Medications That Increase the Risk of Hyperkalemia

Common medications used in patients with CKD and heart failure

Several medications are frequently used in patients with comorbidities associated with poor kidney or heart function. Many of these drugs—like nonsteroidal anti-inflammatory drugs (NSAIDs), digoxin, and K+-sparing diuretics—have been shown to be associated with elevated serum K+.1

This table lists out many of the medications associated with hyperkalemia, inclulding NSAIDs, digoxin, potassium-sparing diuretics, and RAAS inhibitors.

Reproduced with permission from Weiner ID, Linas SL, Wingo CS. Disorders of Potassium Metabolism. In: Johnson R, Fluege J, Feehally J, eds. Comprehensive Clinical Nephrology. 4th ed. Philadelphia, PA: Saunders Elsevier; 2010:118-129.

Key principles in the development of hyperkalemia2

This illustration points out several ways in which the use of certain medication s can lead to hyperkalemia, including  impairing release of renins, impairing the metabolism of  aldosterone, and blocking the aldosterone receptors.

Reproduced with permission from Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med. 2004;351(6):585-592.

Clinical data mine: Explore evidence of RAASi use and its association with hyperkalemia

Of the commonly used medications known to cause hyperkalemia and play a prominent role in the management of CKD and heart failure,8 the effects and implications of RAASi use on serum potassium levels has been the most systematically documented. It has been well documented that the use of RAASi (renin-angiotensin-aldosterone system inhibitors) compounds the risk for hyperkalemia, especially in patients with renal insufficiency.1

(Click on any study below to expand and view clinical evidence.)

Weir et al: Data review of association between the incidence of hyperkalemia and RAASi use in CKD and heart failure patients

In the extensive data review by Weir et al, the authors conclude that the incidence of hyperkalemia (defined as K+ >5.5 mEq/L), in association with RAASi use, is increased in patients with CKD or heart failure.5

  • Hyperkalemia incidence with RAASi monotherapy in patients with hypertension and no risk factors for hyperkalemia: ≤2%
  • Hyperkalemia incidence with RAASi co-administration in patients with hypertension and no risk factors for hyperkalemia: ~5%
  • Hyperkalemia incidence with RAASi use in patients with CKD or heart failure: ~5%-10%

RALES Study: Hyperkalemia rates increased with spironolactone use among heart failure patients

The relationship between hyperkalemia and the use of RAASi therapy has been well established in heart failure patients. In RALES (Randomized Aldactone Evaluation Study), a dose-dependent increase in the incidence of hyperkalemia (serum K+ ≥5.5 mEq/L) was seen in patients taking spironolactone. In the study, patients with symptomatic congestive heart failure continued on their previous therapeutic regimens, which included an angiotensin-converting enzyme (ACE) inhibitor and a loop diuretic with or without digitalis, and were randomized to placebo or varying doses of spironolactone for 12 weeks.13

Rates of Hyperkalemia in Heart Failure Patients on RAASi Therapy13
This bar chart shows the relationship between hyperkalemia and the use of RAASi therapy in heart failure patients in the RALES trial. As the dose of  spironolactone increased, so did the percentage of patients diagnosed with hyperkalemia.

EPHESUS Study: Increased risk of hyperkalemia associated with eplerenone use in heart failure patients

In EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study), a double-blind, placebo-controlled study of the antihypertensive agent eplerenone at doses of 25 to 50 mg/day in patients with severe heart failure, it was shown that there was an increased risk of one or more hyperkalemic events with eplerenone vs placebo as creatinine clearance decreased.14


aEstimated using the Cockroft-Gault formula.

RALES/EMPHASIS rates vs real-world rates: Real-world hyperkalemia rates shown to be higher with RAASi use in heart failure patients

Real-world incidence of hyperkalemia appears to be higher than observed in RAASi clinical trials, as the patient populations in these studies are selected to exclude those at high-risk for hyperkalemia.17,18 An analysis of two major clinical trials of spironolactone use in heart failure patients—the Randomized Aldactone Evaluation Study, or RALES; and Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms, or EMPHASIS—compared to two observational studies shows that hyperkalemia (in this instance, defined as K+ >5.5 mEq/L) occurs more often in actual clinical practice.16,17

In their observational studies, Shah et al and Bozkurt et al applied the trial protocol of RALES to a clinical setting that included a broader patient population and found that less frequent laboratory monitoring as well as deviations from appropriate care and patient follow-up contributed to increased complications with spironolactone-associated hyperkalemia.16,17

In Shah et al, of 551 CHF patients monitored for serum potassium levels within 3 months of starting spironolactone, 15% of patients developed hyperkalemia (K+ >5.5 mEq/L), with 6% classified as severe hyperkalemia (K+ >6.0 mEq/L) vs only 2% of patients in RALES.17 In Bozkurt et al, 24% of CHF patients (N=104) treated with spironolactone developed hyperkalemia (K+ ≥5.2 mEq/L), with 12% classified as serious hyperkalemia (K+ ≥6.0 mEq/L).16

This bar chart compares the rates of hyperkalemia documented in  heart failure patients participating in clinical trials versus heart failure patients in real-world settings. The rates of hyperkalemia are shown to be higher in the clinical trials.

RENAAL Study: Increased risk of adverse kidney outcomes with losartan use among type 2 diabetes mellitus patients

In a post-hoc analysis of patients with type 2 diabetes mellitus participating in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, patients with a drug-induced month 6 serum K+ ≥5.0 mEq/L had a 22% increased risk for developing adverse kidney outcomes such as doubling of serum creatinine (DSCR) or end-stage kidney disease (ESRD). Additionally, after controlling for potential confounders, patients who had a mean serum K+ ≥5.0 mEq/L during follow-up had a 43% higher risk of DSCR or ESRD.10

Inhibition of the RAAS results in elevated serum potassium levels

In patients on RAASi therapy, serum/extracellular K+ is further elevated because these medications, especially MRAs, have a critical impact on the levels or activity of aldosterone. RAASi can interfere with the stimulatory effect of angiotensin II on aldosterone secretion in the adrenal gland, while MRAs block the interaction of aldosterone with its receptor.1,3,4 This prevents K+ resorption back into the distal tubule for urinary excretion, thus further perturbing the extracellular/intracellular K+ balance.1,4,5

Most current treatment guidelines support the practice of RAASi dose adjustments or discontinuation based on serum potassium levels. (See recommended RAASi modifications) While this may reduce the immediate risk of hyperkalemia or lower potassium levels, it may put patients with CKD and heart failure at greater risk for progression or exacerbation of their underlying disease.6-10

Clinical considerations of other common medications and hyperkalemia

Overall, the incidence of hyperkalemia as a result of non-selective NSAID use is fairly infrequent. Nevertheless, it remains a concern in patients with very low kidney function because NSAIDs may further alter function through their effects on renal prostaglandins. Particularly, concomitant use with ACEs and ARBs may worsen functional renal insufficiency. Standard precautions are advised to avoid renal toxicity in these high-risk patients.5

The use of COX-2 inhibitors has also been associated with hyperkalemia because it hinders potassium secretion at the distal tube by inhibiting prostacyclin synthesis. In fact, results suggest that these medications pose a greater threat for increased serum potassium than non-selective NSAIDs.11

Heparin is a medication that impacts the RAAS through multiple mechanisms, including by decreasing the principal stimulus for aldosterone synthesis. This has resulted in hyperkalemia being noted in 7% to 8% of patients treated with at least 5000 U of heparin twice a day.12