Oral anticoagulation reversal:

The missing PCC’s of the puzzle

Jason Makii, Pharm.D., BCPSClinical Pharmacy Specialist, Neurosciences Critical Care

Department of Pharmacy Services, University Hospitals Case Medical Center

Clinical Assistant Professor, Department of Neurology

Case Western Reserve University School of Medicine

Disclosures

• Off-label usage

Objectives

• Describe the pharmacology of prothrombin complex concentrates (PCC)

• Discuss the role of PCC in the reversal of oral anticoagulation

• Apply this presentation content to a patient case

• JF 81 yom– PMH: HTN, CHF, DM, A.fib– Home Meds:

• ASA, coumadin, carvedilol, clonidine, furosemide, lisinopril, metformin, glipizide, aldactone,

– HPI:• Woke up with headache• Progressively worsened → Left sided weakness• GTC seizure in ED

Patient Case

Patient Case

• Labs

1658.5

44.7

14.7

170

142 104 26

4.430 1.5

36.944

3.3

Patient Case

• Labs

• Vitals94 bpm 146/104 O2 Sat 96% (16 bpm)

109 kg

1658.5

44.7

14.7

170

142 104 26

4.430 1.5

36.944

3.3

Imaging…

What do you do?!

Guidelines…

• ICH AHA/ASA 2010• “Correct INR as rapidly as possible”• Vitamin K infusion plus

• Fresh frozen plasma (FFP)• Prothrombin complex concentrate (PCC)• Recombinant factor VIIa

Guidelines…

• Chest 2012• Rapid reversal desirable• Vitamin K with one of the following:

• Prothrombin complex concentrate (PCC)• Fresh frozen plasma (FFP)• Recombinant factor VIIa

Coagulation Review

OAC reversal

• Phytonadione

• Blood Products

• PCC

Phytonadione (Vitamin K)

Phytonadione (Vitamin K)

• Necessary for hepatic synthesis of clotting factors II, VII, IX, X

• Adjunctive therapy for more rapidly acting agents

• Dosing: 10 mg IVPB over 10-20 min– Life-threatening bleeding

(AHA-Class I, LOE: C; Chest Grade 2C)

Morganstern et al. Stroke 2010

Holbrook et al. Chest 2012

Blood Products

• Platelets– ICH with history of anti-platelet use?– AHA – Class IIb; LOE: B

Morganstern et al. Stroke 2010

Blood Products

• Fresh Frozen Plasma– Pro:

• Contains required clotting factors

– II, VII, IX, X

– Cons:• Infection transmission• Infusion reactions (TRALI)• Preparation time• Volume

Morganstern et al. Stroke 2010

Holbrook et al. Chest 2012

– Recommendation• AHA – Class I; LOE: C• Chest – Grade 2C (against use of plasma)

Prothrombin Complex Concentrate (PCC)

• Plasma-derived factor concentrates– 3-factor (3F-PCC): Factors II, IX, X – 4-factor (4F-PCC): Factors II, VII, IX, X– Activated PCC (aPCC): Factors II, aVII, IX, X

Kalus AJHP 2013

3 – Factor PCC

• Pearls:• Contains heparin (Bebulin®)• Exact vial potency indicated on vial• Infuse no faster than:

• 2 mL/ min (Bebulin®) or 10 mL/min (Profilnine®)

Kalus AJHP 2013

3F-PCC Dosing for OAC

Factor based:• Boulis et al. (1999)

• Correction speed and complications • Dose: FIX units = weight (kg) x target factor correction*

(* = 40 to 50)• Results

• Time to correction: 2.95+0.46 hrs for FIX vs. 8.9+1.51 hr for std. treatment (P<0.01)

• FFP volume: 399+ 271 mL for FIX and 2712+346 mL for std. treatment (P<0.0007)

Thrombosis & Hemostasis (1997) 71

3F-PCC Dosing for OAC

Factor based:• Boulis et al. (1999)

• Adverse Reactions• No complications observed in the FIX group• 5/8 patients treated with FFP experienced

complications of fluid overload• MI, SVT, Intubation, O2 desaturation

• No outcome difference attributed to FIX

Thrombosis & Hemostasis (1997) 71

3F-PCC Dosing for OAC

INR Based• van Aart et al. (2006)

• Effectiveness of: • Standard 400 IU FIX• Individualized dosing based on weight and INR

• 400 IU FIX (50 kg, INR 2.8 < 2.1) – 2000 IU FIX (100 kg/INR 7.5 < 1.5)

