Slide 1

Hyperkalemia Management: Current Challenges and Evolving Perspectives Murray Epstein, MD, FASN

Slide 2

RAASi Promotes Kidney-Saving and Life-Saving Benefits in Patients With CKD, Heart Failure, or Diabetes Mellitus CKD, chronic kidney disease; RAASi, renin-angiotensin-aldosterone system inhibitor.

Slide 3

RALES/EMPHASIS-HF: MRAs Improved Survival in Patients With HF HF, heart failure; MRAs, mineralocorticoid receptor antagonists. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709-717.

Slide 4

Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B: EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21. Cumulative KaplanMeier Estimates of Rates of the Primary Outcome and Other Outcomes, According to Study Group

Slide 5

Hyperkalemia Is a Common Complication in Patients With Heart Failure Receiving Mineralocorticoid Receptor Antagonists

Slide 6

Hospitalizations for Hyperkalemia Spiked in Heart Failure Patients After Publication of RALES Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004;351(6):543-551. Online release of RALES Rate of hospital admission for hyperkalemia among patients recently hospitalized for heart failure who were receiving ACEi Rate of Admission for Hyperkalemia (per 1,000 patients) Study Year 1994 10 12 14 8 6 4 2 0 19951996 1997199819992000 2001 The yellow lines and 95% CIs beginning in 1999 represent the projected rates of hospital admissions for hyperkalemia.

Slide 7

Hyperkalemia Is a Major Reason for Discontinuation of MRA 134 HF patients followed in a Portuguese HF clinic Spironolactone use in patients with sCr 2.5 mg/dL and K + 5 mEq/L 25% of patients withdrew from spironolactone therapy (19/76) HF, heart failure; MRA, mineralocorticoid receptor antagonist; sCR, serum creatinine Lopes RJ, et al. Clin Cardiol. 2008;31:509-513. % of Patients * Severe hyperkalemia (6 mEq/L) occurred in 7 patients who withdrew from spironolactone therapy (9.2%). Reason for spironolactone suspension (%) Discontinuation of MRA

Slide 8

In this issue of the The Lancet Diabetes & Endocrinology, Fujita and colleagues 6 report the results of a prospective, double-blind, randomised, placebo-controlled trial of 314 hypertensive non-diabetic patients with albuminuria (urinary albumin-to-creatinine ratio [UACR] 30599 mg/g) treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers or both, who were randomly assigned to either low- dose eplerenone (50 mg/day) or placebo. Background standard antihypertensive treatment was continued to reach therapeutic goals (

Slide 9

The Rationale for Prescribing MRA in Patients With CKD Is Compelling Various experimental and clinical studies have implicated aldosterone, independent of angiotensin II, in the pathogenesis of CV and renal disease a The CV benefits of MRA have been attributed to several mechanisms b - CV remodeling- Oxidative stress - Collagen turnover- Endothelial function Most clinicians are reluctant to use mineralocorticoid receptor antagonists in patients with chronic kidney disease and in patients with end-stage renal disease on hemodialysis because of the risk of this important side-effect (hyperkalemia). c MRAs are contraindicated in patients with an eGFR

Slide 10

MRA, but Not ARB, Added to a Regimen Including Maximal ACEi, Provides Greater Renoprotection in Diabetic Nephropathy Despite a Similar Effect on BP ARB, angiotensin receptor blocker; ACEi, angiotensin-converting enzyme inhibition; BP, blood pressure; DN, diabetic nephropathy; MRA, mineralocorticoid receptor antagonist; UACR, urine albumin-to-creatinine ratio. Mehdi UF et al. J Am Soc Nephrol. 2009;20:2641-2650.

Slide 11

Mean Serum K + Concentration Was Significantly Higher in MRA vs ARB ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor antagonist. Mehdi UF et al. J Am Soc Nephrol. 2009;20:2641-2650. (n = 27) 100 mg once daily (n = 26) 25 mg once daily (n = 27) Hyperkalemia (serum K + >6.0 mEq/L) occurred at least once in 2, 10, and 14 subjects in the placebo, ARB, and MRA groups, respectively (MRA vs placebo, P

Hyperkalemia Will Remain an Issue With LCZ-696 PARADIGM Heart Failure Study PARADIGM-HF selected a population at low risk for hyperkalemia prior to randomization Excluded patients with eGFR 5.5 mmol/L: 16.1% LCZ-696 versus 17.3% ACEi (P =.15) >6.0 mmol/L: 4.3% LCZ-696 versus 5.6% ACEi (P =.007) CV mortality benefit with LCZ-696 versus ACEi demonstrated in patients with eGFR 60 mL/min/1.73 m 2 and

Slide 13

Hyperkalemia versus RAASi: The Catch-22 of Managing Diseases That Benefit From RAASi Therapy!! Prescribe RAASi and Accept Presence of Hyperkalemia? RAASi, renin-angiotensin-aldosterone system inhibitor. Avoid/Discontinue Proven RAASi Therapies? CATCH-22

Slide 14

An extensive study of patients with CKD or heart failure who were treated with RAAS inhibitors revealed an incidence of hyperkalemia of 5%-10% Schrier RW. Nat Rev Nephrol. 2010;6:245-246.

