Rates of Hyperkalemia after Publication of the Randomized Aldactone Evaluation Study
David N. Juurlink, M.D., Ph.D., Muhammad M. Mamdani, Pharm.D., M.P.H., Douglas S. Lee, M.D., Alexander Kopp, B.A., Peter C. Austin, Ph.D., Andreas Laupacis, M.D., and Donald A. Redelmeier, M.D.
Background The Randomized Aldactone Evaluation Study (RALES)demonstrated that spironolactone significantly improves outcomesin 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 areused together.
Methods We conducted a population-based time-series analysisto examine trends in the rate of spironolactone prescriptionsand the rate of hospitalization for hyperkalemia in ambulatorypatients before and after the publication of RALES. We linkedprescription-claims data and hospital-admission records formore 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 recentlybeen hospitalized for heart failure, the spironolactone-prescriptionrate was 34 per 1000 patients in 1994, and it increased immediatelyafter the publication of RALES, to 149 per 1000 patients bylate 2001 (P<0.001). The rate of hospitalization for hyperkalemiarose from 2.4 per 1000 patients in 1994 to 11.0 per 1000 patientsin 2001 (P<0.001), and the associated mortality rose from0.3 per 1000 to 2.0 per 1000 patients (P<0.001). As comparedwith expected numbers of events, there were 560 (95 percentconfidence interval, 285 to 754) additional hyperkalemia-relatedhospitalizations and 73 (95 percent confidence interval, 27to 120) additional hospital deaths during 2001 among older patientswith heart failure who were treated with ACE inhibitors in Ontario.Publication of RALES was not associated with significant decreasesin the rates of readmission for heart failure or death fromall causes.
Conclusions The publication of RALES was associated with abruptincreases in the rate of prescriptions for spironolactone andin hyperkalemia-associated morbidity and mortality. Closer laboratorymonitoring and more judicious use of spironolactone may reducethe occurrence of this complication.
Heart failure affects approximately 5 million persons annuallyin Canada and the United States.1 Medications are the mainstayof therapy, and in the past two decades there has been a shiftaway from the use of diuretics and cardiac glycosides and towardneurohumoral manipulation with angiotensin-converting–enzyme(ACE) inhibitors, beta-adrenergic antagonists, and aldosteroneantagonists.1 Published in September 1999, the Randomized AldactoneEvaluation Study (RALES) demonstrated that treatment with spironolactonesubstantially reduced morbidity and mortality in patients withsevere heart failure.2 Spironolactone is inexpensive and generallywell tolerated, but in these patients it can provoke life-threateninghyperkalemia when combined with ACE inhibitors.3,4,5,6
An early dose-finding study conducted by the RALES investigatorsfound that hyperkalemia was a dose-dependent effect of spironolactone,yet hyperkalemia developed in only a few patients (2 percent)in the active-treatment group in RALES.2,7 The low incidenceof hyperkalemia may reflect unusually close laboratory monitoring,restriction of other drugs that cause hyperkalemia, or exclusionof patients with advanced renal disease or mild hyperkalemiaat baseline.8,9,10 However, clinicians rapidly embraced thefindings of RALES and may not have applied similar restrictionsin clinical practice.11,12 One recent study found, for example,that many patients who received new prescriptions for spironolactoneafter the publication of RALES did not have severe heart failure,about a third had renal insufficiency, and more than a thirdsimultaneously received prescriptions for potassium supplements.13Such differences between the clinical-trial setting and actualpractice are particularly relevant for older patients with heartfailure, most of whom would not have been included in RALES.14
Although the use of spironolactone or other potassium-sparingdiuretics in conjunction with ACE inhibitors increases the riskof hyperkalemia in outpatients, the consequences of this druginteraction at the population level are unknown.15 In this ecologicstudy, we examined trends in the rate of prescriptions for spironolactoneand in the rate of hospitalization for hyperkalemia before andafter the publication of RALES among older patients who weretreated with ACE inhibitors.
Methods
Setting and Design
This study was a population-based, time-series analysis of healthcare databases in Ontario, Canada, from January 1, 1994, toDecember 31, 2001. During this period, Ontario had a populationof about 12.3 million people, of whom approximately 1.3 millionwere 65 years of age or older and had universal access to hospitalcare, physicians' services, and prescription-drug coverage.Databases containing the health care records of individual patientscould be linked and analyzed in an anonymous fashion with theuse of their encrypted, 10-digit health-card numbers.
