New Anticoagulants for Atrial Fibrillation

W. Frank Peacock, MD, FACEP Professor, Emergency Medicine Cleveland Clinic

Anybody on an anticoagulant??

2

Warfarin Use: Scope of the Problem

•

~2 million Americans take warfarin daily

1 •

Conditions associated with its use:

 

AF: 2.5 million Americans

2,3

DVT: 48/100,000 of USA

4   

PE: 69/100,000 of USA

4

Prosthetic heart valves

5

Post AMI to reduce recurrence risk

5 1. Conley M. ABC News. October 23, 2010. Ansell J, et al. Chest. 2008;133:160S-198S.

http://abcnews.go.com

; 2. Fuster V, et al. Circulation. 2006;114: e257-e354; 3. Kneeland PP, et al. Patient Prefer Adherence. 2010;4:51-60; 4. Silverstein MD, et al. Arch Intern Med. 1998;158:585-593; 5.

Anybody got AF?

4

AF Treatment and Impact on ICH

• 2.5 million Americans have AF 1,2 • Among users of warfarin for AF, annual risk of AAICH is 0.3%-1.0% 3 • Similar risk for newer anticoagulants dabigatran and rivaroxaban among users with AF (0.23%-0.50%) 4,5 1. Fuster V, et al. Circulation. 2006;114:e257-e354; 2. Kneeland PP, et al. Patient Prefer Adherence. 2010;4:51-60; 3. Flaherty ML. Semin Neurol. 2010;30:565-572; 4. Connolly SJ, et al; RE-LY Steering Committee and Investigators. N Engl J Med. 2009;361:1139-1151; 5. Patel MR, et al; ROCKET AF Investigators. N Engl J Med. 2011;365:883-891.

5

Anybody every had a head bleed

• UCSD mother ’ s day biomarker conference 6

Incidence of Warfarin-Associated ICH

• Relatively common at large medical centers • Hospital study 1  24% of those with ICH were on warfarin • Population-based survey: 18% of all ICHs associated with anticoagulation 1 8K-10K cases of AAICH occur annually in United States 1 • Incidence appears to be increasing 2,3 • Serial INRs may be poor predictors of ICH and major bleeding 4 1. Aguilar MI, et al. Mayo Clin Proc. 2007;82(1):82-92;2. Lee K, et al. Haemophilia. 2010;16:949-951; 3. Kucher N, et al. Am J Cardiol. 2004;94:403-406; 4. Kucher N, et al. Arch Intern Med. 2004;164: 2176-2179 .

The Impact of Warfarin on ICH

• Warfarin increases the risk of ICH 2- to 5-fold and nearly doubles the mortality associated with ICH 1,2 • 50% of patients with warfarin-associated ICH die within 30 days 1  OR 4.6; 95% CI, 1.0 to 21.8 for 3-month mortality 2 Image courtesy of the Mayfield Clinic. http://www.mayfieldclinic.com/PE-ICH.htm.

1. Aguilar MI, et al. Mayo Clin Proc. 2007;82(1):82-92; 2. Flibotte JJ, et al. Neurology. 2004;63(6):1059-1064.

8

Other Major Bleeding Issues Associated With Anticoagulation

• Gastrointestinal (GI) bleeds are one of the most common and feared complications of oral anticoagulation 1 • INR ≥1.5 associated with greater mortality 1 • Correction of INR to <1.8 reduces mortality 1 • Most patients with severe acute GI bleeding have underlying mucosal disease   Endoscopy is mandatory Most common cause is peptic ulcer 1. Radaelli F, et al. Dig Liver Dis. 2010 Dec 16 [Epub ahead of print]; 2. Choudari CP, et al. Gut. 1994;35:464-466.

9

Warfarin-Associated ICH and Major Hemorrhage

• Annual risk of a major bleeding rate is 3.36% • Annual hemorrhagic stroke rate is 0.38% • ED visits for hemorrhage-related events from anticoagulants and antiplatelet agents 2   60,575 ED visits per year for warfarin 7,654 ED visits per year for antiplatelet agents • Most events occur at an INR between 2.0 and 3.5 (ie, within the conventional therapeutic range) 3 1. Connolly SJ ,et al. N Engl J Med. 2009;361(12):1139-1151; 2. Shehab N, et al. Arch Intern Med. 2010;170(12):1926-1933; 3. Aguilar MI, et al. Mayo Clin Proc. 2007;82(1):82-92.

