new blood products hemorrhagic stroke apr 14 12

New Blood Products and Their Roles in Hemorrhagic Stroke

Doug MorrisonMedical Director of Transfusion Medicine

Fraser Health

New Blood Products in Hemorrhagic Stroke - Outline

Recombinant factor VIIa in ICH

Oral Anticoagulant Associated Intracerebral Hemorrhage

Therapeutic options for reversal of Warfarin

Prothrombin Complex Concentrates

Review of CBS National Distribution Data for PCC

Fraser Health Audit of PCCs

Revised NAC guidelines 2011 (TMAG Perspective)

Possible role for urgent reversal of new oral anticoagulants

rFVIIa : Niastase

Hemophilia with inhibitorscongenitalacquired

Acquired von Willebrand’s disease

Congenital Factor VII deficiency

Congenital platelet dysfunction syndromes

Coagulation pathway

Bleeding -

FVIIa

Original Article

Efficacy and Safety of Recombinant Activated Factor VII for Acute Intracerebral Hemorrhage

Stephan A. Mayer, M.D., Nikolai C. Brun, M.D., Ph.D., Kamilla Begtrup, M.Sc., Joseph Broderick, M.D., Stephen Davis, M.D., Michael N. Diringer, M.D., Brett E. Skolnick,

Ph.D., Thorsten Steiner, M.D., for the FAST Trial Investigators

N Engl J MedVolume 358(20):2127-2137

May 15, 2008

Study Overview

In a previous phase 2 placebo-controlled trial, recombinant activated factor VII (rFVIIa) reduced growth of the hematoma and improved survival and functional outcome in patients with intracerebral hemorrhageThose findings were not reproduced in this phase 3 trial, in which rFVIIa reduced hematoma growth but did not improve clinical outcomes

Kaplan-Meier Survival Curves

Mayer SA et al. N Engl J Med 2008;358:2127-2137

Conclusion

Hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome after intracerebral hemorrhageThe overall frequency of thromboembolicserious adverse events was similar in the three groups; however, arterial events were more frequent in the group receiving 80 μgof rFVIIa than in the placebo group (9% vs. 4%, P=0.04).

The Practical Management of Intracerebral Hemorrhage with Oral Anticoagulatn Therapy -Review

Risk 0.2 % - 0.6 % per year of treatment - VKA70% are intracerebral, 30% subararchnoidOAT-ICH represent 15% of all ICHMany have supratherapeutic INR; however most have a therapeutic INR30 day mortality 12-60% & double that of non-anticoagulated patientsHematoma volume & GCS major determinants

L. Massoti et al; Int. J. of Stroke Vol 6 June 2011: 228- 240

Oral Anticoagulation Therapy Associated Intracerebral Hemorrhage

(OAT-ICH) Hematoma enlargement is a major determinant of the poor prognosis in OAT-ICHOAT-ICH is associated with greater baseline volume of ICH, more hemorrhage expansion & greater mortality than spontaneous ICH Approx 50% of OAT-ICH patients present a secondary volume expansion compared to 17% of non-OAT-ICH patients

L. Massoti et al; Int. J. of Stroke Vol 6 June 2011: 228-240

(OAT-ICH) Urgent Reversal of Coagulopathy

Based on the premise that this will reduce the risk hematoma expansion or re-bleeding and facilitate surgical intervention, if indicated.immediate IV administration of vitamin KFactor replacement– Prothrombin complex concentrates (PCC), or– FFP (15-30 ml/kg)


NIKE Principles in the Reversal of Oral Anticoagulation Therapy Associated Intracerebral Hemorrhage

N – Normalize the INRI – Immediate reversal in all patients, regardless of the size of the hemorrhageK – vitamin K must be included to avoid rebound elevation of the INRE – all levels of INR Elevation require urgent correction


Therapeutic options for reversal of Warfarin

Withhold VKA– Two to three days to reach INR < 1.5

Vitamin K– Oral: slow decrease in INR over 12-24 hr– I.V.: onset in 4-6 hr, INR < 1.5 in 12-16 hr

Factor replacement – 30 IU/kg (70kg)– FFP 2000 ml– PCC 2000 IU (80ml)

Target INR and coagulation factor concentration

Minor bleeding or invasive procedures:– clotting factor levels of 20 – 40% or – an INR of 1.5 – 2.0

