The diuretic spironolactone can cause dangerous hyperkalaemia in patients who are also taking angiotensin converting enzyme (ACE) inhibitors, another drug that, like spironolactone, is used to treat congestive heart failure.
After the publication of a major heart study that promoted the use of spironolactone, prescribing rose, but so did cases of hyperkalaemia, according to Dr David Juurlink, a clinical pharmacologist at the University of Toronto and author of a new study that found a threefold increase in the rates of admission to hospital for high potassium levels across Ontario and a twofold increase in deaths involving high potassium levels (New England Journal of Medicine 2004;351:543-51).
The randomised aldactone evaluation study (RALES), which was reported in 1999, found that spironolactone significantly improved survival for patients with severe congestive heart failure (New England Journal of Medicine 1999;341:709-17).
But the new study has found a complication: when patients with severe heart failure take both spironolactone and an ACE inhibitor, life threatening hyperkalaemia can occur.
The researchers examined trends in the rate of spironolactone prescriptions and the rate of admission to hospital for hyperkalaemia in ambulatory patients before and after the publication of RALES. They linked prescription claims data and admission records for more than 1.3 million adults aged 66 years or older in Ontario, Canada, for the period 1994 to 2001. All the patients were taking ACE inhibitors.
They found that among patients treated with ACE inhibitors who had recently been admitted for heart failure, the prescription rate for spironolactone was 34 per 1000 patients in 1994. Immediately after the publication of RALES, the prescription rate rose, reaching 149 per 1000 patients by late 2001 (P<0.001). But the rate of admission for hyperkalaemia also rose, from 2.4 per 1000 patients in 1994 to 11.0 per 1000 patients in 2001 (P<0.001), and the associated mortality rose from 0.3 per 1000 to 2.0 per 1000 patients (P<0.001).
Compared with expected numbers of events, there were 560 (95% confidence interval 285 to 754) additional hyperkalaemia related admissions and 73 (27 to 120) additional hospital deaths during 2001 among older patients with heart failure who were treated with ACE inhibitors in Ontario. Publication of RALES was not associated with significant decreases in the rates of readmission for heart failure or death from all causes.
“We need to be more careful with this medication [spironolactone],” Dr Juurlink said. “This is a drug that is clearly good in the right patients with adequate monitoring. But in patients with other risk factors for elevations in their potassium, or patients we can't monitor closely, we have to be more judicious in the use of the drug.”
In an accompanying editorial (p 526-8), Dr John McMurray and Dr Eileen O'Meara from the department of cardiology, Western Infirmary, Glasgow, wrote that “it seems that the excess hyperkalemia in clinical practice, as compared with RALES, may largely be explained by the use of higher doses of spironolactone and the treatment of patients who had a lower glomerular filtration rate or whose aldosterone-mediated, compensatory distal tubular potassium excretion was already attenuated.”
“Why did physicians use larger doses of spironolactone than those used in the RALES trial, especially given that these patients were more susceptible to hyperkalemia?” they wrote. “Familiarity with a long-established treatment and lack of the usual educational activities related to the safe use of a new drug may have contributed. Similarly, the index of suspicion and the intensity of surveillance for adverse effects related to a new product would have been higher than those for an established drug.”