Spironolactone is FDA approved to treat essential hypertension, severe heart failure (New York Heart Association Class III-IV), primary hyperaldosteronism (PA), edema in adults (resulting from congestive heart failure, hepatic cirrhosis, or nephrotic syndrome), and hypokalemia.1
The American College of Cardiology (ACC) and American Heart Association (AHA) recommend spironolactone as a treatment for resistant hypertension (RH).2 RH is confirmed by an office blood pressure (BP) of ≥130/80 mm Hg after treatment with ≥3 different antihypertensive medications or office BP of <130/80 mm Hg after treatment with ≥4 antihypertensive medications. In patients with RH, studies have shown that spironolactone has been more effective at lowering BP compared to placebo and as well as compared to alpha and beta blockers.3-5 Engbaek et al. studied the efficacy of spironolactone in 296 patients with RH.3 Participants had a mean baseline BP of 169/88 mm Hg and all were given a low dose (25 – 50 mg daily) of spironolactone for six months. At the one, three, and six month follow-up, BP decreased from baseline by an average of 16.6/7, 23.9/9.7, and 26/10.7 mm Hg, respectively (p<0.001).
The ACC/AHA guidelines recommend spironolactone (12.5 – 25 mg/day) to treat New York Heart Association (NYHA) Class III-IV heart failure with reduced ejection fraction (HFrEF).6 In the Aldactone Evaluation Study (RALES), 1,663 patients with NYHA Class III-IV HFrEF were randomized to 25-50 mg/day spironolactone compared to placebo.7 In the treatment group, 284 of 822 patients died from any cause compared to 386 of 841 patients in the placebo group (relative ratio [RR] = .70, p<0.001). The frequency of cardiac-related hospitalizations was also lower in the treatment group compared to the placebo group (515 hospitalizations vs 753 hospitalizations, RR = .70, p<0.001). Using NYHA Class change to track improvement in heart failure conditions, 41% of patients in the treatment group improved compared to 33% in the placebo group (p<.001). Conditions worsened in 38% in the treatment group compared to 48% in the placebo group (p<.001).
The ACC/AHA guidelines also indicate spironolactone treatment may decrease the risk of hospitalization for patients with NYHA Class III-IV heart failure with preserved ejection fraction who meet other specific criteria (ejection fraction ≥45%, elevated brain-type natriuretic peptide levels or heart failure admission within one year, estimated glomerular filtration rate >30 mL/min, creatinine <2.5 mg/dL, potassium <5.0 mEq/L), (hazard ratio [HR]=0.82, p<0.05).6 This recommendation is based on a study in which the effective dosage ranged from 15 mg to 45 mg daily.8 The mean dose was 25.0 mg daily after eight months of treatment.
The 2016 Endocrine Society Clinical Practice Guideline recommends spironolactone as a non-surgical alternative for the treatment of primary hyperaldosteronism (PA).9 Spironolactone has been shown to be an effective first-line treatment for both pre-operative and post-operative patients.9 In addition, spironolactone has served as a long-term treatment for hypertension in patients with PA.10,11 In one study, 67 patients with PA were given a daily dose of spironolactone for at least four weeks.12 Based on participants’ initial BP and their responsiveness to spironolactone, dosage administration ranged from 50 to 400 mg (mean dose 254 mg). Mean baseline BP decreased from 201/122 mm Hg to 159/101 mm Hg 3-5 weeks after treatment (p<0.001). Reports showed that blood pressure remained controlled in all patients that continued taking spironolactone even after eight years.
Both the American Association for the Study of Liver Diseases and the National Hepatitis C Program deem spironolactone a first-line diuretic for patients with cirrhosis and ascites.13,14 Current guidelines advise initiating treatment with a daily dose of 50 – 100 mg, titrating up to 400 mg as necessary. In a study of 90 patients with ascites resulting from liver cirrhosis, participants were randomized to one of three treatment groups: sequential spironolactone, furosemide alone, or a combination of spironolactone and furosemide.15 Participants in the sequential spironolactone group (n=30) were started on 100 mg/day and monitored every three days for 40 days. The dosage of spironolactone increased up to 400 mg/day followed by the addition of furosemide on the 13th day until patients showed a response of 0.4 – 0.8 kg daily diuresis. In the sequential spironolactone group, 11 of the 22 surviving patients achieved satisfactory diuresis on spironolactone alone. On average, ascites resolved after 16 days of treatment in this group. At the end of the 40-day study, an average dose of 210 mg was administered in the sequential spironolactone group and ascites had resolved in all patients. Researchers suggest that spironolactone alone may be more appropriate for ambulatory patients whereas a combination of spironolactone and furosemide is more appropriate for hospitalized patients who require greater effects and frequent monitoring.
Although spironolactone is not a first-line diuretic for the treatment of severe edema in patients with nephrotic syndrome, it has been used in some instances.16-19 In a study of 10 children with nephrotic syndrome and severe edema, researchers concluded that it was safe and effective to use diuretics (spironolactone and furosemide) alone to treat edematous symptoms.16
Often, spironolactone will be used as a potassium-sparing diuretic to treat or prevent hypokalemia resulting from disease or medication use.3,12,20 For example, thiazide and loop diuretics are commonly used to treat hypertension but can cause hypokalemia.21,22 In the 1996 RALES trial, patients with NYHA Class II-IV congestive heart failure were given either spironolactone or a placebo in addition to their treatment regimen of an angiotensin-converting enzyme inhibitor and a loop diuretic.23 Throughout the 12-week study, 4 out of 40 patients in the placebo group developed hypokalemia whereas only 1 out of 174 patients in the spironolactone group (varying daily doses of 12.5 – 75 mg) developed hypokalemia.
