Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study.
BACKGROUND
The Randomized Aldactone Evaluation Study (RALES) demonstrated that spironolactone significantly improves outcomes in patients with severe heart failure. Use of angiotensin-converting-enzyme (ACE) inhibitors is also indicated in these patients. However, life-threatening hyperkalemia can occur when these drugs are used together.


METHODS
We conducted a population-based time-series analysis to examine trends in the rate of spironolactone prescriptions and the rate of hospitalization for hyperkalemia in ambulatory patients before and after the publication of RALES. We linked prescription-claims data and hospital-admission records for more than 1.3 million adults 66 years of age or older in Ontario, Canada, for the period from 1994 through 2001.


RESULTS
Among patients treated with ACE inhibitors who had recently been hospitalized for heart failure, the spironolactone-prescription rate was 34 per 1000 patients in 1994, and it increased immediately after the publication of RALES, to 149 per 1000 patients by late 2001 (P<0.001). The rate of hospitalization for hyperkalemia 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). As compared with expected numbers of events, there were 560 (95 percent confidence interval, 285 to 754) additional hyperkalemia-related hospitalizations and 73 (95 percent confidence interval, 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.


CONCLUSIONS
The publication of RALES was associated with abrupt increases in the rate of prescriptions for spironolactone and in hyperkalemia-associated morbidity and mortality. Closer laboratory monitoring and more judicious use of spironolactone may reduce the occurrence of this complication.
Juurlink
David N
DN
Department of Medicine University of Toronto, Toronto. dnj@ices.on.ca
Mamdani
Muhammad M
MM
Lee
Douglas S
DS
Kopp
Alexander
A
Austin
Peter C
PC
Laupacis
Andreas
A
Redelmeier
Donald A
DA
D000319:Adrenergic beta-Antagonists / Q000009:adverse effects / Q000627:therapeutic use; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D011307:Drug Prescriptions / Q000706:statistics & numerical data; D004359:Drug Therapy, Combination; D004363:Drug Utilization / Q000639:trends*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy*; D017052:Hospital Mortality / Q000639:trends; D006760:Hospitalization / Q000639:trends; D006801:Humans; D006947:Hyperkalemia / Q000139:chemically induced* / Q000150:complications / Q000401:mortality; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000009:adverse effects* / Q000627:therapeutic use; D010818:Practice Patterns, Physicians' / Q000639:trends; D016032:Randomized Controlled Trials as Topic; D013148:Spironolactone / Q000009:adverse effects* / Q000627:therapeutic use
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone