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Best Evidence for Antithrombotic Agent Reversal in Bleeding

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Best Evidence for Antithrombotic Agent Reversal in Bleeding 3/16/2021 1 JAMES H. PAXTON, MD • DIRECTOR OF CLINICAL RESEARCH • DETROIT RECEIVING HOSPITAL (DRH), DEPARTMENT OF EMERGENCY MEDICINE, WAYNE STATE UNIVERSITY • ATTENDING PHYSICIAN • SINAI-GRACE HOSPITAL (SGH) • DETROIT RECEIVING HOSPITAL (DRH) 2 1 3/16/2021 DISCLOSURES • FUNDED RESEARCH SPONSORED BY: TELEFLEX INC, 410 MEDICAL, HOSPI CORP. 3 OBJECTIVES •AT THE CONCLUSION OF THIS LECTURE, THE LEARNER WILL: • RECOGNIZE COMMON ANTITHROMBOTIC MEDICATIONS ASSOCIATED WITH BLEEDING EMERGENCIES • BE ABLE TO EXPLAIN THE MECHANISMS OF ACTION FOR COMMON ANTITHROMBOTIC MEDICATIONS • UNDERSTAND THE EVIDENCE FOR RAPID REVERSAL OF ANTITHROMBOTIC MEDICATIONS, INCLUDING CONTROVERSIES AND BEST PRACTICES HAVE FEWER NIGHTMARES ABOUT SCENES LIKE THE ONE ON THE NEXT SLIDE? 4 2 3/16/2021 BLEEDING IS BAD 5 WHEN TO REVERSE? • WHEN RISK OF BLEEDING OUTWEIGHS RISK OF REVERSAL: • INTRACRANIAL HEMORRHAGE (ICH) • OTHER CNS HEMATOMA (E.G., INTRAOCULAR, SPINAL) • EXSANGUINATING GASTROINTESTINAL (GI) BLEED • UNCONTROLLED RETROPERITONEAL BLEED • HEMORRHAGE INTO EXTREMITY WITH COMPARTMENT SYNDROME • CONSIDER IN POSTERIOR EPISTAXIS, HEMOTHORAX, PERICARDIAL TAMPONADE 6 3 3/16/2021 ANTITHROMBOTIC AGENTS •ANTI-PLATELET DRUGS •ANTI-COAGULANTS •FIBRINOLYTICS 7 THROMBOGENESIS • Primary component in arterial thrombosis (“white clot”) • Target for antiplatelet drugs • Primary component in venous thrombosis (“red clot”) • Aggregated platelets + • Target for anticoagulants fibrin mesh • Target for fibrinolytics 8 4 3/16/2021 PLATELET AGGREGATION Antiplatelet Drugs Mechanism Aspirin* Inhibit TXA2 synthesis Clopidogrel (Plavix)* Inhibit ADP receptor Prasugrel (Effient)* “-grel” activation Ticagrelor (Brillinta) Dipyridamole (Persantine) Lower Ca++ by elevating “-ol” Cilostazol (Pletal) cAMP Abciximab (ReoPro) Block GPIIb/IIIa receptors Tirofiban (Aggrestat) “-fib / -mab” Eptifibatide (Integrilin) * Permanent inhibition PLATELET LIFESPAN IS ∼8-10 DAYS! 9 REVERSAL OF ANTIPLATELET AGENTS • ACTIVATED CHARCOAL • IF INGESTION IS WITHIN 2-3 HRS (E.G., OVERDOSE), INTUBATED PATIENT • PLATELETS • THROMBOELASTOGRAPHY (TEG) MAY BE USEFUL – LIMITED EVIDENCE • DO NOT TRANSFUSE PLATELETS FOR ICH IF NO SURGICAL INTERVENTION IS PLANNED • CONSIDER 1 UNIT (6-10 PACKS) IF