- ACRONYMS AND DEFINITIONS
- AA - Aldosterone antagonists
- AASLD - American Association for the Study of Liver Diseases
- AHA - American Heart Association
- BNP - B-type natriuretic peptide
- BP - Blood Pressure
- CrCl - Creatinine clearance
- DBP - Diastolic Blood Pressure
- EASL - European Association for the Study of the Liver
- EF - Ejection Fraction
- GFR - Glomerular Filtration Rate
- HCTZ - Hydrochlorothiazide
- HFpEF - Heart failure with preserved ejection fraction
- HTN - Hypertension
- OSA - Obstructive sleep apnea
- MI - Myocardial infarction
- NYHA - New York Heart Association heart failure classification
- PI - Manufacturer's Package Insert
- RCT - Randomized controlled trial
- SBP - Systolic Blood Pressure
- ULN - Upper Limit of Normal
- DRUGS IN CLASS
- Aldosterone antagonists
- Spironolactone (Aldactone®, Carospir®)
- Eplerenone (Inspra®)
- Finerenone (Kerendia®) - finerenone is an aldosterone antagonist, but unlike spironolactone and eplerenone, its chemical structure is not based on a steroid molecule
- Spironolactone + HCTZ
- Aldactazide® (spironolactone + HCTZ)
- MECHANISM OF ACTION
- Aldosterone is a mineralocorticoid secreted by the adrenal glands. Its release is stimulated by rising serum potassium levels and angiotensin II (see potassium regulation for more). Aldosterone acts primarily in the renal collecting duct where it stimulates the uptake of sodium and water in exchange for potassium. The effects of aldosterone are greatly dependent upon the amount of sodium in the renal collecting duct.
- Aldosterone antagonists block the effects of aldosterone in the collecting duct
- Nephron and diuretics illustration - illustration of the nephron and how diuretics work
- FDA-APPROVED INDICATIONS
- Spironolactone
- Primary hyperaldosteronism
- Edematous conditions for patients with:
- Congestive heart failure
- Cirrhosis of the liver accompanied by edema and/or ascites
- Nephrotic syndrome
- Essential hypertension
- Hypokalemia
- Severe heart failure (NYHA class III – IV)
- Eplerenone
- Congestive Heart Failure Post-Myocardial Infarction
- Hypertension
- HYPERTENSION
- Spironolactone
- A Cochrane meta-analysis evaluated trials in which spironolactone was compared to placebo in the treatment of hypertension
- Findings from 2 of the trials included in the analysis are presented here
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 |
- Eplerenone (Inspra®)
- The effects of eplerenone on blood pressure in a 12-week placebo-controlled trial are detailed in the table below
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 |
- Professional recommendations
- AAs are not typically used as first-line agents to treat hypertension unless other indications warrant their use. Spironolactone is used for resistant hypertension (see below).
- See hypertension guidelines for a review of recommended therapies and treatment goals from various professional organizations
- RESISTANT HYPERTENSION
- 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
- 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.
- 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 |
|
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.
- AHA recommendations
- HEART FAILURE WITH REDUCED EJECTION FRACTION (HFrEF)
- Overview
- Spironolactone and eplerenone have been shown to improve survival in heart failure with reduced ejection fraction. 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.
- 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
- 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
- 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
- AHA recommendations
- Summary
- Aldosterone antagonists improve survival in patients with significant heart failure, but they should be used with caution in certain patients because of the potential for hyperkalemia. After the RALES trial was published, the use of spironolactone increased substantially as did hospitalizations and deaths from hyperkalemia. [58]
- See elevated potassium for more information on preventing AA-induced hyperkalemia
- HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFpEF)
- Overview
- The effects of spironolactone in heart failure with preserved ejection fraction were evaluated in the TOPCAT study detailed below
- 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
- Professional recommendations
- LIVER FAILURE (CIRRHOSIS)
- Overview
- Liver failure causes arterial dilation, which can stimulate the renin-angiotensin-aldosterone system (see RAAS illustration). High aldosterone levels combined with reduced oncotic pressure from hypoalbuminemia can cause fluid and sodium retention, leading to severe swelling in the lower extremities and abdomen (ascites).
- Spironolactone and loop diuretics are often used in combination to treat fluid overload in cirrhosis. Spironolactone has been studied in clinical trials, but eplerenone has not; therefore, eplerenone is not recommended. Recommendations for diuretic therapy in cirrhosis from the EASL and AASLD are provided below.
- EASL and AASLD recommendations
- General recommendations in all patients
- Patients should be placed on a sodium-restricted diet of < 2 grams/day (see sodium and salt for more)
- Monitor weight, potassium levels, and kidney function closely. Patients without peripheral edema should target weight loss of ≤ 0.5 kg/day, and patients with peripheral edema may tolerate weight loss up to 1 kg/day.
- A spot urine sodium to potassium ratio (Na/K) may help guide therapy. A ratio of > 1 means that the patient should be losing weight, and if not, dietary noncompliance should be suspected. A ratio ≤ 1 indicated insufficient natriuresis, and increasing diuretics should be considered.
