ALDOSTERONE ANTAGONISTS














  • All values expressed as difference from placebo
  • Study lengths ranged from 6 - 12 weeks
  • Reference [8]
Effects of spironolactone on blood pressure in placebo-controlled trials
25 mg/day
(N=24)		 100 mg/day
(N=24)		 150 mg/day
(N=50)		 200 mg/day
(N=24)
SBP/DBP (mmHg) -10/-2.4 -23/-7.2 -19/-8 -20/- 6.2


  • All values expressed as change from baseline
  • Average baseline BP ∼ 149/95
  • Reference [13]
Effects of eplerenone on blood pressure in a 12-week placebo-controlled trial
Placebo

(N=70)		 25 mg/day
(N=34)		 50 mg/day
(N=63)		 100 mg/day
(N=73)		 200 mg/day
(N=73)
SBP/DBP (mmHg) -1.5/-1 -6.3/-3.8 -6.6/-4 -8.4/-5.3 -10.1/-5.8




Spironolactone vs Clonidine in Resistant Hypertension, Hypertension (2018) [PubMed abstract]
  • The study enrolled 187 patients who met the definition of resistant hypertension after a 12-week drug titration phase
Main inclusion criteria
  • Age 18 - 75 years
  • Meets definition of resistant hypertension after 12-week run-in phase
Main exclusion criteria
  • Secondary hypertension except OSA
  • Patients with indication for beta blocker
  • CrCl ≤ 30 ml/min
  • NYHA stage III or IV heart failure
Baseline characteristics
  • Average age - 55 years
  • Male sex - 45.5%
  • Average office BP - 153/92
  • Average ambulatory BP - 142/86
Randomized treatment groups
  • Group 1 (95 patients): Spironolactone 12.5 - 50 mg once daily
  • Group 2 (92 patients): Clonidine 0.1 - 0.3 mg twice daily
  • Before randomization to study meds, all patients underwent a 12-week open-label forced-titration regimen of 3 antihypertensive drugs (chlorthalidone, enalapril or losartan, and amlodipine). Patients who met the criteria for resistant hypertension were then randomized to open-label spironolactone or clonidine.
  • Spironolactone and clonidine were titrated based on response
Primary outcome: Effective BP control determined by both office BP (defined as a systolic BP < 140 mmHg and diastolic BP < 90 mmHg) and ambulatory BP (defined as a 24-hour mean BP < 130/80 mmHg) after the 12-week treatment period
Results

Duration: 12 weeks
Outcome Spironolactone Clonidine Comparisons
Primary outcome 20.5% 20.8% p=1.0
Average office BP 140/86 138/85 p>0.05
Average ambulatory BP 131/80 134/81 p>0.05
Average daily dose 40 mg 0.35 mg N/A

Findings: Clonidine was not superior to spironolactone in true resistant hypertensive patients, but the overall BP control was low (≈21%). Considering easier posology and greater decrease in secondary end points, spironolactone is preferable for the fourth-drug therapy.
PATHWAY study - Spironolactone vs Doxazosin vs Bisoprolol for Resistant Hypertension, Lancet (2015) [PubMed abstract]
  • The PATHWAY study enrolled 335 patients with resistant hypertension
Main inclusion criteria
  • Clinic SBP ≥ 140 mmHg (≥ 135 mmHg for diabetics)
  • Home SBP (18 readings over 4 days) ≥ 130 mmHg
  • Taking maximally tolerated doses of at least 3 BP meds which had to include an ACE or ARB, calcium channel blocker, and a diuretic
Main exclusion criteria
  • CrCl < 45 ml/min
  • Abnormal potassium on 2 readings
Baseline characteristics
  • Average age 61 years
  • Average home SBP 148 mmHg
  • Average home DBP 84 mmHg
Patients crossed over between 4 groups:
  • Spironolactone 25 - 50 mg once daily for 12 weeks
  • Doxazosin modified release 4 - 8 mg once daily for 12 weeks
  • Bisoprolol 5 - 10 mg once daily for 12 weeks
  • Placebo once daily for 12 weeks
  • Study meds were added to baseline meds. Study meds were given at a lower dose for 6 weeks, followed by forced titration to higher dose for 6 weeks.
Primary outcome: Average home SBP, recorded in the morning and the evening in triplicate, on 4 consecutive days before study visits at week 6 and week 12 for each crossover period
Results