As an anti-androgen, daily doses of spironolactone (50 – 200 mg) have been used for decades for non-FDA approved conditions such as acne vulgaris and hirsutism.24-27 A study of 85 women with inflammatory papular or nodular facial acne of moderate or greater severity demonstrated the utility of spironolactone for acne treatment.27 Participants were given spironolactone 50 to 100 mg/day either alone or in combination with systemic antibiotics, oral contraceptives, or both. Acne resolved in 24 (33%), improved markedly in 24 (33%), and improved partially in 22 (27.4%) participants. The remaining 5 (7%) participants had no acne improvement. In the subgroup of patients with complete acne clearing, 5 (20.8%) were taking spironolactone alone, 10 (41.7%) were taking spironolactone plus an oral contraceptive, 4 (16.7%) were taking spironolactone plus an antibiotic, and 5 (20.8%) were taking spironolactone plus an oral contraceptive and an antibiotic. A similar trend was seen in the marked improvement subgroup. That is, 14 (58.3%) participants took spironolactone plus an oral contraceptive whereas 5 (20.8%) participants were taking spironolactone alone. These findings suggest that in conjunction with another medication, low dose spironolactone may be used for the treatment of acne.
References
- Aldactone (spironolactone) [package insert]. New York, NY: Pfizer, Inc.; 2018.
- Whelton PK, Carey RM, Aronow WS, 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: a Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertens. 2017.
- Engbaek M, Hjerrild M, Hallas J, Jacobsen IA. The effect of low-dose spironolactone on resistant hypertension. J Am Soc Hypertens. 2010;4(6):290-294.
- Rodilla E, Costa JA, Perez-Lahiguera F, Baldo E, Gonzalez C, Pascual JM. Spironolactone and doxazosin treatment in patients with resistant hypertension. Rev Esp Cardiol. 2009;62(2):158-166.
- Williams B, MacDonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015;386(10008):2059-2068.
- Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017.
- Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709-717.
- Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2014;370(15):1383-1392.
- Funder JW, Carey RM, Mantero F, et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916.
- Ferriss JB, Beevers DG, Boddy K, et al. The treatment of low-renin (“primary”) hyperaldosteronism. Am Heart J. 1978;96(1):97-109.
- Quinkler M, Stewart PM. Treatment of primary aldosteronism. Best Practice & Research Clinical Endocrinology & Metabolism. 2010;24(6):923-932.
- Brown JJ, Davies DL, Ferriss JB, et al. Comparison of Surgery and Prolonged Spironolactone Therapy in Patients with Hypertension, Aldosterone Excess, and Low Plasma Renin. Br Med J. 1972;2(5816):729-734.
- Garcia-Tsao G, Lim J. Management and Treatment of Patients With Cirrhosis and Portal Hypertension: Recommendations From the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program. Am J Gastroenterol. 2009;104(7):1802-1829.
- Runyon BA. Management of adult patients with ascites due to cirrhosis: an update. Hepatol. 2009;49(6):2087-2107.
- Fogel MR, Sawhney VK, Neal EA, Miller RG, Knauer CM, Gregory PB. Diuresis in the ascitic patient: a randomized controlled trial of three regimens. J Clin Gastroenterol. 1981;3 Suppl 1:73-80.
- Kapur G, Valentini RP, Imam AA, Mattoo TK. Treatment of severe edema in children with nephrotic syndrome with diuretics alone--a prospective study. Clin J Am Soc Nephrol. 2009;4(5):907-913.
- Nishi S, Ubara Y, Utsunomiya Y, et al. Evidence-based clinical practice guidelines for nephrotic syndrome 2014. Clin Exp Nephrol. 2016;20:342-370.
- Richards D, Aronson JK. Oxford Handbook of Practical Drug Therapy. Oxford University Press; 2005.
- Schrier RW. Diseases of the Kidney and Urinary Tract. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2007.
- Abrishamkar S, Shafiei M, Shafiei M. Spironolactone in preventing hypokalemia following traumatic brain injury. Chin J Traumatol. Dec 2010;13(6):336-340.
- Gennari FJ. Hypokalemia. N Engl J Med. 1998;339(7):451-458.
- Types of Blood Pressure Medications. http://www.heart.org/HEARTORG/Conditions/HighBloodPressure/MakeChangesThatMatter/Types-of-Blood-Pressure-Medications_UCM_303247_Article.jsp#.WZs1DSh942w. Accessed August 21, 2017.
- Pitt B, et al; The Rales Investigators. Effectiveness of Spironolactone Added to an Angiotensin-Converting Enzyme Inhibitor and a Loop Diuretic for Severe Chronic Congestive Heart Failure (The Randomized Aldactone Evaluation Study [RALES]). Am J Cardiol. 1996;78(8):902-907.
- Brown J, Farquhar C, Lee O, Toomath R, Jepson RG. Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. Cochrane Database of Systematic Reviews. 2003(4).
- Goodfellow A, Alaghband-Zadeh J, Carter G, et al. Oral spironolactone improves acne vulgaris and reduces sebum excretion. Br J Dermatol. 1984;111(2):209-214.
- Muhlemann MF, Carter GD, Cream JJ, Wise P. Oral spironolactone: an effective treatment for acne vulgaris in women. Br J Dermatol. 1986;115(2):227-232.
- Shaw JC. Low-dose adjunctive spironolactone in the treatment of acne in women: A retrospective analysis of 85 consecutively treated patients. J Am Acad Dermatol. 2000/09/01/ 2000;43(3):498-502.