10

What is the most hated thing about warfarin??

• (Frank ’ s unscientific survey) 11

Risk Factors for AAICH or Bleeding Events

• Factors increasing the risk of ICH or major bleeding in those receiving warfarin   Use of other medication 1,2 Diet 3    Age 2,4 Genetic factors 2 Comorbidities 2 o Renal or hepatic insufficiency may increase risk of bleeding 1. Narum S, et al. Br J Clin Pharmacol. 2011;71(2):254-262; 2. Levi MM, et al. Neth J Med. 2010;68(2):68-76; 3. Ansell J, et al. Chest. 2008;133:160S-198S; 4. Shehab N, et al. Arch Intern Med. 2010;170(12):1926-1933.

The Pathology of Coagulopathy

13

Warfarin: Mechanism of Action

Vitamin K Warfarin Vitamin K Utilization Impaired CYP450 VII IX X II Synthesis of Dysfunctional Coagulation Factors Slight genetic variation can produce significant differences in dose-response

14

Warfarin: Mechanism of Action (cont)

Decarboxylated zymogen Carboxylated zymogen

Vitamin KH 2

Vitamin K reductase

Vitamin K Vitamin K epoxide

X Vitamin K epoxide reductase

15

The Clinical Applicability of Coagulation Tests

16

Polling Question

Which of the following assays would be considered standard practice for you to order in the case of an AF patient on dabigatran therapy who presents to the ED with symptoms suggestive of ICH?

a) b) c) d) e) Platelet count PT/INR PTT TT Ecarin clotting time (ECT) 17

Ecarin Clotting Time

•

A known quantity of ecarin is added to the plasma of a patient treated with a DTI

•

Ecarin activates prothrombin through a specific proteolytic cleavage, which produces meizothrombin

–

(a prothrombin-thrombin intermediate with a low level of procoagulant enzymatic activity).

•

Crucially, this activity is inhibited by DTI, but not heparin or coumadin or the presence of phospholipid-dependent anticoagulants (e.g., lupus anticoagulant)

•

Thus, the ECT is prolonged in a specific and linear fashion with increasing concentrations of DTI

18

How many have ever ordered an Ecarin Clotting Time?

19

Available Coagulation Assays

• Rapidly available blood tests include  Platelet count  Prothrombin time (PT)  Partial thromboplastin time (PTT)  INR Yuan S, et al. Thromb Res. 2007;120:29-37.

20

Introduction of Novel Anticoagulants Affects Assays

• Dabigatran   • Rivaroxaban  Inhibits both free and fibrin-bound forms of thrombin plus thrombin-induced platelet aggregation Oral, direct factor Xa inhibitor  Oral, direct thrombin inhibitor Inhibits prothrombinase complex-bound and clot associated factor Xa • Global coagulation assays do not necessarily react in same way for newer versus established anticoagulants • No standardized tests for the newer agents Perzborn E, et al. Arterioscler Thromb Vasc Biol. 2010;30:376-381; Samama MM, et al. Clin Chem Lab Med. 2011;49:761-772.

21

Sites of Action of New Anticoagulant Agents

“ X ” = 10a Inhibitor Coumadin Inhibs 2,7,9,10 measure a aPT “ D ” = DTI, aPTT test Figure 1: Site of action of new anticoagulant drugs. From Brighton T. Experimental and clinical pharmacology: new oral anticoagulant drugs – mechanisms of action. Aust Prescr. 2010;33:38-41. Reprinted with permission from Australian Prescriber. 22

Introduction of Novel Anticoagulants Affects Assays

Dabigatran may require

1

• Thrombin clotting time (TT) • Ecarin clotting time (ECT) •

aPTT can provide qualitative assessment, but is less sensitive at supratherapeutic levels of dabigatran

• Data are limited for ACT • PT is less sensitive and of very limited value

Rivaroxaban may require

2

• Chromogenic assays • One-step prothrombinase-induced clotting time test • HepTest with reduced incubation time •

PT less sensitive at low

concentrations; aPTT less sensitive than PT 23 1. van Ryn J, et al. Thromb Haemost. 2010;103:1116-1127; 2. Samama MM, et al. Clin Chem Lab Med. 2011;49:761-772.

