Stop the Bleeding: Management of Drug-induced Coagulopathy. Stacy A. Voils, PharmD, BCPS Critical Care Specialist, Neurosurgery

Transcription

1 Stop the Bleeding: Management of Drug-induced Coagulopathy Stacy A. Voils, PharmD, BCPS Critical Care Specialist, Neurosurgery

2 Objectives Discuss contemporary management of warfarin reversal in patients with severe bleeding Use decision support to prevent errors and optimize dosing of prothrombin complex concentrate (PCC) Review limited data for reversal of newer anticoagulants (Factor Xa inhibitors and direct thrombin inhibitors) in the bleeding patient

3 Reversal of Warfarin

4 Intervention D/C warfarin Vitamin K FFP PCC rfviia Time to INR correction 5 14 days 6 24 hours hours 15 minutes 15 minutes Comments Slow correction, risk for anaphylaxis? Slow infusion, large volume required Potentially prothrombotic, costly Potentially prothrombotic, short half-life, costly Mayo Clin Proc 2007;82(1):82-92

5 Dager et al. rfviia for Reversal of Warfarin 16 patients with traumatic and spontaneous ICH Interventions: rfviia 1.2 mg FFP and vitamin K Outcomes: INR repeated ~10 to 30 minutes after rfviia Mean INR at baseline 2.8 versus 1.1 at follow-up (p< 0.001) Pharmacotherapy 2006;26:

6 rfviia for Reversal of Warfarin Skolnick, et al. 85 healthy volunteers Interventions: Warfarin administered to mean INR 2.5 Randomized to placebo (n=24) or factor 7 at 5, 10, 20, 40 or 80 mcg/kg (n=61) Punch biopsy performed before and after placebo or factor 7 Coagulation tests (PT/INR) assessed before/after intervention Bleeding duration/blood loss assessed before/after intervention Outcomes: PT/INR significantly decreased after all doses of factor 7 (vs. placebo) Bleeding duration/blood loss no different from baseline in any group Blood 2010;116:

7 rfviia for Reversal of Warfarin AHA/ASA Hemorrhagic Stroke Guidelines, July 2010 rfviia does not replace all clotting factors, and although the INR may be lowered, clotting may not be restored in vivo; therefore, rfviia is not routinely recommended as a sole agent for OAC reversal in ICH (Class III; Level of Evidence: C) Stroke 2010;41:epub ahead of print.

8 Prothrombin Complex Concentrate (PCC) Pooled human plasma containing vitamin K-dependent clotting factors Factors II, VII, IX and X Some products contain Protein C/S and heparin (Bebulin) Variable amounts of factor 7 3-factor PCC low or no factor 7 4-factor PCC adequate factor 7 US available products Profilnine, Bebulin (both 3-factor PCCs) Beriplex (4-factor PCC) in Phase III US trials

9 Prothrombin Complex Concentrate (PCC) Boulis, et al. Randomized, controlled trial; 13 patients with ICH Interventions: FFP only (n=8) FFP + PCC IU/kg (n=5) *PCC = Konyne (3-factor) Both groups received IV vitamin K Outcomes: Percent and time to INR correction improved in combination group (p<0.01) No difference in neurologic outcomes More complications in FFP only group (fluid overload) Neurosurgery 1999;45:

10 Prothrombin Complex Concentrate (PCC) Kuwashiro et al. Observational trial, 37 patients with ICH with INR >2 (mean 2.2) Interventions: PCC 500 IU/dose (n=19) *PCC = PPSB-HT (4-factor) Control (n=18) FFP and vitamin K at discretion of physician Outcomes: Hematoma expansion (greater than 1.4X baseline) greater in control group (56% vs. 16%, p=0.017) INR significantly lower at 2 and 24 hours in PCC group (mean INR at 24 hours 1.7 in control group) Only about half of patients in each group received vitamin K (very little FFP) Cerebrovasc Dis 2011;31:170-6.

11 Prothrombin Complex Concentrate (PCC) Imberti et al. Prospective cohort trial, 46 patients with ICH and INR >2 (median 3.5) Interventions: PCC IU/kg (INR based) *PCC = Uman (3-factor) Vitamin K 10 mg IV No blood products allowed in the first 30 minutes Outcomes: % INR values 1.5 at 30 minutes (primary outcome) 89% INR (n=37) 33% INR 4 6 (n=6) 0% INR >6 (n=3) Did not assess hematoma expansion Blood Transfus 2011;9:

12 Group AHA/ASA 2010 ICH Guidelines 1 ACCP 2008 Guidelines Vitamin K antagonists 2 British Committee for Standards in Hematology 2005 Update on Oral Anticoagulation 3 Australasian Society of Thrombosis and Hemostasis 2004: Warfarin Reversal 4 Recommendations 1. Hold warfarin 2. IV Vitamin K 3. FFP, or 4. PCC 5. Factor 7 not recommended 1. Hold warfarin 2. IV Vitamin K 10 mg 3. FFP, or 4. PCC, or 5. Factor 7 1. Hold warfarin 2. IV Vitamin K 5 10 mg 3. PCC 4. FFP not recommended 1. Hold warfarin 2. IV Vitamin K 5 10 mg 3. PCC units/kg and FFP 1. Stroke 2010;41(9): Chest 2008;133;160S-198S. 3. Br Society Hematol 2005;132: Med J Aust 2004;181(9):492-7.

