Annual Meeting September 14, 2019 Direct Oral Anticoagulant Use in - PowerPoint PPT Presentation

Annual Meeting September 14, 2019

Direct Oral Anticoagulant Use in Chronic Kidney Disease Clarissa Reichmann, PharmD, BCACP, BCGP, CACP Assistant Professor of Pharmacy Practice Roseman University of Health Sciences Advanced Clinical Pharmacist Intermountain Healthcare

Disclosure I have no conflicts of interest to disclose. The off-label uses of drugs will be discussed.

Learning Objectives At the conclusion of this activity, pharmacists should be able to successfully: 1. Interpret results of recent studies regarding the use of Direct Oral Anticoagulants in Chronic Kidney Disease.

Learning Objectives At the conclusion of this activity, pharmacy technicians should be able to successfully: 1. Identify Direct Oral Anticoagulants that have been studied in Chronic Kidney Disease.

The Chronic Kidney Disease (CKD) Paradox •Increased risk of bleeding •Increased risk of thromboembolism • Major bleeding • Stroke • 5.5 fold higher in patients with estimated glomerular filtration rate • 5-10 fold higher compared to general (eGFR) <15 ml/min/1.73 m2 and urine population albumin-creatinine ratio more than 300 mg/g compared with those with normal kidney function. Clotting Bleeding

Anticoagulation in CKD DIRECT ORAL ANTICOAGULANTS VITAMIN K ANTAGONISTS (VKAS) (DOACS ) • Narrow therapeutic index • Stable pharmacokinetics • Few drug and food interactions • Variability in patient response • Dietary interactions • Rapid onset • Dietary restrictions • No need for initial bridging • Drug interactions • High comorbid burden • Polypharmacy

DOACs in Randomized Controlled Trials (RCTs)

Randomized Controlled Trials RE ‐ LY (2009) Dabigatran vs. warfarin Stroke or Systemic Major bleeding Embolism Dabigatran 150 mg BID vs. warfarin Overall: 0.66 (0.53 ‐ 0.82) 0.93 (0.81 ‐ 1.07) CrCl: 30 ‐ 49 ml/min 0.56 (0.37 ‐ 0.85) 1.01 (0.79 ‐ 1.30) Dabigatran 110 mg BID vs. warfarin Overall: 0.91 (0.51 ‐ 1.32) 0.80 (0.69 ‐ 0.93) CrCl: 30 ‐ 49 ml/min 0.85 (0.59 ‐ 1.24) 0.99 (0.77 ‐ 1.28)

Randomized Controlled Trials ARISTOTLE (2011) Apixaban vs. warfarin Stroke or Systemic Major bleeding Embolism Overall: 0.88 (0.61 ‐ 1.22) 0.69 (0.60 ‐ 0.80) CrCl: 30 ‐ 49 0.79 (0.55 ‐ 1.14) 0.50 (0.38 ‐ 0.66) ml/min

Randomized Controlled Trials ROCKET ‐ AF (2011) Rivaroxaban vs. warfarin Stroke or Systemic Major bleeding Embolism Overall: 0.79 (0.66 ‐ 0.96) 1.04 (0.90 ‐ 1.20) CrCl: 30 ‐ 49 0.84 (0.75 ‐ 1.23) 0.95 (0.72 ‐ 1.26) ml/min

Randomized Controlled Trials ENGAGE AF ‐ TIMI Edoxaban vs. warfarin Stroke or Systemic Major bleeding Embolism High ‐ dose edoxaban vs. warfarin Overall: 0.79 (0.63 ‐ 0.99) 0.82 (0.71 ‐ 0.95) CrCl: 30 ‐ 49 0.87 (0.72 ‐ 1.04) 0.76 (0.58 ‐ 0.98) ml/min Low ‐ dose edoxaban vs. warfarin Overall: 1.07 (0.87 ‐ 1.31) 0.47 (0.41 ‐ 0.55) CrCl: 30 ‐ 49 1.22 (not reported) 0.37 (not reported) ml/min

More Randomized Controlled Trials Coming… •Trial to Evaluate Anticoagulation Therapy in Hemodialysis Patients with AF • Study completed August 2019, data not readily available •Compare Apixaban and Vitamin-K Antagonists in Patients with AF and ESKD • Estimated completion December 2021