Introduction of Newer Anticoagulants

1-4 Advantages of Newer Anticoagulants

• • No need for regular monitoring Predictable pharmacokinetic and pharmacodynamic • parameters Less need for dose • adjustment Bleeding risk may be lower with some of these new agents • • •

Disadvantages of Newer Anticoagulants

Data on toxicities, bleeding risk, and rebound hypercoagulability are unknown Pharmacoeconomic considerations may limit use in many patients If immediate reversal of anticoagulant effect is necessary, no antidotes have been established 1. Levi MM, et al. Neth J Med. 2010;68(2):68-76; 2. Levy JH, et al. Anesthesiology. 2010;113:726-745; 3. Crowther MA, et al. Blood. 2008;111:4871-4879; 4. Lee K, et al. Haemophilia. 2010;16:949-951.

24

The RE-LY Study: Randomized Evaluation of Long term anticoagulant therapY

Dabigatran Compared to Warfarin in 18,113 Patients with Atrial Fibrillation at Risk of Stroke

Dabigatran

 Dabigatran Etexilate, a pro-drug, is rapidly converted to dabigatran  6.5% bioavailability, 80% excreted by kidney  Half-life of 12-17 hours  Phase 2 data identified 220 mg daily and 150 mg BID as viable doses

RELY Dabigatran for stroke prevention in atrial fibrillation Non-valvular atrial fibrillation at moderate to high risk of stroke or systemic embolism (at least one high risk factor) R Warfarin 1 mg, 3mg, 5 mg (INR 2.0-3.0) N=6000 Dabigatran Etexilate 110 mg b.i.d.

N=6000 Dabigatran Etexilate 150 mg b.i.d.

N=6000

•

Primary objective: Noninferiority to warfarin

•

Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up.

•

Primary end point: Stroke + systemic embolism

Dabigatran: RE-LY Trial

• Dabigatran 110 mg or 150 mg bid vs warfarin to an INR of 2.0-3.0

• 18,113 AF patients randomized • Median follow-up of 2 years • Benefits of – 150 mg dabigatran for stroke reduction – – 110 mg dabigatran for bleeding reduction both doses for ICH reduction over warfarin RE-LY=Randomised Evaluation of Long-term Anticoagulant Therapy.

Wallentin L, et al. Lancet. 2010;376:975-983.

28

RE-LY: Time to Major Bleeding vs Time in Therapeutic Range

Posted with permission from Wallentin L, et al. Lancet. 2010;376:975-983.

29

Stroke Classification

D 110mg D 150mg warfarin D 110 mg vs. Warfarin D 150 mg vs. Warfarin Number rate/yr Number rate/yr Number rate/yr RR 95% CI p RR 95% CI p Ischemic/ Unspecified 159 1.3 %/yr 111 0.9 %/yr 142 1.2 %/yr 1.11

0.89-1.40

0.35

0.76

0.60-0.98

0.03

Hemorrhagic 14 0.1 %/yr 12 0.1 %/yr 45 0.4 %/yr 0.31

0.17-0.56

<0.001

0.26

0.14-0.49

<0.001

7500 extra ICH per year if all use coumadin

Summary

 Dabigatran  150 mg reduced stoke vs warfarin with similar risk of major bleeding  110 mg had a similar rate of stroke as warfarin with reduced major bleeding  Both doses markedly reduced ICH and life threatening hemorrhage  Both doses are free of liver and other major toxicity, although they increase dyspepsia and GI bleeding

Background

Rivaroxaban  Direct, specific, competitive factor Xa inhibitor  Half-life 5-13 hours  Clearance :   1/3 direct renal excretion 2/3 metabolism via CYP 450 enzymes  Oral, once daily dosing without need for coagulation monitoring  Studied in >25,000 patients in post-op, DVT, PE and ACS patients

