Spiro Me Right Round: Safety and Efficacy of Mineralocorticoid Receptor Antagonists in End-Stage Renal Disease

Devon Jacobs, PharmD PGY-2 Internal Medicine Pharmacy Resident

South Texas Veterans Health Care System, San Antonio, TX Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy

Pharmacotherapy Education and Research Center, University of Texas Health San Antonio April 3, 2020

Learning Objectives: 1. Discuss the pathophysiology and impact of end-stage renal disease (ESRD) requiring dialysis2. Explain the rationale for using mineralocorticoid receptors antagonists (MRAs) in ESRD3. Review clinical risks and benefits for use of MRAs in patients with ESRD requiring dialysis4. Evaluate literature investigating use of mineralocorticoid receptor antagonists and cardiovascular outcomes

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Figure 1. Stages of CKD11

I. Chronic kidney disease (CKD) a. Epidemiology1

i. Significant global public health problem2,3 1. 15% (37 million people) are estimated to have CKD in the United States (U.S.) 2. Most adults (90%) do not know they have CKD 3. 38% are ≥65 years old3,4

ii. Functional decline of kidney function by ~1% per year begins naturally after the age of 403 iii. International

1. Age-adjusted death rates increased by 37% from years 1990 to 20135 b. Risk Factors

i. Classified as susceptibility, initiation, and progression risk factors6 (appendix A) ii. Progression risk factors are associated with further decline in kidney function6

1. Diabetes mellitus (HbA1c >7%)7 2. Hypertension (BP >130/80 mmHg)8 3. Proteinuria (ACR ≥ 30 mg/g)1 4. Smoking1,9 5. Obesity (BMI >25 kg/m2)10

c. Diagnosis i. Abnormalities of kidney function or structure for >3

months1 1. One or more markers of kidney damage 2. Decreased GFR <60 ml/min/1.73m2

II. End-stage renal disease (ESRD)/end-stage kidney disease (ESKD) a. Definition1

i. Chronic kidney failure requiring dialysis or kidney transplantation1 ii. Estimated glomerular filtration rate (eGFR) <15 mL/min/1.73m2

b. Epidemiology i. International

1. Approximately 2 million people receive renal replacement therapy for ESRD4,12 ii. U.S.13

1. ~750,000 people receive dialysis for ESRD 2. 124,500 new cases of ESRD reported in year 2017 3. ESRD cases has continued to increase by nearly 20,000 per year since 2010

iii. Texas14 1. 2,019 cases of ESRD per million in 2016

c. Pathogenesis i. Nephron is the functional unit of the kidney and is responsible for filtering, reabsorbing, and

excreting solutes and water15 1. Each adult kidney is composed of ~1 million nephrons 2. Every nephron maintains its own single-nephron eGFR

ii. CKD and ESRD results from a loss in the number of nephrons16

Background

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Figure 2. Renin-angiotensin-aldosterone-system (RAAS)

iii. Mechanisms leading to ESRD6,17 1. Nephron hypertrophy

a. Results from persistent increases in single-nephron eGFR via compensatory glomerular hemodynamic changes

b. Leads to irreversible loss of nephron function due to sustained increases in glomerular pressure

2. Interstitial fibrosis a. Proteinuria recruits inflammatory cytokines causing inflammation and scarring

of the kidney over time 3. Glomerulosclerosis

a. Glomerular arteriolar damage b. Develops from prolonged elevation of glomerular capillary pressure and

increased glomerular plasma flow c. Results in a continuous cycle of nephron destruction

4. Renin-angiotensin-aldosterone-system (RAAS) a. Activation during nephron loss and inadequate nephron compensation b. Causes fluid accumulation to maintain perfusion and eGFR

iv. Consequences of ESRD6 1. Impaired physiologic functions of the kidney

a. Decreased erythropoietin production à anemia b. Decreased vitamin D activation à decreased bone mineral density c. Decreased excretion of fluid and electrolytes à edema and electrolyte

disturbances d. Decreased acid-base regulation à acidosis

2. Annual mortality for ESRD patients receiving HD is up to 20%18 a. Cardiovascular death (~40%)19

i. Hypertension ii. Type 2 diabetes mellitus

iii. Left ventricular hypertrophy and fibrosis iv. Heart failure v. Arrhythmias vi. Sudden cardiac death

angiotensinogen angiotensin I

angiotensin II aldosterone

renin angiotensin converting enzyme

adrenal cortex

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III. Heart Failure (HF) in ESRD a. Epidemiology

i. Incidence of de novo HF in CKD ranges between 17% to 21%20 ii. Estimated 44% of patients on hemodialysis have HF14

iii. Associated with increased all-cause mortality, cardiovascular mortality, and hospitalization21 b. HF and CKD/ESRD occur in bi-directional pattern21

i. HF and CKD/ESRD share multiple risk factors ii. Arteriovenous fistulae or graft access is associated with worsening of ventricular hypertrophy

and increased pulmonary pressures c. Patients are less likely to receive guideline-directed medical therapy due to concerns of hypotension,

decreased kidney function, and hyperkalemia22 d. Modified HF classification system was proposed for ESRD patients to account for dynamic volume

status23 (appendix B)