Sources of Data
We examined the computerized prescription records of the OntarioDrug Benefit Program, which records prescription drugs dispensedto all Ontario residents 65 years of age or older. The overallerror rate in this database is less than 1 percent.16 Hospitalizationrecords were obtained from the Canadian Institute for HealthInformation Discharge Abstract Database, which contains a recordof all hospitalizations, including up to 16 diagnoses for eachadmission. Although the accuracy of coding in this databasehas not been established for all diagnoses, one recent studyshowed a positive predictive value of 90 to 96 percent for thediagnosis of heart failure.17
Identification of Patients and Outcomes
We divided each year of the eight-year study period into threefour-month intervals (January through April, May through August,and September through December), for a total of 24 consecutiveintervals. We chose to use 4-month intervals because the OntarioDrug Benefit Program will not reimburse prescriptions for medicationsupplies exceeding 100 days in duration. We examined the recordsof patients 66 years of age or older; we did not include recordsduring patients' first year of eligibility for prescription-drugcoverage (i.e., when they were 65 years of age) to avoid includingdata from incomplete medication records.
For each four-month interval, we identified every prescriptionfor spironolactone, ACE inhibitors, angiotensin-receptor antagonists,beta-adrenergic antagonists, loop diuretics, nonsteroidal antiinflammatoryagents, potassium supplements, thiazide diuretics, or productscontaining other potassium-sparing diuretics (e.g., amilorideor triamterene). We selected these drugs because they are themost commonly prescribed medications that can influence potassiumlevels. For each interval we also identified all hospital admissionsinvolving a diagnosis of hyperkalemia (International Classificationof Diseases, Ninth Revision [ICD-9] code 276.7) or heart failure(ICD-9 code 428.0), with particular attention to the numberof admissions culminating in death during hospitalization. Ahospitalization involving transfer from one facility to another(e.g., for hemodialysis or other specialized care) was considereda single admission. This research was approved by the ethicsreview board of Sunnybrook and Women's College Health SciencesCentre.
Statistical Analysis
We used time-series analysis to examine patterns in the spironolactone-prescriptionrates and in the rates of hospitalization for hyperkalemia orfor heart failure during the study period. Time-series analysisconsists of several techniques for modeling autocorrelationin temporally sequenced data.18 In the primary analysis, weexamined trends in the spironolactone-prescription rates andin the rates of admission for hyperkalemia or heart failureamong patients receiving ACE inhibitors who had been hospitalizedfor heart failure during the preceding three years. In a secondaryanalysis we examined these rates in all patients who were receivingACE inhibitors, regardless of whether they had a history ofheart failure.
Different approaches were used to assess immediate and delayedeffects related to the publication of RALES. Immediate effectswere assessed with interventional autoregressive integratedmoving-average (ARIMA) models with the use of a ramp function.19An immediate change was defined as one occurring within three4-month intervals (i.e., within 1 year) after the early releaseof the study's findings on the Journal Web site on July 19,1999, 44 days ahead of its publication in print.2 To assessdelayed effects, we used ARIMA models to forecast expected ratesand their 95 percent confidence intervals. We then comparedobserved with predicted rates of spironolactone use and healthoutcomes.20
To address population-wide changes in the use of other drugsthat could influence the risk of hyperkalemia, we examined prescriptionsfor medications of various other classes as dynamic regressorsduring each interval, with lag functions of up to two four-monthintervals included as necessary. The autocorrelation, partialautocorrelation, and inverse autocorrelation functions wereassessed for model parameter appropriateness and seasonality.Stationarity was assessed with the use of autocorrelation functionsand the augmented Dickey–Fuller test.18,21 The presenceof white noise was assessed by examining the autocorrelationsat various lags with use of the Ljung–Box chi-square statistic.19,22All P values were two-sided, and analyses were conducted withthe use of SAS software (version 8.2).
Results
Patients with Heart Failure
The number of patients 66 years of age or older who were treatedwith an ACE inhibitor after hospitalization for heart failurerose gradually over time, from 20,820 in early 1994 to 32,283by late 2001. Among these patients, the spironolactone-prescriptionrate remained relatively constant from early 1994 (34 per 1000patients) until early 1999 (30 per 1000 patients). After thepublication of RALES, however, the rate of prescriptions forthis drug increased by a factor of about five, to 149 per 1000by late 2001 (P<0.001 for the comparison with the study periodpreceding the publication of RALES) (Figure 1). The median doseafter the publication of RALES was 25 mg per day. Patients treatedwith ACE inhibitors who began taking spironolactone after RALESwere, on average, 13 years older than the patients who wereenrolled in RALES. Men and women were equally represented. Mostof the patients were also being treated with a loop diuretic,and more than half had been hospitalized for heart failure withinthe month before they began spironolactone therapy (Table 1).
