Hyperkalemia is a common electrolyte abnormality and is frequently asymptomatic or associated with non-specific mild symptoms, but severe hyperkalemia can lead to cardiac arrhythmias and death.1-4 Depending on the threshold used for hyperkalemia, ranging from 5.0 to 6.0 mmol/L, prevalence of hyperkalemia varies from 1.1% to 10% with a mortality rate of 1 per 1,000 patients.4,5 Medication-induced hyperkalemia is common in everyday clinical practice. One of the main mechanism of drug-induced hyperkalemia is the reduction of renal potassium excretion through inhibition of the renin-angiotensin aldosterone system.4 Many medication classes including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-II receptor blockers (ARBs), and potassium-sparing diuretics are known to increase the risk of hyperkalemia via impairment of renal potassium excretion.1,2,4
ACEIs and ARBs are commonly prescribed for patients with hypertension, congestive heart failure (CHF), and coronary artery disease.5-10 Potassium-sparing diuretics consist of aldosterone antagonists (i.e., spironolactone, eplerenone), amiloride, and triamterene.2 Spironolactone or eplerenone are effective add-on therapies for a patients with poorly controlled hypertension,11 and are commonly prescribed for patients with heart failure because of a significant reduction in cardiovascular death reported in clinical trials.7,12-14 Amiloride or triamterene are frequently prescribed as a fixed‐dose combination with hydrochlorothiazide for essential hypertension because they tend to be relatively ineffective for hypertension when using as monotherapy and they reduce the risk of hypokalemia associated with hydrochlorothiazide administration.15 Due to the common use of ACEIs ARBs, and potassium sparing diuretics, increased awareness of the risk of hyperkalemia will help reduce hyperkalemia related hospital admissions, morbidity, and mortality.4
ACEIs and ARBs cause may cause hyperkalemia through several mechanisms such as reduced aldosterone secretion in adrenal gland and reduced delivery of sodium to the distal nephron.4 The incidence of hyperkalemia ranges from 3-10% of patients treating with ACEI.16,17 A randomized controlled, double-blind, crossover study of 30 patients with stage 3 chronic kidney disease (CKD) treated with olmesartan and enalapril separately for 3 months with 1-week wash-out period, reported a similar increased in potassium after 1 week of treatment with enalapril (0.30 mmol/L) or olmesartan (0.24 mmol/L). A retrospective observational study of 1163 patients on ACEIs and 1168 patients on ARBs, reported hyperkalemia in 20% and 31% of patients, respectively.10 The authors suggested the higher prevalence of hyperkalemia in ARBs group may be due to more patients with CHF and using potassium sparing diuretics.10
K-sparing diuretics, such as spironolactone and eplerenone, can cause hyperkalemia by blocking renal aldosterone receptors.4 Amiloride and triamterene may cause hyperkalemia by blocking sodium reabsorption in the collecting tubule and collecting ducts which leads to a reduction in renal excretion of potassium.4,15 A study found that K-sparing diuretics were strongly predictive of high serum potassium (K>5.0 mmol/L) with an OR= 1.9.18 A nested case-control study of 19,194 patients with newly diagnosed heart failure who were followed over an average of 3.9 years. The use of potassium‐sparing diuretics (including spironolactone, amiloride, eplerenone, triamterene) increased the risk of hyperkalemia by 3-fold. (The risk was slightly higher for spironolactone OR= 3.23 versus amiloride OR= 2.63.1 The risk of hyperkalemia was the greatest during the first month of treatment (OR=9.16) for all potassium‐sparing diuretics, and OR=10.68 for spironolactone.1 A case-control study in hospitalized patients with CHF suggested that average dose of 25-mg/day spironolactone was independently associated with hyperkalemia (K ≥ 5.6 mmol/L) with an OR= 4.18.19 EMPHASIS-HF trail reported the incidence of serum K >5.5 mmol/L and K > 6.0 mmol/L to be 11.8% and 2.5%, respectively in patients with heart failure receiving up to 50 mg daily of eplerenone.20 The use of eplerenone up to 50 mg daily for one month increased potassium levels 0.16±0.51 mmol/L.20