PFA-PLAVIX ASSAY IS POSITIVE (< 194 PRU) • DESMOPRESSIN (DDAVP) • CONSIDER SINGLE IV DOSE FOR INTRACRANIAL HEMORRHAGE • DOSE = 0.3-0.4 MCG/KG IV (NO MAX DOSE) • DECREASED LIKELIHOOD OF HEMATOMA EXPANSION IN FIRST 24 HRS (FELDMAN 2019) THERE IS NO EVIDENCE TO SUPPORT REVERSING ASPIRIN ALONE 10 5 3/16/2021 COAGULATION CASCADE 11 Oral Anticoagulants Warfarin (Coumadin) Inhibits SYNTHESIS of multiple factors ANTICOAGULANTS Dabigatran (Pradaxa) Inhibits ACTIVITY of Factor IIa Rivaroxaban (Xarelto) Inhibits ACTIVITY of Factor Xa Apixaban (Eliquis) Edoxaban (Savaysa) Betrixaban (Bevyxxa) Parenteral Anticoagulants Heparin Inhibits ACTIVITY of multiple factors LMWH: Inhibits ACTIVITY of Factors Xa & IIa Enoxaparin (Lovenox) Dalteparin (Fragmin) Fondaparinux (Arixtra) Inhibits ACTIVITY of Factor Xa Bivalirudin (Angiomax) Inhibits ACTIVITY of Factor IIa 12 6 3/16/2021 Factor Synonyms Source I Fibrinogen Liver CLOTTING II Prothrombin Liver (Vit K-dependent) III Tissue Factor, or Tissue Thromboplastin Liver FACTORS IV Calcium Liver V Labile Factor, or Proaccelerin Liver VI Accelerin Liver VII Stable Factor, or Proconvertin Liver (Vit K-dependent) VIII Antihemophilic Factor A Endothelium IX Christmas Factor, or Plasma Thromboplastin Liver (Vit K-dependent) Component (PTC), or Antihemophilic Factor B X Stuart-Prower Factor Liver (Vit K-dependent) XI Plasma Thromboplastin Antecedent (PTA) Liver XII Hageman Factor, or Glass Factor Liver XIII Fibrin Stabilizing Factor, or Laki-Lorand Factor Liver VITAMIN K-DEPENDENT FACTORS = “2 + 7 = 9, NOT 10” 13 • ACTS IN THE LIVER ONLY WARFARIN EFFECTS • COMPROMISES CARBOXYLATION, PREVENTING PRODUCTION OF GAMMA-CARBOXYGLUTAMIC ACID (GLA) RESIDUES • FACTORS THAT ENTER CIRCULATION WITH GLA RESIDUES ARE UNAFFECTED • PROTEIN C / S ALSO INHIBITED (8 HR / ??) Factor Synonyms Plasma Half-Life II Prothrombin 70 hours VII Stable Factor, or Proconvertin 3-6 hours IX Christmas Factor, or Plasma Thromboplastin 18-24 hours Component (PTC), or Antihemophilic Factor B X Stuart-Prower Factor 40 hours 14 7 3/16/2021 WARFARIN REVERSAL • LONG-ACTING DRUG • TERMINAL ½ LIFE AFTER SINGLE DOSE = 1 WEEK; EFFECTIVE ½ LIFE = 20-60 HOURS (MEAN ∼ 40 HOURS) • METABOLIZED IN THE LIVER (CYP2C9 ALLELE FOR P450 ENZYME) > KIDNEY; DRUG-DRUG INTERACTIONS • TREATMENT • WITHHOLD DRUG, CONSERVATIVE MANAGEMENT, SUPPORTIVE THERAPIES • RESERVE REPLETION OF VIT K-DEPENDENT FACTORS FOR LIFE-THREATENING EVENTS (E.G., EXSANGUINATION, ICH) • RISK FROM