Figure 1. Rate of Prescriptions for Spironolactone among Patients Recently Hospitalized for Heart Failure Who Were Receiving ACE Inhibitors.
Each bar shows the observed spironolactone-prescription rate per 1000 patients during one four-month interval. The line beginning in the second interval of 1999 shows projected prescription rates derived from interventional autoregressive integrated moving-average (ARIMA) models, with I bars representing the 95 percent confidence intervals.
Table 1. Characteristics of Patients Recently Hospitalized for Heart Failure Who Were Receiving ACE Inhibitors and Who Began Spironolactone Therapy before or after the Publication of RALES.
The rate of hospital admission involving a diagnosis of hyperkalemiaamong these patients rose gradually from early 1994 (2.4 per1000) to early 1999 (4.0 per 1000) but increased by a factorof about three after the publication of RALES, to 11.0 per 1000by late 2001 (P<0.001) (Figure 2). Among patients with ahistory of heart failure who were treated with ACE inhibitors,the rate of hyperkalemia-associated with in-hospital death rosegradually from early 1994 (0.3 per 1000) to early 1999 (0.7per 1000) but increased by a factor of about three after thepublication of RALES, to 2.0 per 1000 by late 2001 (P<0.001)(Figure 3). The rate of hospitalization for heart failure declinedgradually during the study period, with no statistically significantchange in this variable after the publication of RALES (P=0.78)(Figure 4). The rate of death from any cause also declined graduallyduring the study period (from 58 per 1000 in early 1994 to 44per 1000 in late 2001), with no significant change after thepublication of RALES.
Figure 2. Rate of Hospital Admission for Hyperkalemia among Patients Recently Hospitalized for Heart Failure Who Were Receiving ACE Inhibitors.
Each bar shows the rate of hospital admission for hyperkalemia per 1000 patients during one four-month interval. The line beginning in the second interval of 1999 shows projected admission rates for hyperkalemia derived from interventional ARIMA models, with I bars representing the 95 percent confidence intervals.
Figure 3. Rate of In-Hospital Death Associated with Hyperkalemia among Patients Recently Hospitalized for Heart Failure Who Were Receiving ACE Inhibitors.
Each bar shows the rate of in-hospital death associated with hyperkalemia per 1000 patients during one four-month interval. The line beginning in the second interval of 1999 shows projected death rates derived from interventional ARIMA models, with I bars representing the 95 percent confidence intervals.
Figure 4. Rate of Readmission for Heart Failure among Patients Recently Hospitalized for Heart Failure Who Were Receiving ACE Inhibitors.
Each bar shows the rate of readmission for heart failure per 1000 patients during one four-month interval. The line beginning in the second interval of 1999 represents projected admission rates derived from interventional ARIMA models, with I bars representing the 95 percent confidence intervals.
Prescription patterns for other drugs also changed during thestudy period. Most of the patients who were receiving ACE inhibitorsfor heart failure also received prescriptions for loop diuretics,and beta-adrenergic antagonists became increasingly popular(Figure 5). The rate of prescriptions for nonsteroidal antiinflammatoryagents was relatively stable, with a slight decline when copaymentbecame required in 1996 and a slight rise after the launch ofselective cyclooxygenase-2 inhibitors in 2000. The associationsamong the publication of RALES, the increase in spironolactoneuse, and the rates of hyperkalemia-related adverse outcomesdid not change appreciably after adjustment for temporal trendsin the use of these other drugs.
Figure 5. Prescription Patterns for Other Medications among Patients Recently Hospitalized for Heart Failure Who Were Receiving ACE Inhibitors.
The curves show trends in prescription rates for various drugs per 1000 patients over the course of the eight-year study period. Patterns of use of angiotensin-receptor antagonists, potassium-sparing diuretics other than spironolactone, and potassium supplements are not shown because baseline rates of use of those medications were low. NSAIDs denotes nonsteroidal antiinflammatory drugs.
All Patients
Because spironolactone is sometimes prescribed to patients withmild heart failure,13 we repeated our analyses in all patientsreceiving ACE inhibitors, regardless of whether they had a historyof hospitalization for heart failure. The number of patientsin this group also increased steadily during the study period,from 151,305 in early 1994 to 356,657 by late 2001.