Slide 15

Hyperkalemia Is a Leading Reason for Not Starting RAASi and the Major Reason for Discontinuation of RAASi in CKD 279 patients with CKD followed up for a mean of 22 months Baseline mean eGFR was 33.3 mL/min/1.73m 2 and the serum K + was 4.73 mEq/L Yildrim T, et al. Ren Fail. 2012;34(9):1095-1099. (80 patients) (51 patients) % of Patients CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; RAASi, renin-angiotensin-aldosterone system inhibitor.

Slide 16

Hyperkalemia Increases With Dual RAAS Blockade in Patients at High Risk for CV Events and/or ESRD ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CV, cardiovascular; ESRD, end-stage renal disease; RAAS, renin-angiotensin-aldosterone system. a. Yusuf S, et al; ONTARGET Investigators. N Engl J Med. 2008;358(15):1547-1559. b. Parving HH, et al; ALTITUDE Investigators. N Engl J Med. 2012;367(23):2204-2213. c. Persson F, et al; AVOID Investigators. Diabetes Care. 2010;33(11):2304-2309. a b c Rate of Hyperkalemia (% of patients)

Slide 17

Current Guidelines Tend to Lessen the Use of Full Recommended Doses of Renin- Angiotensin-Aldosterone System Inhibitors Because of Concerns Related to Hyperkalemia

Slide 18

Guidelines Recommend RAASi Modifications at Various Serum K + Levels Serum K + Threshold Before Change in RAASi Guideline Recommendation >6.0 >5.5 >5.0 ACA/AHA HF a : Maintain MRA 4.0-5.0 ACC/AHA, a ESC HF, b K/DOQI f : Reduce dose of/stop ACEi/ARB, AA if >5.5 HFSA HF c : MRA not recommended >5.0 NICE e : Stop RAASi if >6.0 NICE e : dont start RAASi if >5.0 KDIGO Guidelines do not provide recommendations d K/DOQI f : dont start RAASi if > 5.0 MRA, mineralocorticoid receptor antagonist; RAASi, renin-angiotensin-aldosterone inhibitor. a.Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-239. b.McMurray JJ, et al. Eur Heart J. 2012;33(14):1787-1847. c.Heart Failure Society of America, Lindenfeld J, et al. J Card Fail. 2010;16(6):e1-e194. d.KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;3(1). e.National Institute for Health and Care Excellence (NICE) [UK]. 2008. http://www.nice.org.uk/CG73. f.http://www.kidney.org/professionals/kdoqi/guidelines_bp/guide_11.htm#table131. Serum K + (mEq/L)

Slide 19

Hyperkalemia Prevents Use of Guideline-Recommended RAASi Therapy to Delay Progression to ESRD Kidney Disease Outcomes Quality Initiative, Guideline 11: Use of ACEis and ARBs in CKD In general, highest tolerated doses of ACEi or ARB (RAASi) are recommended If hyperkalemia develops, reduce dose of ACEi or ARB and/or discontinue the ACEi or ARB RAASi treatment in CKD* ~90% of nephrologists: hyperkalemia is top concern with use of RAASi medication** ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; ESRD, end-stage renal disease; RAASi, renin-angiotensin-aldosterone system inhibitor. *Estimates based on data adapted from Treatment Algorithm Quantitative Study, June 2013, N = 386. **Primary market research, April 2012.

Slide 20

RAASis confer substantive benefits including reducing cardiovascular events and retarding progression of renal disease in several disease states, including CHF, CKD, and diabetes mellitus Hyperkalemia will remain an issue with newly introduced drugs such as Neprolysin inhibitors (LCZ-696)PARADIGM Heart Failure Study Hyperkalemia complicates the management of patients with ESRD who are undergoing hemodialysis The wide gap between RAASis prescribing guidelines and realityis hyperkalemia the reason? As a consequence, we need effective and safe treatments to control hyperkalemia and facilitate treatment with optimal recommended doses of RAASis CHF, congestive heart failure; CKD, chronic kidney disease; ESRD, end-stage renal disease; RAASis, renin-angiotensin-aldosterone inhibitors. Conclusions