I. Hemodialysis (HD) and peritoneal dialysis (PD)19 a. Process that facilitates removal of excess water and toxins from the body b. Indicated based on patient clinical status and signs/symptoms of kidney failure

i. In 2017, 87% of ESRD patients were on HD and 10% of patients were on PD14 ii. Low life expectancy: 57% HD and 68% PD patients remain alive at 3 years14

c. Differences between HD and PD19 (Table 1) d. Oxidative stress24

i. Results from accumulation of uremic toxins in ESRD ii. HD promotes formation and accumulation of reactive oxygen species (ROS) via activation of

platelets, complement, and polymorphonuclear white blood cells25,26 1. Stimulates renal ischemia and inflammation causing further glomerular injury and cell

death

II. Transplantation a. Requires donor match, major surgery and lifelong immunosuppressive therapy21

i. 5-year survival >80%14 b. >100,000 ESRD patients on the U.S. transplant waitlist14

Table 1. Advantages and Disadvantages of Hemodialysis Compared to Peritoneal Dialysis19

Advantage Disadvantage • Higher solute clearance • Underdialysis can be detected early • Technique failure rate is low • Hemostasis parameters are better corrected • In-center dialysis enables closer monitoring

• In-center dialysis requires multiple visits • Disequilibrium, hypotension, and muscle cramps • Infections is related to patient choice of membrane • Vascular access increases infections and thrombosis • Decline of residual kidney function is more rapid

Treatment

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III. HF in ESRD21 a. Non-pharmacological – restricted diet (sodium and potassium) b. Pharmacological – limited clinical data to support definitive benefit with traditional HF agents c. HFpEF (LVEF ≥50%)

i. Focused management on blood pressure and volume status ii. No mortality-proven treatments for HFpEF21

d. HFrEF (LVEF <40%) i. B-blocker

1. Ordered preference: carvedilol > bisoprolol > metoprolol succinate28 a. Based on dialyzability of individual agents

ii. RAAS inhibitors

1. ACEi or ARB a. No direct evidence of benefit in patients receiving dialysis2

2. ACEi + ARB

Table 2. B-blocker Efficacy in ESRD Study Design Patients Intervention Outcome Cice et al.

200327 (n=114)

Prospective, RCT

Dialysis with HFrEF (LVEF <35%)

Carvedilol 25mg twice daily vs placebo + standard therapy

Secondary: all-cause mortality (51.7% vs 73.2%, p<0.01); cardiovascular deaths (29.3% vs 34.5%, p<0.00001)

Table 3. ACEi or ARB Efficacy in CKD Study Design Patients Intervention Outcome Edner et al. 201529 (n=1204)

Prospective registry analysis

CKD 4-5 with LVEF ≤39%

RAAS antagonist (ACEi or ARB) vs none

Primary: propensity matched all-cause mortality at 1-year, HR 0.76 (95% CI 0.67-0.86, p<0.001)

Tokmakova et al. 200430 (n=2183)

Prospective RCT

Post-MI patients with LVEF ≤40%

Captopril 25mg twice daily (target) vs placebo

Multivariate adjusted total mortality: superiority for captopril with eGFR <60 ml/min/1.73m2, HR 0.79 (0.65-0.95, p=0.01)

Table 4. ACEi + ARB Efficacy in ESRD Study Design Patients Intervention Outcome Cice et al. 201031 (n=332)

Prospective RCT, multicenter

Dialysis with HFrEF ≤40%

Telmisartan 80mg daily vs placebo + ACEi

Primary: (at 3 years) all-cause mortality (35.1% vs 54.4%, p<0.001); CV mortality (30.3% vs 43.7%, p<0.001); Hospital admission for CHF (33.9% vs 55.1%, p<0.0001); Safety: adverse events (16.3% vs 10.7%, p<0.01) - hypotension

Chan et al. 201132 (n=701)

Retrospective ESRD with low CHF cohort (0.5%)

ACEi + ARB for hypertension

Primary: CV death (ACEi + ARB, HR 1.45), (ACEi + non-ARB anti-HTN agent, HR 1.27) vs (ARB + non-ACEi anti-HTN agent, reference)

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IV. Aldosterone receptor antagonists a. Spironolactone and eplerenone

i. Competitively inhibit aldosterone binding to the mineralocorticoid receptor (MR) in the distal renal tubules33

1. Prevents upregulation of sodium/potassium ATPase pumps and sodium channels 2. Blocks sodium reabsorption while reducing excretion of potassium and hydrogen ions

ii. Pharmacokinetic comparison34 (appendix C) iii. Efficacy of benefit has been shown in specific patient populations

1. HFrEF or HFrEF post-MI 2. Resistant hypertension without ESRD

iv. Aldosterone in ESRD

1. Steroid hormone known to have direct effects on sodium, potassium and extracellular fluid volume regulation via binding to the mineralocorticoid receptor (MR) in the distal convoluted tubule33,39

