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
• 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 CKD

VITAMIN 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 Trials

RE‐LY (2009) Dabigatran vs. warfarin

Stroke or Systemic Embolism Major bleeding

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 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 Trials

ENGAGE AF‐TIMI Edoxaban vs. warfarin

Stroke or Systemic Embolism Major bleeding

High‐dose edoxaban vs. warfarin

Overall:

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. warfarin

Overall:

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

• r aspirin

Major bleeding Dabigatran vs. warfarin 1.76 (1.44‐2.15) Rivaroxaban vs. warfarin 1.45 (1.09‐1.93) Shin et al. Dabigatran, rivaroxaban,

• r apixaban vs. warfarin

All bleeding (major/minor) 1.21 (1.03‐1.42)

Bleeding Risk Decreased

Siontis et. al Apixaban 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 Decreased

Weir 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) Rivaroxaban B) Apixaban C)Dabigatran D)Edoxaban

Test Question-For Technicians

Which of the following were limitations of the

• bservational 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

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