BASELINE PROTHROMBOTIC STATE, OR “OVERSHOOT” THROMBOEMBOLIC COMPLICATIONS WITH REPLETION 15 WARFARIN REVERSAL • VITAMIN K • GRADUAL EFFECT OVER HOURS TO DAYS – INEFFECTIVE FOR LIFE-THREATENING BLEEDS (AS MONOTHERAPY) • NECESSARY TO GIVE IF GIVING FFP OR PCC, TO AVOID REBOUND INR ELEVATIONS • DOSE = 10 MG (FOR LIFE-THREATENING BLEED); “CONSIDER 5-10 MG” IF HEMODYNAMICALLY STABLE • IV GIVEN OVER > 20 MIN TO AVOID ANAPHYLACTOID REACTION; ONSET = 1-2 HRS, PEAK = 4-6 HRS • ANAPHYLACTOID REACTION (NON-IGE-MEDIATED) • THOUGHT TO BE DUE TO POLYETHOXYLATED CASTOR OIL DILUENT (NO LONGER USED) (MI 2014) • SEEN IN <0.03% OF CASES (RIEGERT-JOHNSON 2002) • DO NOT GIVE SQ / IM • CONSIDER RE-DOSING (10 MG IV) FOR ICH IF INR > 1.4 AFTER 24-48 HRS (FRONTERA 2016) 16 8 3/16/2021 WARFARIN REVERSAL • FRESH FROZEN PLASMA (FFP) • INCLUDES ALL FACTORS, PROTEIN C, VWF • DOSE = 10-15 ML/KG; 1 UNIT = 200-250 ML • LIMITED BY TIME THAWING, CROSS-MATCHING, CONCERNS OF VOLUME OVERLOAD, POOR EFFICACY, TRALI, TACO • INTRINSIC INR = 1.5 (NO PROVEN BENEFIT FOR INR < 1.7) • NOT RECOMMENDED FOR REVERSAL A/W INTRACRANIAL HEMORRHAGE (FRONTERA 2016) • RECOMBINANT FACTOR VIIA (NOVOSEVEN®) • 100 U/KG @ $1.94/U = $15,000 / DOSE • MORE PRO-THROMBOTIC IN VITRO THAN PCC; UNCOMMONLY USED FOR WARFARIN REVERSAL • LOW-DOSE (1000-1200 MCG) MORE EFFECTIVE THAN 3FPCC (20 IU/KG) IN REDUCING INR (CHAPMAN 2014) 17 WARFARIN REVERSAL • PROTHROMBIN COMPLEX CONCENTRATE (PCC) • POOLED, VIRUS-INACTIVATED CONCENTRATES OF HUMAN CLOTTING FACTORS • SUPERIOR TO FFP IN WARFARIN-ASSOCIATED INTRACRANIAL HEMORRHAGE (STEINER 2016) • MORE THROMBOEMBOLIC COMPLICATIONS (5-10%, DOSE-DEPENDENT) THAN FFP (DENTALI 2011, MILLING 2016) • THREE-FACTOR PCC (3FPCC) = FACTORS II, IX, X (AND VERY LOW LEVELS OF VII) • PROFILNINE ® / BEBULIN ® • CAN BE COMBINED WITH RECOMBINANT FACTOR VIIA – LIMITED DATA ON EFFICACY 18 9 3/16/2021 WARFARIN REVERSAL • FOUR-FACTOR PROTHROMBIN COMPLEX CONCENTRATE (4FPCC) = ADDS FACTOR VII, PROTEIN C/S • COST = $1.65 / IU = $6,600 FOR 50 IU/KG @ 80 KG • KCENTRA® • BEST EVIDENCE SUPPORTS FIXED DOSING (1,000-1,500 IU; MORE FOR OBESE, ICH, INR>4) (RHONEY 2020) • LEXI-COMP: 25 IU/KG (INR 2 TO <4), 35 IU/KG (INR 4-6), 50 IU/KG (INR >6) • INR CORRECTION FASTER THAN 3PCC, W/SIMILAR MORTALITY, LOS, THROMBOSES, BLOOD USE (HOLT 2018; DEANGELO 2018) • 3.6-8% THROMBOSIS RATES @ 30 DAYS (MAJEED 2017, SCHULMAN 2018) VS. 7.8% FFP (SARODE 2013) • FACTOR EIGHT INHIBITOR BYPASSING ACTIVITY (FEIBA®) = ACTIVATED