Severe injury/bleeding or major surgery: – factor levels of 50 – 60% or – INR of 1.0 – 1.5

% coagulation Factors

PT (sec)

50 %

30 %

100 %

21.81915.51312 3024 32

INR 1 1.7 2.0 2.2 3.01.3

INR and Coagulation Reversal

zone of normal hemostasis

zone of anticoagulation

Dzik WH. Transfusion Therapy: Clinical Principles and Practice, 2nd edition, AABB Press 2005

Frozen Plasma for Immediate reversal of Warfarin

15-30 ml/kg 1050 – 2100 ml (70 kg)Familiar and less expensiveSlow correction due to infusion timeRisks include– Volume overload (TACO)– Allergic reactions– TRALI– Disease transmission

Prothrombin Complex Concentrates (PCCs) for immediate reversal

40 – 120 ml rapidly over 20 – 60 minReconstitution required but no ABO or thawingPredictable effectRisks

• Solvent detergent eliminates risk of enveloped virus• Low risk of thrombosis

PCC – Octaplex® & Beriplex®

Human plasma derived second generationPCCsContain vitamin K dependent factors II, VII, IX, X, Protein C and Protein SUsed in Europe for several years prior to August 2008 introduction of Octaplex® to Canada

PCC Factor levels

One 20mL vial contains:

Component octaplex Beriplex in vivo T1/2

Factor II 220-760 IU 380-800 IU ~60hFactor VII 180-480 IU 200-500 IU ~4hFactor IX 400-620 IU 400-620 IU ~17hFactor X 360-600 IU 500-1020 IU ~31hProtein C 140-620 IU 420-820 IU ~47hProtein S 140-640 IU 240-680 IU ~49hHeparin 80-310 IU 8-40 IU

Sodium citrate 17-27 mM 3 mM

Samama, CM. Prothrombin Complex Concentrates: A Brief Review. Euro J Anaes 2008; 25: 784-789Beriplex Product Monograph, November 2010


Clinical indications for PCCs

Reversal of warfarin therapy or vitamin K deficiency in patients exhibiting major bleeding

Reversal of warfarin therapy or vitamin K deficiency in patients requiring urgent (< 6 hour) surgical procedure.

National Advisory Committee on Blood and Blood products, September 2008

Clinical use of PCCs

Not recommended for:– Elective surgery reversal of oral anticoagulation– Treatment of elevated INRs without bleeding or need

for surgical intervention– Massive transfusion– Coagulopathy associated with liver dysfunction– Patients with recent history of thrombosis, myocardial

infarction, ischemic stroke, or Disseminated Intravascular Coagulation (DIC)

National Advisory Committee on Blood and Blood products, September 2008

Clinical use of PCCs

Contraindicated:– Patients with a history of heparin induced

thromobocytopenia (HIT)

Insufficient evidence for use in pregnant women or pediatric patients.

Octaplex®

monograph dosing recommendations to normalize the INR (< 1.2) within 1 hr

INR 2.0 – 2.5 2.5 – 3.0 3.0 – 3.5 > 3.5ml/kg 0.9 – 1.3 1.3 – 1.6 1.6 – 1.9 > 1.9IU/kg 22.5 – 32.5 32.5 – 40.0 40.0 – 47.5 > 47.570 kg patient 1500 – 2000 2000 – 3000 3000 – 4000 >4000

NAC recommendations are lower, due to the fact the package insert recommendations will correct factor levels to normal despite the fact that normal hemostasis does not require 100% factor levels.

“Activated PCC” - FEIBAActivated PCCs are different productscharacterized by the presence of activated factors (especially VIIa) and used in treatment of patients with coagulation factor inhibitors.FEIBA is licensed and in use in CanadaMore thrombogenic than second generation PCCs – in the 1970’s post operative thrombotic complications occurred in 46% of Hemophilia B patients receiving perioperative PCC

PCC Production

All PCCs undergo at least 1 pathogen reduction step:NanofiltrationSolvent-detergent treatmentPasteurization

However, theoretical concerns exist regarding:Non-lipid enveloped viruses (hepatitis A, parvovirus B19)Prions (vCJD)?Emerging pathogens?

