Spironolactone, hyperkalemia and heart failure

Congestive heart failure (CHF) is one of the most frequent cardiovascular diseases in the industrialised countries with more than 15 million patients worldwide. The age-dependent increase in prevalence and incidence is associated with frequent hospitalisation and a rise in costs for the health care system. The prognosis of symptomatic CHF is poor and comparable to various cancer diseases.

The RAAS in Congestive Heart Failure

A large body of evidence from clinical trials supports a role of the renin-angiotensin-aldosterone system (RAAS) in the pathogenesis of CHF. Therefore, inhibition of the RAAS has become an important tool for the treatment of CHF. Inhibition of the angiotensin converting enzyme (ACE) by ACE-inhibitors (ACE-I) and blockade of the angiotensin II type 1 receptor (AT1R) has been shown to decrease mortality and morbidity in patients with heart failure and post-myocardial infarction. However, despite ACE-I therapy, aldosterone concentrations rise in a significant number of patients (“aldosterone escape phenomenon”). Aldosterone levels correlate with the risk of cardiovascular events and have detrimental effects on the vasculature and the myocardium (1). In patients in NYHA class III and IV, inhibition of the aldosterone receptor with ACE-I can increase survival and reduce morbidity (2; 3). The RALES study (2) showed that a low-dose inhibition (25-50mg spironolactone) of the aldosterone receptor can significantly improve survival in patients NYHA III-IV. Results of the EPHESUS trial (3) with eplerenone -a selective aldosterone receptor antagonist- suggest that in addition, patients with NYHA I-III and post-myocardial infarction benefit from aldosterone antagonists.

Current Guidelines

According to current guidelines (4), treatment with aldosterone receptor antagonists is advised in addition to the standard therapy with ACE-I and/or AT1-R antagonists in patients with NYHA III-IV. To avoid severe hyperkalemia (2.0% in RALES, 5.5% in EPHESUS) the dose should be adapted to 25mg/d. Electrolyte concentrations should be followed closely.

Implementation of the Results of the RALES Study and Hyperkalemia

The revival of spironolactone, an inexpensive and well tolerated substance was expected to improve survival and hospitalisation of symptomatic patients with CHF.
Juurlink et al. (5) demonstrated that after the publication of the RALES study prescriptions for spironolactone in Ontario, Canada increased significantly from 34 per 1000 patients in 1994 to 149 per 1000 patients in 2001 (p<0.001). This group of patients (>66 years of age) were treated with an ACE-I after hospitalisation for heart failure and received a median dose of 25mg spironolactone. However, at the same time, the rate of hospitalisation for hyperkalemia increased from 2.4 in 1994 to 11.0 per 1000 patients in 2001 (p<0.001). This increase in hyperkalemia rates was associated with a concomitant increase in mortality from 0.3 to 2.0 per 1000 patients (p<0.001). Surprisingly, neither the rate of hospitalisation for heart failure (p=0.78), nor the rate of death from any cause declined significantly from 1994 to 2001. Similar results were obtained in the group of patients who received ACE-inhibition but did not have a history of recent hospital admission due to heart failure.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

Conclusion:

According to current guidelines, the use of spironolactone accomplishes the standard therapy with ACE-I and/or AT1-R antagonists in patients with NYHA III-IV to improve survival of symptomatic patients with CHF (RALES Study). However, the recently published observational study by Juurlink et al. suggests that spironolactone-associated hyperkalemia in elderly patients with ACE-I treatment is more frequent in daily practice than expected and associated with a significant increase in mortality. In addition, the rate of hospitalisation and overall death was not decreased with the enhanced use of spironolactone in this observational study.
Therefore, in clinical practice the concomitant use of ACE-I and spironolactone has to be accompanied with:

• a closer monitoring of potassium concentrations
• careful evaluation of pre-disposing and developing factors for hyperkalemia (e.g. renal function, diabetes)
• doses restricted to 25mg per day

to avoid iatrogenic hyperkalemia with its associated mortality.