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Reversing the New Anticoagulants - UCSF Medical …

11/6/20131 Reversing the New AnticoagulantsSusan C. Lambe, MDAssistant Clinical ProfessorDepartment of Emergency MedicineUniversity of California, San FranciscoDisclosureRoadmap for today11/6/20132 Roadmap for today Characteristics of novel Anticoagulants Approach to the bleeding patient Specific reversal agents UCSF guidelinesScope of Problem Prevalence atrial fibrillation million in 2005 million by 2050 VTE = 900K/yr in US 1-2% of adults take warfarinWarfarin1920s Outbreak hemorrhagic disease in cattle in northern US and Canada1933 Isolated by Karl Link1948 Rodenticde1954 Approved in humansWARF-arinWisconsin Alumni Research FoundationCoumarin.

11/6/2013 7 Dabigatran Metabolism • Decreased effect with P-gP inducers • Rifampin • Increased effect with P-gP inhibitors • Dronedarone • Ketoconazole, Itraconazole • …

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Transcription of Reversing the New Anticoagulants - UCSF Medical …

1 11/6/20131 Reversing the New AnticoagulantsSusan C. Lambe, MDAssistant Clinical ProfessorDepartment of Emergency MedicineUniversity of California, San FranciscoDisclosureRoadmap for today11/6/20132 Roadmap for today Characteristics of novel Anticoagulants Approach to the bleeding patient Specific reversal agents UCSF guidelinesScope of Problem Prevalence atrial fibrillation million in 2005 million by 2050 VTE = 900K/yr in US 1-2% of adults take warfarinWarfarin1920s Outbreak hemorrhagic disease in cattle in northern US and Canada1933 Isolated by Karl Link1948 Rodenticde1954 Approved in humansWARF-arinWisconsin Alumni Research FoundationCoumarin.

2 Plant molecule in sweet clover11/6/20133 Warfarin Disadvantages Bridging Drug and food interactions Long half-life Close monitoring requiredWhy New Anticoagulants ? Rapid onset/shorter half-life Fewer drug and no food interactions No lab monitoring Equivalent to warfarin Prevention of stroke, VTE Bleeding ratesNew anticoagulant Disadvantages Limited experience treating bleeding No proven reversal agent No monitoringWhat s in a name? Direct Thrombin inhibitors (DTIs) Novel Oral Anticoagulants (NOACS) Target Specific Oral Anticoagulants (TSOACS)11/6/20134 Roadmap for today Characteristics of novel Anticoagulants Approach to the bleeding patient Specific reversal agents UCSF GuidelinesNew Anticoagulants Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis )New Anticoagulants Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis )

3 Dabigatran Indications FDA approved Stroke prevention in non-valvular afib Under FDA review VTE prophylaxis in hip or knee replacement Approved in Europe/Canada11/6/20135 Dabigatran Dose Stroke prevention 150 mg, po bid Renal insufficiency 75 mg, po bid DVT prophylaxis 220 mg, po qdDabigatran Mechanism Direct Thrombin (Factor IIa) inhibitor Blocks conversion of fibrinogen to fibrinDabigatran Pharmacology Dabigatran etexilate = inactive pro-drug Rapidly absorbed Active form binds active site of thrombin Inhibits free and clot-bound thrombin11/6/20136 Dabigatran Pharmacokinetics Predictable Rapid onset Peak plasma level at 2 hours Half-life 14-17 hoursDabigatran Pharmacokinetics No food interactions.

4 Few drug interactions Fixed dosing can be used No need for routine monitoring or dose adjustmentDabigatran Metabolism 85% excreted via the kidneys Use caution with renal dysfunction Low protein binding Eliminated by hemodialysisDabigatran Metabolism NOTmetabolized by p450 system Substrate of efflux transporter P-glycoprotein Inducers ( , rifampin) reduce effect inhibitors ( , verapamil) increase effect11/6/20137 Dabigatran Metabolism Decreased effect with P-gP inducers Rifampin Increased effect with P-gP inhibitors Dronedarone Ketoconazole, Itraconazole Verapamil Amiodarone Quinidine ClarithromycinNew Anticoagulants Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis )FACTOR Xa INHIBITORSR ivaroxaban (Xarelto )Apixaban(Eliquis )

5 Indications Rivaroxaban/Apixaban Stroke prevention in non-valvular atrial fib Rivaroxaban only VTE prophylaxis post-joint replacement DVT/PE prophylaxis and treatment11/6/20138 Rivaroxaban and Apixaban DoseNon-valvular afib Rivaroxaban, 20 mg po qd Apixaban, 5 mg po qdDVT/PE Rivaroxaban, 15 mg po qdDVT prophylaxis Rivaroxaban,10 mg po qdRivaroxaban and Apixaban MechanismSelective, direct, factor Xa inhibitorsRivaroxaban and Apixaban Pharmacology Highly protein bound Not easily dialyzed Few drug interactionsRivaroxaban and Apixaban Pharmacokinetics Similar to dabigatran Predictable Not affected by age, sex, body weight Fixed dose Peak at 2 3h Half life 7-14h11/6/20139 MetabolismRivaroxaban Excretion 2/3rdrenal 1/3rdliver Dose adjusted for reduced CrClApixaban Excretion 2/3rdliver.