13

14

15

16 Reversal of Direct Thrombin Inhibitors

17 Available Direct Thrombin Inhibitors Lepirudin Bivalirudin Argatroban Dabigatran (Pradaxa ) FDA approved 10/19/2010 for stroke prevention in non-valvular atrial fibrillation 1 st oral direct thrombin inhibitor T1/2 significantly increased with renal insufficiency (13 18 hours) Decrease dose by half for CrCl ml/min

18 Reversal of Direct Thrombin Inhibitors Animal data Mice administered dabigatran prior to induction of intracerebral hemorrhage (ICH) Intervention: PCC 100 IU/kg Plasma Factor 7 Saline Results: PCC and plasma (less consistently) prevented hematoma expansion reversed tail bleeding Factor 7 ineffective Stroke 2011 Oct 13 (ahead of print)

19 Ann Pharmacother 2011;45(9):e47. Reversal of Direct Thrombin Inhibitors Case reports Post-cardiopulmonary bypass bleeding Lepirudin utilized during case due to HITT history Factor 7 salvage therapy (35 mcg/kg) Bleeding slowed allowing chest closure, CT placement Peri-operative bleeding during AAA repair Bivalirudin utilized due to heparin allergy Factor 7 salvage therapy (20 mcg/kg) visual clot formation within 4 minutes Pharmacotherapy 2006;26:

20 Reversal of Direct Thrombin Inhibitors Hemodialysis Six healthy patients with ESRD Dabigatran 50mg single dose 4-hour hemodialysis session Dabigatran concentrations measured at 2 and 4 hours 62% removed at 2 hours 68% removed at 4 hours Clin Pharmacokinet 2010;49:

21 Reversal of Direct Thrombin Inhibitors Dabigatran PI recommendation for bleeding complications Maintain adequate hydration/diuresis (80% renal clearance) Hemodialysis removes ~60% of drug over 2-3 hours (limited data) Consider plasma, factor 7 or PCC (clinical usefulness not established) Measurement of aptt or ecarin clotting time (ECT) may help guide therapy

22 Reversal of Factor Xa Inhibitors

23 Available Factor Xa Inhibitors Arrhythmia/EP Fondaparinux (Arixtra ) Public Citizen urges FDA not to approve rivaroxaban for use in AF October 21, 2011 Sue Hughes Rivaroxaban (Xarelto ) FDA approved 7/1/2011 for DVT/PE prevention in patients with knee/hip replacement FDA approval for atrial fibrillation pending? 1 st oral factor Xa inhibitor Arrhythmia/EP 11/4/2011 Avoid in patients with estimated CrCl < 30 ml/min FDA approves rivaroxaban for stroke prevention in AF patients November 4, 2011 Apixaban (Eliquis ) FDA NDA 2011 for DVT/PE prevention and atrial fibrillation? Oral factor Xa inhibitor

24 Reversal of Factor Xa/Direct Thrombin Inhibitors RCT, crossover trial in 12 healthy male volunteers, mean 24 y.o. Rivaroxaban 20mg twice daily (n=6) for 2.5 days Dabigatran 150mg twice daily (n=6) for 2.5 days Intervention 50 IU/kg PCC or placebo *PCC=Cofact (3-factor) Blood sampled at 15 min, 30 min, 1, 2, 4, 6, and 24 hours after infusion 11-day washout period Intervention repeated Circulation 2011;124:

25 Reversal of Factor Xa/Direct Thrombin Inhibitors Results (rivaroxaban) Prothrombin time (PT) and endogenous thrombin potential (ETP) completely reversed in 15 minutes Both measures sustained at 24 hours Results (dabigatran) APTT, endogenous thrombin potential (ETP), or ecarin clotting time (ECT) not reversed with PCC APTT normalized at 24 hours Circulation 2011;124:

26 Controversies Should FFP be administered along with factor replacement for warfarin reversal? Is there a difference between 3-factor and 4-factor PCCs? Efficacy? Safety? Is factor replacement useful for reversing newer anticoagulants? What is the optimal dose of pharmacologic factor replacement? Are clinical outcomes affected by mode of anticoagulation reversal?

27 Questions?