X TF/VIIa IX VIIIa IXa Rivaroxaban Va Xa II IIa Fibrinogen Fibrin

Adapted from Weitz

et al

, 2005; 2008

ROCKET Study Design

Atrial Fibrillation Risk Factors

• • • • •

CHF Hypertension Age



75 Diabetes OR At least 2 or 3 required* Stroke, TIA or Systemic embolus Rivaroxaban 20 mg daily 15 mg for Cr Cl 30-49 ml/min

Randomize Double Blind / Double Dummy (n ~ 14,000)

Warfarin INR target - 2.5

(2.0-3.0 inclusive) Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-CNS Systemic Embolism

* Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

Primary Efficacy Outcome

Stroke and non-CNS Embolism 6 5 Event Rate Rivaroxaban 1.71

Warfarin 2.16

Warfarin

4 3

Rivaroxaban

2

HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001

1 0 0 120 240 360 480 600 720 840 960

Days from Randomization

No. at risk: Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634 Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655 Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population

Primary Efficacy Outcome

Stroke and non-CNS Embolism

On Treatment

N= 14,143

ITT

N= 14,171 Rivaroxaban Warfarin Event Rate Event Rate 1.70

2.15

HR (95% CI) 0.79 (0.65,0.95) P-value 0.015

2.12

2.42

0.88 (0.74,1.03) 0.117

Rivaroxaban better Warfarin better Event Rates are per 100 patient-years Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations

Summary



Efficacy

:  Rivaroxaban: non-inferior to warfarin for prevention of stroke and non-CNS embolism.

 Rivaroxaban was superior to warfarin while patients were taking study drug.

 By intention-to-treat, rivaroxaban was non-inferior to warfarin but did not achieve superiority.



Safety

:   Similar rates of bleeding and adverse events.

Less ICH and fatal bleeding with rivaroxaban.



Conclusion

:  Rivaroxaban is a proven alternative to warfarin for moderate or high risk patients with AF.

Apixaban versus Warfarin in Patients with Atrial Fibrillation

Results of the ARISTOTLE Trial • • • • Novel oral factor Xa Inhibitor Rapid absorption Half life 12 hours 25% renal elimination

Atrial Fibrillation with at Least One Additional Risk Factor for Stroke

Inclusion risk factors  Age ≥ 75 years  Prior stroke, TIA, or SE  HF or LVEF ≤ 40%  Diabetes mellitus  Hypertension

Randomize

double blind, double dummy (n = 18,201)

Major exclusion criteria  Mechanical prosthetic valve  Severe renal insufficiency  Need for aspirin plus thienopyridine

Apixaban 5 mg oral twice daily (2.5 mg BID in selected patients) Warfarin (target INR 2-3)

Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device

Primary outcome: stroke or systemic embolism

Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death

Primary Outcome

Stroke (ischemic or hemorrhagic) or systemic embolism

P (non-inferiority)<0.001

21% RRR

Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year

HR 0.79 (95% CI, 0.66

–0.95); P (superiority)=0.011

No. at Risk Apixaban Warfarin 9120 9081 8726 8620 8440 8301 6051 5972 3464 3405 1754 1768

Major Bleeding

ISTH definition

31% RRR

Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year

HR 0.69 (95% CI, 0.60

–0.80); P<0.001

No. at Risk Apixaban Warfarin 9088 9052 8103 7910 7564 7335 5365 5196 3048 2956 1515 1491

Compared with warfarin, apixaban (over 1.8 years) prevented • 6 Strokes • 15 Major bleeds • 8 Deaths 4 hemorrhagic 2 ischemic/uncertain type per 1000 patients treated.

Summary

Treatment with apixaban as compared to warfarin in patients with AF and at least one additional risk factor for stroke: • Reduces stroke and systemic embolism by 21% (p=0.01) • Reduces major bleeding by 31% (p<0.001) • Reduces mortality by 11% (p=0.047) with consistent effects across all major subgroups and with fewer study drug discontinuations on apixaban than on warfarin, consistent with good tolerability.