2. MRs are expressed in multiple cell types beyond the kidneys40 3. Aldosterone breakthrough39,41

a. Serum aldosterone increase of >10% from baseline at 6-12 months after initiating an ACEi or ARB

b. Incidence of 28-53% at 1 year c. High aldosterone levels linked to proinflammatory and profibrotic pathways

i. Endothelial dysfunction ii. Glomerulosclerosis

iii. Interstitial fibrosis iv. Vascular remodeling42

1. Left ventricular hypertrophy 2. Carotid intima-media thickening 3. Cardiac fibrosis 4. Heart failure

v. LURIC trial: Plasma aldosterone associated with increased CVD mortality and sudden cardiac death with lower renal function (excluded ESRD)43

4. Endogenous aldosterone elevation does not always occur in ESRD44 a. Physiologic response to endogenous aldosterone can increase despite normal

aldosterone concentrations in ESRD patients45

v. Hyperkalemia 1. Pre-dialysis potassium ≥5.6 mEq/L is associated with negative cardiovascular outcomes46

a. Induction of fatal arrhythmias 2. KDIGO guidelines cautions use of MRAs in CKD or worsening renal function1 3. ACC/AHA/HRS HF guidelines recommend considering discontinuation of MRAs if serum

potassium is >5.5 mEq/L or worsening renal function47,48 a. Major clinical trials excluded patients with eGFR <30 mL/min/1.73 m2

4. Colonic excretion and routine dialysis regulate potassium levels in ESRD patients49

Table 5. Mineralocorticoid Receptor Antagonist Efficacy in HF and HTN Populations Study (HF or HTN)

RALES35

(HF) EMPHASIS-HF36

(HF) ASCOT37

(HTN) PATHWAY-238

(HTN)

Main Outcome

Spironolactone reduced all-cause mortality by 30% at 2 years

Eplerenone reduced all-cause mortality by 22% at 1.8 years

Spironolactone reduced BP by mean 22/10 mmHg at 1 year

Spironolactone reduced SBP by mean 5-10 mmHg at 12 weeks

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V. Literature for MRA use in patients on dialysis is limited by:

a. Small sample sizes b. Duration of follow-up c. Varying population comorbidities d. Variable endpoints for cardiovascular outcomes

Table 6. Effect of mineralocorticoid receptor antagonists in patients on dialysis50,51

Study (n) Dialysis Characteristic Duration Intervention Outcomes Gross et al. 200552 (n=8)

HD Oligo-anuric 2wk Spironolactone 50mg BID

Pre-dialysis SBP reduction of 10.6 mmHg

Taheri et al. 200953 (n=16)

HD LVEF <45% 6mo Spironolactone 25mg TIW post-HD

LVEF improved (CFB of 6.2 ± 2.64 vs 0.83 ± 4.9 placebo)

Vakusich et al. 201054 (n=53)

HD No residual renal function

24mo Spironolactone 50mg TIW post-HD

Carotid IMT was reduced over time vs placebo

Taheri et al. 201255 (n=18)

PD NYHA 3-4 CHF 6mo Spironolactone 25mg TIW

LVEF improved (25.7 ± 7.3% vs 33.3 ± 7.8% placebo; p=0.002)

Ni et al. 201456 (n=82) HD Refractory HTN 3mo Spironolactone 25mg daily (add-on therapy)

10.9/5.8 mmHg mean reduction/24-h vs placebo

Ito et al. 201457 (n=158)

PD Concurrent ACEi/ARB

24mo Spironolactone 25mg daily

LVMI improved at 6, 18, 24mo vs nothing

Feniman-De-Stefano et al. 201558 (n=17)

HD LVH 6mo Spironolactone 25mg daily

LVMI reduced from 77 ± 14.6 to 69 ± 10.5 g/m2 from baseline (p<0.04)

Walsh et al. 201559 (n=154)

HD RRT ≥ 3mo 3mo Eplerenone titrated up to 50mg daily

No difference in drug-discontinuation from hyperkalemia or hypotension vs placebo

Lin et al. 201660 (n=253)

HD and PD

Non-CHF 24mo Spironolactone 25mg daily

Absolute reduction of 10.8% in CCV mortality vs placebo (HR 0.42, 95% CI 0.26-0.78); LVMI reduced by 8.7 g/m2

ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; BID = twice daily; CCV = cardiovascular and cerebrovascular; CHF = congestive heart failure; CFB = change from baseline; HD = hemodialysis; HTN = hypertension; wk = week; mo = month; IMT = intima-medial thickness; SBP = systolic blood pressure; LVEF = left ventricular ejection fraction; LVH = left ventricular hypertrophy; LVMI = left ventricular mass index; NYHA = New York Heart Association; PD = peritoneal dialysis; RRT = renal replacement therapy; TIW = three times weekly

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Is it safe and effective to use mineralocorticoid receptor antagonists to reduce cardiovascular events in patients with end-stage renal disease on dialysis?