Samama, CM. Prothrombin Complex Concentrates: A Brief Review. Euro J Anaes 2008; 25: 784-789 Samama, CM. Prothrombin Complex Concentrates: A Brief Review. Euro J Anaes 2008; 25: 784-789

PCCs: Concerns

ThrombogenicityEspecially with high risk patients, repeated dosingAttempt to minimize by inclusion of proteins C & S, heparin, +/- antithrombinMeta-analysis of PCC use for rapid VKA reversal found thrombotic incidence was 1.8% (95% CI = 1.0-3.0%) for 4-factor PCCs (0.7% for 3-factor PCCs)1

Exacerbation of coagulopathy/DIC (esp. in liver disease)Heparin induced thrombocytopeniaAllergic/anaphylactic reactionsPathogen transmission

1. Dentali F et al. Thromb Haemostasis. 2011; 106(3): 429-438. 1. Dentali F et al. Thromb Haemostasis. 2011; 106(3): 429-438.

PCCs in CanadaMay 2007: Health Canada approves Octaplex® for rapid reversal of warfarin or VKD in patients exhibiting major bleeding or requiring urgent (<6hrs) surgery

July 2008: CBS begins distributing Octaplex®

Sept 2008: NAC Recommendations for the Use of Octaplex®

Nov 2010: Health Canada approves Beriplex® P/N

July 2011: Updated NAC Recommendations for the Use of PCCs

Aug 2011: CBS begins distributing Beriplex® P/N

National Advisory Committee on Blood and Blood Products

NAC provides professional leadership and advice in matters directly affecting the practice of transfusion medicine in hospitals, includingutilization of blood & blood productsNAC reports to the provincial and territorial (PT) Ministries of Health and Canadian Blood Services (CBS) via the PT/CBS Blood Liaison Committee Two representatives are appointed by each P/T MoH + four CBS representatives.

Adult dose: 40mL (2 vials = 1000 IU FIX activity) and10mg vit K IV

Higher dose may be necessary for extremes of weight or INRMaximum total dose: 120mL (6 vials = 3000 IU FIX activity)Administered IV at rate not exceeding 2-3mL/min (2-3 vials/hr)

Post-dose monitoring: INR @ 10-15min, clinical outcomes day 1 & 30

http://transfusionontario.org/media/docs/octaplex%20recommendations%20final%20Sept%2016%202008.pdfhttp://transfusionontario.org/media/docs/octaplex%20recommendations%20final%20Sept%2016%202008.pdf

NAC 2008 PCC Recomendations

Fraser Health PCC audit

PCC orders screened by on-call hematopathologistGenerally following NAC recommendations with individualization of the dosage– Patients weight & INR– Nature of the bleeding & degree of urgency– Recommend PT (INR) 15 min after infusion & repeat if

necessary– Emphasis on IV vitamin K

Feb-Dec 2010 Cases by Site

11

3

10

35

8

26

3

8

0

5

10

15

20

25

30

ARH BH CGH ERH LMH PAH RCH RMH SMH

# of

Cas

es

2010 FHA Octaplex Audit Feb – Dec 2010 (11 months – 71 cases)


Indications for the Use of Octaplex in FHA% of 71 cases Feb - Dec 2010

40.8%

35.2%

15.5%

11.3%

12.7% 1.4%

Pre-procedural

ICH

GIB

Trauma

Medical/SurgicalHemorrhageEpistaxis


Distribution of Octaplex DosesFeb-Dec 2010

0

5

10

15

20

25

500 1000 1500 2000 2500 3000+

Dose of Octaplex Given

Nu

mb

er

of

Pati

en

ts


Weight-based Dosing of OctaplexFeb-Dec 2010

0

5

10

15

20

25

30

35

0 to 10 10 to 20 20 to 30 30 to 40 >40

Dose given (units per kg)

Nu

mb

er

of

Pati

en

ts


Mean Dose of Octaplex Over Time

875

1286

1500 1500 14541544

1385

1769

0

400

800

1200

1600

2000

BeforeFeb 09

Feb-Apr09

May-July 09

Aug-Oct 09

Nov-Feb 09

Feb-June 10

July-Sept 10

Oct-Dec 10

INR Results post infusion 2010 FHA Octaplex Audit

Feb – Dec 2010 (11 months – 71 cases)