Management of Coagulopathy

43

Treatment Approaches

• Fresh frozen plasma (FFP) • Prothrombin complex concentrates (PCC) • Vitamin K (phytonadione) • Recombinant factor VIIa Image courtesy of http://www.rothomed.com/blood-products.html.

44

8th ACCP Guideline

for Management of Nontherapeutic INRs INR Bleeding Action

 5.0  9.0

Standard Risk Recommend omitting 1-2 doses warfarin (1C) High Risk Suggest omitting 1 dose warfarin and giving 1.0-2.5 mg oral vitamin K (2A)  9.0

No bleeding Recommend holding warfarin and giving 2.5-5.0 mg oral vitamin K (1B) Any Major bleeding Recommend holding warfarin and giving 10 mg IV vitamin K supplemented with FFP or PCC or rFVIIa (all 1C) 45 Adapted from Ansell J, et al. Chest. 2008;133:160S-198S.

Published Guidelines for Reversal of Warfarin Anticoagulation in Patients With ICH

Society (Year) Australian (2004) British Standards (2005) EU Stroke (2006) ACCP (2008) AHA (2010) French (2010) Vitamin K IV (5-10 mg) IV (5-10 mg) IV (5-10 mg) IV (10 mg) IV (NS) Oral or IV (10 mg) Plasma (mL/kg) Yes (NS) Yes (15) Yes (10-40) Yes (NS) Yes (10-15) Yes (NS)‡ AND OR OR OR OR OR PCC (U/kg) Yes (NS)* Preferred (50) Yes (10-50) Preferred (NS) Yes (NS) Preferred (25-50) rFVIIa NS NS NS Yes† No No

*If a 3-factor PCC is administered, FFP is also recommended as a source of FVII †Use of PCCs or rFVIIa may vary depending on availability ‡Use of plasma only when PCCs not available Goodnough LT, et al. Blood. 2011;117:6091-6099.

46

Fresh Frozen Plasma

• •

Advantages of FFP

factors required for hemostasis, as well as fibrinogen and other plasma proteins 3

1

Widely available and is USA standard of care • Allows partial reversal of coagulopathy Contains all coagulation

Disadvantages of FFP 1

• • • • • Need compatibility testing Need time to thaw Hard to give large vol. rapidly Intravascular vol. challenges Complications: e.g., TRALI or • blood-borne infection 2 TRALI: a leading cause of • transfusion-related mortality 2 If very high INRs/profound decreases in vitamin K-dep factors, replacement can ’ t be achieved with tolerable FFP doses 47 1. Lee K, et al. Haemophilia. 2010;16:949-951; 2. Vlaar AP, et al. Neth J Med. 2009;67(10):320-326. 3 . Godier A, et al.

J Thromb Haemost

. 2010;8:2592-2595;

Fresh Frozen Plasma (cont) Factor Fibrinogen (g/L) F II (%) F V (%) F VII (%) F VIII (%) F IX (%) F X (%)

Chowdhury P, et al. Br J Haematol 2004;125:69-73.

FFP 10 mL/kg 0.4

16 10 11 10 8 16 FFP 30 mL/kg 1.0

41 69 85 17 28 37

48

Hemorrhagic Stroke and FFP Administration Was INR reversed in 24 hours?

Characteristic Door to CT time CT to FFP time Dose of FFP CT to vit. K Any vit. K given Dose of vit. K IV route SC/IM route Time in ED after CT No (n=12) Median (IQR) 65 (30 to 90) min 210 (100 to 375) min 2 (1 to 5) units 245 (37 to 361) min 58% 7.5 (0 to 10) mg 0% 100% 242 (200 to 412) min Yes (n=57) Median(IQR) 40 (25 to 85) min 90 (60 to 205) min 4 (2 to 6) units 87 (25 to 210) min 81% 10 (5 to 10) mg 30% 70% 227 (185 to 340) min

49

P

Value 0.5

0.02

0.1

0.2

0.1

0.5

0.2

0.2

0.3

Goldstein JN, et al. Stroke 2006;37;151-155.

