Managing Hyperkalemia- Potential Impact on the Use of RAAS ... · (Mild Hyperkalemia) Baseline...
Transcript of Managing Hyperkalemia- Potential Impact on the Use of RAAS ... · (Mild Hyperkalemia) Baseline...
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.
• PMH- diabetes, CKD stage II-III
• Outpatient cardiac meds:- carvedilol 25 mg bid- sacubitril/valsartan 49/51 mg bid- spironolactone 12.5 mg daily- bumetanide 1 mg bid- KCl 20 meq daily
Physical Examination
• BP 126/84 mmHg, pulse 86 reg, RR 24, O2
sat 94%
• SOB but able to speak in full sentences
• JVP 15 cm, bibasilar rales, S3, 2-3 + LE
edema
• Labs – Na+ 134, K+ 4.8, Cr 1.56, BUN 43
Course in the Hospital• Patient is given 2 mg bumetanide IV and
supplemental nasal oxygen.
• She has a urine output of 2.3 L over the first 24 hours with only 1 L input. She feels less SOB.
• Diuresis continues over the next 3 days with progressive improvement in her symptoms.
• Weight is down 7 lbs from admission.
However….
• Labs on the morning of day 4 in the hospital show a creatinine and BUN that are both slightly elevated from baseline at 1.66/49. Her K+ is 5.4.
• What are your next steps?
Hyperkalemia in Patients During Heart Failure Hospitalization
Formiga F. Eu J Int Med. 2019 Feb;60:24-30
5.0 meq/l
Factors Associated With Hyperkalemia
Shah KB et al, JCF Volume 46, Issue 5, 2005, 845–849
Association Between Renal Function and Hyperkalemia in HF Patients
Drug-Induced Hyperkalemia
• ACEi’s, ARB’s and sacubitril-valsartan combination• K+-sparing diuretics, spironolactone
• Bactrim (trimethoprim), pentamidine• NSAIDs
• Beta blocker (both non-selective and B2 selective)
• Heparin• Digoxin (supratherapetuic levels)
• Succinylcholine (intubation in ICU, Surgery)* • Calcineurin inhibitors (cyclosporine, tacrolimus [FK506])
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.
Characteristics of New Potassium
Binding AgentsCharacteristic Patiromer Zirconium Cyclosilicate (ZS-9)
GI Absorption Non-absorbable Non-absorbable
Molecular structure Organic polymer
Mechanism of Action Ca-K exchange Na-K exchange
Relative K Affinity - 25-fold > Na
Site of Action Colon Upper/Lower GI tract
K selectivity relative to SPSS - 120-fold
Onset of [K]p lowering 7 hours 2 hours
crystalline inorganic cation exchange compound
Baseline serum K+ 5.1-<5.5 mEq/L(Mild Hyperkalemia)
Baseline serum K + 5.5-<6.5 mEq/L(Moderate/Severe Hyperkalemia)
Part A: 4-week Treatment Phase (Single-Blind)
Primary endpoint:• Mean change in serum potassium
from Baseline to Week 4
Secondary endpoint:• Proportion of patients with serum
potassium level of 3.8 mEq/L to < 5.1 mEq/L at Week 4
Subjects with CKD* on RAASi
(n=243)
8.4g per day(total daily dose)†
(n=92)
16.8g per day (total daily dose)†
(n=151)
Week 4 Part A Baseline Part A
Starting Patiromer Dose
All patients were on stable dose of at least one RAAS inhibiting agents*estimated glomerular filtration rate 15-60 ml/min/1.73m2
† dose titrated as needed to maintain target serum K+ 3.8 mEq/L to < 5.1 mEq/L
Patiromer:OPAL-HK
1. VELTASSA [package insert]. Redwood City, CA. Relypsa, Inc. 2015. 2. Weir M, et al. N Engl J Med. 2015;372(3):211-21.
OPAL-HK Study Part A:Efficacy Results
Patiromer Starting DoseBaseline K+ [Mean (SD)]: 5.31 mEq/L (0.57)
(n=90)
5.74 mEq/L (0.40)
(n=147)
Overall Population*5.58 mEq/L (0.51)
(n=237)
-0.65
-1.23
-1.01
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
Cha
nge
in
Seru
m P
otas
sium
(mEq
/L)
(95% CI -0.74, -0.55)
(95% CI -1.31, -1.16)
(95% CI -1.07, -0.95)
Mild HKModerate/Severe HKTotal
Primary Endpoint:
Weir M, et al. N Engl J Med. 2015;372(3):211-221.
OPAL-HK: Primary and Secondary Efficacy Endpoints
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
adjuncts to heart failure therapy.