Faculty. DOACs and Reversal Agents: Disclosures. Considerations for Health-System Pharmacists. Learning Objectives

Transcription

1 Faculty DOACs and Reversal Agents: Considerations for Health-System Pharmacists Mark A. Munger, PharmD, FCCP, FACC, FHFSA Professor of Pharmacotherapy Adjunct Professor, Internal Medicine University of Utah Salt Lake City, Utah Presented in partnership with the ICHP Annual Meeting Disclosures Learning Objectives Mark A. Munger, PharmD, FCCP, FACC, FHFSA has no financial relationships to disclose relating to the subject matter of this presentation. Outline the pharmacologic profiles, clinical characteristics, patient-centric considerations, and cost-effectiveness of DOACs Evaluate the role of DOACs in the management of VTE and AF-related stroke risk reduction and bleeding risk Describe new and emerging DOAC reversal agents and their clinical utility in patients who may require interruption of anticoagulant therapy Develop or augment protocols for patients requiring the prompt reversal of DOACs due to risk of bleeding, severe bleeding, or urgent/emergent invasive procedures DOAC = direct oral anticoagulant. The Ideal Anticoagulant Oral, fixed dosage (preferably once daily) Rapid onset Rapid offset of action Perhaps not in valves? o need for renal or hepatic adjustment Predictable pharmacokinetics/dynamics o need to ever switch therapies Wide therapeutic window o need for routine anticoagulation effect monitoring Low propensity for food/drug interactions Available antidote Reasonable cost ew Oral Anticoagulants Pharmacodynamics & Pharmacokinetics Property MOA Direct IIa Bioavailability 6 7% 8% 5% 62% Tmax 1.5 hours 2 4 hours 2 3 hours 1 2 hours T½ hours 9 13 hours 8 15 hours 8 11 hours Hepatic Metabolism o Yes Yes Yes Drug Interactions P-gp CYP3A4 CYP3A4 P-gp Protein Binding 35% 9% 87% 55% Dialyzable Yes o o o Measurement ECT, TT, aptt Anti-Xa, PT Anti-Xa, dpt Anti-Xa, PT Renal Elimination 8% 35% 25% 4% Renal Dosing Yes Yes o? Yes Antidote o o o o

2 ew Oral Anticoagulants Pharmacodynamics & Pharmacokinetics Property MOA Direct IIa Bioavailability 6 7% 8% 5% 62% Tmax 1.5 hours 2 4 hours 2 3 hours 1 2 hours T½ hours 9 13 hours 8 15 hours 8 11 hours Hepatic Metabolism o Yes Yes Yes Drug Interactions P-gp CYP3A4 CYP3A4 P-gp Protein Binding 35% 9% 87% 55% Dialyzable Yes o o o Measurement ECT, TT, aptt Anti-Xa, PT Anti-Xa, dpt Anti-Xa, PT Renal Elimination 8% 35% 25% 4% Renal Dosing Yes Yes o? Yes Antidote o o o o Special Instructions Pre-Procedure Dosing Diet Considerations Comparison of Agents Warfarin one Stop 5-6 days prior procedure May need bridging Consistent intake of Vitamin K containing foods Cost $4/month + $2/IR (Annual cost $1) Do not chew, break open capsules - bioavailabiity by 75% Keep in original bottle and tightly capped. Must use within 4 months of opening Skip 2-8 doses depending on procedure and renal function. o need for bridging one Stop > 24 hours before OR and other interventions one Stop hours before elective OR and other interventions one one one $2-4/month Patient Assistance Program (Annual Cost $24-48) $3/month (AWP) CarePath TM Patient Support and Assistance Program (Annual Cost $35) $25/month (AWP) Eliquis 36 Support Patient Support and Assistance Program (Annual Cost $3) DOACs: Clinical Trials AFib-Which Agent? Stroke Prophylaxis/AF VTE Prevention DVT/PE Treatment non Valvular AFIB RE-LY RE-OVATE RE-MODEL RE-MOBILIZE ROCKET-AF RECORD 1-4 RE-COVER I RE-COVER II EISTEI DVT EISTEI PE Cost prohibitive, Drug interactions CrCL<15-3, ASA needed? Contraindicated medication Low compliance suspected warfarin ARISTOTLE AVERROES EGAGE AF TIMI 48 ADVACE 1-3 STARS E-3 STARS J-5 STARS J-4 AF = atrial fibrillation; VTE = venous thromboembolism; DVT = deep vein thrombosis; PE = pulmonary embolism. AMPLIFY HOKUSAI-VTE BID dosing not possible GI bleed, high bleed risk, >75 Dyspepsia On warfarin with poor TTR or monitoring issues Onset of Anticoagulant Effect: Clinical Implications in VTE Choosing an Anticoagulant Current VTE treatment LMWH* VKA Bridging 15 mg BID LMWH* 6 mg QD Switching Day 1 Day 6-11 At least 3 months 15 mg BID X 3 weeks, then 2 mg QD 1 mg BID X 1 week, then 5 mg BID Day 1 Single drug approach At least 3 months A 75-year-old man requires anticoagulation therapy for non-valvular AF. He is also taking carbamazepine and his creatinine clearance is 31 ml/min. Which of the following is the best choice for this patient? Warfarin 4. *Or UFH or fondaparinux.

3 ew Oral Anticoagulants Pharmacokinetics & Pharmacodynamics Property MOA Direct IIa Bioavailability 6-7% 8% 5% 62% Tmax 1.5 hours 2-4 hours 2-3 hours 1-2 hours T½ hours 9-13 hours 8-15 hours 8-11 hours Hepatic Metabolism o Yes Yes Yes Drug Interactions P-gp CYP3A4 CYP3A4 P-gp Protein Binding 35% 9% 87% 55% Dialyzable Yes o o o Measurement ECT, TT, aptt Anti-Xa, PT Anti-Xa, dpt Anti-Xa, PT Renal Elimination 8% 35% 25% 4% Renal Dosing Yes Yes o? Yes Antidote Yes o o o aptt = activated partial thromboplastin time; dpt = dilute prothrombin time; ECT = Ecarin clotting time; MOA = mechanism of action; PT = prothrombin time; TT = thrombin time. US Food and Drug Administration. Accessed February 25, 216. Role of Clotting Assays for DOACs Measuring vs. Monitoring (direct thrombin inhibitor) ECT or TT best (diluted TT very good) There is an effect on the aptt PT/IR lacks sensitivity to be useful, apixaban, edoxaban (direct Xa inhibitors) Anti-Xa is probably the best test There is an effect on the PT (rivaroxaban > apixaban) Less variability in PT compared to IR aptt lacks sensitivity to be useful IR = international normalized ratio; PT = prothrombin time; aptt = activated prothrombin time Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 215. Xarelto [package insert]. Titusville, J: Janssen Pharmaceuticals, Inc.; 211. Eliquis [package insert]. Princeton, J: Bristol-Myers Squibb Company; 215. Savaysa [package insert]. Parsippany, J: Daiichi Sankyo, Inc.; 215. Supportive Care Massive Transfusion Considerations Mechanical compression Surgical hemostasis Electrical tissue cauterization Vessel ligation Application of hemostatic agents (gelatins, collagens, oxidized celluloses, thrombin and fibrin sealants, synthetic glues) Fluid resuscitation (.9% normal saline or lactated ringers, dextran, or albumin) Maintain renal function (maintain blood pressure and fluid status) Blood product transfusion Definition 3% to 4% blood volume loss with hypotension 1 units PRBC in 24 hours Transfuse entire blood volume in 24 hours 5% replacement in 3 hours 4 units PRBC in 4 hours (ongoing need is foreseeable) 1:1:1 of PRBC, platelets, FFP (by volume) HCT of 29% Platelet count of 88 x 13/mm 3 Clotting factor activity of 62% Reconstituted whole blood May need cryoprecipitate Concerns Dilutional thrombocytopenia Citrate induced hypocalcemia Hyperkalemia Acidosis Kaatz S, et al. Am J Hematol. 212;87(Suppl 1):S141-S145. PRBC = packed red blood cells; FFP = fresh frozen plasma; HCT = hematocrit. Shander A, et al. Pharmacotherapy. 27;27(9 Pt 2):57S-68S. Blood Products FFP PRBC PCC apcc Prepared from fresh whole blood or from plasma collected from apheresis 8% to 92% plasma from multiple donors Whole Blood (FFP) IgG 8% to 2% citrate anticoagulant Platelet Rich Various Immune Globulins Variability between units Frozen within 8 hours Shelf-life 12 months Platelets Similar risk to other blood product infusions PCC = prothrombin complex concentrate; apcc = activated prothrombin complex concentrate; IgG = immunoglobulin. Patanwala AE, et al. Annals of Pharmacother. 211;45.