Warfarin Reversal: Vitamin K

Hours

From Lubetsky A, et al. Arch Intern Med. 2003;163:2469-2473.

1. DeZee KJ, et al. Arch Intern Med. 2006;166:391-397; 2. Lubetsky A, et al. Arch Intern Med. 2003;163:2469-2473. • • • •

Reversal agent Liver can synthesize vitamin K-dependent proteins Risks: anaphylaxis 1 Efficacy:



Effect as early as 4 hours, but at 24 hrs, INR is still 2.5-3 2

50

Oral Vitamin K

•

Advantages 1,2

Shown to be effective in reducing raised INRs without omission of warfarin • Effectively reduced 24-hr INR to  4.0 in  three-quarters of patients with excessive anticoagulation (INR  10.0) who were receiving warfarin • •

Disadvantages 1,2

No therapeutic usefulness in settings that require rapid warfarin reversal Takes several hours to achieve clinical effect 1. DeZee KJ, et al. Arch Intern Med. 2006;166:391-397; 2. Hanley JP. J Clin Pathol. 2004;57:1132-1139.

51

PCC Anticoagulation Reversal Mechanism Preprothrombinase Complex PCCs Prothrombinase Complex Coagulation protein levels are critical to progress to amplification

Figure based on cell-based coagulation mode adapted from Monroe DM, et al. Arterioscler Thromb Vasc Biol. 2006;26:41-48.

52

Prothrombin Complex Concentrates

Activated

• Includes activated coagulation factors to allow for bypassing FVIII inhibitor   For treatment of hemophilia with inhibitors Factor eight inhibitor bypassing activity (FEIBA) is only activated PCC available in United States Goodnough LT, et al. Blood. 2011;117:6091-6099.

53

Prothrombin Complex Concentrates

•

Non-Activated

Categorized based on presence or absence of sufficient levels of FVII 1

•

3-factor PCCs (II, IX, X) available in United States

•

4-factor PCCs (II, IX, X, and VII) available in Europe, under study in US



2 trials under way in US to assess effects of 4-factor PCCs as rapid reversal agents in presence of anticoagulant-associated coagulopathy or in anticoagulated patients requiring urgent surgery or invasive procedures 2,3

•

Case series and retrospective analyses indicate rapid correction of INR with both 3-factor and 4-factor PCCs in setting of urgent anticoagulant reversal 4-7



To date, no demonstrable differences in clinical outcome when PCC compared to FFP 4,8

1. Goodnough LT, et al. Blood. 2011;117:6091-6099; 2. Clinicaltrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00803101?term=beriplex&rank=3. Accessed August 2, 2011; 3. Clinicaltrials.gov. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00618098?term=octaplex&rank=1. Accessed August 2, 2011; 4. Fredriksson K, et al. Stroke. 1992;23:972-977; 5. Lankiewicz MW, et al. J Thromb Haemost. 2006;4:967-970; 6. Makris M, et al. Thromb Haemost. 1997;77:477-480; 7. Cartmill M, et al. Br J Neurosurg. 2000;14:458 461; 8. Sjöblom L, et al. Stroke. 2001;32:2567-2574.

54

Warfarin Reversal: PCCs

•

A generic term



Used to describe concentrated pooled plasma products

•

Typically, contain a combination of vitamin K-dep factors; some include proteins C and S 1

Adapted from Pabinger I, et al. J Thromb Haemost. 2008;6:622-631.

1. Pabinger I, et al. J Thromb Haemost. 2008;6:622-631; 2. Holland H, et al. Trans Pract. 2009;49:1171-1177.

•

Different preparations (3 vs 4 coagulation factors) are available in different countries 2

PCCs* Available for Reversal of Warfarin-Associated Coagulopathy

Product (Manufacturer) Factor Levels II VII IX X Available in US:

PCCs, 3-factor (II, IX, X) Profilnine SD (Grifols)† Bebulin VH (Baxter)†

Available outside US:

PCCs, 4-factor (II, VII, IX, X) Beriplex (CSL Behring) a Octaplex (Octapharma) b Cofact (Sanguin) c Prothromplex T (Baxter) d PPPSB-HT e