Duration: 12 weeks on each drug
Average decrease in SBP from baseline (mmHg)
Spironolactone Doxazosin Bisoprolol Placebo
12.8 8.7 8.3 4.1
  • The decrease in SBP with spironolactone was significantly greater than all other treatments (p<0.0001 for all comparisons)
  • The average change in CrCl while taking spironolactone was -10 ml/min
  • The average change in serum potassium while taking spironolactone was +0.43 mmol/L
  • 2% of patients had a serum potassium > 6 mmol/L while taking spironolactone [103]

Findings: Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition.




RALES Trial - Spironolactone vs Placebo in Severe Heart Failure with Reduced EF, NEJM (1999) [PubMed abstract]
  • The RALES trial enrolled 1663 patients with NYHA class III or IV heart failure and an EF ≤ 35%
Main inclusion criteria
  • NYHA class IV heart failure within 6 months of enrollment and NYHA class III or IV heart failure at enrollment
  • Treated with ACE inhibitor and loop diuretic
  • EF ≤ 35%
Main exclusion criteria
  • Primary operable valvular heart disease
  • Serum creatinine > 2.5 mg/dl
  • Potassium level > 5.0 mEq/L
Baseline characteristics
  • Average age 65 years
  • Average EF - 25.4%
  • Average BP - 122/75
  • NYHA class: II - 0.4% | III - 70% | IV - 29%
  • Baseline meds: Loop diuretics - 100% | ACE inhibitors - 95% | Digoxin - 73% | Beta blockers - 10%
Randomized treatment groups
  • Group 1 (841 patients) Placebo once daily
  • Group 2 (822 patients) Spironolactone 25 - 50 mg a day (average dose during the study was 26 mg)
  • Spironolactone was started at 25 mg once daily and increased after 8 weeks if deemed appropriate
Primary outcome: All-cause mortality
Results

Duration: After an average follow-up of 2 years, the trial was stopped early due to a clear benefit with spironolactone
Outcome Placebo Spironolactone Comparisons
Primary outcome 45.9% 34.5% HR 0.70, 95%CI [0.60 - 0.82], p<0.001
Hospitalization for heart failure 35.7% 26.2% HR 0.65, 95%CI [0.54 - 0.77], p<0.001
Median increase in potassium (first year) 0 0.30 mEq/L p<0.001
Median increase in creatinine (first year) 0 0.05 - 0.10 mg/dl p<0.001
Gynecomastia in men 1% 9% p<0.001
Breast pain in men 0.1% 2% p=0.006

Findings: Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure
EPHESUS Trial - Eplerenone vs Placebo in Heart Failure with Reduced EF after MI, NEJM (2003) [PubMed abstract]
  • The EPHESUS trial enrolled 6632 patients who had heart failure after a recent myocardial infarction
Main inclusion criteria
  • Myocardial infarction within past 3 - 14 days
  • EF ≤ 40%
  • Clinical heart failure defined as pulmonary rales, chest X-ray showing pulmonary venous congestion, or the presence of a third heart sound (diabetics with left ventricular dysfunction were also eligible)
Main exclusion criteria
  • Serum creatinine > 2.5 mg/dl
  • Potassium level > 5.0 mEq/L
  • Taking potassium-sparing diuretic
Baseline characteristics
  • Average age 64 years
  • Average EF - 33%
  • Average BP 119/72
  • Symptomatic heart failure - 90%
  • Average serum potassium - 4.3 mEq/L
  • Average CrCl - 79 ml/min
  • Baseline meds: ACE/ARB - 87% | Beta blocker - 75% | Diuretics - 60%
Randomized treatment groups
  • Group 1 (3313 patients) - Eplerenone 25 - 50 mg once daily (average dose in study was 42.6 mg)
  • Group 2 (3319 patients) - Placebo once daily
  • Eplerenone was started at 25 mg once daily and increased after 4 weeks
Primary outcomes:
  • 1. Death from any cause
  • 2. Death from cardiovascular causes or hospitalization for heart failure, acute myocardial infarction, stroke, or ventricular arrhythmia
Results