Table 7. Matsumoto et al. J Am Coll Cardiol. 2014;63(6):528-536.61

Objective To assess whether spironolactone treatment reduces the high incidence of cardiovascular and cerebrovascular (CCV) morbidity and mortality in hemodialysis patients

METHODS Design Prospective, multicenter, randomized, controlled, open-label trial at 5 Japanese outpatient HD clinics

Patient Population

Exclusion Criteria • Hx of noncompliance (including HD

noncompliance) • Unstable vascular access • Hypotension • Hepatic failure • Active malignancy • Any life-threatening disease other than

ESRD

Inclusion Criteria

• HD patients o 3 times a week for at least 2 years

• ≥30 years of age • Pre-HD average serum potassium level <6.5

mEq/L for at least 2 months • 24-h urinary output of <500 mL

Intervention • Spironolactone 25mg daily vs control o Pre-enrollment medications known to affect potassium were not changed

(e.g., ACEi, ARB, loop diuretics, and ion exchange resins) • Serum potassium levels were repeated twice a month • 3-year follow-up • Intervention held if K+ >6.8 mEq/L, gynecomastia, breast pain or as medically necessary per

treating physician • No per protocol changes in HD procedures

Outcomes Efficacy: • Primary: composite of death or hospitalization from cardiovascular and cerebrovascular (CCV)

events (i.e. heart failure, ventricular arrhythmias, myocardial infarction, angina pectoris, aortic dissecting aneurysm, stroke, transient ischemic attack, SCD)

• Secondary: all-cause mortality Safety: • Any adverse events

Clinical Question

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Table 7. Matsumoto et al. J Am Coll Cardiol. 2014;63(6):528-536.61 (Continued)

Statistical Analysis

• Patient characteristics summarized using descriptive statistics (significance, p<0.05) • Outcomes: Univariate analyses using the Cox-Mantel test, then multivariate analyses with Cox

proportional hazards model – intention-to-treat o Hazard ratio adjustment for sex, duration of dialysis, and cardiothoracic index (CTR) o For multiple CCV events observed in a single patient, the first event was analyzed for

the primary outcome • Needed 600 subjects to detect a hazard-ratio reduction of 40% for mortality in treatment

group at 2-sided alpha level of 0.05 and 80% power. RESULTS

Sample Size • 309 patients included in final study population

Baseline Characteristics

Variable Spironolactone 25 mg/day (n=157) Control (n=152) p-value

Age, yrs ± SD 67.4 ± 12.3 67.7 ± 11.2 NS Sex, male n (%) 113 (72) 90 (59) <0.05 Duration of dialysis, mo, n ± SD 99.9 ± 82.2 127.7 ± 94.2 <0.01 Principle cause of ESRD, n (%) NS Diabetes 50 (32) 47 (31) - Hypertension 20 (13) 7 (5) - Glomerulonephritis 61 (39) 66 (43) - Polycystic kidney disease 8 (5) 11 (7) - Other 18 (11) 21 (14) - Blood pressure, mm Hg ± SD Systolic 152.1 ± 22.5 148.8 ± 22.8 NS Diastolic 77.4 ± 13.6 76.2 ± 11.8 NS Medical History, n (%) Atrial fibrillation 13 (8) 20 (13) NS PCI 22 (14) 13 (9) NS Cardiac surgery or aorta surgery 5 (3) 4 (3) NS Medication, n (%) ACEI 14 (9) 15 (10) - ARB 64 (41) 57 (36) - ACE, ARB, or both 67 (43) 62 (41) NS Beta-blocker 14 (9) 13 (9) NS Ion exchange resin 24 (15) 21 (14) NS

Laboratory Cardiothoracic ratio, % ± SD 49.5 ± 4.9 51 ± 5.3 <0.01 Urea reduction ratio, % ± SD 69.6 ± 4.7 68.6 ± 5.5 NS Hemoglobin, g/dl ± SD 10.3 ± 1 10.4 ± 2 NS Serum albumin, g/dl ± SD 3.84 ± 0.26 3.76 ± 0.29 <0.05 Serum creatinine, mg/dl ± SD 11.3 ± 2.4 11.4 ± 7.8 NS

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ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; CAD = coronary artery disease; CCV = cerebrovascular and cardiovascular; CHF = congestive heart failure; CTR = cardiothoracic ratio; ESRD = end-stage renal disease; HD = hemodialysis; Hx = history; PCI = percutaneous intervention; SCD = sudden cardiac death; SD = standard deviation

Table 7. Matsumoto et al. J Am Coll Cardiol. 2014;63(6):528-536.61 (Continued)

Outcomes Efficacy

Variable, n (%) Spironolactone

25mg/day (n=157)

Control (n=152)

Hazard Ratio (HR) (95% CI) p-value

Primary: composite 9 (5.7) 23 (12.5) 0.404 (0.202-0.809) 0.017 Cardiovascular event 5 (3.2) 12 (7.9) 0.438 (0165-1.110) 0.113 SCD 4 (2.5) 5 (3.2) 0.787 (0.213-2.910) 0.980 Cerebrovascular event 4 (2.5) 11 (7.2) 0.379 (0.138-1.045) 0.106 Secondary: all-cause death 10 (6.4) 30 (19.7) 0.355 (0.191-0.662) 0.002 CCV death 5 (3.2) 12 (7.9) 0.430 (0.166-1.115) 0.136 • Primary adjusted HR (sex, duration of dialysis, CTR): 0.379 (0.173-0.832), p=0.016 – NNT 15

Safety

Variable Spironolactone

25mg/day (n=157)

Control (n=152)

Hazard Ratio (95% CI) p-value

Hyperkalemia, n (%) 3 (1.9) 0 (0) - - Breast pain, n (%) 9 (3.2) 0 (0) - - Gynecomastia, n (%) 7 (2.5) 0 (0) - -

