Abstract & Commentary
Synopsis: Patients treated with spironolactone and ACE inhibitors for congestive heart failure (CHF) have a markedly increased risk of hyperkalemia. In severe heart failure, while each of these drugs is effective, their combination may increase the risk of death if hyperkalemia is not prevented or quickly realized and treated.
Source: Juurlink DN, et al. N Engl J Med. 2004;351:543-551.
In 1999, the Randomized Aldactone Evaluation Study (RALES) clinical trial was published in the New England Journal of Medicine showing that spironolactone was highly effective in managing severe heart failure.1 This was good news since spironolactone is an inexpensive drug and most primary care physicians are familiar with its use as a weak diuretic for hypertension and advanced liver disease. The risk of hyperkalemia using spironolactone is well known, but is generally mild if low doses are used, and low doses were shown to be effective in CHF. In the RALES clinical trial, there was a 30% reduced risk of death over 2 years in patients with severe heart failure, including patients also taking an ACE inhibitor.
However, in real world practice, Juurlink and colleagues found among a large Canadian population that spironolactone use in CHF was associated with increased hospital admissions for hyperkalemia and increased mortality (0.3 per 1000 to 2.0 per 1000 patients). The crux of the problem was the combined use of spironolactone and ACE inhibitors in patient with severe heart failure, often accompanied by some degree of renal insufficiency.
In an editorial in the same issue, McMurray and O’Meara describe the problem as the combined suppression of aldosterone in these elderly patients. In a controlled clinical trial, patients are carefully selected and monitored.2 In the real world of undifferentiated patients and less stringent monitoring, different outcomes may occur. It is clear that using both spironolactone and an ACE inhibitor in elderly patients with severe heart failure and renal insufficiency is dangerous.
Comment by Joseph E. Scherger, MD, MPH
Monitoring for serum potassium has been a standard part of patient care for hypertension and CHF. However, ever since the reduction in use of digoxin and diuretics together there has been a relaxation in concern about potassium problems. Now, with the polypharmacy often used with CHF patients, we have a new, clearly delineated concern. Use spironolactone and an ACE inhibitor together with extreme care. What is remarkable about this study is that the follow-up of an excellent clinical trial that showed lives saved resulted in an increased mortality in real world practice. I have not seen such a clear example of how carefully controlled research may result in much different outcomes from regular clinical practice. This result is humbling, and reinforces the caution that must be used when medications which show great promise individually are used together.
This study and the editorial are followed by a review article on managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system.3 My awareness of the risk of hyperkalemia has been heightened by these articles. Seems like it’s back to the days of thinking about potassium very seriously in patients with heart failure when certain medications are used.
Dr. Scherger, Clinical Professor, University of California, San Diego, is Associate Editor of Internal Medicine Alert.
1. Pitt B, et al. N Engl J Med. 1999;341:709-717.
2. McMurray JJV, O’Meara E. N Engl J Med. 2004;351:526-528.
3. Palmer BF. N Engl J Med. 2004;351:585-592.