DOACs in Observational Cohort Studies

Bleeding Risk Increased Study Interventions Outcome Measured Hazard Ratio Dabigatran vs. warfarin Dabigatran or 1.76 (1.44 ‐ 2.15) rivaroxaban vs. warfarin Chan et al. Major bleeding or aspirin Rivaroxaban vs. warfarin 1.45 (1.09 ‐ 1.93) Dabigatran, rivaroxaban, All bleeding Shin et al. 1.21 (1.03 ‐ 1.42) or apixaban vs. warfarin (major/minor)

Bleeding Risk Decreased Siontis et. al Apixaban vs. warfarin Stroke or Intracranial Gastrointestinal systemic Major Bleeding Death Bleeding Bleeding embolism 0.88 (0.69 ‐ 1.12) 0.72 (0.59 ‐ 0.87) 0.79 (0.49 ‐ 1.26) 0.86 (0.72 ‐ 1.02) 0.85 (0.71 ‐ 1.01)

Thrombosis Risk Decreased Weir et al. Rivaroxaban vs. warfarin Ischemic Composite of Major Bleeding Stroke VTE, MI, Stroke eCrCl ≥ 80 0.82 (0.31 ‐ 2.20) 0.49 (0.27 ‐ 0.90) 1.20 (0.66 ‐ 2.20) ml/min eCrCl >50 ‐ 0.46 (0.20 ‐ 1.10) 0.97 (0.56 ‐ 1.66) 1.25 (0.75 ‐ 2.12) <80 ml/min eCrCl ≤ 50 0.09 (0.01 ‐ 0.72) 0.56 (0.26 ‐ 1.18) 1.20 (0.66 ‐ 2.20) ml/min **Dialysis patients excluded**

In Summary… • There are limited data available regarding the use of DOACs in CKD • Patients with CKD may benefit from DOAC use • Risk of bleeding may be increased, especially in patients with advanced kidney disease • Future studies are needed

Test Question-For Technicians Which of the following drugs are currently being evaluated in a randomized controlled trial in patients with CKD? A) Rivaroxaban B) Apixaban C)Dabigatran D)Edoxaban

Test Question-For Pharmacists Which of the following were limitations of the observational studies evaluating the use of DOACs in CKD? A) Short duration of DOAC treatment B) Dialysis patients were sometimes excluded C) Multiple drugs were sometimes grouped together during evaluations D) A, B, C

References 1. Ha JT, Badve S, Jun M. Recent evidence for direct oral anticoagulants in chronic kidney disease. Curr Opin Nephrol Hypertens 2019; 28:2510261. 2. Herzog CA, Asinger RW, Berger AK, et al. Cardiovascular disease in chronic kidney disease. A clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2011; 80:572 ‐ 586. 3. Molnar AO, Bota SE, Garg AX, et al. The risk of major hemorrhage with CKD. J Am Soc Nephrol 2016; 27:2825 ‐ 2832. 4. Yang F, Hellyer J, Than C, et al. Warfarin utilization and anticoagulation control in patients with atrial fibrillation and chronic kidney disease. Heart 2017; 103:818 ‐ 826. 5. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, et al. Dabigatran versus Warfarin in Patients with Atrial Fbirllation. N Engl J Med 2009; 361:1139 ‐ 1151. 6. Granger C, Alexander JH, McMurray JV, Lopes RD, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 356:981 ‐ 992. 7. Patel MR, Mahaffey KW, Garg J, Pan G, et al. Rivaroxaan versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883 ‐ 891. 8. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369:2093 ‐ 2104. 9. Shin J, Secora A, Alexander G, et al. Risks and benefits of direct oral anticoagulants across the spectrum of GFR among incident and prevalent patients with atrial fibrillation. Clin J Am Soc Nephrol 2018: 13:1144 ‐ 1152. 10. Weir MR, Berger JS, Ashton V, et al. Impact of renal function on ischemic stroke and major bleeding rates in nonvalvular atrial fibrillation patients treated with warfarin or rivaroxaban: a retrospective cohort study using real ‐ world evidence. Curr Med Res Opin 2017; 33:1891 ‐ 1900. 11. Siontis K, Zhang X, Eckard A, et al. Outcomes associated with apixaban use in patients with end ‐ stage kidney disease and atrial fibrillation in the United States. Circulation 2018: 138:1519 ‐ 1529. 12. Chan KE, Edelman ER, Wenger J, et al. Dabigatan and rivaroxaban use in atrial fibrillation patients on hemodialysis. Circulation 2015; 131:972 ‐ 979.