Duration: Average of 16 months
Outcome Eplerenone Placebo Comparisons
Primary outcome (overall mortality) 14.4% 16.7% HR 0.85, 95%CI [0.75 - 0.96], p=0.008
Primary outcome (composite) 26.7% 30% HR 0.87, 95%CI [0.79 - 0.95], p=0.002
Hospitalization for heart failure 10.4% 11.8% HR 0.85, 95%CI [0.74 - 0.99], p=0.03
Increase in potassium (first year) 0.30 mEq/L 0.20 mEq/L p<0.001
Increase in creatinine (first year) 0.06 mg/dl 0.02 mg/dl p<0.001
Hyperkalemia (≥ 6 mEq/L) 5.5% 3.9% p=0.002
Hypokalemia (< 3.5 mEq/L) 8.4% 13.1% p<0.001
Drug discontinuation 15.9% 14.9% N/A

Findings: The addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure
EMPHASIS-HF Trial - Eplerenone vs Placebo in Heart Failure with Reduced EF, NEJM (2011) [PubMed abstract]
  • The EMPHASIS-HF trial enrolled 2737 patients with NYHA class II heart failure
Main inclusion criteria
  • Age ≥ 55 years
  • NYHA class II heart failure
  • EF ≤ 30% or 30% to 35% and QRS > 130 msec
  • Treatment with ACE/ARB and beta blocker
  • Hospitalization within 6 months for cardiovascular reason or BNP ≥ 250 pg/ml
Main exclusion criteria
  • Acute myocardial infarction
  • GFR < 30 ml/min
  • Potassium level > 5.0 mEq/L
  • Need for potassium-sparing diuretic
Baseline characteristics
  • Average age 69 years
  • Average EF - 26%
  • Average BP 124/75
  • QRS duration > 130 msec - 26%
  • Average duration of heart failure - 4.7 years
  • Ischemic heart failure - 69% | Nonischemic - 31%
  • Average GFR - 71 ml/min
  • Baseline meds: Diuretic - 84% | ACE inhibitor - 77% | ARB - 19% | Beta blocker - 87%
Randomized treatment groups
  • Group 1 (1364 patients) - Eplerenone 25 - 50 mg once daily (average dose in study was 39 mg)
  • Group 2 (1373 patients) - Placebo once daily
  • Eplerenone was started at 25 mg once daily and increased after 4 weeks. For patients with GFR 30 - 49 ml/min, eplerenone was started at 25 mg every other day and increased to 25 mg once daily.
Primary outcome: Composite of death from cardiovascular causes or hospitalization for heart failure
Results

Duration: After a median follow-up of 21 months, the trial was stopped early due to a clear benefit with eplerenone
Outcome Eplerenone Placebo Comparisons
Primary outcome 18.3% 25.9% HR 0.63, 95%CI [0.54 - 0.74], p<0.001
Overall mortality 12.5% 15.5% HR 0.76, 95%CI [0.62 - 0.93], p=0.008
Hospitalization for heart failure 12% 18.4% HR 0.58, 95%CI [0.47 - 0.70], p<0.001
Increase in serum potassium 0.16 mEq/L 0.05 mEq/L p<0.001
Increase in serum creatinine 0.09 mg/dl 0.04 mg/dl N/A
Hyperkalemia (≥ 5.5 mEq/L) 11.8% 7.2% p<0.001
Hypokalemia (< 3.5 mEq/L) 7.5% 11% p=0.002
Decrease in systolic blood pressure 2.5 mmHg 0.3 mmHg p=0.001
Drug discontinuation 16.3% 16.6% N/A