• Results – target INR 15 min. after dose• 89% individualized vs. 43% standard dose

(p < 0.001)

Thrombosis Research (2006) 118

3F-PCC Dosing for OAC

INR Based• van Aart et al. (2006)

• Adverse Reactions• 4/93 patients

• 2 non-bleeding CVA from hypotension• 2 sepsis

• No outcomes differences evaluated

Thrombosis Research (2006) 118

4 – Factor PCC

KCentra®• Indication: Urgent reversal of acquired coagulation factor

deficiency induced by Vitamin K antagonist therapy in adult patients with acute major bleeding

• KCentra®• FDA approved April 2013• Indicated for acquired coagulation factor deficiency

induced by vitamin K antagonist (e.g., warfarin) therapy in adult patients with acute major bleeding

Kalus AJHP 2013

KCentra Package Insert 2013

4 – Factor PCC

J Thromb Hemost 2008; 6

• Pabinger et al. 2008– Efficacy and Safety of stratified Beriplex ® P/N

• Primary: Normalization of INR at 30 min following PCC• Secondary: Hemostatic efficacy in acute bleed and preventing

major bleeding during interventional procedures

– Results• INR < 1.3 @ 30 min in 40/43 patients• Clinical hemostasis was very good in 40/43

4 – Factor PCC

J Thromb Hemost 2008; 6

• Pabinger et al. 2008– Adverse reactions

• 25/43 experienced ADE– 6 classified as serious (3 deaths)

» Death: 1 PE related to PCC, 2 infection» Survivors: Gastric Ca, Duodenal ulcer, stroke

while on UFH

– No outcomes differences evaluated

4 – Factor PCC

• Dosing

• Pearls:• Contains heparin• Exact vial potency indicated on vial• Infuse @ 3 units/kg/min, up to 210 units/min

Kcentra Package Insert 2013

Pre treatment INR 2 – <4 4 – 6 >6Dose of Kcentra (units of Factor IX) / kg body weight

25 35 50

Maximum dose (units of Factor IX) 2500 3500 5000

Activated PCC

FEIBA package insert 2013

• Factor Eight Inhibitor Bypassing Agent (FEIBA)– Anti-inhibitor coagulant complex indicated for use

in hemophilia A and B patients with inhibitors for:• Control and prevention of bleeding episodes• Peri-operative management• Routine prophylaxis to prevent or reduce the frequency

of bleeding episodes

Activated PCC

FEIBA package insert 2013

• Factor Eight Inhibitor Bypassing Agent (FEIBA)– Two formulations available

• Vapor heated• Nanofiltration

– Contains• Non-activated factors II, IX, and X• Activated factor VII• Does not contain heparin

Activated PCC

Int J Emerg Med (2009) 2

• FEIBA for reversal of warfarin induced coagulopathy– Wojcik et al (2009)

• Retrospective review of FFP practices vs. FEIBA protocol– 500 units of FEIBA when INR < 5– 1000 units of FEIBA when INR > 5

• Primary Endpoint: INR normalization• Secondary Endpoint: Survival of patients

Activated PCC

Int J Emerg Med (2009) 2

• FEIBA for reversal of warfarin induced coagulopathy– Wojcik et al (2009)

• Results– 36/72 FEIBA patients had 30 min. INR <1.4 vs. 23/69 FFP

patients (P=0.017)– No difference in survival or length of hospital stay between

the two cohorts

• Adverse Reactions– 5/72 FEIBA patients had ADE possibly related to FEIBA

» MI, CR-DVT, 2-ACS, MVRV fib arrest

Prothrombin Complex Concentrate (PCC)

• Pro– Less volume– Rapid INR reversal– No need for blood type

and cross match

• Con– No large outcome studies– Thromboembolic

complications

– Recommendation• AHA – Class IIa; LOE: B• Chest – Grade 2C

Morganstern et al. Stroke 2010

Holbrook et al. Chest 2012

Target-specific oral anticoagulation

• Direct thrombin inhibitors• Dabigatran (Pradaxa®)

• Factor Xa inhibitors• Rivaroxaban (Xarelto®)• Apixaban (Eliquis®)

