Aldosterone Antagonists in the Treatment of Heart Failure

Todd R. Marcy; Toni L. Ripley


Am J Health Syst Pharm. 2006;63(1):49-58. 

In This Article

Hyperkalemia Induced by Aldosterone Antagonists

As previously discussed, aldosterone acts in the renal cortical collecting ducts by inducing synthesis of proteins that constitute the Na+,K+-ATPase pump. The pump acts to re-absorb sodium and water in exchange for potassium, which is then eliminated in the urine.[13] Consequently, aldosterone antagonism can cause hyperkalemia. Hyperkalemia is an established adverse effect of both spironolactone and eplerenone.[45,51]

The symptoms of hyperkalemia begin with muscle weakness. As serum potassium levels rise, symptoms progress to more significant muscle twitching, weakness, nausea, and cramping.[69] Cardiac conduction abnormalities can begin with peaked T waves at serum potassium concentrations of 5.5–6.0 meq/L. As serum potassium values increase, the P–R and QRS intervals become prolonged and conduction abnormalities become more severe, eventually resulting in life-threatening ventricular fibrillation or asystole.

The major clinical trials of aldosterone antagonists in heart failure have found dosage-related elevations in serum potassium values.[4,5] In RALES, serum potassium concentrations increased by a mean of 0.30 mmol/L in the spironolactone-treated group, compared with no change in the placebo group (p < 0.001).[4] Of the patients taking spironolactone in RALES, 2% developed serious hyperkalemia (≥6.0 mmol/L), compared with 1% of patients in the placebo group. In a RALES pilot study, 13% of patients receiving 25 mg of spironolactone daily developed hyperkalemia (≥5.5 mmol/L).[62] Hyperkalemia developed in 20% and 24% of patients receiving spironolactone 50 and 75 mg/day, respectively.

In EPHESUS, potassium concentrations increased by 0.2 mmol/L in the placebo group and 0.3 mmol/L in the eplerenone-treated group.[5] Serious hyperkalemia (i.e., serum potassium concentration of ≥6.0 mmol/L) occurred in 5.5% and 3.9% of patients receiving eplerenone and placebo, respectively (p = 0.002).

Retrospective and clinic-based evaluations of aldosterone antagonists indicate that a higher rate of hyperkalemia than that reported in EPHESUS is likely.[6,70,71,72] This may be due to exclusion of high-risk patients, increased frequency of monitoring, different dosages of aldosterone antagonists, and less frequent use of concurrent medications affecting electrolyte balance, compared with usual practice. RALES and EPHESUS excluded patients with serum creatinine concentrations of ≥2.5 mg/dL or serum potassium concentrations of ≥5.0 mmol/L.[4,5] In RALES, only 10% of patients in the placebo group and 11% receiving spironolactone were taking a β-blocker, which may modestly contribute to hyperkalemia. In both major trials, serum potassium values were vigilantly monitored, especially during dosage adjustments.

The use of aldosterone antagonists in heart failure dramatically increased in 1999 after publication of RALES. Since that time, several case reports and case series have linked aldosterone antagonism in heart failure with life-threatening hyperkalemia, especially in combination with ACE inhibitors or ARBs.[70,71,72,73,74,75,76]

A Canadian-based retrospective analysis evaluated the prescribing patterns of spironolactone and hyperkalemia-associated hospitalizations in patients age 66 years or older.[6] The prescription rate of spironolactone for patients who had been hospitalized for heart failure increased from 30 per 1000 patients in 1994–99 to 149 per 1000 patients in 1999–2001 (p < 0.001). The median daily dose of spironolactone after the publication of RALES was 25 mg. The rate of hospitalization involving a diagnosis of hyperkalemia increased from 2.4 per 1000 patients in 1994 to 4.0 per 1000 patients in 1999 and to 11.0 per 1000 patients in 2001 (p < 0.001). The inhospital death rate associated with hyperkalemia and heart failure increased from 0.7 per 1000 patients in early 1999 to 2.0 per 1000 patients by late 2001 (p < 0.01). However, the rate of death from any cause declined from 58 per 1000 patients in early 1994 to 44 per 1000 patients by late 2001. However, this decline was not significant.

Importantly, this trial did not evaluate causality. With a nearly fivefold increase in the use of spironolactone, one would assume that more patients would have developed hyperkalemia. The number of hospitalizations or deaths that would have been prevented in the absence of hyperkalemia remains unclear. This study identified an increase in hyperkalemia and strongly associated that increase with the increased use of spironolactone. However, these observational data do not firmly establish a causal link between hyperkalemia and adverse outcomes. Risk factors for developing hyperkalemia include renal insufficiency, diabetes mellitus, advanced heart failure, advanced age, and concurrent drug therapy.

