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

Background

Renal dysfunction is common in atrial fibrillation (AF)

• 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

60% 4% 36%

Mild to moderate (eGFR 30-89 ml/min) Severe (eGFR < 30 ml/min) Normal (eGFR> 90 ml/min)

eGFR= estimated glomerular filtration rate

Background

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 m2 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

• 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.

CKD=chronic kidney disease

Renal dysfunction increases complications in AF patients

Background

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

Renal dysfunction increases complications in AF patients (cont.)

Oral Anticoagulants for Non-valvular AF (NVAF)

“No dose adjustment necessary for renal impairment” Renal impairment associated with need for reduced doses and less stability* Down regulation of hepatic CYP450 isoenzymes? Conflicting evidence re: utility for stroke prevention in AF patients with CKD

*Dahal K, et al. CHEST 2016; 149(4):951-959

Warfarin Direct oral anticoagulants (DOACs)

All renally eliminated to some degree Large AF RCTs excluded patients with severe renal impairment Estimation of renal function necessary for patient selection and dosing Performance vs. warfarin at varying degrees of renal function helpful in selecting optimal AF therapy

Estimating Renal Function

• 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

May be estimated with: 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

• 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 Renal function cutoffs varied between trials17-20 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

Estimating Renal Function

BID = twice daily; CrCl = creatinine clearance; P-gp = P-glycoprotein; QD = once daily; SCr = serum creatinine. aNot 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. bShould be taken with the evening meal. cApixaban 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. dLabeling 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. eLabeling 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.

Fanikos J et al. Am J Med 2017;130:1015-1023.

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 CHADS2 score (riva 3.5; edox 2.8, apixa and dabi 2.1)
• Inclusion of patients with atrial flutter
• Timing of documentation of atrial fibrillation21,22
• 21. Dobesh PP. Drugs. 2015;75:1627-1644 22. Dobesh PP. J Atr Fibrillation. 2016;9:66-74

CrCl >80 mL/min CrCl >50–95 mL/min CrCl >50–80 mL/min CrCl 30–50 mL/min

% of enrolled HRa (95% CI) % of enrolled HRa (95% CI) % of enrolled HRa (95% CI) % of enrolled HRa (95% CI) Dabigatran

25,32,39,b

31.2 0.69 (0.43, 1.12) NR NR 45.8 0.65 (0.47, 0.88)c 18.5 0.48 (0.31, 0.76)d

Rivaroxaban

27,36,39,e

22.0 0.93 (0.67, 1.31) NR NR 45.1 0.90 (0.70, 1.14) 31.4 0.81 (0.60, 1.10)

Apixaban

24,33,39,f

26.0g 0.87 (0.60, 1.26)g NR 0.79 (0.61, 1.02)g 48.1g 0.78 (0.58, 1.04)g NR 0.70 (0.48, 1.03)g

Edoxaban

26,34,39,h

37 1.33 (0.97, 1.81) 58.3 0.78 (0.64, 0.96) 43 0.68 (0.54, 0.86) 19.5 0.87 (0.65, 1.18)

aComparisons should not be made across drugs within CrCl ranges; HR presented are for each DOAC vs warfarin within the CrCl

range provided. b150-mg dose ceGFR >50–≤80 mL/min deGFR≥30–≤50 mL/min e20 mg daily or 15 mg daily if CrCl 15–50 mL/min once daily with evening meal f5 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 gIn patients with stable renal function over time h60 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

SSE relative to warfarin for the DOACs stratified by renal function

• 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

SSE: CrCl >80 mL/min

SSE event rates for rivaroxaban, apixaban and dabigatran similar, and slightly numerically lower, compared with warfarin. 32,33,36 SSE events for edoxaban were similar, but slightly numerically higher compared with warfarin.34

0.71 1.60 0.82 1.28 1.05 1.7 0.94 0.97 1 2 3 4 Dabigatran Rivaroxaban Apixaban Edoxaban

CrCl ≥80 mL/min

n = 53 n = 92 n = 61 n = 70 n = 68 n = 65 n = 28 n = 41

% / year

DOAC Warfarin

• 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

SSE: CrCl >95 ml/min

Edoxaban post hoc sub-analysis

Trend toward lower efficacy relative to warfarin for SSE (HR 1.36 [0.88-2.1], p=0.08) Net clinical outcome (SSE + MB + all cause death) at least as favorable as warfarin across renal subgroups.34

Rivaroxaban subgroup analysis

Numerically, although not significantly, higher rate of SSE events relative to warfarin (HR 1.47 [ 0.81-2.68]) The interaction was significantly different relative to patients with CrCl ≤ 95 mL/min, in whom a stroke risk reduction was

• bserved (p=0.033).36

No peer-reviewed phase 3 subanalyses of dabigatran or apixaban in this population

• 34. Bohula EA. Circulation. 2016;134:24-36
• 36. Lindner SM. Circulation. 2017;135:1001-1003

SSE: CrCl >50-80 mL/min

(Normal to mild renal impairment) DOACs are associated with a reduced risk of SSE relative to warfarin

21..