• Secondary adjusted HR: 0.335 (0.162-0.693), p=0.003 – NNT 8

• Blood pressure change from baseline was not significant in spironolactone group (n=98)

• therapy – NNH 24 • Probabilities: anti-MRSA with standard vs without standard vs standard therapy alone (11.6%

vs 12.7% vs 8.6%)

Table. Adjusted Risk Ratios for 30-Day Mortality Among Primary and Subgroup Inverse Probability-Weighting Analyses ^Hx of MRSA infection/colonization in ≤1 year or ≥2 of following: hx hospitalization, nursing home, previous IV abx use #Positive blood or respiratory culture within 2 days of admission Secondary endpoints:

• Kidney injury: aRR 1.4 (95% CI, 1.3-1.5)

Authors’ Conclusions

• Low dose spironolactone can be administered safely to long duration HD patients, and it may reduce CCV events and all-cause mortality

Reviewer’s Critique Strengths • Background potassium altering medications were continued (e.g., ACEi, ARB)

• Dialysis components were controlled • Heart failure guideline recommended dosing of spironolactone • Analysis adjusted for statistically different baseline characteristics • Oligo-anuric population (urine output <500 mL/24 hours)

Limitations • Japanese population, open-label design, no placebo • Small sample size • Ambiguous exclusion and discontinuation parameters • Unknown heart failure status and ejection fraction • Unknown change in mean serum potassium

Take-home points

• Spironolactone may be efficacious in reducing CCV events in patients with ESRD on HD • Several limitations decrease the generalizability of results • Spironolactone appears to be safe in patients receiving dialysis with twice monthly monitoring • Spironolactone efficacy and safety in specific heart failure populations cannot be drawn from

this study

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Table 8. Charytan et al. Kidney Int. 2019;95(4):973-982.62

Objective To evaluate the safety and tolerability of spironolactone and generate preliminary estimates of efficacy compared to placebo in patients receiving maintenance HD

METHODS Design Prospective, parallel-group, double-blind, randomized, placebo-controlled, multiple-dosage trial

among 4 U.S. academic medical centers Patient Population

Exclusion Criteria • Serum potassium ≥6.5 mEq/l

o Unscheduled HD past 3 months o Potassium ≥6 mEq/l within 2 weeks

• Pre-HD SBP <100 mmHg within 2 weeks • ≥2 HD sessions with BP <80 mmHg within

1 month o Tx for side effects (e.g., hypotension)

• Digoxin, spironolactone, eplerenone or ACEi/ARB combination

• Hypersensitivity to spironolactone

Inclusion Criteria

• Age 18-85 years • Maintenance HD ≥6 months or 3-6 months

if no change in target dry weight or hospitalizations for 2 and 6 weeks

• Compliance to birth control (women of child-bearing age) x4 weeks after study

Intervention • Spironolactone 12.5mg, 25mg, 50mg, or placebo daily (1:1:1:2 randomization) o 9-month total follow-up duration, monthly telephone/clinic visits

• 6-week dose escalation phase with weekly follow-up o Dose increased every 2 weeks until target dose reached

• Serum potassium monitored 3-5 days after dose change, 2 weeks, then monthly • Dosing can be decreased x2 before discontinuation (blinded) • Permanent discontinuation of study drug if serum potassium ≥7 mEq/l • Adherence measured via pill counts

Outcomes Safety: • Primary: Incidence of serum potassium >6.5 mEq/l and serious hypotension (requiring

hospitalization or treatment in emergency department – not contributed by cardiovascular or infectious state)

• Secondary: Hyperkalemia requiring hospitalization, mean potassium at follow-up, interdialytic hypotension

Efficacy: • Primary: Change in diastolic function measured by mitral annular E’ velocity • Secondary: change in left ventricular mass index (LVMI)

Statistical Analysis

• Based on incidence rate in intention-to-treat populations • Generalized estimating equations using regression models: Poisson for repeat events,

binomial for binary or incidence measures, and Gaussian for continuous measures • Needed 125 subjects for 80% power to detect 0.1 mEq/l difference in potassium levels

between groups.

RESULTS Sample Size • 129 patients included in final study population

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Table 8. Charytan et al. Kidney Int. 2019;95(4):973-982.62 (Continued)

Baseline Characteristics Variable

Spironolactone treatment Placebo (n=51) 12.5 mg/day

(n=27) 25 mg/day

(n=26) 50 mg/day

(n=25) Age, yrs (SD) 55.1 (13.6) 53.3 (13.5) 55.5 (9.8) 56.8 (11.5) Sex, male n (%) 15 (55.6) 19 (73.1) 19 (76) 32 (62.7) Dialysis ≥1 year, n (%) 23 (85.2) 23 (88.5) 23 (92) 47 (92.2) Comorbidities, n (%) Diabetes 13 (48.1) 14 (53.8) 15 (60) 24 (47.1 Hypertension 24 (88.9) 23 (88.5) 23 (92) 50 (98) CAD 1 (3.7) 8 (30.8) 7 (28) 12 (23.5) CHF 2 (7.4) 4 (15.4) 5 (20) 10 (19.6) Medication, n (%) ACEi or ARB 9 (33.3) 8 (30.8) 7 (28) 15 (29.4) Beta-blocker 12 (44.4) 12 (46.2) 15 (60) 22 (43.1) Blood pressure, mm Hg, mean (SD) Systolic 135.6 (22.7) 141.1 (19.4) 140.9 (25) 140 (18.9) Diastolic 75 (8.3) 81.1 (15.3) 76.1 (12.1) 78.2 (11.6) Laboratory, mean (SD) Potassium, mEq/l 4.7 (0.5) 4.8 (0.6) 4.8 (0.7) 4.8 (0.6) 24-hr urine, ml, median (IQR) 0 (0-289) 99.7 (0-464) 3.9 (0-219) 0 (0-142)