Patients < 1.5 1.5-1.7 1.8-2.0 >2.0

< 1 hr%

38 2463%

987%

4 1

1-4 hr 26 1973%

385%

3 1

Total< 4 hr

64 4367%

1286%

7 1


Clinical Effect of Octaplex in 46 Bleeding Patients Feb-Dec 2010

0%

10%

20%

30%

40%

50%

60%

Stop Decrease Same Increase Can't tell


Outcome in 35 Surgical Patients After Octaplex Feb-Dec 2010

97.2%

2.8%0%

20%

40%

60%80%

100%

120%

No excessive bleeding Excessive bleeding


Thrombotic events & Deaths71 patients Feb-Dec 2010

0

5

10

15

20

MI Stroke DVT/PE Death

Thromboembolic Events 2010 FHA Octaplex Audit


Ischemic Stroke (4 patients)– 3 deceased (FH-81, 104, 109)– 1 survived (FH-139)

Venous thrombosis (2 patients)– 1 died from cardiogenic shock with evidence of

thrombosis of tricuspid valve (FH-127) – 1 survived pulmonary embolus (FH-76)

Myocardial Infarction – Deceased patient FH-81 above

Deaths 2010 FHA Octaplex Audit


Associated with thromboembolic event (4)– Ischemic stroke (FH-104 & 109)– Ischemic stroke & MI (FH-81)– Thrombosis of tricuspid (FH-127)

Not associated with thromboembolism and thought secondary to presenting illness (12)

Octaplex® and Beriplex® to be used interchangeably

Special patient populations: insufficient evidence to recommend use in patients on direct thrombin or FXa inhibitors (dabigatran, rivaroxaban)

Major change = dosing recommendations:INR < 3.0 → 40mL (2 vials = 1000 IU)INR 3.0-5.0 → 80mL (4 vials = 2000 IU)INR >5.0 → 120mL (6 vials = 3000 IU)

Stressed preference for IV vitamin K over PO (never IM/SC)

Highlighted the lack of strong RCT evidence of clinical efficacy in this area warrants continued data collection

http://www.nacblood.ca/resources/guidelines/nac-pcc-recommendations-june-2011-final.pdfhttp://www.nacblood.ca/resources/guidelines/nac-pcc-recommendations-june-2011-final.pdf

NAC 2011 Recommendations

BC TMAG’s view of revised 2011 NAC guidelines

Endorse the NAC recommendations “for the treatment of critical bleeding”– INR < 3.0 →

40mL (2 vials = 1000 IU)

– INR 3.0-5.0 →

80mL (4 vials = 2000 IU)– INR >5.0 →

120mL (6 vials = 3000 IU)

However, in the absence of critical bleeding, dosing should reflect the patient’s weight, INR and urgency of the situation with titration of the dose whenever possible.

Novel Oral Anticoagulants

Reversible, direct inhibitors of common pathway coagulation factors:– Thrombin (FIIa) = dabigatran (Pradax®)– FXa = rivaroxaban (Xarelto®), apixaban

2008: dabigatran and rivaroxaban licensed by Health Canada for post-hip and knee replacement thromboprophylaxis

Oct 2010: dabigatran approved by Health Canada for stroke prevention in patients with atrial fibrillation

All 3 agents have completed or are nearing completion of trials in atrialfibrillation, acute VTE treatment, and secondary VTE prevention

Novel Oral AnticoagulantsUnlike warfarin, these agents have a broad therapeutic index

Routine laboratory monitoring is not required

Both agents undergo mainly renal excretion with a T1/2 of approx 12 hrs– Dabigatran (35% protein bound) is amenable to dialysis, but not

rivaroxaban– Can give activated charcoal for acute (<2hrs) overdose of either drug

But, if a patient anticoagulated with these drugs presents with life threatening bleeding (i.e. ICH) or requires emergency surgery...– How do we assess their degree of anticoagulation?– Can we urgently reverse the anticoagulant effects of these drugs?

