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Hospitalizations and deaths from high potassium levels soar in heart failure patients after publication of major drug trial


Hospitalizations and deaths from hyperkalemia (life-threatening levels of potassium) have risen dramatically after publication of a landmark clinical trial that promoted a drug for the treatment of heart failure.

In 1999, the Randomized Aldactone Evaluation Study (RALES) demonstrated that the drug spironolactone significantly improved survival in patients with severe heart failure. However, spironolactone can cause life-threatening hyperkalemia when taken with angiotensin-converting enzyme (ACE) inhibitors – drugs that are recommended as a key treatment for heart failure.

To examine the impact RALES had on spironolactone prescribing and patient outcomes, researchers tracked hospital admissions for more than one million Ontarians aged 66 years and older between 1994 and 2001.


  • Among ACE inhibitor-treated patients with a recent hospital admission for heart failure, the rate of spironolactone use increased about fivefold from 34 per 1000 patients in 1994 to 149 per 1000 patients by late 2001.
  • The hospitalization rate for hyperkalemia rose about threefold from 2.5 per 1000 patients in 1994 to 11.0 per 1000 patients in 2001. The associated mortality also rose about threefold from 0.3 per 1000 patients in 1994 to 2.0 per 1000 patients in 2001.
  • Compared to expected numbers of adverse events, the publication of RALES was associated with at least 560 excess hospital admissions for hyperkalemia and 73 excess deaths among older Ontarians receiving ACE inhibitors for heart failure during 2001 alone.

“Much of this harm likely results from inadequate monitoring and the extension of the RALES findings to patients at increased risk of hyperkalemia, including many who would have been excluded from the original trial,” said lead author and Institute for Clinical Evaluative Sciences (ICES) scientist Dr. David Juurlink. “As a result, spironolactone appeared much safer in initial reports than in subsequent widespread clinical use.”

Dr. Juurlink cautions that withholding spironolactone from appropriate patients is not the answer. “Instead, doctors should consider risk factors for hyperkalemia when selecting patients for spironolactone therapy, minimize the use of other medications that cause hyperkalemia, and closely monitor kidney function and potassium levels after starting the drug” he said.

The study, “Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study”, is in the August 5, 2004 issue of the New England Journal of Medicine (NEJM).

Author affiliations: ICES (All authors); Departments of Medicine (Drs. Juurlink, Lee, Laupacis, and Redelmeier), Pharmacy (Dr. Mamdani), Public Health Sciences (Dr. Austin), and Health Policy, Management and Evaluation (Drs. Juurlink, Mamdani, Lee, Austin, Laupacis, and Redelmeier) at the University of Toronto.

ICES is an independent, non-profit organization that uses population-based health information to produce knowledge on a broad range of healthcare issues. Our unbiased evidence provides measures of health system performance, a clearer understanding of the shifting healthcare needs of Ontarians, and a stimulus for discussion of practical solutions to optimize scarce resources. ICES knowledge is highly regarded in Canada and abroad, and is widely used by government, hospitals, planners and practitioners to make decisions about care delivery and to develop policy.


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