 300 P rote in C (%) P rote in S (%) i.v . PCC

i.v., intravenous; PCC, prothrombin complex concentrate Ostermann et al. Thromb Haemost 2007; 98: 790–7

(17)

• Not recommended for:

▫ Elective reversal of oral anticoagulant therapy pre – invasive procedure. ▫ Treatment of elevated INRs without bleeding or need for surgical

intervention.

▫ For management of vitamin K antagonist overdose with elevated INR but without bleeding

▫ Massive transfusion

▫ Coagulopathy associated with Liver dysfunction

▫ Patients with recent history of thrombosis, myocardial infarction or Disseminated Intravascular Coagulation (DIC)

(18)

Thrombotic events post PCC

• Current PCC does not contain activated factors

• The reported rate of thrombotic events post PCC

varies:

▫ Metanalysis of 27 studies: 1.8% in patients treated with four factor PCC (Dentali 2011)

▫ Abstracts: 3.6% (Song 2010), 6.8% (Varga 2010), 3.7% (Moayedi 2011)

(19)

Comparison of fresh frozen plasma and prothrombin complex concentrate for the

reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study

Vox Sanguinis

Volume 99, Issue 3, pages 251-260, 19 MAY 2010 DOI: 10.1111/j.1423-0410.2010.01339.x

(20)

Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in

patients undergoing cardiopulmonary bypass surgery: a randomized study

R. Demeyere,1 S. Gillardin,1 J. Arnout2 & P. F. W. Strengers3,4, Vox Sanguinis (2010) 99, 251–260

• RCT, 40 pts, INR>2.1

▫ 20 received 2 units FFP, 400ml pre and post CPB ▫ 20 received PCC, ½ the manufacturer

recommended dose pre and post CPB ▫ Second dose

 30% of PCC group versus 100% of FFP group ▫ No difference in blood loss

(21)

Vox Sanguinis

(22)

Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing

cardiopulmonary bypass surgery: a randomized study

Treatment group

Preoperative 15’ post CPB 60’ post CPB

PCC Number 20 Median

(range)

2.7 (1.6-4.4) 1.6(1.2-2.2) 1.6(1.3-2.2) FFP Number 20

Median (range)

(23)

Vox Sanguinis

(24)

Plasma versus PCC in rapid

warfarin reversal

• Conclusions:

▫ PCC provided more rapid and complete correction of INR as compared to FFP

• However, it remains unclear if this led to

improved clinical outcomes

▫ Literature suggests that patients may continue to bleed despite reaching their target INR after PCC administration whereas good hemostasis may be observed in those who did not reach their target (Solbeck et al 2012)

(25)

Plasma versus PCC in rapid warfarin

reversal

Plasma PCC

• Human

• No viral inactivation

• Large volume (15 mL/kg; 770-1500 mL)

• Risk of TRALI, TACO and anaphylaxis

• Needs to be thawed

• Requires ABO group

• Human

• Virally inactivated, prion reduction process

• Small volume 40-80 mL

• Risk of thrombosis, allergic reaction

• Lyophilized, needs to be reconstituted

(26)

(27)

(28)

Indication for replacement transfusion

▫ in bleeding patients or patients at risk of bleeding requiring an invasive procedure.

▫ Coagulation parameters:

 INR >1.5 times the midpoint of the normal range or INR>1.65.

 Specific coagulation factor assay with < 30%

(29)

• Coagulation factor levels of 25-30% considered

adequate for good hemostasis.

• What do INR results mean in relation to factor

levels ?

(30)

More than one factor

deficiency

and coagulation testing

▫ Burns et al. Am J Clin Pathol. 1993 Aug;100(2):94-8

▫ If a single coagulation factor is at 50% and all other factors at 100% levels, the PT and aPTT values are within normal range. ▫ However, when two coagulation factors are at 75% and all other

factors at 100% levels, the resulting PT and APTT were prolonged over the clotting times of 50% factor-deficient plasma.

