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




Overview
  • Resistant hypertension is defined as hypertension that remains elevated (SBP ≥ 140, DBP ≥ 90) despite treatment with at least 3 blood pressure medications, one of which must be a diuretic (typically a thiazide or loop diuretic)
  • Because spironolactone can have a profound effect on blood pressure, it is often used to treat resistant hypertension
  • Two trials that compared spironolactone to other medications in resistant hypertension are detailed below
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.



Overview
  • Spironolactone and eplerenone have been shown to improve survival in patients with significant heart failure
  • In the RALES trial, spironolactone improved outcomes in patients with severe heart failure. In the EPHESUS trial, eplerenone improved outcomes in patients with heart failure after a recent MI, and in the EMPHASIS-HF trial, eplerenone was effective in patients with NYHA class II heart failure. All three trials are detailed below.
RALES Trial - Spironolactone vs Placebo for Severe Heart Failure, 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 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, 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
2013/2017 AHA recommendations
  • Aldosterone antagonists are recommended in patients who meet the following criteria:
    • NYHA class II - IV heart failure with an EF ≤ 35%
    • Patients with NYHA class II should have a history of prior cardiovascular hospitalization or elevated plasma natriuretic peptide levels (see BNP for more)
    • Serum creatinine levels should be ≤ 2.5 mg/dl in men, and ≤ 2.0 mg/dl in women (alternatively, GFR should be > 30 ml/min)
    • Potassium levels should be < 5.0 mEq/L
    • Monitor electrolytes (especially potassium), and kidney function 2 - 3 days following initiation, and at 7 days after initiation or drug titration. After that, check monthly for 3 months and then every 3 months from then on. [109,111,112]
  • AHA recommended dosing
    • Spironolactone
      • Starting: 12.5 - 25 mg once daily
      • Maintenance: 25 mg once daily OR 25 mg twice a day
      • Average dose achieved in trials: 26 mg once daily
      • Increase dose at intervals of 2 weeks as tolerated
    • Eplerenone
      • Starting: 25 mg once daily
      • Maintenance: 50 mg once daily
      • Average dose achieved in trials: 42.6 mg once daily
      • Increase dose at intervals of 2 weeks as tolerated [111,112]
StraightHealthcare analysis
  • Aldosterone antagonists improve survival in patients with significant heart failure, but should be used with caution in certain patients because of the potential to increase potassium levels
  • After the RALES trial was published, the use of spironolactone increased substantially as did hospitalizations and deaths from high potassium levels [58]
  • See elevated potassium under side effects below for further discussion on AA and potassium



Overview
  • Heart failure with preserved ejection fraction (HFpEF), also referred to as "diastolic heart failure," is a syndrome where the signs and symptoms of heart failure are present in patients with a normal ejection fraction
  • HFpEF is thought to be caused by reduced ventricular compliance, meaning the left ventricle does not relax appropriately when it is filling with blood
  • The ideal treatment of HFpEF has not been defined, and results from good clinical trials are lacking
  • Since spironolactone has been shown to improve outcomes in heart failure with reduced EF, the TOPCAT study was performed to evaluate its effects in HFpEF
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

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
2017 AHA recommendations
  • Aldosterone antagonists might be considered to decrease hospitalizations in patients with HFpEF who meet the following criteria:
    • Ejection Fraction ≥ 45%
    • Elevated BNP levels or heart failure admission within 1 year
    • GFR > 30 ml/min
    • Creatinine < 2.5 mg/dl
    • Potassium < 5.0 mEq/L [111]
StraightHealthcare analysis
  • In the TOPCAT trial, spironolactone decreased the risk of hospitalization for heart failure, but did not have a significant effect on mortality
  • The optimal medical management of heart failure with preserved EF has not been determined









Increased urination

Elevated potassium (hyperkalemia)
Overview
  • One of the most significant actions of aldosterone antagonists is their potential to raise potassium levels
  • This effect may be beneficial in some cases (e.g. to counteract potassium loss from loop diuretics), but it may also lead to hyperkalemia which can be dangerous
  • After the RALES trial (see heart failure above) was published, the use of spironolactone increased substantially as did cases of hospitalization for hyperkalemia and death from hyperkalemia [58]
Clinical Trials
  • In 3 large heart failure trials involving spironolactone and eplerenone (see heart failure above), the average potassium level rose by 0.16 - 0.30 mEq/L in patients receiving AA [15,16,17]
  • In the EPHESUS trial, cases of serious hyperkalemia (defined as > 6.0 mEq/L) were 5.5% in the eplerenone group versus 3.9% in the placebo group. In patients with a creatinine clearance < 50 ml/min, incidence of hyperkalemia was 10.1% with eplerenone versus 5.9% with placebo. [16]
Risk Factors for hyperkalemia
  • Kidney disease (GFR < 60 ml/min) or serum creatinine > 1.6 mg/dl
  • Diabetes
  • Dehydration (from diuretics, diarrhea, etc.)
  • Advanced age
  • Medications - see drug interactions below
  • High Dietary potassium - salt substitutes, nuts, dried fruit, etc.
  • Potassium supplements [11,59,60]
Measures to help prevent hyperkalemia
  • Do not prescribe if serum creatinine is ≥ 2.5 mg/dl in men, or ≥ 2.0 mg/dl in women
  • Do not prescribe if GFR < 30 ml/min
  • Do not prescribe if there was a recent increase in serum creatinine > 25%
  • Do not prescribe if serum potassium > 5.0 mEq/L
  • Decrease dose or stop treatment if potassium rises above 5.0 mEq/L
  • Avoid potassium supplements if serum potassium is > 3.5 mEq/L
  • Check serum potassium and creatinine within 3-7 days after starting AA or after any dosage increase
  • Check serum potassium and creatinine monthly for first 3 months, then quarterly for a year, and then every 6 months [11,19, 60]
  • The eplerenone PI has guidelines for adjusting eplerenone doses based on serum potassium values. Those recommendations are presented in the table below.

