Managing Hyperkalemia- Potential Impact on the Use of RAAS Inhibitors Barry Greenberg MD Distinguished Professor of Medicine Director Advanced Heart Failure Treatment Program University of California, San Diego 25 th Annual San Diego Heart Failure Symposium June 28-29, 2019 La Jolla, CA
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Managing Hyperkalemia-Potential Impact on the Use of
RAAS Inhibitors
Barry Greenberg MDDistinguished Professor of Medicine
Director Advanced Heart Failure Treatment ProgramUniversity of California, San Diego
25th Annual San Diego Heart Failure SymposiumJune 28-29, 2019
La Jolla, CA
Case Presentation
• 63 yo female with longstanding NICM admitted for weight gain of 23 lbs, SOB and ankle swelling.
Modified from Palmer BF. N Engl J Med. 2004;351(6):585-592.
Medications Associated with Hyperkalemia
2016 ACC/AHA/HFSA Heart Failure Guideline Update
Pharmacological Treatment for Stage C HFrEF
ARNI = angiotensin receptor blocker and neprilysin inhibitor; COR = class of recommendation; LOE = level of evidence.
Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-239.
1. Granger CB, et al. Lancet. 2003;362:772-776. 2. The SOLVD Investigators. N Engl J Med. 1991;325:293-302. 3. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.
Impact of ACEIs, ARBs and ARNIs on Mortalityin Patients with HFrEF
10
20
30
ACEInhibitor2
AngiotensinReceptorBlocker1
0
Dec
reas
e in
Mor
talit
y (%
)
18%
20%
AngiotensinNeprilysinInhibitor3
15%
2013 AHA/ACC/HFSA Guidelines
Aldosterone receptor antagonists are recommended in patients with NYHA class II-IV, LVEF of ≤35%,to reduce morbidity and mortality.
I IIa IIb III
Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-239.
554/3,319 478/3,313 .85 .008(.75, .96)
Hazard Log-rankPlacebo
Aldosterone
Antagonist Ratio P Value
Primary Endpoint: All-Cause Mortality
EPHESUSPost-MI
284/822386/841 .70 <.001(.60, .82)
RALESAdvanced HF
Trial
Pitt B. N Engl J Med. 2003;348:1309-1321. Pitt B. N Engl J Med. 1999;341:709-717.
Zannad F, et al. N Engl J Med. 2011;364:11-21
Trials With Mineralicorticoid
Receptor Antagonists
EMPHASISMilder HF
.76(.62, .93)
.008356/1373 249/1364
Admitted 2011-2013 withWorsening of Chronic HF
(n=1250)
>1 year Follow-Up(n=444)
Not Candidates for MRA Based on
Inclusion/ Exclusion Criteria (n=173)
Fulfilled Criteria for MRA Use(n=271)
<1 Year Follow Up(n=806)
No MRA on Admission
(n=210)
MRA on Admission(n=61)
Discharged without MRA
(n=164)MRA Initiated at DC
(n=46)
Receiving an MRA at Time of Hospital Discharge(n=105)
MRA Maintained during
Hospitalization (n=59)
MRA Discontinued
(n=2)
Only 105 of 271 (39%) Eligible Patients Were Taking anMRA at Hospital Discharge
DC with MRA
(n=105) (-) OFF MRA(n=35)
(+) ON MRA(n=70)
• (+) ON MRA (n = 70)– MRA Tx to discharge, LVAD or OHT– Without interruption– With 1 or fewer drug discontinuations and
tolerated therapy for > 180 days (6 months)
• (-) OFF MRA (n = 35)– 2 or more discontinuations– 1 discontinuation without restart and tx
duration < 180 days (6 months)
A
0
5
10
15
0
2
4
6
8
10
0
2
4
6
8
All-Cause Hospitalizations
+ -
p = 0.0010
Cardiovascular Hospitalizations
+ -
p = 0.0032
Heart Failure Hospitalizations
+ -
p = 0.0019 (+) ON MRA (-) OFF MRA
0.0
0.5
1.0
1.5
2.0
2.5
Episodes of Hyperkalemia/Patient
p = 0.0006+
-
0 500 1000 1500 20000
50
100
Days
Perc
ent S
urvi
val
(%)
p < 0.02 (+) ON MRA(-) OFF MRA
Survival
DC with MRA
(n=105) (-) OFF MRA(n=35)
(+) ON MRA(n=70)
• (+) ON MRA (n = 70)– MRA Tx to discharge, LVAD or OHT– Without interruption– With 1 or fewer drug discontinuations and
tolerated therapy for > 180 days (6 months)
• (-) OFF MRA (n = 35)– 2 or more discontinuations– 1 discontinuation without restart and tx
duration < 180 days (6 months)
A
0
5
10
15
0
2
4
6
8
10
0
2
4
6
8
All-Cause Hospitalizations
+ -
p = 0.0010
Cardiovascular Hospitalizations
+ -
p = 0.0032
Heart Failure Hospitalizations
+ -
p = 0.0019 (+) ON MRA (-) OFF MRA
0.0
0.5
1.0
1.5
2.0
2.5
Episodes of Hyperkalemia/Patient
p = 0.0006+
-
0 500 1000 1500 20000
50
100
Days
Perc
ent S
urvi
val
(%)
p < 0.02 (+) ON MRA(-) OFF MRA
Survival
Stopping an MRA is associated with worse outcomesincluding increased mortality
Use of GDMT in HFrEF – Results of the CHAMP-HF Registry
McMurray et al., NEJM. 2014.