Outcomes Safety

Variable Spironolactone treatment Placebo

(n=51)

P-value (trend) 12.5 mg/day

(n=27) 25 mg/day

(n=26) 50 mg/day

(n=25) Primary: Patients with event, n (%) Serum K+>6.5 mEq/l 4 (14.8) 4 (15.4) 8 (32) 32 (62.7) 0.04 Hypotension 2 (7.4) 0 (0) 3 (12) 0 (0) 0.01 Secondary: Hyperkalemia admit 2 (7.4) 0 (0) 7 (28) 6 (11.8) <0.001 Req. adjustment 2 (7.4) 5 (19.2) 7 (28) 13 (25.5) <0.001 Inter-dialytic hypotension 4 (14.8) 6 (23.1) 5 (20) 6 (11.8) 0.7 Per-pt mean K+, mEq/l (SD) 4.84 (0.44) 4.76 (0.43) 4.93 (0.41) 4.82 (0.48) 0.2 • Cerebrovascular accident, cardiovascular death, and all-cause death: no difference

Efficacy

Variable Spironolactone treatment Placebo

(n=51)

P-value (trend) 12.5 mg/day

(n=27) 25 mg/day

(n=26) 50 mg/day

(n=25) Primary: Change from baseline, cm/s (SD)

Early diastolic mitral velocity -0.2 (1) -0.1 (1.2) 0.3 (1.6) 0.1 (1.1) 0.5 Secondary: Change from baseline, % (SD) Left ventricle ejection fraction 1 (4.7) -0.7 (7.3) 1.3 (3.7) 1.8 (4.1) 0.03 • Adherence: 80-86% across all groups; common reason to discontinue: hyperkalemia (44%)

• Primary adjusted HR (sex, duration of dialysis, CTR): 0.379 (0.173-0.832), p=0.016 – NNT • Secondary adjusted HR: 0.335 (0.162-0.693), p=0.003 – NNT

• Blood pressure change from baseline was not significant in spironolactone group (n=98)

Authors’ Conclusions

• Spironolactone was well tolerated compared with placebo • Higher dosages associated with increased hyperkalemia and hypotension

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ACEi = angiotensin converting enzyme inhibitor; adjustment = dialysate or drug discontinuation; ARB = angiotensin receptor blocker; CAD = coronary artery disease; CHF = congestive heart failure; ESRD = end-stage renal disease; HD = hemodialysis; IQR = interquartile range; K+ = potassium; LVMI = left ventricular mass index; pt = patient; RAAS = renin-angiotensin-aldosterone system; req = required; SD = standard deviation

Table 8. Charytan et al. Kidney Int. 2019;95(4):973-982.62 (Continued)

Reviewer’s Critique Strengths • Double-blind, placebo-controlled design at U.S. medical centers

• Background RAAS system inhibitors were continued (e.g., ACEi, ARB) • Analysis on dosing range of spironolactone on pertinent safety outcomes • Assessed adherence and per-patient mean serum potassium • Implemented a protocol algorithm for management of hyperkalemia

Limitations • Differences in baseline characteristics • Young and healthy population included versus previous literature • Small sample size and short follow-up duration • Intermediate efficacy outcome may not directly relate to cardiovascular outcomes • Limited amount of heart failure reduced ejection fraction patients were included • Take-home

points • Spironolactone ≤25 mg/day is safe vs placebo for ESRD patients on maintenance HD

o Spironolactone 50 mg/day appears to be associated with higher risk for hyperkalemia and hypotension requiring medical services

• Safety data from this study is more generalizable to U.S. population • Spironolactone efficacy on intermediate outcomes for cardiovascular outcomes is not

different vs placebo; however, limitations exist for a type II error

Table 9. Hammer et al. Kidney Int. 2019;95(4):983-991.63

Objective To study the effect of spironolactone on cardiovascular (CV) parameters and safety in patients with ESRD undergoing HD

METHODS Design Prospective, multicenter, randomized, placebo-controlled trial among 20 outpatient dialysis centers

across Germany Patient Population

Exclusion Criteria • MRA treatment (≤6 months) • Hx of hyperkalemia

o Pre-HD K+ ≥6.5 mEq/l ≥3 episodes in previous 3 months

o Pre-HD K+ ≥6 mEq/l • Arterial hypotension (SBP <100 mmHg) • Estimated life expectancy <12 months • Allergy to spironolactone

