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