PCC (APCC) • USED FOR HEMOPHILIA FOR DECADES; DOSE = 50-100 U/KG Q 6-12 HRS UNTIL RESOLUTION • HAS ACTIVATED FACTOR VII, AND NO HEPARIN (UNLIKE KCENTRA®) FACTOR VII = SHORT ½ LIFE, INITIATES EXTR. PATHWAY = MORE PROTHROMBOTIC 19 SOURCE: FRONTERA 2016 20 10 3/16/2021 REBOUND AFTER WARFARIN REVERSAL IF INR > 1.4 AFTER 24-48 HRS FOLLOWING PCC, CONSIDER FFP / RE-DOSING VIT K 21 DIRECT ORAL ANTICOAGULANTS (DOACS) Drug Factor Inhibited Cmax (Hrs) Half-Life (Hrs) Reversal Agents Dabigatran (Pradaxa) Factor IIa 2 12-17 Idarucizumab (Praxbind), PCC Rivaroxaban (Xarelto) 2-4 5-9 Apixaban (Eliquis) 1-3 12 Factor Xa Andexanet Alfa (Andexxa), PCC Edoxaban (Savaysa) 1-2 10-14 Betrixaban (Bevyxxa) 3-4 19-27 22 11 3/16/2021 DABIGATRAN (PRADAXA) REVERSAL • IDARUCIZUMAB (PRAXBIND) • HUMANIZED MONOCLONAL ANTIBODY FRAGMENT (BINDS DABIGATRAN) • 350X HIGHER AFFINITY TO DABIGATRAN THAN THROMBIN • ONLY FDA-APPROVED REVERSAL AGENT FOR DABIGATRAN • RE-VERSE AD TRIAL (POLLACK 2015) • ONSET IN MINUTES, CLINICAL HEMOSTASIS ∼ 11.4 HRS • 6.3% THROMBOEMBOLIC EVENTS @ 90 DAYS (90% IN PTS NOT RE-INITIATED ON ANTICOAGULATION) • DOSE = 5 GM IV, ADMINISTERED IN TWO 2.5 GM DOSES • COST = $3,600 / 5-GM DOSE • PCC MAY BE USED (MARLU 2012, SCHULMAN 2017), BUT LIMITED EVIDENCE OF EFFICACY 23 FACTOR XA INHIBITOR REVERSAL • ANDEXANET ALFA (ANDEXXA) • RECOMBINANT, MODIFIED FACTOR XA MOLECULE (“FACTOR XA DECOY”) – FDA APPROVED 2018 • HIGH AFFINITY FOR ALL FACTOR XA INHIBITORS • DOSING • EDOXABAN / BETRIXABAN = 800 MG IV BOLUS @ 30 ML/MIN, THEN 8 MG/MIN FOR UP TO 120 MIN (HIGH DOSE) • APIXABAN / RIVAROXABAN = 400 MG IV BOLUS @ 30 ML/MIN, THEN 4 MG/MIN FOR UP TO 120 MIN (LOW DOSE) OR HIGH DOSE (DEPENDS ON AMOUNT AND TIMING OF LAST DOSE) • COST = $22,000 / DOSE • 10% THROMBOTIC RATE, 82% ACHIEVED GOOD CONTROL OF HEMORRHAGE (CONNOLLY 2019) 24 12 3/16/2021 FACTOR XA INHIBITOR REVERSAL • ANDEXANET ALFA (ANDEXXA) • ONLY REVERSES INHIBITION EFFECT DURING THE ACTUAL 2-HOUR INFUSION (REBOUND @ 4 HRS) • THEORY = ALLOWS A HEMOSTATIC PLUG TO FORM BEFORE REBOUND • ANNEXA-4 TRIAL (CONNOLLY 2019) • HETEROGENEOUS POPULATION, 352 PTS (64% ICH, 26% GIB), WITHIN 18 HRS OF LAST DOSE • MOSTLY APIXABAN (55%) > RIVAROXABAN (36%) > ENOXAPARIN (6%), EDOXABAN (3%) • 92% REDUCTION IN ANTI-FACTOR XA ACTIVITY W/ DOACS; 75% REDUCTION W/ENOXAPARIN • LACK OF CONTROL GROUP • ONLY 58% OF PATIENTS IN THE UPDATE WERE ELIGIBLE FOR EFFICACY ANALYSIS
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