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Annual MeetingSeptember 14, 2019
Direct Oral Anticoagulant Use in Chronic Kidney Disease
Clarissa Reichmann, PharmD, BCACP, BCGP, CACPAssistant Professor of Pharmacy Practice
Roseman University of Health Sciences
Advanced Clinical PharmacistIntermountain 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
• Major bleeding• 5.5 fold higher in patients with
estimated glomerular filtration rate (eGFR) <15 ml/min/1.73 m2 and urine albumin-creatinine ratio more than 300 mg/g compared with those with normal kidney function.
•Increased risk of thromboembolism• Stroke
• 5-10 fold higher compared to general population
Bleeding Clotting
Anticoagulation in CKDVITAMIN K ANTAGONISTS (VKAS)
•Narrow therapeutic index•Variability in patient response
• Dietary interactions• Dietary restrictions
• Drug interactions• High comorbid burden• Polypharmacy
DIRECT ORAL ANTICOAGULANTS (DOACS)
•Stable pharmacokinetics• Few drug and food interactions
•Rapid onset• No need for initial bridging
DOACs in Randomized Controlled Trials (RCTs)
Randomized Controlled TrialsRE‐LY (2009)
Dabigatran vs. warfarin
Stroke or Systemic Embolism Major bleeding
Dabigatran 150 mg BID vs. warfarinOverall: 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. warfarinOverall: 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 TrialsARISTOTLE (2011)
Apixaban vs. warfarin
Stroke or Systemic Embolism Major bleeding
Overall: 0.88 (0.61‐1.22) 0.69 (0.60‐0.80)
CrCl: 30‐49 ml/min 0.79 (0.55‐1.14) 0.50 (0.38‐0.66)
Randomized Controlled Trials
ROCKET‐AF (2011)Rivaroxaban vs. warfarin
Stroke or Systemic Embolism Major bleeding
Overall: 0.79 (0.66‐0.96) 1.04 (0.90‐1.20)
CrCl: 30‐49 ml/min 0.84 (0.75‐1.23) 0.95 (0.72‐1.26)
Randomized Controlled TrialsENGAGE AF‐TIMI
Edoxaban vs. warfarin
Stroke or Systemic Embolism Major bleeding
High‐dose edoxaban vs. warfarinOverall: 0.79 (0.63‐0.99) 0.82 (0.71‐0.95)
CrCl: 30‐49 ml/min
0.87 (0.72‐1.04) 0.76 (0.58‐0.98)
Low‐dose edoxaban vs. warfarinOverall: 1.07 (0.87‐1.31) 0.47 (0.41‐0.55)
CrCl: 30‐49 ml/min 1.22 (not reported) 0.37 (not reported)
•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
More Randomized Controlled Trials Coming…
DOACs in Observational Cohort Studies
Bleeding Risk Increased
Study Interventions Outcome Measured Hazard Ratio
Chan et al.
Dabigatran or rivaroxaban vs. warfarin or aspirin Major bleeding
Dabigatran vs. warfarin1.76 (1.44‐2.15)
Rivaroxaban vs. warfarin1.45 (1.09‐1.93)
Shin et al. Dabigatran, rivaroxaban, or apixaban vs. warfarin
All bleeding (major/minor) 1.21 (1.03‐1.42)
Bleeding Risk Decreased
Siontis et. alApixaban vs. warfarin
Stroke or systemic embolism
Major Bleeding Intracranial Bleeding
Gastrointestinal Bleeding Death
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 DecreasedWeir et al.
Rivaroxaban vs. warfarin
Ischemic Stroke
Composite of VTE, MI, Stroke Major Bleeding
eCrCl ≥ 80 ml/min
0.82 (0.31‐2.20) 0.49 (0.27‐0.90) 1.20 (0.66‐2.20)
eCrCl >50‐<80 ml/min
0.46 (0.20‐1.10) 0.97 (0.56‐1.66) 1.25 (0.75‐2.12)
eCrCl≤ 50 ml/min
0.09 (0.01‐0.72) 0.56 (0.26‐1.18) 1.20 (0.66‐2.20)
**Dialysis patients excluded**
•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
In Summary…
Which of the following drugs are currently being evaluated in a randomized controlled trial in patients with CKD?A) RivaroxabanB) ApixabanC)DabigatranD)Edoxaban
Test Question-For Technicians
Which of the following were limitations of the observational studies evaluating the use of DOACs in CKD?A) Short duration of DOAC treatmentB) Dialysis patients were sometimes excludedC) Multiple drugs were sometimes grouped together during evaluationsD) A, B, C
Test Question-For Pharmacists
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.
References