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