6 Biliary 1/3rdrenalCoagulation Assays Not routinely necessary Indications Major bleeding Overdose Emergent surgeryCoagulation AssaysDabigatran Peak/trough 20-300 ng/ml aPTT Prolonged at >50 ng/ml Normal at 25 ng/ml Thrombin time Prolonged at 3 ng/ml Normal at 1 ng/mlCoagulation AssaysDabigatran aPTTnot useful Thrombin time If normal, dabigatrannotpresent11/6/201310 Coagulation AssaysRivaroxaban/Apixaban Peak/trough 25-400 ng/ml aPTT Prolonged at 120 ng/ml Normal at 60 ng/mlCoagulation AssaysRivaroxaban/Apixaban Anti-factor Xaassay No assay for rivaroxabanavailable Ask for assay calibrated for enoxaparin Estimate of rivaroxaban/apixabanactivityRoadmap for today Characteristics of novel Anticoagulants Approach to the bleeding patient Specific reversal agents UCSF guidelinesApproach to Bleeding Discontinue anticoagulant Compress Fluid

7 Replacement, transfusion11/6/201311 Approach to BleedingConsider emergent reversal Intracranial Pericardial Intraspinal Hemorrhagic shock Drug overdose Emergency surgeryRoadmap for today Characteristics of novel Anticoagulants Approach to the bleeding patient Specific reversal agents UCSF guidelinesReversal AgentsNO ROLE FOR VITAMIN K IN REVERSAL OF NEW ORAL ANTICOAGULANTSR eversal: Options Hemodialysis(dabigatranonly) Prothombincomplex concentrate (PCC) Recombinant Factor VIIa (rFVIIa) aPCC (FEIBA )11/6/201312 Reversal: HemodialysisFor Reversing dabigatranEvidence 6 healthy volunteers w ESRD 62% removed after 2 hours 68% removed after 4 hoursRivaroxaban/apixaban too highly protein-bound for HDStangier, 2010 Reversal: PCCTwo preparations Kcentra 4-factor PCC (II, VII, IX, X) Bebulin 3-factor PCC (II, IX, X)Reversal: Specific AgentsHuman studiesAnimal studiesSpecific AntidotesReversal.

8 Specific AgentsHuman studiesAnimal studiesSpecific Antidotes11/6/201313 Reversal: Specific AgentsHuman studies 5 studies, 2011-2013 Healthy volunteers Anticoagulants : dabigatran, rivaroxaban, apixaban Reversal agents PCC aPCC rFVIIa Outcome: clotting assaysReversal: Human StudiesErenberg, 2011 Study design N=12 subjects Dabigatran or rivaroxaban po x d Treated with PCC bolus iv Measured PT and ETP over 24 hoursReversal: Human StudiesErenberg, 2011 Findings PCC reversed PT, ETP in rivaroxaban treated patients PCC did not reverse dabigatranReversal: Human StudiesMarlu, 2012 Study design N=10 men Dabigatran or rivaroxaban po x 1 Collected blood samples Treated blood (PCC, rFVIIa, aPCC)11/6/201314 Reversal: Human StudiesMarlu, 2012 Findings Dabigatran rFVII amost effective Rivaroxaban PCC most effectiveReversal: Human StudiesKhoo, 2013 Dabigatran+aPCC Study design N=8 subjects on dabigatran Blood treated with aPCCR eversal.

9 Human StudiesKhoo, 2013 Findings aPCC reversed dabigatranReversal: Human StudiesDinklaar, 2013 Rivaroxaban+PCC Study Design N=9 subjects PCC added to rivaroxaban-treated samples Coagulation assays performed11/6/201315 Reversal: Human StudiesDinklaar, 2013 Rivaroxaban+ PCC Findings mixed results PCC Normalized thrombin generation Did not normalize PT Dose of PCC required depended on type of assayReversal: Human StudiesKorber, 2013 Rivaroxaban+ PCC/rFVIIa Study design N=10 subjects Blood samples treated with rivaroxaban Added PCC and rVIIa Performed clotting assaysReversal: Human StudiesKorber, 2013 Rivaroxaban+ PCC/rVIIa Findings PCC had no effect on clotting tests rVIIa reversed PT and clotting factor time prolongationHuman Studies: SummaryDabigatran Reversed with aPCC in 2/2 studiesRivaroxaban Reversed with PCC in 3/4 studies11/6/201316 Human studies.

10 Limitations Variable designs Healthy volunteers Reversal agents added to blood samples Clotting tests proxy for bleedingReversal: Specific AgentsHuman studiesAnimal studiesSpecific antidotesReversal: Animal studies 6 studies, 2008-2013 Anticoagulants : Dabigatran Rivaroxaban Apixaban Reversal agents PCC rFVIIa aPCC (FEIBA ) Fibrinogen FFP Outcomes Clotting assays BleedingReversal: Animal StudiesVan Ryn, 2008 Study Design Rats infused w high dos


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