4 PCC Developed for hemophilia B Dose based on amount of factor IX ow mainly treated with recombinant human factor IX Types (many different products) 3-factor: II, IX, and X 4-factor: II, IX, X, and VII Activated PCC (FEIBA): II, IX, X and VIIa Contain varying concentrations of protein C and S, and may have heparin Concentration of clotting factors about 25 higher than in human plasma FEIBA = factor eight inhibitor bypassing activity. Patanwala AE, et al. Ann Pharmacother. 211;45(7-8): Shander A, et al. Pharmacotherapy. 27;27(9 Pt 2):57S-68S. PCC (continued) PCC Product Factor II Factor VII Factor IX Factor X 4-Factor PCC Beriplex (Europe) Octaplex (Europe) Kaskadil (Europe) Cofact (Europe) Factor PCC Profilnine (USA) Bebulin (USA)?? 1? Factor content ratios are based on the content of factor IX All PCC products contain about 2 to 3 U/mL of factor IX Brand names are included in this table for participant clarification purposes only. o product promotion should be inferred. Levy JH, et al. Anesthesiology. 28;19(5): FFP vs PCC FFP ($25) requires larger volumes to provide the same quantity of clotting factors compared to PCC ($45) FFP usual dose 15 to 2 ml/kg ( L) FFP dose in critically ill 3 ml/kg (2.4 L) PCC dose typically 1 to 2 ml/kg (2 ml) Risk of allergic reactions and bacterial infection FFP has same risk as PRBC PCC undergoes viral inactivation FFP requires thawing (3-45 min) PCC recommended over FFP for reversal of warfarin activity Shander A, et al. Pharmacotherapy. 27;27(9 Pt 2):57S-68S. Patanwala AE, et al. Ann Pharmacother. 211;45(7-8): Holbrook A, et al. Chest. 212;141(2 Suppl):e152S-e184S. Reversal of / by PCC (etherlands) Randomized, double-blind, placebo controlled, crossover study Healthy male participants (=12) Anticoagulants 2 mg bid 2.5 days 15 mg bid 2.5 days PCC Cofact (4-factor PCC) 5 IU/kg single bolus Eerenberg ES, et al. Circulation. 211;124(14): Reversal of and by PCC 3-Factor vs 4-Factor PCC for Reversal Seconds PT P <.1 Seconds aptt P =.21 Randomized, single-center, open-label trial 35 healthy participants 2 mg bid with meals 9 doses PCC given 4 hours after last dose Factor PCC (Profilnine ) 5 U/kg 1 T = h 2 h 4 h 6 h 24 h min min Time PCC or 2 mg BID placebo for two and infusion a half days PCC 15 mg BID for two and a half days h 2 h min min Time PCC or placebo infusion 4 h 6 h 24 h PCC 4-Factor PCC (Beriplex ) 5 U/kg Eerenberg ES, et al. Circulation. 211;124(14): Levi M, et al. J Thromb Haemost. 214;12(9):

