Objectives NewNew OrOral Aal Anticnticoagulantsoagulants 2018-04-03آ  NewNew OrOral Aal...

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Transcript of Objectives NewNew OrOral Aal Anticnticoagulantsoagulants 2018-04-03آ  NewNew OrOral Aal...

  • 7/30/2013

    1

    47th Annual Meeting ҉ August 2-4, 2013 ҉ Orlando, FL

    Clinical Pearls for New Drugs: The New Oral Anticoagulants

    David Parra, Pharm.D., FCCP, BCPS Clinical Pharmacy Specialist, Cardiology

    West Palm Beach VAMC

    Clinical Associate Professor Department of Experimental and Clinical Pharmacology

    College of Pharmacy, University of Minnesota

    Presenter Disclosure Information

    Financial Disclosure: I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation

    Unlabeled/Unapproved Uses Disclosure: Edoxaban (atrial fibrillation), dabigatran (venous thromboembolism), apixaban (venous thromboembolism)

    The views expressed in this presentation reflect those of the author, and not necessarily those of the Department of Veterans Affairs

    Objectives

    • Discuss new antithrombotic drug therapies in the treatment of venous thromboembolism (VTE), atrial fibrillation, and stroke

    • Summarize findings from pivotal trials with the new oral anticoagulants (NOA) in non-valvular atrial fibrillation and VTE

    • Recognize ongoing concerns with these new agents, and how pharmacists can assist in assuring their safe and effective use

    New Oral AnticoagulantsNew Oral Anticoagulants

    Dabigatran etexilate Apixaban, Edoxaban, and Rivaroxaban

    • Oral direct thrombin inhibitors

    • Prodrug rapid biotransformation to active drug

    • Inhibit free and fibrin-bound FIIa activity

    • Fixed dosing - no coagulation monitoring required

    • Max inhibition of FIIa after 1–4 h

    • T½: dabigatran, 12–17 h

    • Few food/less drug interactions

    • Renal excretion: 80%

    • Oral direct FXa inhibitors

    • Directly acting compound – no biotransformation

    • Inhibit free and fibrin-bound FXa activity, and prothrombinase

    • Fixed dosing - no coagulation monitoring required

    • Max inhibition of FXa after 1–4 h

    • T½: apixaban 12 h; edoxaban 9-11h, rivaroxaban 5–9 h (11-13 elderly)

    • Few food/less drug interactions

    • Renal excretion: 25%, 50%, 36% resp.

    Efficacy of NOA versus Warfarin in Atrial Fibrillation

    Endpoint (ITT)

    Study Drug CHADS2 TTR RR

    (95% CI) NNT/yr

    Non- inferior

    Superior

    Stroke or systemic embolism

    RE-LY

    D-150

    2.1-2.2 64%

    0.66 (0.53-0.82)

    172 Yes Yes

    D-110 0.91

    (0.74-1.11) N/A Yes No

    ROCKET-AF R 3.5 55% 0.88

    (0.75-1.03) N/A Yes No

    ARISTOTLE A 2.1 62% 0.79

    (0.66-0.95) 303 Yes Yes

    ITT = intention to treat; D-150 = dabigatran 150mg twice daily; D-110 = dabigatran 110mg twice daily; R = rivaroxaban; A = apixaban; TTR = time within therapeutic range for the warfarin arm of the respective studies; NNT/yr = number needed to treat per year with new oral anticoagulant versus warfarin to prevent one primary endpoint , N/A = not applicable as risk reduction was not statistically significant

    Safety of NOA versus Warfarin in Atrial Fibrillation

    • Intracranial hemorrhage – Less with all NOA versus warfarin

    – NNT/year from 196-500

    • Major hemorrhage

    – Less with apixaban or with D-110

    • NNT/year 104 and 153 respectively

    – No difference with rivaroxaban or with D-150

    • Gastrointestinal hemorrhage – More with rivaroxaban or with D-150

    – No difference with apixaban or with D-110

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  • 7/30/2013

    2

    New Oral Anticoagulants Venous Thromboembolism Trials

    • Favorable evidence as a whole

    • Caveats with trial designs (especially prevention trials)

    • Currently only rivaroxaban FDA approved for any VTE indications

    • Patient and facility factors will determine integration into practice

    Dabigatran Rivaroxaban Apixaban

    VTE Prevention RE-NOVATE, RE-MODEL, RE-MOBILIZE,

    RECORD 1-4, MAGELLAN, XAMOS

    ADVANCE 1-3, ADOPT

    VTE Treatment RE-COVER 1 and 2

    EINSTEIN DVT, EINSTEIN PE,

    AMPLIFY,

    Extended VTE Treatment/Secondary Prophylaxis

    RE-MEDY, RE-SONATE

    EINSTEIN EXT AMPLIFY-EXT

    Not all a Bed of Roses: Selected Issues

    • Adherence

    • Renal function

    • Drug interactions

    • Shifting benefit/risk profile

    • Periprocedural management

    • Special populations

    Adherence

    Study Discontinuation Rate % by end of study

    P-value NOA Warfarin

    RE-LY 20.7-21.1 16.6 < 0.0001

    ROCKET-AF 23.7 22.2 0.03

    ARISTOTLE 25.3 27.5 0.001

    ⎯ Area for active research ⎯ Opportunity for local initiatives ⎯ Smartphone applications/SMS messages ⎯ Pill boxes-not with dabigatran ⎯ Manufacturer support programs