(31)

More than one factor deficiency

and coagulation testing

▫ Similar findings were obtained in patients with mild factor reductions caused by warfarin treatment.

▫ These data indicate that prolongations of the PT and APTT in disorders of coagulation affecting multiple factors represent less of a reduction in factor levels than is generally appreciated.

▫ This may explain the poor clinical correlation between abnormalities in these test results and clinical bleeding in acquired disorders of hemostasis.

(32)

International Normalized Ratio Versus Plasma Levels of

Coagulation Factors in Patients on Vitamin K Antagonist Therapy Gene Gulati, PhD; Megan Hevelow, MS; Melissa George, DO; Eric Behling, MD; Jamie Siegel, MD. Arch Pathol Lab Med—Vol 135, April 2011

(33)

Vox Sanguinis

(34)

CDHA Plasma transfusion guidelines

• Of note 1: Prothrombin complex concentrate

(PCC) products (Octaplex or Beriplex) are

recommended for patients on warfarin with an

elevated INR

(>1.7)

who are bleeding or are

going for an invasive or operative procedure

within 6 hours.

(35)

(36)

Prothrombin complex transfusions

(37)

OCTAPLEX THE HALIFAX EXPERIENCE (2009)

M. Almohammadi1, I.Sadek1, A.Shawwa1, M.Alzahrani2, E. Kahwash1 Department of Pathology and Laboratory Medicine and 2Medicine, Capital District Health Authority and Dalhousie University, Halifax, NS, Canada

Patients who met NAC guidelines for indication

• One dose of 40ml reasonably

corrected INR in the vast majority of patients.

• Moreover, this single dose was enough to stop the bleeding in all patients except one patient who was on non steroidal

anti-inflammatory drugs presenting with massive upper GI bleeding.

• In terms of outcome, no

documented events of DVT or PE were recorded in this group.

INR Post-octaplex INR Pre-octaplex Patients N=38 1.6 3.9 Bleeding N=22 1.6 3.3 Pre-op N=16

(38)

(39)

(40)

PC Dosing recommendation

• Manufacturer dosing recommendation is based

on INR reversal to <1.3

• Most clinical reports are based on INR reversal

to <1.5 to 1.7.

• Double the dose would be required to decrease

INR from 1.7 to 1.3.

(41)

”Effects of fresh-frozen plasma transfusion on

prothrombin time and bleeding in patients with

mild coagulation abnormalities

”

Abdel-Wahab et al. TRANSFUSION 2006; 46:1279-1285

• when FFP was transfused to patients with an INR between 1.1 and 1.85 (PT 13.1-17 sec):

▫ less than 1% exhibited complete correction of INR within 8 hours of transfusion

▫ 15% corrected halfway to normal

(42)

Toward Rational Fresh Frozen Plasma Transfusion

The Effect of Plasma Transfusion on Coagulation Test Results

(43)

Fresh-frozen plasma transfusion in patients with mild coagulation abnormalities at a

(44)

(45)

Toward Rational Fresh Frozen Plasma Transfusion

The Effect of Plasma Transfusion on Coagulation Test Results

(46)

RECOMMENDATIONS FOR USE OF PROTHROMBIN

COMPLEX CONCENTRATES IN CANADA

• In 2008,

• recommendations for appropriate use of the prothrombin complex concentrate (PCC) in Canada were developed by the National Advisory Committee (NAC), disseminated widely and posted on the website (www.nacblood.ca).

• Recommended dose 40 ml or 1000 Unit of factor IX

• At that time octaplex® was the only available PCC.

• Beriplex was approved for use in Canada in 2011

(47)

Multi-Institutional Audit of octaplex® &

Comparison with National Recommendations

S. Nahirniak, J. Callum, C. Doncaster, Y. Lin, M.C. Poon, L. Whitman

(48)

Multi-Institutional Audit of octaplex® &

Comparison with National Recommendations

(49)

Multi-Institutional Audit of octaplex® &

Comparison with National Recommendations

On Behalf of the PCC Working Group of the National Advisory Committee on Blood & Blood Products of Canada*

• The working group would also like to highlight that

50% of patients in the audit responded to the

previously recommended standardized dose of 1000 IU(40 mL octaplex®).

