New Oral Anticoagulants (NOACs)

New Oral Anticoagulants (NOACs) Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) Janice Lawson, MD Tallahassee Memorial Hospital Cancer and Hematology Specialists

Disclosure No financial conflicts of interest Brief discussion regarding off-label use of PCCs for anticoagulant reversal

Goals of discussion How do the NOAC s work Important considerations FDA-approved indications Peri-procedural management Subpopulation considerations

FDA approval Heparin Warfarin Enoxaparin Fondaparinux Dabigatran Rivaroxaban Apixaban Edoxaban 1930 1954 1993 2001 2010 2011 2012 2015

Leung The Hematologist 2011

Why do the NOACs seem better than warfarin? Weitz. Hematology 2012. 536-540

Parameter Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) Target Thrombin Factor Xa Factor Xa Dosing Fixed, once or twice daily (can t crush) Fixed, once or twice daily (with food) Fixed, twice daily Prodrug? Yes No No Half-life (hr) 7-17 (wide variability) 7-13 6-14 Peak Conc (hr) 1-3 2-4 1-3 Renal/Biliary Cl 80%/20% 66%/33% 25%/75% Potential Drug Interactions Potent P-gp inhibitors Potent CYP3A4 and P-gp inhibitors Potent CYP3A4 and P-gp inhibitors Dose adjustments (afib) CrCl 15-30: 75mg BID; CrCl<15: CI Severe hepatic dz: CI CrCl 15-50:15mg QD CrCl<15: CI Severe hepatic dz: CI Any 2 (>80yo, <60kg, Cr>1.5) or CrCl 15-24: 2.5 BID. Sev hepatic dz: CI Safe in Pregnancy? No No No Antidote? No No No TRIALS EXCLUDED PATIENTS WITH CRCl of less than 25-30ml/min Monitoring? PTT, thrombin time Anti-Xa level,?pt Anti-Xa level

Drug-drug interactions NOACs are substrates for CYP3A4 and/or P-glycoprotein enzymes Rivaroxaban Apixaban Edoxaban Dabigatran Interactions 3A4/P-gp 3A4/P-gp P-gp P-gp Strong dual inducers: Reduce effect Rifampin, carbamazepine, phenytoin, phenobarbital, St. John s wort Strong dual inhibitors: Increase effect ketoconazole/itraconzaole, HIV protease inhibitors, Strong P-gp inhibitors: Increase effect Amiodarone, dronedarone (multaq), verapamil, quinidine

NOACs & Reversal No true reversal agents for new oral anticoagulants Three main antidotes for NOACs are being investigated FFP, cryoprecipitate, platelets, protamine NOT generally useful Despite the fact that standard coagulation studies (PT/PTT) may be prolonged Prothrombin complex concentrates (PCCs Profilnine; Kcentra) and/or recombinant VIIa (Novoseven) may be useful Doesn t reverse/not an antidote. NOT 100% reliable. May help generate thrombin (HIGH concentration of factors) Risk of thrombosis (main side effect) in an already high-risk population To be used ONLY in life-threatening bleeding/emergent surgery

Patient Concerns: Bleeding Lack of reversal agents/antidotes may make some patients reluctant to use NOACs Life-threatening/fatal bleeding are reduced by up to 50% for NOACs vs warfarin Outcomes with NOAC-associated major bleeding are no worse than with warfarin Yang. Vasc Health Risk Manag. 2014 Sarode, et al. Circulation. 2013 Majeed, et al. Thromb Haemost Medscape Education

Atrial fibrillation VTE prophylaxis after THA/TKA VTE treatment and secondary prophylaxis FDA-APPROVED INDICATIONS