Coagulation Review

ApixabanRivaroxaban

Dabigatran

Target specific oral anticoagulation

Dabigatran Apixaban Rivaroxaban

Target Thrombin FXa FXa

T1/2 (h) 12-17 9-14 9-13

Dosing 75-150 mg BID 2.5 – 5 mg BID 10 – 30 mg Daily

Peak Plasma conc. 2 – 3 h 1 – 3 h 2 – 4 h

Protein Binding ~35% 87% 92 – 95 %

Renal Elimination 80% 25% 66%

Metabolism Potent P-gp inducers/inhibitors

CYP3A4P-gp inducers/inhibitors

CYP3A4P-gp inducers/inhibitors

Monitoring Not required Not required Not required

Miesbach Thromb Hemost 2012

Dabigatran

• Annals of Pharmacotherapy• September 2012

• 2.5 h HD session: • TT decreased from 90.6 sec 60.2 sec (UL 19.9)

Rates of Major Bleeding ComplicationsIndication Study Sever Bleeding Incidence

VTE prevention after hip replacement

RECORD 1 Rivaroxaban 10 mg QD: 0.3 %Enoxaparin 40 mg QD: 0.1 %

VTE prevention after hip replacement

RECORD 3 Rivaroxaban 10 mg QD: 0.6 %Enoxaparin 40 mg QD: 0.5 %

VTE prevention after hip or knee replacement

RE-NOVATE and RE-MODEL

Dabigatran 150 mg QD 1.3%Enoxaparin 40 mg QD 1.3%

Stroke prevention in atrial fibrillation

RE-LY Dabigatran 150 mg BID: 3.1%Warfarin QD: 3.4%

Secondary prevention of ACS

APPRAISE-2 Apixaban 5 mg BID: 1.3%Placebo: 0.5%

Stroke prevention in atrial fibrillation

ARISTOTLE Apixaban 5 mg BID: 2.13%Warfarin: 3.09%

Miesbach Thromb Hemost 2012

Eerenberg et al. (2011)

• 12 healthy male volunteers• Age: 24+ 4; BMI: 23+3 kg/m2

• Laboratory Assessment• Prothrombin time (PT)• Endogenous thrombin potential (ETP)• Activated partial thromboplastin time (aPTT)• Thrombin clotting time (TT)• Ecarin clotting time (ECT)

Eerenberg et al. (2011)

• Study Design

Eerenberg et al. (2011)

• Rivaroxaban

Eerenberg et al. (2011)

• Dabigatran

Eerenberg et al. (2011)

• Conclusions• PCC neutralized the surrogate markers of bleeding for

rivaroxaban• PCC has no effect on the surrogate markers of bleeding

for dabigatran

Dabigatran / FEIBA – Case Reports

J Emerg Med 2014

FEIBA = 40 units/kg

FEIBA = 27.5units/kg

FEIBA = 26 units/kg

Antidotes…

• aDabi-Fab (Dabigatran)• 350 times greater affinity for Dabigatran than

thrombin

• PRT4445, Portola Pharmaceuticals• Andexanet alfa completed Phase 1 and 2 studies in 65

patients

Expert Opin Investig Drugs 2013Blood 2013

Dabigatran (PI information)

• No specific reversal agent available• HD can remove dabigatran, but limited use as treatment

for bleeding• aPCC, rFVIIa, 3F-PCC may be considered, but no clinical

trials data• Protamine and Vitamin K are not expected to work• Consider platelets if thrombocytopenic or have history of

long term anti-platelet use

Apixaban (PI information)

• No specific reversal agent available• Not expected to be dialyzable• Protamine and Vitamin K are not expected to work• No experience with antifibrinolytic agents• No scientific rationale for desmopressin or aprotinin• PCC, aPCC or rFVIIa may be considered, but lack clinical

studies• Charcoal reduces absorption of apixaban

Rivaroxaban (PI information)

• No specific reversal agent available• High protein binding, not expected to be dialyzable• Protamine and Vitamin K are not expected to work• Partial PT reversal was seen with PCC in healthy volunteers• aPCC or rFVIIa have not been evaluated

Patient Case

• Received 2500 units Kcentra• Wt. 110 kg, INR 3.3

• Mild neurological deficits• Resumes ADL• Occasionally disoriented• Some short term memory loss

• Discharged to Rehab after 10d hospital stay

Summary

• PCC preferred agents for reversal of warfarin associated hemorrhage

• 4F-PCC may have a role in FXa inhibitor reversal

• aPCC may have a role in DTI reversal• Specific antidotes for DTI and FXa inhibitors

are currently in development

Oral anticoagulation reversal:

The missing PCC’s of the puzzle

Jason Makii, Pharm.D., BCPSClinical Pharmacy Specialist, Neurosciences Critical Care

Department of Pharmacy Services, University Hospitals Case Medical Center

Clinical Assistant Professor, Department of Neurology

Case Western Reserve University School of Medicine