- Once an adequate response is achieved, diuretics should be tapered to their lowest effective dose
- Mild ascites (only detectable on ultrasound)
- Mild ascites may be treated with spironolactone alone. Starting dose is 100 mg/day, titrated by 100 mg every 3 - 7 days as needed to a maximum of 400 mg/day. The full effect of dose increases may not be realized for 72 hours.
- If weight loss is not adequate or high potassium levels develop, furosemide may be needed
- Moderate or recurrent ascites (detectable on physical exam or ≥ 3 episodes per year)
- Moderate or recurrent ascites is typically treated with spironolactone and furosemide combined
- Starting doses are spironolactone 100 mg/day + furosemide 40 mg/day. Dosing in a 100:40 ratio of spironolactone to furosemide typically keeps potassium levels in the normal range. Dosing may be increased every 3 - 5 days to a maximum of 400 mg/day for spironolactone and 160 mg/day for furosemide. The full effect of dose increases may not be realized for 72 hours.
- Diuretic therapy should be stopped and reassessed for any of the following:
- Hepatic encephalopathy develops
- Sodium levels < 120 mEq/L
- Serum creatinine > 2.0 mg/dl
- Potassium levels are too high or low
- Severe muscle cramps develop [91,92,114]
- ACNE
- Overview
- Spironolactone's antiandrogenic effects make it beneficial in the treatment of female acne. In men, side effects, including gynecomastia, limit its use. A number of small, short-term studies have found spironolactone to be effective in reducing inflammatory acne lesions. In most studies, doses of 25 - 200 mg a day were used; doses ≤ 100 mg/day are typically effective and carry a lower risk of side effects. [106]
- The 24-week trial detailed below compared the effects of spironolactone to placebo in women with facial acne
- The trial enrolled 410 women with facial acne significant enough to warrant oral antibiotics
Main inclusion criteria
- Women ≥ 18 years
- Facial acne for ≥ 6 months
- Acne sufficient to warrant oral antibiotics
Main exclusion criteria
- Very mild acne
- Previous spironolactone therapy
- Isotretinoin within 6 months
- Oral antibiotics within a month
- Taking ACE/ARB/K-sparing diuretic
- Elevated serum potassium
Baseline characteristics
- Average age 29 years
- White race - 84%
- Average age of acne onset - 16 years
- Acne severity: Mild - 46% | Moderate - 40% | Severe - 13%
Randomized treatment groups
- Group 1 (201 patients): Spironolactone 50 mg once daily for 6 weeks, then 100 mg/day
- Group 2 (209 patients): Placebo
- Topical treatments were continued, but subjects were asked not to change them
- Other oral therapies were not allowed, except for oral contraceptives if the woman had been taking them for ≥ 3 months
- Blinded therapy was continued for 24 weeks; however, after 12 weeks, participants in both groups could receive usual care, such as oral antibiotics, hormonal treatments, or isotretinoin, if judged necessary by their usual clinical team
Primary outcome: Mean Acne-QoL symptom subscale score (range 0-30, where higher scores reflect improved quality of life) at 12 weeks, adjusted for baseline variables.
Results
Duration: 12 weeks | |||
Outcome | Spironolactone | Placebo | Comparisons |
---|---|---|---|
Baseline Acne-QoL score | 13.2 | 12.9 | N/A |
Primary outcome (12 weeks) | 19.2 | 17.8 | Diff 1.27 (0.07 to 2.46) |
Primary outcome (24 weeks) | 21.2 | 17.4 | Diff 3.45 (2.16 to 4.75) |
Headache | 20% | 12% | p=0.02 |
Dizziness | 19% | 12% | p=0.07 |
|
Findings: Spironolactone improved outcomes compared with placebo, with greater differences at week 24 than week 12. Spironolactone is a useful alternative to oral antibiotics for women with acne.
- Professional recommendations
- See acne treatment for recommendations from the AAD and AAP
- In animal studies, spironolactone has been shown to cause feminization of the male fetus; therefore, concomitant contraception may be indicated
- Spironolactone-induced hyperkalemia in healthy young females is rare, and the American Academy of Dermatology (AAD) does not recommend routine potassium monitoring during therapy. They also state that spironolactone may be used safely with drospirenone, a progestin structurally related to spironolactone found in many OCPs. [110]
- Summary
- In the study above, spironolactone had a modest effect on acne at 12 weeks that improved at 24 weeks. Even though other treatments were allowed after 12 weeks, they didn't appear to be utilized substantially, which suggests spironolactone's effect builds with continued use.
- SIDE EFFECTS
- Increased urination
- AA may promote diuresis and increased urination. The effect is more pronounced when it is combined with loop and thiazide diuretics.
- Elevated potassium (hyperkalemia)
- One of the most significant actions of aldosterone antagonists is their potential to raise potassium levels. This effect may be desirable in some cases (e.g. hypokalemia from loop diuretics), but it may also lead to hyperkalemia which can be dangerous. After the RALES trial was published, the use of spironolactone increased substantially as did cases of hospitalization for hyperkalemia and death from hyperkalemia. Evidence from trials, risk factors, and measures to prevent hyperkalemia are discussed below. [58]
- Studies
- 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.