Findings: Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms





TOPCAT Study - Spironolactone vs Placebo in Heart Failure with Preserved EF, NEJM (2014) (PubMed abstract)
  • The TOPCAT study enrolled 3445 patients with symptomatic heart failure and an EF ≥ 45%
Main inclusion criteria
  • Age > 50 years
  • One clinical sign of heart failure
  • EF ≥ 45%
  • SBP < 140 or < 160 if taking ≥ 3 meds
  • Hospitalization for heart failure within previous 12 months or BNP ≥ 100 pg/ml
Main exclusion criteria
  • GFR < 30 ml/min
  • Serum creatinine ≥ 2.5 mg/dl
  • Potassium level > 5.0 mEq/L
Baseline characteristics
  • Median age 69 years
  • Median EF - 56%
  • Median BP - 130/80
  • Median serum potassium - 4.3 mEq/L
  • Median GFR - 65 ml/min
  • NYHA class: I - 3.2% | II - 64% | III - 33% | IV - 0.5%
  • Baseline meds: Diuretic - 82% | ACE/ARB - 84% | Beta blocker - 78%
Randomized treatment groups
  • Group 1 (1722 patients) - Spironolactone 15 - 45 mg once daily (average dose in study was 25 mg)
  • Group 1 (1723 patients) - Placebo once daily
  • Spironolactone was started at 15 mg once daily and increased to a maximum of 45 mg once daily during the first 4 months
Primary outcome: Composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure
Results

Duration: Average of 3.3 years
Outcome Spironolactone Placebo Comparisons
Primary outcome 18.6% 20.4% HR 0.89, 95%CI [0.77 - 1.04], p=0.14
Overall mortality 14.6% 15.9% HR 0.91, 95%CI [0.77 - 1.08], p=0.29
Hospitalization for heart failure 12% 14.2% HR 0.83, 95%CI [0.69 - 0.99], p=0.04
Hyperkalemia (> 5.5 mEq/L) 18.7% 9.1% N/A
Hypokalemia (< 3.5 mEq/L) 16.2% 22.9% N/A
Doubling serum creatinine to a value above ULN 10.2% 7% N/A
Breast tenderness/enlargement causing discontinuation 2.5% 0.3% p<0.001
Drug discontinuation 34.3% 31.4% p=0.074
  • A secondary analysis of the TOPCAT study found an unusually large difference in the number of outcome events between geographic regions. In Russia/Georgia (N=1678), the incidence of the primary outcome was 4-fold lower than in the Americas (N=1767); this led researchers to suspect that a number of patients without heart failure were enrolled in the Russia/Georgia regions. A post hoc analysis that excluded the Russia/Georgia data found that spironolactone significantly improved the primary outcome. [PMID 25406305]

Findings: In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure












  • Measure serum potassium before initiating eplerenone therapy, within the first week, and at one month after the start of treatment or dose adjustment. Assess serum potassium periodically thereafter.
  • Reference [Inspra PI]
Eplerenone dose adjustments in heart failure based on serum potassium
Serum Potassium (mEq/L) Dose Adjustment
< 5.0
  • 25 mg every other day to 25 mg once daily
  • 25 mg once daily to 50 mg once daily
5.0 - 5.4
  • No adjustment
5.5 - 5.9
  • 50 mg once daily to 25 mg once daily
  • 25 mg once daily to 25 mg every other day
  • 25 mg every other day to withhold
≥ 6.0
  • Withhold and restart at 25 mg every other day when potassium levels fall to <5.5 mEq/L