Hyperkalemia associated with potassium-sparing diuretics appears to be dose dependent. High dose K-sparing diuretics (i.e, spironolactone > 25 mg/day, eplerenone > 50 mg/day) was reported to be associated with hyperkalemia.11 A randomized control trial in patients with hemodialysis also reported increased hyperkalemia incidence (0.89 events per patient-year) with 50 mg spironolactone vs. 0.23 events per patient-year with 25 mg.21 According to the Randomized Aldactone Evaluation Study [RALES], patients with symptomatic heart failure who received conventional therapy of an ACEI, loop diuretic, and optional digitalis, the addition of 12.5, 25, 50 and 75 mg spironolactone increased the incidence of hyperkalemia (serum potassium ≥ 5.5 mmol/L) by 5%, 13%, 20%, and 24%, respectively.22 The authors concluded that daily doses of 12.5 to 25 mg of spironolactone co-administered with conventional therapy was safe and effective in patients with heart failure.22 One retrospective study that randomly sampled 600 patients who developed hyperkalemia during hospitalization reported a mean daily increase in serum potassium of 0.52 vs 0.40 mmol/L/day, (p= 0.007) for patients receiving high-dose potassium-sparing diuretics (amiloride > 10 mg/day or spironolactone > 25 mg) vs patients receiving low-dose potassium-sparing diuretics.23
Concurrent use of ACEIs or ARBs and K-sparing diuretics may further increase the risk of hyperkalemia. A retrospective cohort study of 100 patients with decompensated class III or IV CHF suggested that the risk of hyperkalemia is about 24 times higher with concurrent use of ACEIs and spironolactone compared to ACEIs alone.7 A nested case-control study of 622,285 patients aged 65 or greater who were treated with ACEIs, found that approximately 0.4% were subsequently admitted to the hospital due to hyperkalemia.24 Compared to those without hospitalization, the hospitalized patients were 20 times more likely to have received potassium-sparing diuretic within one week of hospitalization.24 Another nested case-control study of 1,491,894 heart failure patients receiving long-term ACEIs/ARBs therapy reported that the risk of hyperkalemia hospitalization was approximately 13 times more likely in patients who received spironolactone within 14 days before the hospitalization.25 A case series reported 44 patients treated with spironolactone and ACEIs or ARBs admitted to a nephrology unit with severe hyperkalemia (K range: 6.04 – 9.65 mmol/L).26 Most of them had decreased creatinine clearance, two of them expired and six of them required chronic dialysis.26 Other fatal cases have been reported with concurrent use of amiloride or spironolactone with ACEIs.27
Risk factors that have been associated with hyperkalemia include impaired renal function,3,8,18,19,23,28,31 diabetes mellitus,3,11,18,19,23,28 infrequent serum potassium monitoring,2,3 and elevated baseline potassium level3. The odds ratio of hyperkalemia with various risk factors included severe renal impairment OR=3.12,, use of ACEIs or ARBs OR=2.64, use of potassium-sparing diuretics OR=2.07, and diabetes mellitus OR=1.53.23 In patients with renal disease, compared to eGFR ≥60 mL/min/1.73m2, the risk of hyperkalemia increased to approximately 2-fold, 5-fold, and 16-fold for eGFR of 45–59, 30–44, and <30 mL/min/1.73m2, respectively.1 Diabetes mellitus increases the risk of hyperkalemia about 2-fold.1 Serum K > 4.3 mEq/L was found to be an independent baseline predictor of increased serum K > 6 mEq/L.28 The risk of hyperkalemia is 3-fold higher in patients with baseline K>4.5 mEq/L compared to those with normokalaemic.29
Artifacts for implementers
- Click to download a PDF of the flow diagram
- Click to download the computable Drools code and associated OMOP Value sets
- Click to view the ACE inhibitors and ARBs value sets
- Clinic to view the potassium-sparing diuretic value sets
- Serum potassium – LOINC 2823-3
- Kidney function – LOINC 48642-3 or 48643-1
- Click to add comments or ask questions on the Discussion forum
- (Pending): PDF short implementation guide
Webinar on 9/23/20
- Michel A, Martin-Perez M, Ruigomez A, Garcia Rodriguez LA. Risk factors for hyperkalaemia in a cohort of patients with newly diagnosed heart failure: a nested case-control study in UK general practice. Eur J Heart Fail. 2015;17(2):205-213.
- Chang AR, Sang Y, Leddy J, et al. Antihypertensive medications and the prevalence of hyperkalemia in a large health system. Hypertension. 2016;67(6):1181-1188.
- Berkova M, Berka Z, Topinkova E. Arrhythmias and ECG changes in life threatening hyperkalemia in older patients treated by potassium sparing drugs. Biomedical papers. 2014;158(1):084-091.
- Ben Salem C, Badreddine A, Fathallah N, Slim R, Hmouda H. Drug-induced hyperkalemia. Drug Saf. 2014;37(9):677-692.