    Renal Function

    • Patients excluded from pivotal trials if significant renal dysfunction – RE-LY (dabigatran) and ROCKET-AF (rivaroxaban) if CrCl <

    30ml/min

    – ARISTOTLE (apixaban) if CrCl < 25ml/min

    • Dose reductions (Afib) as follows – Dabigatran 75mg bid if CrCl 15-30ml/min

    – Rivaroxaban 15mg daily if CrCl 15-49ml/min

    – Apixaban 2.5mg twice daily if patient had 2 of following: age > 80, weight < 60kg or SCr > 1.5mg/dl

    Renal Function

    • Avoid nephrotoxic drugs (e.g. NSAIDs)

    • Avoid interacting drugs if renal impairment present

    • Monitor yearly in all

    – Every 6 months if CrCl 30-60ml/min

    – Every 3 months if CrCl < 30ml/min

    – In event of acute illness

    European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013:15;625-651

    Drug Interactions - Dabigatran

    • P-gp inducers

    – Rifampin (avoid)

    • P-gp inhibitors

    – Consider dose reduction to 75mg bid if CrCl 30-50ml/min

    • Dronedarone, systemic ketoconazole

    – Avoid if CrCl 15-30ml/min

    • Dronedarone, systemic ketoconazole, verapamil, amiodarone, quinidine, clarithromycin

    • Pharmacodynamic interactions

    Dabigatran etexilate prescribing information, Boehringer Ingelheim Pharmaceuticals, Inc., 2012

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  • 7/30/2013

    3

    Drug Interactions - Rivaroxaban

    • Avoid use with combined strong CYP3A4 inhibitors and P-gp inhibitors

    - Ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan

    • Avoid use with combined P-gp and strong CYP3A4 inducers

    - Carbamazepine, phenytoin, rifampin, St. John’s wort

    Rivaroxaban prescribing information. Janssen Pharmaceuticals, Inc. 2013

    Drug Interactions - Rivaroxaban

    • Combined P-gp and weak-moderate CYP3A4 inhibitors

    – Use with caution with rivaroxaban if CrCl 15-50 mL/min only if potential benefit justifies the potential risk

    • Amiodarone, diltiazem, verapamil, chlorampehnicol, cimetidine, quinidine, ranolazine, dronedarone, felodipine, erythromycin, and azithromycin

    − Use allowed in ROCKET-AF

    − No increase in bleeding noted in those with CrCl 30 to < 50ml/min on combined P-gp and weak-moderate CYP3A4 inhibitors

    Rivaroxaban prescribing information. Janssen Pharmaceuticals, Inc. 2013

    Drug Interactions - Apixaban

    • Combined strong CYP3A4 inhibitors and P-gp inhibitors

    – Ketoconazole, itraconazole, ritonavir, clarithromycin

    – Reduce dose to 2.5mg twice daily

    – If already receiving 2.5mg twice daily then avoid

    • Avoid use with combined P-gp strong CYP3A4 inducers

    – Carbamazepine, phenytoin, rifampin, St. John’s wort

    Apixaban prescribing information. Bristol Myers Squibb Company, 2012

    Drug Interactions

    • Role of the pharmacist

    – Recognize significant drug interactions

    – Consider other factors (e.g. age, renal function)

    – Anticipate potentially significant interactions

    • e.g. cyclosporine, tacrolimus

    – Remain vigilant

    Other Selected Issues

    • Shifting benefit/risk profile

    – Age, renal function, history of GI bleed, time within therapeutic range with warfarin

    • Periprocedural management

    – Establish local policy and procedures

    – Package inserts are useful

    – Consider rapid onset/quick offset

    Other Selected Issues

    • Special populations – Avoid temptation to extrapolate benefits/risks

    – Example: mechanical prosthetic valves

    • RE-ALIGN trial with dabigatran terminated early

    • Greater thromboembolic events (valve thrombosis, MI, CVA/TIA)

    • Excess major bleeding (pericardial effusions)

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  • 7/30/2013

    4

    New Oral Anticoagulants

    = The End of Anticoagulation Clinics

    Recommended Resources

    • http://www.acforum.org/index.htm

    • http://clotcare.com/

    • European Heart Rhythm Association Practical Guide on the use