Renal Function Considerations for Stroke Prevention in Atrial - PowerPoint PPT Presentation

Renal Function Considerations for Stroke Prevention in Atrial Fibrillation Wednesday, March 28, 2018, 1:00PM ET Presenters: John Fanikos, RPh, MBA Curt Mahan, PharmD Paul Dobesh, PharmD, FCCP, BCPS

Presenters John Fanikos, RPh, MBA Paul Dobesh, PharmD, FCCP, BCPS Director, Pharmacy Business & Financial Services Associate Professor of Pharmacy Practice Brigham and Women’s Hospital College of Pharmacy Assistant Professor of Clinical Pharmacy Practice University of Nebraska Medical Center Northeastern University Omaha, NE Massachusetts College of Pharmacy Boston, MA Michael Streiff, MD Associate Professor of Medicine Charles E. Mahan, PharmD, RPh, PhC Johns Hopkins University Clinical Pharmacist, Pharmacist Clinician Medical Director, AMS & Outpatient Clinics & Presbyterian Healthcare Services Staff Physician Clinical Assistant Professor of Pharmacy Johns Hopkins Comprehensive Hemophilia University of New Mexico College of Pharmacy Treatment Center Albuquerque, New Mexico Baltimore, MD, USA

Background Renal dysfunction is common in atrial fibrillation (AF) Mild to moderate 36% (eGFR 30-89 ml/min) 60% Severe (eGFR < 30 ml/min) Normal 4% (eGFR> 90 ml/min) eGFR= estimated glomerular filtration rate 1. Pokorney SD. Am Heart J. 2015;170:141-148, 148.e141 2. Proietti M. EBioMedicine. 2016;8:309-316 3. Go AS. Circulation. 2009;119:1363- 1369 4. Hart RG. Clin J Am Soc Nephrol. 2011;6:2599-2604 5. Kakkar AK. PLoS One. 2013;8(5):e63479 6. Olesen JB. N Engl J Med. 2012;367: 625-635 7. Boriani G. Sci Rep. 2016;6: 30271

Background Renal dysfunction increases complications in AF patients Increased risk of systemic embolic events (hazard ratio [HR] 1.49; P < .001) and bleeding (HR 2.24; P < .001) relative to those without CKD. 6 eGFR <60 mL/min/1.73 m 2 associated with 43% higher risk of incident stroke. 8,9 Proteinuria & reduced eGFR associated with higher rates of thromboembolism in patients with non-valvular AF, independent of other stroke risk factors. 3 NHANES survey: patients with CKD had additional stroke risk factors, including diabetes (40.4%), hypertension (31.0%), and cardiovascular disease (39.5%). 10 CKD=chronic kidney disease 3. Go AS. Circulation. 2009;119:1363-1369 6. Olesen JB. N Engl J Med. 2012;367: 625-635 8. Masson P. Nephrol Dial Transplant. 2015;30:1162-1169 9. Lee M. BMJ. 2010;341:c4249 10. United States Renal Data System. 2015 USRDS Annual Data Report: Epidemiology of Kidney Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2015.

Background Renal dysfunction increases complications in AF patients (cont.) CKD patients with AF 67% more likely to progress to end-stage renal disease than those without AF. 11 Patients with CKD have higher risk of death from any cause (HR 2.37; P < .001) and myocardial infarction (HR 2.00; P < .001) than those without CKD. 6 Survival after incident AF decreases progressively with decreasing renal function (P < .0001). 12 Disruptions in platelet function and platelet-vessel wall interactions in patients with renal impairment may result in increased bleeding. 6. Olesen JB. N Engl J Med. 2012;367: 625-635 11. Bansal N. Circulation. 2013;127:569-574 12. Nelson SE. J Am Heart Assoc. 2012;1:e002097

Oral Anticoagulants for Non-valvular AF (NVAF) Warfarin Direct oral anticoagulants (DOACs) “No dose adjustment necessary for renal All renally eliminated to some degree impairment” Renal impairment associated with need Large AF RCTs excluded patients with severe renal impairment for reduced doses and less stability* Down regulation of hepatic CYP 450 Estimation of renal function necessary isoenzymes? for patient selection and dosing Performance vs. warfarin at varying Conflicting evidence re: utility for stroke degrees of renal function helpful in prevention in AF patients with CKD selecting optimal AF therapy *Dahal K, et al. CHEST 2016; 149(4):951-959

Estimating Renal Function May be estimated with: • Modification of Diet in Renal Disease (MDRD) equation (eGFR) 13 • Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (eGFR) 14 • Cockcroft-Gault (C-G) equation, which estimates creatinine clearance (CrCl) 15 C-G, using actual body weight, used in all phase 3 direct oral DOAC trials. 16-20 13. Levey AS. Ann Intern Med. 2006;145:247-254 14. Levey AS. Ann Intern Med. 2009;150:604-612 15. Cockroft DW. Nephron. 1976;16: 31-41 16. Michels WM. Clin J Am Soc Nephrol. 2010;5:1003-1009 17. Connolly SJ. N Engl J Med. 2009;361: 1139-1151 18. Patel MR. N Engl J Med. 2011;365:883-891 19. Granger CB. N Engl J Med. 2011;365: 981-992 20. Giugliano RP. N Engl J Med. 2013;369:2093-2104