5 Absolute PT (s) Factor vs 4-Factor PCC for Reversal (continued) 3-Factor PCC / Saline infusion at 4 h Time (h) Three-factor PCC (n=12) Saline (n=12) Prestudy Baseline Factor PCC / Saline infusion at 4 h Time (h) Four-factor PCC (n=1) Saline (n=12) Prestudy Baseline Kcentra First available 4-factor PCC in the United States Provided as a lyophilized powder Reconstituted with provided 2 ml diluent Cost: 8 Kg = $4 to $58 Pre-Treatment IR 2-<4 4-6 >6 Dose in units/kg Maximum dose Levi M, et al. J Thromb Haemost. 214;12(9): Kcentra [package insert]. Kankakee, IL: CSL Behring LLC; 214. Kcentra 4-Factor PCC for Reversal Study Treatment Baseline 3 Min 1 Hr 2-3 Hr 6-8 Hr 12 Hr 24 Hr Acute Major Bleeding Study Kcentra (=98) (=14) 3.9 (1.8-2.) 3.6 ( ) 1.2 (.9-6.7) 2.4 ( ) 1.3 (.9-5.4) 2.1 ( ) 1.3 (.9-2.5) 1.7 ( ) 1.3 (.9-2.1) 1.5 (1.-3.) 1.2 (.9-2.2) 1.4 (1.-3.) Subgroup Major Bleeding Study Kcentra Fluid Overload Fluid Overload (%) (%) All Subjects 13 6 (5.8) (12.8) With history of CHF 46 4 (8.7) (25.) Without history of CHF 57 2 (3.5) 65 3 (4.6) Subgroup Acute Major Bleeding Study Kcentra TE Events TE Events (%) (%) All Subjects 13 9 (8.7) 19 6 (5.5) With history of TE event 69 8 (11.6) 79 3 (3.8) Without history of TE event 34 1 (2.9) 3 3 (1.) 1.2 (.9-3.8) 1.3 (1.-2.9) Double-blind, placebo-controlled, randomized, crossover trial 93 healthy participants 6 mg single dose of edoxaban 3 doses of 4-factor PCC (Beriplex ) 1, 25, and 5 IU/kg 5 mm diameter/5 mm depth punch biopsy Endpoints Bleeding duration and bleeding volume ETP and PT time Zahir H, et al. Circulation. 215;131(1): Factor PCC for Reversal (continued) Reversal Suggestions ETP Mean Ratio Bleeding Duration Mean Post 4F-PCC Ratio Post 4F-PCC Infusion to Baseline (%) Infusion to Baseline (%) A C Complete Reversal Complete Reversal F-PCC PT Mean Change Bleeding Volume Mean Post 4F-PCC Ratio Post 4F-PCC Infusion to Baseline (%) Infusion to Baseline (%) B D Complete Reversal Method Oral activated charcoal Yes Yes Yes Hemodialysis Yes o o FFP o o o rfviia Unclear Unclear Unclear 3-factor PCC Unclear 5 U/kg 5 U/kg 4-factor PCC 5 U/kg 25-5 U/kg 25-5 U/kg Activated PCC 5 U/kg 5 U/kg 5 U/kg *Some protocols call for 1 unit of 3-factor PCC with 2 to 4 units of FFP Zahir H, et al. Circulation. 215;131(1):82-9. Kaatz S, et al. Am J Hematol. 212;87 Suppl 1:S141-S145.