Eplerenone dose adjustments in heart failure based on serum potassium | |
---|---|
Serum Potassium (mEq/L) | Dose Adjustment |
< 5.0 |
|
5.0 - 5.4 |
|
5.5 - 5.9 |
|
≥ 6.0 |
|
- Treatment
- See RAAS inhibitor-induced hyperkalemia for recommendations on treating hyperkalemia
- Gynecomastia (spironolactone)
- 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
- Spironolactone has progesterone-like properties and antiandrogen (testosterone) properties
- This may cause breast tenderness in some women
- In long-term studies, around 17% of women complain of breast tenderness while taking spironolactone
- Breast tenderness is dose-dependent with an incidence of around 5% with low-dose spironolactone and 30% for doses of 200 mg a day [106]
- Irregular menses
- Because spironolactone has antiprogesterone properties, it may cause irregular periods in some women
- Irregular menses is dose-dependent with an incidence of 18% at doses of 50 - 100 mg/day and 70% at doses of 200 mg/day [106]
- Sodium loss
- Aldosterone antagonists promote sodium loss and may lead to hyponatremia in some cases. In the RALES trial, there was no significant difference in serum sodium levels between the spironolactone group and placebo group [17]
- CONTRAINDICATIONS
- Spironolactone
- Anuria - not producing urine
- Acute kidney failure
- High potassium (Hyperkalemia)
- Addison's disease
- Concomitant use of eplerenone
- Eplerenone (Inspra®)
- All patients
- Serum potassium > 5.5 mEq/L at initiation
- Creatinine clearance ≤ 30 mL/min
- Concomitant administration of CYP3A4 strong inhibitors
- Patients treated for hypertension
- Type 2 diabetes with microalbuminuria
- Serum creatinine > 2.0 mg/dL in males or > 1.8 mg/dL in females
- Creatinine clearance < 50 mL/min
- Concomitant administration of potassium supplements or potassium-sparing diuretics (e.g., amiloride, spironolactone, or triamterene)
- PRECAUTIONS
- 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®)
- Spironolactone is used in cirrhosis
- See liver failure above
- Breast cancer (spironolactone)
- 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]
- Pregnancy
- Spironolactone has been shown to be teratogenic in animal studies
- There have been no reports of birth defects in humans exposed to spironolactone
- Male fetuses could theoretically be adversely affected by the antiandrogen properties of spironolactone
- Caution should be used if spironolactone is to be used in women of childbearing potential (particularly for acne) [106]
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- 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 - AA may raise potassium levels and cause hyperkalemia. When taken with other potassium-raising medications, the risk is increased. While it is often appropriate to combine AA with other potassium-raising drugs, patients and providers should be aware of the potential risks. See RAAS inhibitor-induced hyperkalemia for recommendations on addressing hyperkalemia in AA-treated patients.
- Examples of medications that may raise potassium levels include:
- ARBs (valsartan, olmesartan, etc.)
- ACE inhibitors
- Aliskiren (Tekturna®)
- Cyclosporine (Neoral®)
- ENaC inhibitors (triamterene, amiloride)
- Finerenone (Kerendia®)
- Heparin - heparin raises potassium secondarily by inhibiting aldosterone synthesis. LMWH does not appear to have the same effect. [113]
- Penicillin G potassium injection (1 million units contains 1.68mEq of potassium)
- Potassium supplements (K-Dur®, etc)
- Tacrolimus (Prograf®)
- Trimethoprim (part of Bactrim® and Septra®)
- Voclosporin (Lupkynis®)
- 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 (16.4 mEq per 1/4 teaspoon). 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®)
- Abiraterone (Zytiga®) - spironolactone binds androgen receptors and may increase PSA levels in patients treated with abiraterone, an androgen biosynthesis inhibitor used to treat prostate cancer
- Cholestyramine - cases of hyperkalemic metabolic acidosis have been reported in patients receiving cholestyramine with spironolactone
- CYP3A4 substrates - spironolactone is an irreversible inhibitor of CYP3A4 in vitro. Doses of CYP3A4 substrates may need to be adjusted when combining.
- CYP2C8 substrates - spironolactone is an irreversible inhibitor of CYP2C8 in vitro. Doses of CYP2C8 substrates may need to be adjusted when combining.
- 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. In patients taking digoxin, measure serum digoxin levels before initiating spironolactone with an assay that does not interact with spironolactone. Reduce the digoxin dose by 15 - 30% or reduce dosing frequency when starting spironolactone. Monitor digoxin levels closely. [60, 82, 105]
- Metabolism and clearance
- Eplerenone (Inspra®)
- CYP3A4 - sensitive substrate
- Spironolactone (Aldactone®)
- CYP3A4 - major substrate and inhibitor
- CYP2C8 - minor substrate and inhibitor
- P-glycoprotein - inducer
- DOSING
- LONG-TERM SAFETY
- Spironolactone has been used since the 1960s
- Eplerenone was approved in the U.S. in 2002
- Both drugs appear safe when prescribed appropriately
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