Dabigatran

Why Dabigatran in Atrial Fibrillation?

standard doseno monitoringno drug interactionsimproved outcomes– Thromboembolism:150 mg bid RR 0.66 (0.52 –

0.82) vs warfarindecreased bleeding complications

Dabigatran Bleeding Risk

End Point Warfarin (%)

Dabigatran 110mg (%)


Major Bleeding 3.36 2.71 3.11

Dabigatran Bleeding RiskEnd Point Warfarin

(%)Dabigatran 110mg(%)


Intracranial BleedingAge >75 yrs 0.61 0.14 0.26Age >75 yrs 1.0 0.37 0.41**

**p = 0.28

? Underestimation of real life bleeding risk, due to comorbidities & use in renal insufficiency and the need for lower dosing in elderly patients

Laboratory tests for Novel Anticoagulants

There is currently no single laboratory test routinely available that provides specific evaluation of the anticoagulation effect of Dabigatran or other novel anticoagulants.Dabigatran excretion is prolonged in patients with abnormal renal function. Creatinine/GFR measurement is essential in bleeding patients.


A normal INR and PTT should exclude the presence of significant levels of Dabigatran or other novel anticoagulants in most, but not all, patients.The most sensitive test for the presence of Dabigatran is the Thrombin Time – a normal result excludes the presence of this drug, but not the other new oral anticoagulants.


There are currently no locally available tests that accurately quantifies Dabigatran anticoagulant activity or that of the other novel anticoagulants.

The most sensitive test for the presence of Direct Factor Xa inhibitors is the PT/INR.

No Antidote for Dabigatran

PCC (Octaplex/Beriplex) and recombinant Factor VIIa (rFVIIa) have not been evaluated in clinical settings, and have NOT been demonstrated to improve coagulation assays in experimental and volunteer studies. These agents have been shown to decrease bleeding in a rat tail vein model despite absence of reversal of coagulation parameters.

rfVIIa

Animal & in vitro Data

Rivaroxaban– Rat tail model: bleeding time prolongation due to rivaroxaban

corrected with 50 IU/kg Beriplex® (7 vial dose for 70kg adult) but not with 25 IU/kg dose1

Dabigatran– Rabbit kidney injury model: Beriplex® corrected bleeding time

and amount of blood loss in dose-dependent fashion2

– Rat tail model: bleeding time prolongation due to dabigatran corrected with 50 and 100U/kg Feiba and 100ug/kg rFVIIa; PTT elevation partially corrected with rFVIIa but not with Feiba3

– Human plasma: Feiba corrected dabigatran-inhibited ETP4

1. Pezborn E, et al. 21st International Congress on Thrombosis [abstract]. Pathophysiol Haemost Thromb. 2010;37:A10-OC2512. van Ryn J, et al. 21st International Congress on Thrombosis [abstract]. Pathophysiol Haemost Thromb. 2010;37: A94 –P486

3. van Ryn J, et al. 13th Congress of the European Hematology Association [abstract]. Haematologica. 2008;93:148 – 03704. Van Ryn J, et al. Thromb Haemost 2010; 103: 1116–1127

1. Pezborn E, et al. 21st International Congress on Thrombosis [abstract]. Pathophysiol Haemost Thromb. 2010;37:A10-OC2512. van Ryn J, et al. 21st International Congress on Thrombosis [abstract]. Pathophysiol Haemost Thromb. 2010;37: A94 –P486

3. van Ryn J, et al. 13th Congress of the European Hematology Association [abstract]. Haematologica. 2008;93:148 – 03704. Van Ryn J, et al. Thromb Haemost 2010; 103: 1116–1127

PCC = 50 IU/kg Cofact® (3500 IU = 7 vials for 70kg adult)

CIRCULATIONAHA.111.029017. Published online before print September 6, 2011CIRCULATIONAHA.111.029017. Published online before print September 6, 2011

Study Methods (cont.)12 healthy male paid volunteers

PPP samples taken pre-drug, pre-reversal agent, and post-reversal agent at 15 min, 30 min, 1 hr, 2 hrs, 4hrs, 6hrs, 24 hrs

Lab measurements used:– Rivaroxaban: PT, endogenous thrombin potential (ETP)– Dabigatran: aPTT, TT, ecarin clotting time (ECT)


Rivaroxaban Results

High-dose PCC completely overcame rivaroxaban inhibition of FXain the PT and ETP laboratory assay systems


Dabigatran Results

High-dose PCC had no detectable effect on dabigatran inhibition of thrombin in the PT and ETP laboratory assay systems