• The 2011 NAC dosing recommendations for

prothrombin complex concentrate should be based on the INR as below.

• INR <3.0 40 mL PCC (1000 IU)

• INR 3.0-5.0 80 mL PCC (2000 IU)

(50)

OCTAPLEX THE HALIFAX EXPERIENCE (2009)

M. Almohammadi1, I.Sadek1, A.Shawwa1, M.Alzahrani2, E. Kahwash1 Department of Pathology and Laboratory Medicine and 2Medicine, Capital District Health Authority and Dalhousie University, Halifax, NS, Canada

(51)

Nova Scotia provincial data

0 2 4 6 8 10 12 14 16 INR

Pre and Post INR with 40 mL octaplex

Pre INR Post INR

(52)

Utilization Guideline for Prothrombin Complex

Concentrates in Nova Scotia

February 2012

• Recommended dosage

40 ml (1000 unit)

• PCC dose of 80 mL may be administered to:

▫ patients who are on anticoagulants with an INR greater than or equal to 5.1 and the patient is

bleeding, or requiring urgent surgery or invasive procedure

(53)

Poor Prognosis in Warfarin-Associated Intracranial

Hemorrhage Despite Anticoagulation Reversal

Dowlatshahi, Dar MD, PhD; Butcher, Kenneth S. MD, PhD; Asdaghi, Negar MD, MSc; Nahirniak, Susan MD; Bernbaum, Manya L. BSc; Giulivi, Antonio MD; Wasserman, Jason K. MD, PhD; Poon, Man-Chiu MD; Coutts, Shelagh B. MD Stroke : Volume 43(7), July 2012, p 1812–1817

• Multi institution Canadian study

 Between 2008 and 2010, 141 patients received PCC

for aaICH

 Median INR was 2.6

 Median dose 40 ml or 1000 units

(54)

Poor Prognosis in Warfarin-Associated Intracranial

Hemorrhage Despite Anticoagulation Reversal

Dowlatshahi, Dar MD, PhD; Butcher, Kenneth S. MD, PhD; Asdaghi, Negar MD, MSc; Nahirniak, Susan MD; Bernbaum, Manya L. BSc; Giulivi, Antonio MD; Wasserman, Jason K. MD, PhD; Poon, Man-Chiu MD; Coutts, Shelagh B. MD Stroke : Volume 43(7), July 2012, p 1812–1817

• Multi institution Canadian study

 PCC therapy reversed anticoagulation in 71.8% of

patients within 1 hour of treatment.

 Thrombotic event rate over 7 days 2%

 Total 30-day thrombotic event 5%

 Mortality rates remained high and clinical outcomes

were generally poor despite correction of the coagulopathy.

(55)

CDHA experience

2009-2011

• Standard dose is 40 ml

▫ 251 doses of PCC ▫ 215 patients.

(56)

CDHA experience

2011

Indication INR pre Dose Type Dose Amount INR post

intra cranial

hemmorhage 1.9 Initial 40 1.4

Intracranial hemorrhage

4.6 Initial 40 2.5

Subsequent 40 1.5

Subsequent 40 1.6

subdural hematoma/ evacuation/Burr

holes 2 Initial 40 (blank)

subdural

hematoma 2.2 Initial 40 1.3

intracraneal

(57)

CDHA

2011

Patients receiving a second dose

• Mostly to decrease INR <1.8 • Excpet for INR of 16

• Half received 20 ml

Indication INR pre Dose Type

Dose Amou

nt INR post

Surgical/Invasive Procedure

2.5 Initial 40 1.4 Subsequent 20 1.5 Surgical/Invasive

Procedure

2 Initial 40 1.6 1.6 Subsequent 20 1.6 Surgical/Invasive

Procedure

4.4 Initial 40 3 3 Subsequent 40 1.9 1.9 Subsequent 40 1.7 Actively Bleeding 11.1 Initial 40 1.5 Subsequent 20 1.3 Surgical/Invasive