  • 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
Summary
  • Aldosterone antagonists improve outcomes in heart failure, but these patients are often at greater risk for elevated potassium levels
  • When using AA in this population, it is important to understand the potential risk and take appropriate precautions

Gynecomastia (spironolactone)
Overview
  • Spironolactone has progesterone-like properties and antiandrogen (testosterone) properties
  • Eplerenone does not have these properties
  • Spironolactone can cause breast enlargement (gynecomastia) and breast tenderness in men
  • Gynecomastia typically resolves when spironolactone is stopped, but it may remain for a significant amount of time [60]
Clinical studies
  • In the RALES trial, about 10% of spironolactone-treated patients experienced gynecomastia compared to 1% of placebo-treated patients. In the TOPCAT trial, breast tenderness or enlargement lead to drug discontinuation in 2.5% of spironolactone-treated patients. [17,108]
  • The effect also appears to be dose-dependent. In one study, 7% of men receiving < 50 mg a day experienced gynecomastia where 52% of men taking more than 150 mg a day experienced gynecomastia. [63]
Summary
  • Spironolactone may cause gynecomastia in some men. Eplerenone does not cause gynecomastia.
  • Gynecomastia typically resolves after drug discontinuation

Breast tenderness in women

Irregular menses

Low sodium






Kidney disease
Eplerenone (Inspra®)
  • CrCl < 50 ml/min (patients treated for hypertension): DO NOT USE
  • CrCl ≤ 30 ml/min (all patients): DO NOT USE
Spironolactone (Aldactone®)
  • Use with caution in kidney disease
  • Manufacturer makes no specific dosage recommendations

Liver disease
Eplerenone (Inspra®)
  • Mild-to-moderate liver disease (Child-Pugh A and B) - no dose adjustment necessary
  • Severe liver disease (Child-Pugh C) - has not been studied
Spironolactone (Aldactone®)

Breast cancer (spironolactone)
Overview
  • The antiandrogen and progestogenic effects of spironolactone are thought to promote an estrogenic state through various mechanisms
  • Because of this, there has been a concern that spironolactone may promote breast cancer
  • In the 1970s, there were case reports of breast cancer in patients taking spironolactone. There were also reports of breast tumors in animals treated with spironolactone. [106]
  • Recent studies have evaluated the association of spironolactone with breast cancer and found no significant link [PMID 24189467, 22797844]
Summary
  • There is no good evidence that spironolactone increases the risk for breast cancer

Pregnancy


Spironolactone and eplerenone

  • Lithium - aldosterone antagonists may reduce the clearance of lithium. Aldosterone antagonists should not be taken with lithium if possible. Lithium levels should be monitored closely in patients taking aldosterone antagonists.
  • Medications that can raise potassium levels - Aldosterone antagonists have the potential to raise potassium levels. When taken with other medications that raise potassium, the risk may be compounded. While it is often appropriate to prescribe aldosterone antagonists with these medications, patients and providers should be aware of the potential risks (see elevated potassium above)
  • NSAIDS (Advil®, ibuprofen, naprosyn, etc.) - NSAIDS can block the therapeutic effect of aldosterone antagonists. Patients should monitor for decreased effectiveness of aldosterone antagonists when taking NSAIDS for extended periods.
  • Salt substitutes (No Salt®, No-Salt®, etc.) - salt substitutes typically have a high amount of potassium. Patients should be aware that this may contribute to elevated potassium levels seen with aldosterone antagonists.

Eplerenone (Inspra®)

  • CYP3A4 strong inhibitors - DO NOT COMBINE. Eplerenone is a CYP3A4 sensitive substrate.
  • CYP3A4 moderate inhibitors - when eplerenone is taken with CYP3A4 moderate inhibitors, the following dosing is recommended:
    • Post-MI heart failure: do not exceed 25 mg once daily
    • Hypertension: starting dose should be 25 mg once daily. May increase to a maximum of 25 mg twice a day.
    • Check serum potassium and serum creatinine within 3 – 7 days after starting concomitant therapy with a CYP3A4 moderate inhibitor
  • NSAIDs - Check serum potassium and serum creatinine within 3 – 7 days after starting concomitant therapy with an NSAID

Spironolactone (Aldactone®)

  • Digoxin (Lanoxin®) - Spironolactone has been shown to increase blood levels of digoxin. Spironolactone has also been shown to interfere with many of the assays used to measure digoxin levels. Based on the available data, it is difficult to quantify the effect of spironolactone on digoxin levels. [60, 82, 105]

Metabolism and clearance
Eplerenone (Inspra®)
  • CYP3A4 - sensitive substrate
Spironolactone (Aldactone®)