Inclusion Criteria

• Age ≥18 years • Maintenance HD (≥3 months)

o At least 3 HD sessions/week

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Table 9. Hammer et al. Kidney Int. 2019;95(4):983-991.63 (Continued)

Intervention • Placebo run-in phase of 2-4 weeks • Spironolactone 50mg daily vs matching placebo (1:1)

o 25mg daily x 2 weeks if treatment restarted after hyperkalemia episode • Potassium levels drawn before each HD session

o Interventions temporarily held or discontinued for hyperkalemia (≥6 mEq/L) until level <5.5 mEq/l

• 40-week follow-up duration • Patients followed for 4 weeks after treatment discontinuation for safety analysis

Outcomes Efficacy: • Primary: Change in left ventricular mass index (LVMI) • Secondary: Change in blood pressure, cardiac function, or functional capacity

Safety: • Change in potassium levels, moderate hyperkalemia (6-6.5 mEq/l), severe hyperkalemia (≥6.5

mEq/L), change in residual renal function if ≥500 mL/day output

Statistical Analysis

• Efficacy: required 2 LVMI readings and 1 dose to mimic intention-to-treat o ANCOVA performed on primary outcome o Generalized linear model used to assess functional capacity outcomes o Descriptive statistics utilized for other variables/outcomes

• Needed 66 subjects for 80% power to detect 7g/m2 difference in LVMI with SD of 10g/m2. Anticipated 39 (32%) drop-out

RESULTS Sample Size • 97 patients included in final study population

Baseline Characteristics Variable Spironolactone

50 mg/day (n=50) Placebo (n=47) All-patients (n=97)

Age, yrs ± SD 60.6 ± 13.1 59.9 ± 13.4 60.3 ± 13.2 Sex, male, n (%) 40 (80) 35 (74.5) 75 (77.8) Duration of HD, mo, median (IQR) 35 (17-60) 45 (14-80) 42 (15.7-74.5) Co-morbidities, n (%) Diabetes 16 (32) 16 (34) 32 (33) Hypertension 39 (78) 46 (97.9) 85 (87.6) CAD 19 (38) 17 (36.2) 36 (37.1) HF (LVEF <40%) 3 (6) 1 (2) 4 (4) LVH 25 (50) 19 (40.4) 44 (45.4) Medication, n (%) ACEi or ARB 29 (58) 26 (55.3) 55 (56.7) Beta-blocker 34 (68) 34 (72.3) 68 (70.1) Potassium binder 2 (4) 1 (2.1) 3 (3) Laboratory, n (%) Residual renal function 24 (48) 23 (48.9) 47 (48.5)

Jacobs 15

ACEi = angiotensin converting enzyme inhibitor; ARB =angiotensin receptor blocker; CV = cardiovascular; GFR = glomerular filtration rate; HF = heart failure; IQR = interquartile range; LVEF = left ventricular ejection fraction; LVH = left ventricular hypertrophy; LVMI = left ventricular mass index

Table 9. Hammer et al. Kidney Int. 2019;95(4):983-991.63 (Continued)

Outcomes Efficacy Variable, n (%) Mean difference in change (95% CI) p-value

Primary: LVMi, g/m2 -2.27 (-6.94, +2.41) 0.337 Secondary: LVEF, % -1.94 (-5.15, +1.28) 0.235 Office systolic/diastolic, mmHg -1.25 (-9.51, +7.01)/1.51 (-4.43, +7.45) 0.764/0.912 24-h systolic/diastolic, mmHg -2.24 (-7.91, +3.42)/-1.16 (-4.61, +2.29) 0.433/0.505 Distance, 6-min walk test -0.36 (-52.13, +51.4) 0.989

Safety Variable Spironolactone Placebo p-value

Serum potassium, mEq/L ± SD 5.02 ± 0.052 4.88 ± 0.054 0.061 Moderate hyperkalemia (6-6.5 mEq/L), events, n 155 80 0.034 Severe hyperkalemia (≥6.5 mEq/L), events, n 14 24 0.225 Change in measured GFR 4.7 à 4 4.2 à 4.3 0.595

Authors’ Conclusions

• Treatment with spironolactone 50mg daily in HD patients had no significant effect on surrogate CV endpoints but resulted in higher incidence of moderate hyperkalemia

Reviewer’s Critique Strengths • Study design was placebo-controlled, randomized, double-blind, and multi-center

• Assessed treatment effect on residual renal function • MRI was utilized to assess structural efficacy outcomes • Implemented protocol to adjust treatment dose or dialysate potassium concentration

Limitations • Not generalizable to patients receiving peritoneal dialysis • Small sample size, short duration • Analysis on surrogate marker for cardiovascular events • Incidence of LVH at baseline is modestly low, possibly reduced efficacy results • Minimal population with HF with LVEF <40% were included

Take-home points

• Efficacy outcomes, although surrogate endpoints, did not show significant reductions from baseline. This differs from previous literature.