- Stevens MS, Dunlay RW. Hyperkalemia in hospitalized patients. Int Urol Nephrol. 2000;32(2):177-180.
- Ahuja TS, Freeman D, Jr., Mahnken JD, Agraharkar M, Siddiqui M, Memon A. Predictors of the development of hyperkalemia in patients using angiotensin-converting enzyme inhibitors. Am J Nephrol. 2000;20(4):268-272.
- Cruz CS, Cruz AA, Marcilio de Souza CA. Hyperkalaemia in congestive heart failure patients using ACE inhibitors and spironolactone. Nephrol Dial Transplant. 2003;18(9):1814-1819.
- Espinel E, Joven J, Gil I, et al. Risk of hyperkalemia in patients with moderate chronic kidney disease initiating angiotensin converting enzyme inhibitors or angiotensin receptor blockers: a randomized study. BMC Res Notes. 2013;6:306.
- Omboni S, Volpe M. Angiotensin receptor blockers versus angiotensin converting enzyme inhibitors for the treatment of arterial hypertension and the role of olmesartan. Adv Ther. 2019;36(2):278-297.
- Sadjadi SA, McMillan JI, Jaipaul N, Blakely P, Hline SS. A comparative study of the prevalence of hyperkalemia with the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers. Ther Clin Risk Manag. 2009;5(3):547-552.
- Sica DA. Mineralocorticoid receptor antagonists for treatment of hypertension and heart failure. Methodist Debakey Cardiovasc J. 2015;11(4):235-239.
- 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.
- Struthers A, Krum H, Williams GH. A comparison of the aldosterone-blocking agents eplerenone and spironolactone. Clin Cardiol. 2008;31(4):153-158.
- Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309-1321.
- Epstein M, Calhoun DA. Aldosterone blockers (mineralocorticoid receptor antagonism) and potassium-sparing diuretics. J Clin Hypertens (Greenwich). 2011;13(9):644-648.
- Reardon LC, Macpherson DS. Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors. How much should we worry? Arch Intern Med. 1998;158(1):26-32.
- Johnson ES, Weinstein JR, Thorp ML, et al. Predicting the risk of hyperkalemia in patients with chronic kidney disease starting lisinopril. Pharmacoepidemiol Drug Saf. 2010;19(3):266-272.
- Henz S, Maeder MT, Huber S, Schmid M, Loher M, Fehr T. Influence of drugs and comorbidity on serum potassium in 15 000 consecutive hospital admissions. Nephrol Dial Transplant. 2008;23(12):3939-3945.
- Ramadan FH, Masoodi N, El-Solh AA. Clinical factors associated with hyperkalemia in patients with congestive heart failure. J Clin Pharm Ther. 2005;30(3):233-239.
- Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21.
- Charytan DM, Himmelfarb J, Ikizler TA, et al. Safety and cardiovascular efficacy of spironolactone in dialysis-dependent ESRD (SPin-D): a randomized, placebo-controlled, multiple dosage trial. Kidney Int. 2019;95(4):973-982.
- Pitt B, Zannad F, Remme W, et al. 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.
- Indermitte J, Burkolter S, Drewe J, Krahenbuhl S, Hersberger KE. Risk factors associated with a high velocity of the development of hyperkalaemia in hospitalised patients. Drug Saf. 2007;30(1):71-80.
- Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA. Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA. 2003;289(13):1652-1658.
- 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.
- Wrenger E, Müller R, Moesenthin M, Welte T, Frölich JC, Neumann KH. Interaction of spironolactone with ACE inhibitors or angiotensin receptor blockers: analysis of 44 cases. BMJ. 2003;327(7407):147-149.
- Chiu TF, Bullard MJ, Chen JC, Liaw SJ, Ng CJ. Rapid life-threatening hyperkalemia after addition of amiloride HCl/hydrochlorothiazide to angiotensin-converting enzyme inhibitor therapy. Ann Emerg Med. 1997;30(5):612-615.
- Pitt B, Bakris G, Ruilope LM, DiCarlo L, Mukherjee R. Serum potassium and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Circulation. 2008;118(16):1643-1650.
- Eschmann E, Beeler PE, Kaplan V, Schneemann M, Zund G, Blaser J. Patient- and physician-related risk factors for hyperkalaemia in potassium-increasing drug-drug interactions. Eur J Clin Pharmacol. 2014;70(2):215-223.
Creation and Revision DatesCreated: 9/17/2020
Last revision: 9/17/2020
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