Atrial fibrillation trials Trial Patients/ Mean CHADS 2 Drug Comparator Primary Efficacy Outcome (CVA) Primary Safety Outcome (major bleeding) RELY 18,000/ 2.1 ARISTOTLE 18,000/ 2.1 Dabigatran 110mg BID or 150mg BID Apixaban 5mg BID* Warfarin 110: Noninf 150: Superior 110: less Warfarin Superior Less 150: same ENGAGE AF 21,000/ 2.8 ROCKET 14,000/ 3.5 Edoxaban 30mg QD or 60mg QD Warfarin *Both: Noninf Rivaroxaban Warfarin Noninferior Same 20mg QD Less (30mg: less GI) * boxed warning for patients with CrCl > 95ml/in Connolly NEJM 2009 Patel NEJM 2011 Connolly NEJM 2011 Granger NEJM 2011

Dosing strategies Trial RELY (Dabigatran) ROCKET AF (Rivaroxaban) ARISTOTLE (Apixaban) ENGAGE AF (Edoxaban) Dosing Strategies (vs dose-adjusted warfarin to target INR 2.0-3.0) Dabigatran 110mg BID (low) or 150mg BID (high) Rivaroxaban 20mg QD Dose adjustment 15mg daily for CrCl of 30-49 ml/min Apixaban 5mg BID Dose adjustment 2.5mg BID if 2 or more factors present 1) Age >/= 80, Body weight </= 60kg, SCr >/= 1.5 mg/dl Edoxaban 60mg QD (low) or 30 mg QD (high) Dose adjustment halved if 1 of the factor CrCl 30-50 ml/min, Body weight </= 60kg; OR concomitant use of p-gp inhibitor verapamil, quinidine, and dronedarone One size does NOT fit all! Connolly NEJM 2009 Patel NEJM 2011 Granger NEJM 2011 Giugliano NEJM 2013

THA/TKA VTE prophylaxis trials Primary Efficacy Outcome: Total VTE and death Prophylactic rivaroxaban (10mg qday, 6-8 hrs post-op) superior Pooled analysis: Non-significant trend towards increased bleeding although still low Biased reporting of adverse events Could LMWH still be more appealing than rivaroxaban? Erikkson Annu Rev Med 2011

VTE trials Trials Patient Drug Comparator Efficacy Outcome (recurrent VTE) EINSTEIN -DVT/PE 3,500 / 4,800 Rivaroxaban 15mg BID x 3wks 20mg QD x 12mo Enoxaparin warfarin 12mo Non-inferior Safety Outcome (major bleeding) Same/Better RECOVER 2,500 Parenteral x 9d Dabigatran 150mg BID x 6mos Parenteral warfarin 6mo Non-inferior Same AMPLIFY 5,300 Apixaban 10mg BID x 1 wk 5mg BID x 6 mo Enoxaparin warfarin 6 mo Non-inferior Better HOKUSAI -VTE 8,300 Parenteral x 5-10d Edoxaban 60mg (30mg*) QD x 3-12 mo * CrCl 30-50ml/min, wt<60kg Parenteral warfarin 6mo Non-inferior Same/Better EINSTEIN Inv, NEJM 2010 Schulman, NEJM 2009 Agnelli, NEJM 2013 Hokusai Inv NEJM 2013

Dabigatran (Pradaxa) Rivaroxaban (Xarelto) Apixaban (Eliquis) PERI-PROCEDURAL CONSIDERATIONS

Peri-procedural considerations Balance risks of bleeding vs risks of clotting Patients at the highest risk of peri-procedural bleeding tend to also have an increased risk of thrombosis (elderly, active cancer) Evidence to support peri-procedural recs is weak observational data, subset review of trial patients, and consensus documents/expert opinions Short half-life of NOACs may be an advantage Rapid interruption and reintroduction Likely no need for standard peri-procedure heparin bridging

Fawole, et al. Cleve Clin J Med. 2013; 80(7): 443-51

Lab assessment PT aptt Dabigatran (Pradaxa) Less useful (higher Rx conc) Useful (less sensitive) Rivaroxaban (Xarelto) May be useful (variably sensitive) Not useful Apixiban (Eliquis) Not useful Not useful Thrombin time Useful Not useful Not useful Anti-Xa assay Not useful Useful Useful Labs may be useful for qualitative assessment, but not for quantitative use (ie. not for monitoring levels) Garcia. J of Thromb and Haem. 2012; 11: 245-252 Fawole, et al. Cleve Clin J Med. 2013; 80 (7): 443-451