• Included population size, characteristics and short follow-up may confound efficacy results • Longer and more robust clinical trials are warranted to assess efficacy endpoints • Spironolactone 50mg/day is generally safe in ESRD patients receiving HD; however, increased

incidence of hyperkalemia suggests 25mg/day might be optimal

Jacobs 16

I. Spironolactone has minimal effects on serum potassium levels in patients with ESRD requiring HD vs placebo50,51

a. Recent trials parallel findings for spironolactone safety in ESRD with maintenance HD61-63 b. Insufficient evidence for eplerenone

II. Mineralocorticoid receptor antagonists (MRAs), specifically spironolactone, is associated with surrogate

cardiovascular endpoint benefit (e.g., LVMI, LVEF, carotid intima-media thickness)50,51 a. Hammer et al. found no difference in LVMI, further warranting larger and longer clinical investigations63 b. There is insufficient data for eplerenone and similar cardiovascular benefits

III. There is insufficient data in effect of spironolactone among different type of dialysis procedures (HD vs PD)50,51

IV. Optimal dosing of spironolactone for cardiovascular benefit in ESRD requiring dialysis cannot be definitely

determined at this time. a. Charytan et al. and literature suggest spironolactone 25mg daily confers minimal risk for hyperkalemia

and hemodynamic complications compared to higher doses62,63

V. Differences in study populations, follow-up durations, and inconsistent intermediate efficacy outcomes without recent mortality analyses warrants review of future study results

CCV = cardiovascular and cerebrovascular; dec = decreased; HD = hemodialysis; LVMI = left ventricular mass index; U.S. = United States

I. Spironolactone 25mg daily is safe in patients with ESRD on dialysis; however, there is insufficient clinical data to

recommend use of spironolactone for efficacy at this time

II. Clinical grey areas for possible benefit of spironolactone 25mg daily in patients with ESRD on HD: a. Established maintenance HD >1 year with at least 3x HD sessions weekly b. Low risk for non-compliance to HD sessions c. Minimal or no history of hyperkalemia d. Heart failure with reduced ejection fraction e. Resistant hypertension

Table 10. Summary of recent literature assessing safety and efficacy of spironolactone in ESRD with maintenance HD Study (n) Dialysis Characteristic Duration Intervention Safety Efficacy Matsumoto et al. 201461 (n=309)

HD Oligo-anuric, older population

36mo Spironolactone 25mg daily

Hyperkalemia: 1.9% vs 0%

Absolute change: 6.8% dec. CCV events 13.3% dec. all death

Charytan et al. 201962 (n=129)

HD U.S., multi-racial

9mo Spironolactone 12.5, 25, 50mg daily

Hyperkalemia, 25mg dose: 15.4% vs 62.7%

No change in early diastolic mitral velocity

Hammer et al. 201963 (n=97)

HD Residual renal function, 49%

10mo Spironolactone 50mg daily

Hyperkalemia, moderate: 155 vs 80 events

No change in LVMI

Summary

Recommendation

Jacobs 17

I. ALCHEMIST64

a. Phase 3, large, randomized, multi-center European trial of spironolactone 25 mg daily compared to placebo in patients with ESRD on dialysis

i. Status: recruiting 825 patients ii. Study period: June 2013 – June 2023

iii. Inclusion: LVH or LVEF <40% iv. Primary outcome: time to onset of first incident non-fatal MI, ACS, hospitalization for HF,

nonfatal stroke, or cardiovascular death II. ACHIEVE65

a. Phase 3, large, randomized, double-blind, multi-center trial of spironolactone 25 mg daily compared to placebo in patients with ESRD on dialysis

i. Status: recruiting 2750 patients ii. Study period: July 2017 – September 2023

iii. Inclusion: HD and PD patients iv. Primary outcome: cardiovascular death or hospitalization for HF

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7. American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020:43(1):S66-S76.

8. Whelton P, Carey R, Aronow W, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):1269-1324.

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14. National Institutes of Health. 2018 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; 2018.

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Appendix B. ADQI Heart Failure in ESRD Classification System23

Appendix C. Comparison of Drug Properties Between Spironolactone and Eplerenone34

Variable Spironolactone Eplerenone

Absorption Increased with food No effect with food Plasma protein binding >90% ~50% MR affinity High 10-20-fold lower MR selectivity Non-selective High Half-life 1-2h/10-35h (active metabolites) 4-6h Metabolism Liver (non-CYP-dependent) Liver (CYP 3A4) Active Metabolites Canrenone None Mild/moderate HTN (efficacy) ++ ++ Resistant HTN (efficacy) +++ ++ Anti-androgenic SEa ++++ - Metabolic SEb ++ - Hyperkalemia +++ ++ Renal function decline ++ +

CYP = cytochrome P; HTN = hypertension; MR = mineralocorticoid receptor; SE = side-effects aLoss of libido, gynecomastia/mastodynia, and menstrual irregularities bWorsening glycemic control (increase of hemoglobin A1c and cortisol)

Appendix A. Criteria for CKD (either of the following present for >3 months)1

Markers of kidney damage (one or more) • Albuminuria (AER ≥ 30 mg/24 hours; ACR ≥ 30 mg/g [≥3 mg/mmol]

• Urine sediment abnormalities • Electrolyte and other abnormalities due to tubular disorders • Abnormalities detected by histology • Structural abnormalities detected by imaging • History of kidney transplantation

Decreased GFR • GFR <60 ml/min/1.73 m2 (GFR categories G3a-G5)

Appendices