6 Idarucizumab RE-VERSE AD Trial Design Development Injected mice with dabigatran derived hapten-coupled with carrier proteins Creation of murine antibody to dabigatran Group A (n=51) Patients on dabigatran with serious bleeding Group B (n=39) Patients on dabigatran requiring an urgent procedure FC portion removed Fab portion fully humanized Affinity 35-fold compared to thrombin Does not bind other thrombin substrates FV, FVIII, FXIII, fibrinogen, protein C PAR-1, vwf, on impact on platelet aggregation Schiele F, et al. Blood. 213;121(18): Pollack CV Jr, et al. Thromb Haemost. 215;114(1): g of IV idarucizumab Two 5 ml 2.5 g bolus infusions no more that 15 minutes apart Primary endpoint: Maximum % reversal of anticoagulant effect of dabigatran Diluted thrombin time and ecarin clotting time Other endpoints: Unbound dabigatran and idarucizumab concentrations Clinical outcomes Pollack CV Jr, et al. Engl J Med. 215;373(6): RE-VERSE AD Patient Characteristics RE-VERSE AD Results and Conclusion Group A Median age = 77 years CrCl = 59 ml/min <3 ml/min: 1% 3 to 5 ml/min: 27% Dose 15 BID: 27% 11 BID: 67% Atrial fibrillation: 92% Time since last dose <12 hrs: 33% 12 to <24 hrs: 41% 24 hrs: 26% Group B Median age = 76 years CrCl = 65 ml/min <3 ml/min: 18% 3 to 5 ml/min: 15% Dose 15 BID: 38% 11 BID: 62% Atrial fibrillation: 1% Time since last dose <12 hrs: 38% 12 to <24 hrs: 26% 24 hrs: 36 % Unbound Idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes Concentration of Unbound A. Group A B. Group B Time of Blood Sample Idarucizumab (mmol/liter) C. 5, 45, 4, 35, 3, 25, 2, 15, 1, 5, Concentration of Idarucizumab Group A D. Group B Time of Blood Sample Pollack CV Jr, et al. Engl J Med. 215;373(6): Pollack CV Jr, et al. Engl J Med. 215;373(6): Andexanet Alfa (PRT6445)* AEXA-A and AEXA-R (Phase 3) Acts as a factor Xa decoy and retains high affinity for all direct factor Xa inhibitors Change in serine to alanine to eliminate catalytic activity and prevent prothrombin cleavage to thrombin γ-carboxyglutamic acid domain removed to prevent anticoagulant effect Retains high affinity for AT inhibitor complex and can reverse anticoagulant effects of enoxaparin and fondaparinux Part 1: All participants received 4 days DOAC therapy 5 mg twice daily (55 73-years-old) OR 2 mg once daily (5 65-years-old) Andexanet bolus only 4 mg OR 8 mg Part 2: All participants received 4 days DOAC therapy 5 mg twice daily (5 73-years-old) OR 2 mg once daily Factor Xa Andexanet Alfa *Andexanet alfa has only completed Phase 2 trials (proof-of-concept). Lu G, et al. at Med. 213;19(4): Portola Pharmaceuticals. Accessed on February 11, 216. Andexanet bolus + 2 hour infusion 4 mg + 48 mg (4 mg/min) OR 8 mg + 96 mg (8 mg/min) Siegal DM, et al. Engl J Med. 215;373(25):

7 Time Courses of before and after Administration of Andexanet Case Study: Background A Study, Andexanet Bolus End of Bolus 25 (=9) 2 Andexanet (=24) Hours since Bolus C Study, Andexanet Bolus plus Infusion End of Bolus End of Infusion 25 (=8) 2 Andexanet (=23) Hours since Bolus B Study, Andexanet Bolus End of Bolus (=14) Andexanet (=27) D Study, Andexanet Bolus plus Infusion End of Bolus End of Infusion 4 (=13) 3 Andexanet (=26) Hours since Bolus 76-year-old male Presentation: fell in home with trauma to right occipital plate Sx: headache (9/1), R vision blurred A&O: 1 BP 82/58 mmhg; HR 92 bpm (Afib) Creatinine: 1.4 mg/dl (CrCl: 52 ml/min) Atrial fibrillation 5 years (CHA2DS2-VASc: 6 [high risk for stroke]) Hx: Type 2 DM, HT, osteoarthritis Meds: 15 mg BID (last dose 12 hours ago), HCTZ 25 mg qday, lisinopril 1 mg qday, ibuprofen 2 mg PR osteo pain, metformin/glipizide 2.5/5 mg BID Siegal DM, et al. Engl J Med. 215;373(25): What to Do? Patient is sent for cranial CT scan: Results: small acute subarachnoid hemorrhage in the L occipital lobar region Thank you Which of the following should be instituted in this patient? 1. Supportive measures to maintain circulatory support and renal function 2. Supportive measures with administration of activated charcoal now 3. Supportive measures with administration of 4-factor PCC (Beriplex ) 5 U/kg now 4. Supportive measures with administration of idarucizumab 5 g now Questions?