Novel Oral Anticoagulants: Practical considerations in VTE Ido Weinberg, MD MSc Assistant Professor of Medicine Harvard Medical School Massachusetts General Hospital

Disclosures I do not have disclosures relevant to this talk

Background Nat Rev Cardiol. 2013 Jul;10(7):397-409

Background – Cont’d Eur J Intern Med. 2014 Sep;25(7):600-6 Points to make: Rapid onset Moderate half-life Varying elimination pathways. Dabigatran mostly renal Drug interactions exist Eur J Intern Med. 2014 Sep;25(7):600-6

Background – Cont’d Can Fam Physician. 2014 Nov;60(11):989-95

Rivaroxaban VTE dosing http://www.xareltohcp.com/dvt-pe/dosing-and-administration.html

Apixaban VTE dosing * No dose adjustment for renal impairment http://www.eliquis.com/eliquis/hcp/dosing-administration Apixaban package insert. Accessed 1/4/2015 at http://packageinserts.bms.com/pi/pi_eliquis.pdf

Dabigatran dosing Dabigatran package insert. Accessed 1/4/2015 at http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf

Drug interactions: CYP3A Inhibitors Inducers Amiodarone Carbamazepine Clarythomycin Phenytoin Diltiazem St John’s Wort Ketoconazole Phenobarbital Fluoxetine Verapamil Rifampin Merli G. Throm Thrombolysis 2011

Drug interactions: P-Glycoproteins Substrates Inhibitors Inducers Colchicine Amiodarone Carbamazepine Cyclosporine Clarithromycin Rifampin Digoxin Erythromycin St John’s Wort Fexofenadine Ketoconazole Tipranavir Indinavir Quinidine Morphine/Sirolimus Saqunavir/Verapamil Merli G. Throm Thrombolysis 2011

Between Warfarin and rivaroxaban ? http://www.xareltohcp.com/dvt-pe/dosing-and-administration.html

Between Warfarin and apixaban http://www.eliquis.com/eliquis/hcp/dosing-administration

Between Warfarin and dabigatran Dabigatran package insert. Accessed 1/4/2015 at http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf

Less severe ICH with Rivaroxaban vs. Warfarin All rivaroxaban patients had afib, while 79% of warfarin patients had afib Stroke. 2014 Sep;45(9):2805-7

Less bleeding with NOAC’s vs. Warfarin 12 RCT involving 102607 patients were combined in a meta-analysis The second reference is just a smaller meta-analysis that showed similar results Blood. 2014 Oct 9;124(15):2450-8 J Thromb Haemost. 2014;12(3):320-8

Net clinical benefit for NOACs for VTE (and Afib) Nat Rev Cardiol. 2014 Dec 2. doi: 10.1038/nrcardio.2014.204. [Epub ahead of print]

Management of NOAC-related bleeding Prothrombin complex concentrates (PCC) contain high doses of vitamin K-dependent coagulation factors and variable amounts of proteins C and S. Four-factor PCC (factors II, VII, IX, X) is commercially available in Europe and Canada 3-factor PCC (factors II, IX, X) is licensed for use in the USA. There is little clinical data regarding PCC use to reverse bleeding. There is data from healthy volunteers and animal studies PCC increases the chance for thrombosis Charcoal – in vitro evidence for dabigatran removal rFVIIa – Not associated with improved bleeding in NOACs Eur Heart J. 2013 Feb;34(7):489-498b

NOACS safe in CKD (CrCl<50 ml/min) Most of the studies did not have any patients with CrCl<30. Nonetheless NOACs have been approved for use in CrCl 15-30 Apixaban dose was reduced to 2.5 mg BID in renal failure J Am Soc Nephrol. 2014 Mar;25(3):431-42

Renal failure – Suggested dosing Can Fam Physician. 2014 Nov;60(11):989-95

NOAC effect can be assumed from common coagulation studies Dabigatran - TCT – Most sensitive to detect the presence of dabigatran. Prolonged PT is sensitive to dabigatran, but normal PT is not sensitive to its absence Rivaroxaban - Chromogenic Xa – sensitive to rivaroxaban. Prolonged PT is sensitive to rivaroxaban, but normal PT is not sensitive to its absence. Apixaban – Chromogenic Xa – most useful to detect apixaban Normal TCT / normal PT / Normal chromogenic Xa  Not much coagulation effect by dabigatran, rivaroxaban, apixaban, respectively Eur Heart J. 2013 Feb;34(7):489-498b

NOACs affect hypercoagulable studies Courtesy of Dr. Jessica Mintz

Peri-procedural anticoagulation cessation: Consider VTE and procedural risk Blood. 2012 Oct 11;120(15):2954-62

Peri-procedural NOAC comparable to Coumadin Circulation. 2012 Sep 25;126(13):1630-9

Suggested pre-procedural NOAC dosing Blood. 2012 Oct 11;120(15):2954-62 Heidbuchel H et al. EHRA Practical guidelines. European heart journal. 2013

Suggested post-procedural NOAC dosing Blood. 2012 Oct 11;120(15):2954-62

Peri-procedural management: Expert consensus: Short half-life  Pre-procedural interruption: 1 or 2 day Fast onset of action  Rapid restitution of anticoagulant activity after the procedure No heparin bridging therapy Eur Heart J. 2014 Jul 21;35(28):1888-96

NOACs can be used in frail patients (but know the risks) NOAC effect in elderly and low body mass patients Anticoagulation efficacy* Bleeding risk* Apixaban = Dabigatran ↑ (in patients > 85 years) Rivaroxaban = / ↑ * Compared to Warfarin, per sub-group analysis of phase III trials for DVT/PE/Afib Frailty = Old / low body mass Eur J Intern Med. 2014 Sep;25(7):600-6

Anticoagulation choices: Special scenarios Yeh et al. Evolving use of new oral anticoagulants. Blood 2014

NOAC FAQ

Does it matter if NOACs are taken with meals? Dabigatran capsules should be taken with meals to reduce the risk of dyspepsia Rivaroxaban should be taken with a meal to enhance absorption Apixaban can be taken with or without meals Clin Gastroenterol Hepatol. 2013 Mar;11(3):246-52 Int J Clin Pharmacol Ther. 2013 Jul;51(7):549-61 Br J Clin Pharmacol. 2013 Feb;75(2):476-87

Which NOACs can be crushed? Apixaban and rivaroxaban Can Fam Physician. 2014 Nov;60(11):997-1001 Clin Gastroenterol Hepatol. 2013 Mar;11(3):246-52 Int J Clin Pharmacol Ther. 2013 Jul;51(7):549-61 Br J Clin Pharmacol. 2013 Feb;75(2):476-87

Can NOAC users take nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen? Short term – Probably yes Long term – Probably no (increased bleeding) Prefer acetaminophen when possible Consider other anti-platelet agents (ASA, clopidogrel etc.) only when a dual indication exists (increased bleeding) Thromb Haemost. 2012 Jul;108(1):183-90 Thromb Res. 2012 Aug;130(2):147-51 Eur Heart J. 2013 Feb;34(7):489-498b

Where is information lacking? Cancer Antiphospholipid antibody-related thrombosis Liver dysfunction CrCl < 15 ml/min High-risk PE HIT Superficial vein thrombophlebitis

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