Wrenger and colleagues[76] reported a case series of 44 patients with heart failure admitted for hyperkalemia who were taking spironolactone plus an ACE inhibitor or ARB. The average serum potassium concentration on admission was 7.7 mmol/L. Eighty percent of these patients (n = 35) had diabetes. Thirty-four had a baseline creatinine clearance (CLcr) of ≤30 mL/min. In a case series of 25 patients with heart failure and severe hyperkalemia (>6.0 mmol/L) who were taking spironolactone and an ACE inhibitor, the average serum creatinine (SCr) concentration was 1.9 mg/dL.[75] Patients' mean age was 74 years. The RALES pilot study identified an increased risk for hyperkalemia in patients with a baseline SCr concentration of >1.6 mg/dL.[62] Smaller case series have associated hyperkalemia with renal insufficiency.[73,74] Patients with an SCr concentration of >2.5 mg/dL were excluded from both RALES and EPHESUS.[4,5] It has been suggested that spironolactone be avoided in patients with a CLcr of ≤30 mL/min[74,77,78]; eplerenone is contraindicated in patients with a CLcr of ≤30 mL/min.[51]

Diabetes has been associated with hyperkalemia in heart failure patients taking an aldosterone inhibitor.[70,71,76,77,79] In a retrospective review, Anton and colleagues[70] identified 110 patients treated with both an ACE inhibitor or ARB and spironolactone. Of these patients, 26 developed severe hyperkalemia (≥6 mmol/L) during a 12-month observation period. Of the 52 diabetic patients in the study, 25 developed hyperkalemia (odds ratio [OR], 2.23; 95% CI, 1.02–4.89) (p = 0.045). Fourteen of these 25 patients had severe hyperkalemia (OR, 1.41; 95% confidence interval, 0.58–3.41).

The mechanism of increased risk of hyperkalemia in diabetic patients is not completely understood. Chronic diabetes mellitus is a common cause of hyporeninemic hypoaldosteronism, which causes decreased aldosterone availability and subsequent potassium retention.[76,77,80,81] Insulin deficiency can contribute to hyperkalemia, as insulin stimulates the shift of potassium to the intracellular space.[77,80] Further, renal insufficiency as a consequence of diabetes predisposes this population to electrolyte disturbances.

Cruz and colleagues[71] retrospectively reviewed patients admitted for decompensated heart failure and treated with an ACE inhibitor with or without spironolactone. Of the 49 patients taking both agents, 16 developed hyperkalemia (≥5.5 meq/mL), 7 cases of which were severe (≥6.0 meq/mL). All 7 patients with severe hyperkalemia had NYHA class IV heart failure. The OR for hyperkalemia in patients with class IV versus class III heart failure was 5.2 (p = 0.04). The authors suggested that a contributing factor to the increased rate of hyperkalemia was acute renal deterioration, which is more strongly associated with NYHA functional class than with baseline SCr levels. Baseline SCr values were similar among patients with class III and IV heart failure. The effect of ACE inhibitor dosages on the development of hyperkalemia among NYHA functional classes was not addressed.

Svensson et al.[72] identified 125 consecutive patients in a heart failure clinic, 86% of whom were taking an ACE inhibitor or ARB. Spironolactone was added or continued in each patient. Logistic regression was performed for baseline serum creatinine concentrations, age, sex, LVEF, and use of ACE inhibitors or β-antagonists, but not for ACE inhibitor dosage. Ten percent of the study patients developed severe hyperkalemia (≥6.0 meq/mL). The OR for the development of severe hyperkalemia was 3.36 for each progressive NYHA functional class (95% CI, 1.17–9.69).

A normal product of aging is impaired release of renin, resulting in hypoaldosteronism[82] and an increased risk of hyperkalemia similar to that seen in diabetic patients. Age is also associated with declining CLcr, which may contribute to the increased frequency of hyperkalemia in the elderly.

Several drugs contribute to the development of hyperkalemia in patients taking an aldosterone antagonist. ACE inhibitors and ARBs are strongly associated with serious hyperkalemia in patients taking an aldosterone antagonist. When compared with other ACE inhibitors, captopril was associated with fewer cases of hyperkalemia when taken with spironolactone.[62] Nonsteroidal anti-inflammatory drugs,[83] β-blockers,[84] potassium-sparing diuretics, potassium supplements, cyclosporine,[77] tacrolimus,[85] trimethoprim,[86] and heparin[87] can all increase the risk of hyperkalemia in patients taking aldosterone antagonists.