Deniz Yavas, PharmD PGY-2 Ambulatory Care Pharmacy Resident Detroit Veterans Affairs Medical Center } Most common arrhythmia 0.4-1% of Americans (2.2 mil people) 1,2 } Incidence increases with age 6% (65 years or older) 3 10% (80 years or older) 3 The speaker has no actual or potential Conflict of Interest in relation to this presentation 1 Go, A. et al. JAMA 2001;285(18):2370-5. 2 Furberg, C. et al. Am J Cardiol.1994;74(3):236-41. 3 Lloyd-Jones, D. et al. Circulation 2010;121(7):e46-e215. } Stroke: 5x more likely w/af Stroke Risk (%) CHADS 2 Score Adapted from Gage, B. et al. JAMA. 2001;285 (22): 2864-2870. } Anticoagulants approved for AF Vitamin K antagonists (standard of care) Warfarin (Coumadin ) Target-specific oral anticoagulants (TSOACs) Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) **Non-valvular AF** Wolf,P. et al. Stroke. 1991;22:983-8. Advantages Faster onset of action Fixed dosing Few dietary restrictions Disadvantages No antidote for major bleeding More difficult to assess patient compliance More expensive Fewer drug interactions No routine lab monitoring Similar (if not superior) safety and efficacy Taken from http://atvb.ahajournals.org 1
Year Dabigatran Rivaroxaban Apixaban 2010 FDA approved - 2011 Formulary (VA) FDA approved - 2012 Formulary (VA) 2013 2014 FDA approved + Nonformulary (VA) Trial Drugs Results RE-LY 1 ROCKET-AF 2 ARISTOTLE 3 Dabigatran vs. Warfarin Rivaroxaban vs. Warfarin Apixaban vs. Warfarin Dabigatran 150mg BID: Superior (stroke ppx) Non-inferior (major bleeding) Non-inferior Stroke ppx Major bleeding Superior Stroke ppx Major bleeding 1 Connolly, S. et al. NEJM. 2009;361:1139-1151. 2 Patel, M. et al. NEJM. 2011;365:883-891. 3 Granger, C. et al. NEJM. 2011;365(11):981-992. } RE-LY and ROCKET-AF trials showed the following: Higher rates of bleeding in patients 75 years or older (elderly) vs. warfarin Outcome Age 75 years Relative Risk Dabigatran* Warfarin Major bleeding 5.10 4.37 1.18 Extracranial bleeding 4.68 3.44 1.39 Outcome Age < 75 years Relative Risk Dabigatran* Warfarin Major bleeding 2.12 3.04 0.70 Extracranial bleeding 1.91 2.44 0.78 * Dabigatran 150mg BID Adapted from Eikelboom, J. et al. Circulation. 2011;123: 2363-2372. Outcome Age 75 years Hazard Ratio Rivaroxaban Warfarin Major bleeding 4.86 4.40 1.11 Clinically relevant non-major bleeding 15.61 13.54 1.15 Outcome Age < 75 years Hazard Ratio Rivaroxaban Warfarin Major bleeding 2.69 2.79 0.964 Clinically relevant non-major bleeding 9.22 9.87 0.94 Adapted from Halperin J. et al. Stroke. 2012;43 } To assess which medication, dabigatran or rivaroxaban, may be safer in the elderly Veteran AF population Examine Incidence of bleeding and thrombosis Other factors associated w/ adverse events 2
} Rivaroxaban expected to be safer Features Dabigatran Rivaroxaban Dosing 150mg BID 20mg with dinner Renal Adjustment 75mg BID (15-30 ml/min) 15mg with dinner (15-50 ml/min) Bioavailability 6.5% 80% Half-Life 14-17 hours 5-12 hours Renal Elimination 80% 66% Drug Interactions Pgp CYP3A4/Pgp } 1 of 8 VA hospitals in Veterans Integrated Service Network (VISN) 11 } Established 1996 } Main hospital 2 community-based outpatient clinics } 108-bed hospital } 5 days/week 8:00 AM - 3:00 PM } 2 full-time pharmacists } Face-to-face visits } Point of care INR testing (warfarin) } Retrospective chart review Patients 75 YO in VISN 11 Received dabigatran or rivaroxaban from January 1, 2011-June 30, 2013 for non-valvular AF stroke prophylaxis } Matched based on: Gender Race Age CrCl CHADS 2 score Hx of TIA/CVA } All patients assessed for appropriate renal dosing based on ABW 37 patients prescribed either dabigatran or rivaroxaban 9 Matched-pairs created 3
Age (years) 75-79 80-84 85-89 90-94 9 Matched-pairs created based on CrCl (ml/min) 30-59 60-90 >90 CHADS 2 score 1 2 3 4 5 6 Primary Outcome: Thrombosis + all types of bleeding Secondary Outcome: Patient characteristics that influenced primary outcome VARIABLE 9 Matched Pairs (n=18) Gender Male=18 (100%) Race African-American=2 (11.1%) Caucasian=16 (88.9%) Average Age (Years) 81±4 (Range: 75-89) Average CrCl (ml/min) *60±17 (Range: 37-90) Average CHADS 2 Score 3±1 (Range: 2-6) History of stroke 4 (22.2%) * Cockroft Gault ABW } Average CrCl: 65 ± 17 ml/min (Range: 50-87) } Primary outcome occurred in 5 patients (28%) No significant difference between dabigatran and rivaroxaban 2 dabigatran 3 rivaroxaban } Aspirin dosed at 81mg daily 4
} At least 1 clinically significant drugdrug interaction 4/5 pts that experienced 1º outcome } Appropriate renally-adjusted doses 66.7% initially dosed by AC pharmacist All monitored by Pharmacist-run AC clinic } Safety profiles of dabigatran & rivaroxaban appear similar in this limited # of patients } Bleeding risk appears é in patients 75yo receiving TSOAC & antiplatelet therapy } Providers may need to re-assess risks vs. benefits of low-dose aspirin + TSOAC } Small sample size 18 patients No CrCl < 37 ml/min Renal function a factor in determining safety of medications } Jennifer Clemente, PharmD, BCPS } Katelyn Starr, PharmD, BCACP } Cindy Mansfield, Pharmacy ADPAC Which of the following is an advantage that target-specific oral anticoagulants offer to patients over warfarin? A) More drug-drug interactions B) Fewer dietary restrictions C) Slower onset of action D) Less predictable pharmacokinetics What percent of a dabigatran and rivaroxaban dose, respectively, is eliminated by the kidneys? A) 13%, 74% B) 74%, 13% C) 80%, 66% D) 66%, 80% 5
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