% / year

DOAC Warfarin

• 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.

1.25 2.2 1.16 1.49 1.83 2.4 1.5 2.17 1 2 3 4 Dabigatran Rivaroxaban Apixaban Edoxaban

CrCl 50–<80 mL/min

n = 70 n = 103 n = 77 n = 98 n = 122 n = 176 n = 125 n = 141

SSE: CrCl ≤ 50 mL/min

All DOACs reduced SSE to a greater extent than warfarin in patients with moderate renal impairment (CrCl 30-50 mL/min) in individual trials

21..

% / year

DOAC Warfarin

• 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.

1.53 2.9 1.62 2.3 2.7 3.5 2.3 2.7 1 2 3 4

Dabigatran Rivaroxaban Apixaban Edoxaban

CrCl < 50 mL/min

n = 82 n = 36 n = 57 n = 45 n = 61 n = 91 n = 78 n = 96

Major bleeding relative to warfarin for the DOACs stratified by renal function

CrCl >80 mL/min CrCl >50–95 mL/min CrCl >50–80 mL/min CrCl 30–50 mL/min

% of enrolled HRa (95% CI) % of enrolle d HRa (95% CI) % of enrolled HRa (95% CI) % of enrolled HRa (95% CI) Dabigatran

25,32,39,b

31.3 0.90 (0.65, 1.25) NR NR 45.8 0.92 (0.75, 1.14)c 18.4 1.02 (0.77, 1.34)d Rivaroxaban

27,36,39,e

31.7 1.26 (0.95, 1.67) NR NR 45.7 0.94 (0.76, 1.15) 22.4 1.03 (0.79, 1.35) Apixaban

24,33,39,f

26.0g 0.80 (0.60, 1.07) g NR 0.74 (0.61, 0.94)g 48.1g 0.76 (0.62, 0.94)g 15 0.53 (0.39, 0.71) Edoxaban

26,34,39,h

37 0.86 (0.60, 1.22)i 58.3 0.89 (0.75, 1.04) 43 0.88 (0.73, 1.07) 19.5 0.76 (0.58, 0.98)

aComparisons should not be made across drugs within CrCl ranges; HR presented are for each DOAC vs warfarin within the CrCl range provided.

b150-mg dose ceGFR 50–<80 mL/min deGFR ≥30–≤50 mL/min e20 mg daily or 15 mg daily if CrCl 15–50 mL/min once daily with evening meal f5 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 gIn patients with stable renal function over time h60 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 iCrCl>80–95

• 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

Major Bleeding: CrCl >80 mL/min

Bleeding rates for dabigatran, apixaban and edoxaban similar, and slightly numerically lower, compared with warfarin32-34 Bleeding rates for rivaroxaban similar, but slightly numerically higher compared with warfarin36 Composite of major or non-major clinically relevant bleeding similar for rivaroxaban and warfarin, and no significant treatment interaction36

% / year

DOAC Warfarin

• 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.

2.04 3 1.33 2.44 2.43 2.4 1.66 2.85 1 2 3 4 5 6

Dabigatran Rivaroxaban Apixaban Edoxaban

CrCl ≥80 mL/min

n = 81 n = 95 n = 83 n = 103 n = 112 n = 89 n = 57 n = 70

DOACs are associated with a lower bleeding risk relative to warfarin.

% / year

DOAC Warfarin

3.35 3.5 2.14 2.44 3.7 3.7 2.84 2.85 1 2 3 4 5 6

Dabigatran Rivaroxaban Apixaban Edoxaban

CrCl 50–<80 mL/min

n = 188n = 209 n = 136n = 176 n = 136n = 176 n = 176 n = 191

• 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.

Major Bleeding: CrCl >50-80 mL/min

• In patients with moderate renal impairment (CrCl 30-50

ml/min), MB reduced with apixaban (HR 0.53 [0.39-0.71]) and edoxaban (HR 0.76 [0.58-0.98]) relative to warfarin33, 34

• Similar to warfarin for dabigatran or rivaroxaban.32, 36

21..