Procedure

1.7 Initial 40

Subsequent 20 1.8 Actively Bleeding

2.7 Initial 40 2.7 Subsequent 40 1.5 Subsequent 40 1.2 Surgical/Invasive

Procedure

3.4 Initial 40 2 Subsequent 40 1.5 Surgical/Invasive

Procedure

3.8 Initial 40 1.9 Subsequent 20 1.7 Actively Bleeding

4.6 Initial 40 2.5 Subsequent 40 1.6 Subsequent 40 1.5 Actively Bleeding 16.6 Initial 40 2.9 Subsequent 20 2.5 Surgical/Invasive

Procedure

2.8 Initial 40

Subsequent 40 1.3 Surgical/Invasive

Procedure

2.8 Initial 40

(58)

(59)

(60)

Appropriateness of Frozen plasma and PCC

transfusion in Canada. Tinmouth et al

• Jan-March 2011.

• PCC transfusions;

▫ 15 episodes of PCC transfusions ▫ 4 episodes INR<1.5 (&1.7) (26%)

 3 pre surgical procedure

(61)

• New Oral

(62)

Illustration showing the sites of action of new anticoagulants in the coagulation cascade.

Hankey G J , Eikelboom J W Circulation 2011;123:1436-1450

(63)

(64)

Direct thrombin

Inhibitors

•Dabigatran binds the active site of free and fibrin-bound thrombin to impede the coagulation process by 1- preventing the conversion of fibrinogen to fibrin

2- preventing the feedback activation of Factors VII, XI, and V by thrombin and thrombin-related platelet activation

(65)

Bleeding Risk with Dabigatran in the Frail Elderly

N Engl J Med 2012; 366:864-866, March 2012.

• Audit of bleeding events in New Zealand

▫ Estimated 7000 patients on Dabigatran in 2011 ▫ 44 bleeding episodes in 2 months

▫ Major factors;

 Prescriber error (INR>2 )  impaired renal function,  patient age >80

 complications arising from the lack of a reversal agent.

(66)

Guide to the management of bleeding in patients taking dabigatran.

(67)

Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Erenberg et al.Circulation. 2011 Oct 4;124(14):1573-9

• CONCLUSION:

▫ Prothrombin complex concentrate immediately

and completely reverses the anticoagulant effect of rivaroxaban in healthy subjects

▫ but has no influence on the anticoagulant action of dabigatran at the PCC dose used in this study.

(68)

Reversal of dabigatran anticoagulation by prothrombin complex concentrate (Beriplex P/N) in a rabbit model.Pragst I et al. J. Thrombosis and Haemost 2012 Jul 20

• Conclusions.

▫ In this animal study, PCC showed potential as an agent for reversing the effects of dabigatran.

(69)

Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban

A randomised crossover ex vivo study in healthy volunteers. Marlu et al. Thrombosis and Haemostasis 2012: 108/2 (Aug) pp. 201-403

• Conclusion;

• Some non-specific reversal agents appear to be

able to reverse the anticoagulant activity of

rivaroxaban or dabigatran.

 The effect of PCC on reduced thrombin generation after administration of dabigatran was less pronounced.

 Activated PCC and recombinant factor (F)VIIa had some modest, effect.

▫ However, clinical evaluation is needed regarding haemorrhagic situations, and a meticulous risk-benefit evaluation regarding their use in this context is required.

(70)

Guide to the management of bleeding in patients taking dabigatran.

(71)

• Plasma products and transfusion guidelines

• Prothrombin Concentrate Products

Effectiveness

• National and Provincial PCC guidelines

▫ INR level >1.7

▫ Dosing recommendations

• CDHA utilization of PCC

(72)