Available outside US:

PCCs, 3-factor (II, IX, X) Prothromplex HT (Baxter) f  150  35  100  100 24-38 IU/mL  5 IU/mL 24-38 IU/mL 24-38 IU/mL 20-48 IU/mL 10-25 IU/mL 20-31 IU/mL 22-60 IU/mL 14-38 IU/mL 9-24 IU/mL 25 IU/mL 18-30 IU/mL 14-35 IU/mL 7-20 IU/mL 25 IU/mL 14-35 IU/mL 30 IU/mL 25 IU/mL 30 IU/mL 30 IU/mL 20 IU/mL 20 IU/mL 20 IU/mL 20 IU/mL 30 IU/mL ---------- 30 IU/mL 130 IU/mL *Non-activated.

†Product insert specifies: “ Indicated for replacement of factor IX in patients with hemophilia B. Not indicated for treatment of factor VII deficiency.

” a UK, EU; b UK, Canada, EU; c EU; d Austria; e Japan; Blood: Journal of the American Society of Hematology by American Society of Hematology. Copyright 2011. Reproduced with permission of American Society of Hematology (ASH) in the format “ f Australia.

presentation ” via Copyright Clearance Center.

56

Prothrombin Complex Concentrates Advantages

• • • • • • Normalizes INR more rapidly than FFP 1,2 Can be administered rapidly without the need for matching the blood group 1 No need to thaw 1 May require smaller volumes 3 Specific method for replacing deficient clotting factors 3 Restores overall thrombin generation 4

Disadvantages

• • • • • Effect on clinical outcomes unproved 2,5 Possible thrombogenic effects 5 Contraindicated in DIC and AT deficiency 5 Variety of products and factors (only 1 offered in the US), makes it difficult to extrapolate results from one study to the next 5 Small study using PCC containing low amounts of Factor VII as a single agent demonstrated inadequate lowering of INR 6 1. Pabinger I, et al. J Thromb Haemost. 2008;6:622-631; 2. Aguilar MI, et al. Mayo Clin Proc. 2007;82(1):82-92; 3. Lee K, et al. 467; 6. Holland L, et al. Transfusion. 2009;49:1171-1177.

57

Author Evans (2001) Lankiewicz (2006) Vigue (2007) Pabinger (2007) Tanaka (2008) Chong (2010) Kuwashiro (2011) PCC Beriplex P/N Proplex-T Kaskadil Beriplex P/N Beriplex P/N Patient Characteristics (n=186) Acute major bleeding at various sites (n=10) ICH (62%), GI bleeding (19%), and OR need (7%) (n=58) Acute operation for ICH (n=18) Outcome Metrics Median INR reduced from 20.0 to 1.1

Median INR from 3.8 to 1.3

INR <1.5 in all pateints Acute bleeding (n=17)/ emergency operation (n=26) In rat and human anticoag models; PCC vs rFVIIa (n=17) Profilnine SD PPSB-HT Nichiyaku SDH and ICH (n=7) Acute AAICH (n=50) Median INR 1.2-1.3 for 48 h PCC and rFVIIa shortened PT, only PCC increased thrombin 4 patients – good neuro outcome at 30 days Poorer outcomes in non PCC group among pts with INR >2.0 at admission

Evans G, et al. Br J Haematol. 2001;115:998-1001. Lankewicz MW, et al. J Thromb Haemost. 006;4:967-970; Vigue B, et al. Intens Care Med. 2007;33:721-725; Pabinger I, et al. J Thromb Haemost. 2008;6:622-631; Tanaka KA, et al. Thromb Res. 2008;122:117-123. Chong CT, et al. Anaesth Intens Care. 2010;38:474-480; Kuwashiro T, et al. Cerebrovasc Dis. 2011;31:170-176.

Recombinant Factor VIIa

• Procoagulant agent approved for bleeding complications of hemophilia; used to treat AAICH off-label 1 • rFVIIa induces coagulation through thrombin generation at the site of vessel injury by activating the tissue factor-dependent coagulation pathway 2 Posted with permission from Midathada MV, et al. Am J Clin Pathol. 2004:121.