Patients Excluded Due to Elevated K+ Levels During Run-in Period Veils Number of Patients with Elevated K+ Due to Treatment
Hyperkalemia Was Common in PARADIGM-HF
Long-Term Hyperkalemia Management Strategies
Strategy Limitation
Dietary K+ restriction of 40-60 mmol/day
Potassium is common ingredient in many foodsRestricts consumption of healthy foodsLow K+ diet often expensive
KayexalateWarnings related to serious gastrointestinal (GI) adverse eventsPrecaution related to sodium
RAASi reduction Limiting the prescription of drugs known to be effective in these populations
Low K+ Diet Is the First Step in Chronic Management, but
Compliance Is Difficult
Potassium-Rich Foods
KAYEXALATE (Sodium Polystyrene Sulfonate) Is Not
the Answer • Can cause colonic necrosis (particularly when used with
sorbitol).
• Should not be used in patients who do not have normal bowel function or in patients at risk of developing constipation or impaction.
• Administration presents patient with obligatory salt and water load (e.g. each g of SPS contains 100 mg of Na+ and the average daily dose of SPS is 15-60 g/day).
FDA: Food and Drug AdministrationReferences: http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm186845.htm accessed 12/10/2014Kayexalate PI December 2010. Sterns 2010; J Am Soc Nephrol 21: 733–735, 2010.; Kayexalate is a registered trademark of Sanofi Aventis
Changes in RAAS Inhibitor Dose In Response to Hyperkalemia
Epstein M et al. Am J Manag Care. 2015;21:S212-S220
52%41%
16% 21%
22%
26%
0%
15%
30%
45%
60%
75%
Perc
ent o
f Hyp
erka
lem
ia E
vent
s Maintained Dose Down-titrated Dose Discontinued
Moderate-to-Severe Hyperkalemia
47%
Among Patients on RAAS Inhibitor at Maximum Dose
Mild Hyperkalemia (Potassium 5.1-5.4 mEq/L)
(23,556 events) (11,608 events)
38%
Percent Mortality by Prior RAAS Inhibitor Dose
Epstein M et al. Am J Manag Care. 2015;21:S212-S220
9.8%13.7%
5.0% 4.1%
20%
27%
10% 8.2%
22.4%
30.1%
13.1%11.0%
0%
10%
20%
30%
40%
CKD Stages 3-4(N = 43,288
total patients acrossdose categories)
Heart Failure(N = 20,529
total patients acrossdose categories)
Diabetes(N = 79,087
total patients acrossdose categories)
Total Population(N = 201,655
total patients acrossdose categories)
% P
atie
nts
Maximum Dose Submaximum Dose Discontinued
Hyperkalemia in Heart Failure
• Unmet need for a safe and effective chronic therapy for prevention and treatment of hyperkalemia in HF patients on ACE-I, ARBs, MRA, and ARNI therapies.
Weir MR, et al. N Engl J Med. 2015;372(3):211-221.
Base-line
Mea
n Se
rum
K+
(mEq
/L)
Secondary Efficacy Endpoint:
76% of subjects had serum K+ in the target
range (3.8 to <5.1 mEq/L) at week 4
Study included 243 patientswith CKD who were takinga RAAS blocker
Phase 3 Part B: Exploratory Endpoints
0%
20%
40%
60%
80%
100%
Placebo
Patiromer62%
16%
44%
94%
Requiring any adjustment of RAASi (ie, down-titration or discontinuation) or
patiromer dose increase due to
hyperkalemia at any time during Part B
Receiving any dose of a RAASi at the
end of Part B
Pro
po
rtio
n o
f S
ub
ject
s (%
)P<0.001* P<0.001*
Weir MR, et al. N Engl J Med. 2015;372(3):211-221.
Mean Change in Serum PotassiumOver 1 Year (AMETHYST-DN)
Mean (95% CI) Serum Potassium over 52 weeks
Bakris GL, et al. JAMA 2015;314(2):151-161.
Mea
n (9
5% C
I) Se
rum
Pot
assi
um (m
Eq/L
)
Study Visit (week) Follow-Up (day)
Baseline Serum K+ ˃5.0 – 5.5 mEq/L
Baseline Serum K+ ˃5.5 – ˂6.0 mEq/L
BL 2 4 6 8 12 16 20 24 28 32 36 40 44 48 52 14 28
N= 301 (start of study)
N= 173 (study end)
ZS-9: A Novel First-in-Class Inorganic Crystalline Compound Designed
Specifically to Trap K+
Adapted from: Stavros F, et al. PLoS One. 2014;9(12):e114686.
In Vitro, ZS-9 is More Selective for Potassium than Kayexalate (SPS)
Adapted from: Stravos et al. PLOSONE 2014
ZS-9 Lowers K+ in Hyperkalemic Patients
Kosiborod M, et al. JAMA. 2014;312(21):2223-2233.
Effect of Sodium Zirconium Cyclosilicate on Potassium Lowering for 28 Days Among Outpatients With Hyperkalemia: The HARMONIZE Randomized Clinical Trial JAMA. 2014;312(21):2223-2233.
Mean Serum Potassium Levels Over 48 Hours With ZS-9
Dose-Dependent Serum K+ Reduction Over 48 Hours in HF Patients on RAASi
Source: El-Shahawy M, et al. Oral Presentation During a Late-Breaking Clinical Trial Session at the Heart Failure Society of America (HFSA) 18th Annual Scientific Meeting, Sep 15, 2014,
New Therapies For Hyperkalemia
• Hyperkalemia is common in patients with HF, CKD and/or
diabetes.
• High levels of potassium may lead to dose reduction or
discontinuation of RAAS inhibitors.
• Current treatments for hyperkalemia have limitations.
• Both patiromer and ZS-9 are newly available agents that
are safe and effective to treat hyperkalemia.
• Use of these new agents are likely to become important