The potassium-sparing action of spironolactone increases the risk of the serious but uncommon side effect of hyperkalemia, particularly among patients with reduced kidney function and patients who are also taking other drugs that affect the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs).1–7
Hyperkalemia can be a medical emergency because of its effect on the heart.8 It can lead to life-threatening arrythmias. Manufacturer’s prescribing information recommend that serum potassium levels should be monitored regularly during spironolactone therapy.1 Hyperkalemia is defined as elevation of the serum potassium level at or above 5.5 mmol/L, but the cut-off of serious hyperkalemia varies in different studies generally between 5 – 6 mmol/L. Reported rates of hyperkalemia among patients taking spironolactone range from 1.1%,5 1.6%,6 2.6%,3 4%,4 and 12%.7
Abbas et al analyzed health insurance claims data of 1,491,894 German patients between 2007 and 2010 with a diagnosis of heart failure who were using an ARB or an ACEI and determined their rates of hospitalization for hyperkalemia.9 (There was no information available in the data set as to the potassium levels used to define the hyperkalemia.) 1,062 patients were identified who were also taking spironolactone in addition to the ARB or ACEI. These patients were then matched (on age, gender, start date and length of follow-up) with 10,620 controls to estimate the effect of spironolactone use on the development of hyperkalemia in this population. The risk of developing hyperkalemia was strongly associated with the use of spironolactone in these patients with an odds ratio [OR] of 13.59 (95% confidence interval [CI] [11.63 – 15.88]) in all and an OR of 11.05 (95% CI [8.67 – 14.08] in those with information on New York Heart Association stage of disease.
Vardeny et al used data from the Randomized Aldactone Evaluation Study trial to assess the risk of hyperkalemia in patients taking spironolactone.10 1,663 patients with class III or IV heart failure and left ventricular ejection fraction <35% were randomized to treatment with spironolactone or placebo. Patients remained on spironolactone until their potassium levels reached 5.5 mmol/L. After one month of therapy, the average potassium levels in the spironolactone arm were significantly higher compared to placebo (4.54 ± 0.49 versus 4.28 ± 0.50 mmol/L, p<0.001). These levels remained elevated throughout the trial. Although the highest levels of potassium were associated with an increased risk for mortality, those taking spironolactone had lower mortality rates at all levels of potassium, compared to placebo. The authors concluded that spironolactone use in this population was associated with improved survival, even in the setting of moderate hyperkalemia, and that monitoring of the potassium levels during treatment is an appropriate caution during spironolactone use.
The prescribing information for spironolactone also warns that excessive water loss from the drug can cause dehydration, hypotension, and worsening of renal function in patients who are also taking ARBs or ACEIs.1 Kidney dysfunction is also more likely in patients who are also taking aminoglycosides, cisplatin, and nonsteroidal anti-inflammatory drugs. Other electrolyte imbalances can occur while taking spironolactone, such as hyponatremia, hypomagnesemia, hypocalcemia, hypochloremic alkalosis, hyperuricemia, and hyperglycemia. While these risks can be minimized with regular monitoring of serum electrolytes, they can pose a serious risk to vulnerable patients.8
Gastric hemorrhage has been reported as a side effect of spironolactone.1 Gulmez et al conducted a case-control study in Denmark to estimate the risk of upper gastrointestinal bleeding (UGIB) in spironolactone users.11 Among 3,652 cases of UGIB from 1995 to 2006, the use of spironolactone significantly increased the risk of UGIB compared to age- and gender-matched controls (OR 2.7, 95% CI [2.2 – 3.2].
Because of the known endocrine effects of spironolactone, the possibility that use of this drug might increase the risk of certain endocrine cancers has been considered.1,4,5 Using a primary care database, the Clinical Practice Research Datalink, MacKenzie et al conducted a matched cohort study that compared cancer rates in the United Kingdom of 74,272 patients exposed to spironolactone matched 1:2 with unexposed controls.12 In this study, there was no evidence of an increased risk of any cancer associated with spironolactone use, but spironolactone use was associated with a significantly lower risk of prostate cancer (hazard ratio 0.69, 95% CI [0.60 – 0.80], p<0.001).
Other less common but serious case reports from the manufacturer include Stevens-Johnson syndrome, toxic epidermal necrolysis, and agranulocytosis.1 Information about the frequency of these reports is not given.
References
- Aldactone-spironolactone [package insert] New York, NY: Pfizer, Inc; 2016.
- Kolkhof P, Bärfacker L. Mineralocorticoid receptor antagonists: 60 years of research and development. J Endocrinol 2017; 234 (1): T125-T140.
- Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens 2003; 16 (11 I): 925-930.
- Chapman N, Dobson J, Wilson S, et al. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 2007; 49 (4): 839-845.
- De Souza F, Muxfeldt E, Fiszman R, Salles G. Efficacy of spironolactone therapy in patients with true resistant hypertension. Hypertension 2010; 55 (1): 147-152.
- Lane DA, Shah S, Beevers DG. Low-dose spironolactone in the management of resistant hypertension: a surveillance study. J Hypertens 2007; 25 (4): 891-894.
- Ouzan J, Pérault C, Lincoff AM, Carré E, Mertes M. The role of spironolactone in the treatment of patients with refractory hypertension. Am J Hypertens 2002; 15 (4 I): 333-339.
- Mount DB. Fluid and Electrolyte Disturbances. In: Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine, 20e. New York, NY: McGraw-Hill Education; 2018.
- Abbas S, Ihle P, Harder S, Schubert I. Risk of hyperkalemia and combined use of spironolactone and long-term ACE inhibitor/angiotensin receptor blocker therapy in heart failure using real-life data: a population- and insurance-based cohort. Pharmacoepidemiol Drug Saf 2015; 24 (4): 406-413.
- Vardeny O, Claggett B, Anand I, et al. Incidence, predictors, and outcomes related to hypo- and hyperkalemia in patients with severe heart failure treated with a mineralocorticoid receptor antagonist. Circ Hear Fail 2014; 7 (4): 573-579.
- Gulmez SE, Lassen AT, Aalykke C, et al. Spironolactone use and the risk of upper gastrointestinal bleeding: A population-based case-control study. Br J Clin Pharmacol 2008; 66 (2).
- Mackenzie IS, Morant S V., Wei L, Thompson AM, MacDonald TM. Spironolactone use and risk of incident cancers: a retrospective, matched cohort study. Br J Clin Pharmacol 2017; 83 (3): 653-663.