How about restarting? For patients at high risk for thromboembolism, consider administering a reduced dose of NOAC on the evening after surgery and on POD #1: Dabigatran, 75mg qday; Rivaroxaban, 10mg qday; or Apixiban 2.5mg bid In general, no need for post-operative heparin or LMWH bridging, unless patient s status precludes taking oral medications or if there are concerns about absorption. Connolly. J Thromb Thrombolysis. 2013; 36: 212-222

Elderly Antiplatelet therapy Cancer patients SUBPOPULATIONS

Elderly Patients in clinical trials have been younger than those in practice RELY (dabi): 40% age >/= 75 ROCKET (riva): 25% age >/= 78 But how many of our patients are >/= 80? Intrinsic factors that increase their risk of bleeding Falls Low body weight (</= 60 kg) Comorbidities (renal impairment, hepatic dysfunction, malignancy, less buffering capacity in the GI tract, capillary fragility) Need to follow more closely Schulman Thrombosis Research 2013 Maddula J Thromb Thrombolysis 2013

Age and Efficacy/Safety Schulman Thrombosis Research 2013 Eikelboom Circulation 2011

Antiplatelet therapy Role of Triple Therapy: Atrial fibrillation with concomitant CAD requiring PCI is present in 20-30% of patients with atrial fibrillation Requirement of dual antiplatelet regimen (ASA + ADP inhibitor clopidogrel - to prevent in-stent thrombosis) in addition to anticoagulation for CVA prevention Data is Limited: Aspirin (<100mg/d): RE-LY (Dabi) 20%, ROCKET (Riva) 35%, ARISTOTLE (Apixa) 30% Patients on dual antiplatelet therapy were excluded from ROCKET (Riva) and ARISTOTLE (Apixa) Huber, Am Heart J 2014; Schulman,Thrombosis Research 2013; Furie, Stroke 2012

Data from ACS patients Triple Therapy ATLAS ACS2-TIMI 51 Rivaroxaban (2.5mg or 5mg bid) + standard medical therapy (ASA +/- thienopyridine) Both doses increased the rates of major bleeding and ICH APPRAISE2 Apixaban + ASA +/- thienopyridine for ACS. Stopped early due to increased major bleeding and no significant reduction in recurrent ischemic events. PIONEER AF-PCI Trial - Rivaroxaban + DAPT vs Warfarin + DAPT ( d/c of thienopyridine) vs Rivaroxaban + clopidogrel (Rivaroxaban doses: 2.5 mg bid, 10/15mg qday) Huber, Am Heart J 2014; ClinicalTrials.gov: NCT01830543

Cancer Patients Up to 20% of all cancer patients (2 nd leading cause of death) NOACs appeared at least as effective as warfarin Some points to remember: Approx 5% or less of patients enrolled in NOAC trials had cancer Comparison arm warfarin, not LMWH (standard of care) Concern about drug-drug interactions (biologics) Chemotherapy related GI toxicities (compliance and absorption) None of the trials were dedicated VTE in cancer trials Rivaroxaban vs dalteparin (Select-d trial) Edoxaban vs dalteparin Current opinion: Insufficient data to support NOACs in the upfront management of VTE in cancer patients.

Efficacious Safe Convenient What DO we know?

What DON T we know? Effective in real world settings? 20% non-adherence negative impact on efficacy? - Cost Long term data? Short term follow-up in clinical trials (~2 years) vs 50 years for warfarin Is lack of monitoring a good thing? Lost opportunity for repetitive patient education? Prescribe-and-forget drug? Average time spent educating patient on rationale, efficacy, and safety of new med is < 1 minute* * Tarn Patient Educ Counsel 2008.