1. Aguilar MI, et al. Mayo Clin Proc. 2007;82(1):82-92; 2. Goodnough LT, et al. Arch Pathol Lab Med. 2007;131:695-701.

59

Warfarin Reversal: Factor VIIa

• • • •

Recombinant product 1 Reduces time to INR correction 1 Risk of thromboembolic complications 2 While the INR is reversed, clinical hemostasis is not normalized 2,3

•

Requires FFP to normalize levels of factors II, IX, and X 2

60 1. Freeman WD, et al. Mayo Clin Proc. 2004;79(12):1495-1500; 2. Beshay JE, et al. J Neurosurg. 2010;112-307-318; 3. Skolnick BE, et al. Blood. 2010;116:693-701.

Recombinant Factor VIIa

Advantages

• • •

Acceptable safety profile Rapid reversal of INR 2 1 Short half-life may make induction of thrombogenic state less likely than with an infusion of PCC 2 Disadvantages

• •

Thrombotic events (rare) 1 Give with caution if

•

hypercoagulability present 1 Use in ICH and non-

•

hemophilia 1 bleeding is off label Recommendation in AAICH is only if <4 hrs since symptom

• •

onset 1 More trials are necessary 1 Unclear how accurately INR reflects coagulation status after rFVIIa infusion 2

1. Goodnough LT, et al. Arch Pathol Lab Med. 2007;131:695-701; 2. Aguilar MI, et al. Mayo Clin Proc. 2007;82(1):82-92.

Off-label rFVIIa

• • Retrospective review of 12,644 hospitalizations in patients receiving rFVIIa 1  125 cases in 2000; 17,813 in 2008...... 143-fold increase in use  ICH accounts for 11% of 2008 cases Despite increased off-label use, review of benefits and harm of rFVIIa for suggests no mortality reduction with its use 2    16 RCTs, 26 comparative observational studies, 22 noncomparative observational studies analyzed For ICH, mortality not improved with rFVIIa use across a range of doses Increased rate of arterial thromboembolism with medium- and high-dose use 1. Logan AC, et al. Ann Intern Med. 2011;154:516-522; 2. Yank V, et al. Ann Intern Med. 2011;154:529-540.

Limitations of Warfarin Reversal Agents

Ansell J, et al. Chest. 2004;126:2045-2335.

Dabigatran Reversal

• Specific antidote lacking for dabigatran 1  Elderly patients may be at increased risk for bleeding events, based on 2 recently published case reports 2 • Limited evidence to support use of reversal agents 3 • FFP  No clinical evidence demonstrating reversal of dabigatran ’ s anticoagulant effects 1,3 1. van Ryn J, et al. Thromb Haemost. 2010;103:1116-1127; 2. Legrand M, et al. Arch Intern Med. 2011;171:1285-1286; 3. Crowther MA, et al. J Thromb Haemost. 2009;7(suppl 1):107-110.

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Dabigatran Reversal (cont)

• PCCs  Animal studies indicate potential for reversing effects of dabigatran • Reduction of BT prolongation in rat tail model of template bleeding 1,2 • rFVIIa  Normal volunteer and ex vivo data suggest antagonism of anticoagulant effects 2 • Time  Half-life of dabigatran is  12-17 hours 3 1. van Ryn J, et al. Haematologica. 2008;93(suppl 1):abstract 0370; 2. van Ryn J, et al. Thromb Haemost. 2010;103:1116 1127; 3. Praxada [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2011. 65

Rivaroxaban Reversal

•

No specific antidote to reverse effects

1,2 •

Preclinical studies suggest that rFVIIa or FEIBA may reverse anticoagulant effects of the agent

1,2 •

Time as reversal agent



Half-life is



5-9 hours in healthy individuals and



11-13 hours in the elderly

3 1. Gruber A, et al. Poster presented at: American Society of Hematology 50th Annual Meeting and Exposition; December 6-9, 2008; San Francisco, CA; 2. Perzborn E, et al. Pathophysiol Haemost Thromb. 2007;36(suppl 1):A40; 3. Xarelto [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2011.

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