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TRANSCRIPT
7/30/2013
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47th Annual Meeting ҉ August 2-4, 2013 ҉ Orlando, FL
Clinical Pearls for New Drugs:The New Oral Anticoagulants
David Parra, Pharm.D., FCCP, BCPSClinical Pharmacy Specialist, Cardiology
West Palm Beach VAMC
Clinical Associate ProfessorDepartment 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 Warfarinin Atrial Fibrillation
Endpoint (ITT)
Study Drug CHADS2 TTRRR
(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-1100.91
(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 Warfarinin 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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New Oral AnticoagulantsVenous 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
StudyDiscontinuation Rate % by end of study
P-valueNOA 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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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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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 of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013:15;625-651
“Careful and considerate prescribing is crucial—you're not giving chocolates to patients, you are giving powerful anticoagulants.
They will work well if you give them correctly and use them appropriately.”
-Gregory Lip, MD
theheart.org.; Jun 20, 2012. Accessed at http://www.theheart.org/article/1417787.do
Bottom Line
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