Estimating Renal Function Renal function cutoffs varied between trials 17-20 • Calculated CrCl ≤ 30 mL/min for dabigatran • Calculated CrCl <30 mL/min for edoxaban and rivaroxaban, • Serum creatinine>2.5 mg/dL or a calculated CrCl of<25 mL/min for apixaban Use of equations other than C-G may result in incorrect DOAC dosing Large database study showed renal function estimations other than C-G would result in failure to reduce rivaroxaban or edoxaban doses in 28% of patients, and 18%-21% of doses among dabigatran patients. 23 17. Connolly SJ. N Engl J Med. 2009;361: 1139-1151 18. Patel MR. N Engl J Med. 2011;365:883-891 19. Granger CB. N Engl J Med. 2011;365: 981-992 20. Giugliano RP. N Engl J Med. 2013;369:2093-2104 23. Schwartz JB. J Am Geriatr Soc. 2016;64:1996-2002

Fanikos J et al. Am J Med 2017;130:1015-1023. BID = twice daily; CrCl = creatinine clearance; P-gp = P-glycoprotein; QD = once daily; SCr = serum creatinine. a Not recommended for patients with CrCl <30 mL/min taking concomitant P-gp inhibitors; the dose should be reduced or avoided in patients with CrCl 30-50 mL/min who use concomitant P-gp inhibitors. b Should be taken with the evening meal. c Apixaban should be reduced to a dose of 2.5 mg BID in patients for whom 2 of the following apply: serum creatinine >1.5 mg/dL, age ≥80 years old, body weight ≤60 kg; apixaban may be administered to patients on hemodialysis at a dose of 5 mg unless dose administration is warranted based on reduction criteria. d Labeling suggests rivaroxaban may be administered to patients on hemodialysis at a dose of 15 mg unless dose administration is warranted based on reduction criteria; however, as it has not been adequately studied in a large-scale clinical trial, use in this population should be avoided whenever possible. e Labeling suggests apixaban may be administered to patients on hemodialysis at a dose of 5 mg unless dose administration is warranted based on reduction criteria; however, as it has not been adequately studied in a large scale clinical trial, use in this population should be avoided whenever possible.

Methods Evaluation of existing evidence as to safety and efficacy of oral anticoagulants for NVAF at varying levels of renal function • Pre-specified subgroup analyses • Metanalyses Patient populations enrolled in phase 3 NVAF studies also differed in: • Risk for cardiac dysfunction • Diabetes and heart failure (riva and edox > apixa and dabi) • Mean CHADS 2 score (riva 3.5; edox 2.8, apixa and dabi 2.1) • Inclusion of patients with atrial flutter • Timing of documentation of atrial fibrillation 21,22 21. Dobesh PP. Drugs. 2015;75:1627-1644 22. Dobesh PP. J Atr Fibrillation. 2016;9:66-74

SSE relative to warfarin for the DOACs stratified by renal function CrCl CrCl CrCl CrCl >80 mL/min >50–95 mL/min >50–80 mL/min 30–50 mL/min HR a (95% CI) HR a (95% CI) HR a (95% CI) HR a (95% CI) % of % of % of % of enrolled enrolled enrolled enrolled Dabigatran 31.2 0.69 NR NR 45.8 0.65 18.5 0.48 25,32,39,b (0.43, 1.12) (0.47, 0.88) c (0.31, 0.76) d Rivaroxaban 22.0 0.93 NR NR 31.4 0.81 45.1 0.90 27,36,39,e (0.67, 1.31) (0.70, 1.14) (0.60, 1.10) Apixaban 26.0 g 48.1 g 0.87 NR 0.79 0.78 NR 0.70 24,33,39,f (0.60, 1.26) g (0.61, 1.02) g (0.48, 1.03) g (0.58, 1.04) g Edoxaban 37 1.33 58.3 0.78 43 0.68 19.5 0.87 26,34,39,h (0.97, 1.81) (0.64, 0.96) (0.54, 0.86) (0.65, 1.18) a Comparisons should not be made across drugs within CrCl ranges; HR presented are for each DOAC vs warfarin within the CrCl range provided. b 150-mg dose c eGFR >50–≤80 mL/min d eGFR≥30–≤50 mL/min e 20 mg daily or 15 mg daily if CrCl 15–50 mL/min once daily with evening meal f 5 mg twice daily or 2.5 mg twice daily if ≥ 2 of : age ≥80 years, body weight ≤60 kg, serum creatinine ≥1.5 mg/dL g I n patients with stable renal function over time h 60 mg daily or a 50% dose reduction to 30 mg daily for CrCl 30–50 mL/min, body weight of ≤60 kg, or use of a potent P-gp inhibitor 24. http://packageinserts.bms.com/pi/pi_eliquis.pdf 25. http://docs.boehringeringelheim.com/Prescribing%20Information/PIs/Pradaxa/Pradaxa.pdf. 26. http://dsi.com/prescribing-information- portlet/getPIContent?productName=Savaysa&inline=true 27. https://www.xareltohcp.com/shared/product/xarelto/prescribing-information.pdf. 32. Hijazi Z. Circulation. 2014;129:961-970 33. Hohnloser SH. Eur Heart J. 2012;33:2821-2830. 34. Bohula EA. Circulation. 2016;134:24-36. 36. Lindner SM. Circulation. 2017;135:1001-1003 39. Del-Carpio Munoz F. Am J Cardiol. 2016;117: 69-75