Problem: these assays are merely surrogates for clinical bleeding tendency


Management of Bleeding Novel Anticoagulants

oral charcoal if ingestion within 2 hoursmechanical compression if possible and surgical intervention where indicatedcrystalloid replacement and hemodynamic support, ensure maintenance of urine output (aggressive diuresis)


blood product transfusion as indicatedfor anemia, thrombocytopenia or coagulopathy unrelated to dabigatranhemodialysis, particularly in the setting of overdose or renal impairmentConsult Hematology


the use of FFP, PCC, activated PCC or rFVIIa on a routine basis cannot be recommended as part of an effective reversal protocol based on the current medical literatureNonetheless, there are case reports that describe the use of FEIBA, rFVIIa or PCCs (Octaplex or Beriplex) and these agents are being used off-label to treat ICH in many Canadian hospitals, without any published evidence of efficacy.


There is slightly more evidence of efficacy in humans of the use of PCC when dealing with bleeding associated with Rivaroxaban, possibly by overwhelming the inhibitor with Factor XAnecdotal reports suggest that FEIBA may be more effective than Octaplex or Beriplex in the context of Dabigatran

Factor VIIa for Dabigitran

In a controlled trial on healthy subjects the Melagatran-induced effects on PTT, TGP & platelet aggregation were not affectedBased on these results it appears that VIIa is not effective in reversing DTIFAST study in non-anticoagulated ICH

…So What To Recommend?Supportive therapy, diuresis +/- dialysisConsider antifibrinolytic therapy Tranexamic acid

(10 mg/kg IV or 25 mg/kg orally, rounded to the nearest 500 mg.)

For acute life threatening bleeds or urgent (<6hrs) surgery:– Clinician to discuss case with on-call hematopathologist for

possible administration of “reversal agent”– Current recommendation of VGH hematology / hematopathology

groups is 3000 IU PCC IV infusion (6 vials = 120 mL)– Outcomes (bleeding, thrombosis, death) should be monitored

Rationale:– Attempt to overcome inhibition by increasing IIa and Xa

generation– Avoid higher thrombosis risk of rFVIIa and FEIBA

ConclusionsFactor VIIa not recommended for treatment of ICHFor urgent warfarin reversal, NAC 2011 recommendations advocate PCC dosage according to INR:– INR < 3.0 →

40mL (2 vials = 1000 IU)

– INR 3.0-5.0 →

80mL (4 vials = 2000 IU)– INR >5.0 →

120mL (6 vials = 3000 IU)

Very little evidence to guide situations that warrant immediate reversal of new anticoagulants– Current VGH recommendation = 3000 IU PCC– This is likely to change as the literature evolves!

The End

Beriplex® vs Octaplex®

Similar content of vitamin K dependent factors including protein C & SPlus anti-thrombin III (0.6 IU/ml) & albuminProtein Z (36 IU/ml - ?proteolysis of Xa)Less heparin (0.5 IU/ml vs 6.0 IU/ml)Pasteurization vs S/D (both nano-filtered)

PCC Factor levels

One 20mL vial contains:

Component octaplex Beriplex in vivo T1/2

Factor II 220-760 IU 380-800 IU ~60hFactor VII 180-480 IU 200-500 IU ~4hFactor IX 400-620 IU 400-620 IU ~17hFactor X 360-600 IU 500-1020 IU ~31hProtein C 140-620 IU 420-820 IU ~47hProtein S 140-640 IU 240-680 IU ~49hHeparin 80-310 IU 8-40 IU

Sodium citrate 17-27 mM 3 mM



REVNEWANTICO…

Study in Healthy Volunteers of the Reversion by Haemostatic Drugs of the Anticoagulant Effect of New Anti-thrombotics (REVNEWANTICO)– 10 healthy male volunteers, open-label, no control arm– Each given single dose of 20mg dabigatran or 150 mg rivaroxaban– Reversal agents:

• Dabigatran = PCC, rFVIIa, Feiba• Rivaroxaban = rivaroxaban decoy (FXa-GLAless)

– Primary outcome = thrombin generation time normalization– Secondary outcomes:

• Dabigatran = normalization of TT and aPTT• Rivaroxaban = normalization of PT and anti-Xa activity

– Completion date: June 2011

http://clinicaltrials.gov/ct2/show/NCT01210755http://clinicaltrials.gov/ct2/show/NCT01210755

new blood products hemorrhagic stroke apr 14 12

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