% / year

DOAC Warfarin

5.5 4.7 3.15 4 5.49 4.6 5.3 5.3 1 2 3 4 5 6

Dabigatran Rivaroxaban Apixaban Edoxaban

CrCl ≤50 mL/min

n = 129 n = 116 n = 100 n = 132 n = 82 n = 130 n = 106 n =106

Major Bleeding: CrCl ≤ 50 mL/min

• 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.

Severe Renal Dysfunction

(CrCl 15-30 ml/min)

Edoxaban 15 mg daily in NVAF patients with CrCl 15 - <30 mL/min

• Compared to 60 mg (30-mg reduced dose) in CrCl

50 mL/min over a 12-week period.40

• At 2 weeks, pre-dose edoxaban concentrations in severe renal impairment

significantly higher than in normal or mild renal impairment administered 30 mg edoxaban

• Similar to normal/mild renal impairment receiving 60 mg edoxaban

Apixaban open-label, parallel-group, single-dose study

• CrCl >80 vs. >50-80 vs. 30-50 vs. <30 not yet on dialysis41
• No effect on max apixaban concentrations after single 10-mg dose
• Apixaban exposure increased with increasing renal impairment
• 40. Koretsune Y. Circ J. 2015;79:1486-1495 41. Chang M. J Clin Pharmacol. 2016;56:637-645.

Patients on Hemodialysis

• Suggest comparable pharmacokinetics and pharmacodynamics

to patients with moderate to severe renal dysfunction

• Did not evaluate repeat dosing, accumulation or effects at

steady state

• Apixaban and rivaroxaban FDA-approved for use in NVAF

patients on intermittent hemodialysis 24,27

• As they have not been adequately studied in this population,

use of all DOACs should be avoided until better evidence is available

Small (n= 8-10) single-dose studies of apixaban, rivaroxaban and edoxaban 42,44,45

• 24. http://packageinserts.bms.com/pi/pi_eliquis.pdf 27. https://www.xareltohcp.com/shared/product/xarelto/prescribing-

information.pdf 42. Wang X. J Clin Pharmacol. 2016;56:628-636 44. Dias C. Am J Nephrol. 2016;43:229-236 45. Parasrampuria

• DA. Thromb Haemost. 2015;113:719-727

Emerging Evidence in Hemodialysis

Mavrakanas, et el. 2017

• Repeat doses of apixaban 2.5 mg and 5 mg twice daily

evaluated in patients on hemodialysis

• At steady-state, apixaban 5 mg BID increased exposure 2-5.7

times relative to 2.5 mg twice daily

• Results suggest the approved 5-mg twice daily dose for this

patient population may lead to supratherapeutic drug exposure

Ongoing trials

• RENAL-AF (NCT02942407)
• 43. Mavrakanas TA. J Am Soc Nephrol. 2017 Mar 16. http://dx.doi.org/10.1681/ASN.2016090980.

Patients with Worsening Renal Function

• May be related to decrease in vascular inflammation via FIIa

and Fxa inhibition DOACs may be associated with better preservation of renal function compared to warfarin * 26.3% and 13.6% of rivaroxaban and apixaban NVAF patients, respectively, had decreasing renal function (≥ 20% decrease in CrCl)31,47 Rivaroxaban and apixaban associated with lower relative risk of SSE and MB compared with warfarin in patients with decreasing renal function over time31, 47 Dabigatran and rivaroxaban showed significantly slower decrease in renal function compared to warfarin46,47

* Yao XY. JACC 2017; 70: 2621-32 31. Hijazi Z. JAMA Cardiol. 2016;1: 451-460 46. Bohm M. J Am Coll Cardiol. 2015;65:2481-2493

• 47. Fordyce CB. Circulation. 2016;134:37-47.

Conclusions

Patients with renal impairment are at increased risk for thromboembolic and bleeding events, a risk that increases over time Following DOAC dosing recommendations as calculated by C-G, utilizing actual body weight, is critical for avoiding improper dosing of patients In mild or moderate renal impairment, DOACs are associated with reduced SSE and MB relative to warfarin Until we have more data, DOACs should be avoided in severe renal impairment or hemodialysis whenever possible, despite labeling The DOACs may confer a better renal risk-benefit profile than warfarin in those with decreasing renal function over time Additional assessments may be warranted to ensure optimal use of DOACs in patients with very high or low renal function

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