As expected, spironolactone use was infrequent among these patients,and the rate of use remained relatively constant from early1994 until early 1999 (12 per 1000). The rate increased by afactor of almost three after the publication of RALES, risingto 32 per 1000 by late 2001. The rate of hospital admissionfor hyperkalemia in this group of patients rose slightly fromearly 1994 (0.9 per 1000) to early 1999 (1.2 per 1000) but morethan doubled after the publication of RALES, to 2.8 per 1000by late 2001 (P<0.001). The rate of in-hospital hyperkalemia-associateddeath also rose gradually, from early 1994 (0.10 per 1000) untilearly 1999 (0.17 per 1000), but more than doubled after thepublication of RALES, to 0.39 per 1000 by late 2001 (P<0.001).Both the rate of admission for heart failure and the rate ofdeath from any cause in these patients declined steadily overtime, with no statistically significant change after the publicationof RALES.
Additional Observations
We repeated our analyses after stratification according to theuse of beta-adrenergic antagonists, because these drugs mayincrease the risk of hyperkalemia and because their use increasedsubstantially during the study period.24,25 The publicationof RALES was associated with similar increases in hospital admissionsfor hyperkalemia and in hyperkalemia-associated mortality amongpatients who were receiving beta-adrenergic antagonists andamong those who were not receiving beta-adrenergic antagonists.
To explore whether increased rates of survival among patientswith severe heart failure may have influenced our findings,we examined the median score on the Charlson comorbidity indexamong patients hospitalized for hyperkalemia during the studyperiod.26,27 The publication of RALES was not associated witha significant change in this score. It was, however, associatedwith significantly higher rates of hospital admission for renalinsufficiency — a finding consistent with the known diureticeffect of spironolactone.
To estimate the excess number of admissions and in-hospitaldeaths associated with hyperkalemia after the publication ofRALES, we compared observed annualized rates with those predictedwith the use of ARIMA models. Among the patients who were treatedwith ACE inhibitors after hospitalization for heart failure,the publication of RALES was associated with approximately 560(95 percent confidence interval, 285 to 754) additional hyperkalemia-relatedhospitalizations and at least 73 (95 percent confidence interval,27 to 120) excess in-hospital deaths in Ontario during 2001.These estimates are conservative because spironolactone is oftengiven to patients with less severe heart failure, many of whommay not have been hospitalized recently.13 Among the broadergroup of all patients 66 years of age or older who were treatedwith ACE inhibitors in Ontario, the publication of RALES wasassociated with 1485 (95 percent confidence interval, 1150 to1802) additional hyperkalemia-related hospital admissions and171 (95 percent confidence interval, 129 to 219) additionalin-hospital deaths during 2001. These estimates correspond toapproximately 37,000 additional hospitalizations and 4200 additionaldeaths each year in the United States, or about 100 admissionsand 12 deaths each day.
Discussion
We found that the publication of RALES was associated with anabrupt increase in the rate of prescriptions for spironolactoneamong older patients in Ontario who were treated with ACE inhibitors,regardless of whether or not they had previously been hospitalizedfor heart failure. This finding suggests that a major clinicaltrial can significantly influence prescription practices inthe absence of direct marketing forces from the pharmaceuticalindustry. We also observed considerable increases in the ratesof hospital admission for hyperkalemia and subsequent in-hospitaldeath. This excess morbidity and mortality persisted after adjustmentfor temporal changes in the prescription rates of other commonlyused drugs that can cause hyperkalemia.
Our data are population-based but exclude data related to suddendeath outside the hospital or in the emergency department aswell as data from patients younger than 66 years of age. Asa result, our analysis probably underestimates the increasein hyperkalemia-associated morbidity and mortality after thepublication of RALES. Sudden, out-of-hospital death from hyperkalemiamay be erroneously attributed to underlying heart disease, andwe speculate that such deaths may partly explain why no decreasein the rate of death from all causes was evident after the publicationof RALES. Regardless, our findings indicate that spironolactone-relatedhyperkalemia is a much greater problem in everyday practicethan in the setting of a clinical trial. Specifically, we estimatethat every 1000 additional prescriptions for spironolactoneissued after RALES led to 50 additional admissions for hyperkalemia.
We believe there are at least six reasons why hyperkalemia isa more common occurrence in clinical practice than it was inthe carefully controlled setting of RALES. Physicians may notmonitor potassium levels closely in patients receiving spironolactone,13may neglect baseline attributes that predispose patients tohyperkalemia (e.g., diabetes mellitus),8,9 and may overlookconditions that develop during therapy (e.g., renal dysfunction).They may prescribe inappropriately high doses of spironolactone28or other medications that contribute to hyperkalemia.24 Somepatients may purposefully increase their dietary potassium intake,as is often recommended during treatment with diuretics suchas furosemide. Finally, physicians may extend the RALES findingsto patients who, unlike the patients in that study, do not haveleft ventricular systolic dysfunction (e.g., those with diastolicdysfunction or cor pulmonale).
Several limitations of our study should be noted. The findingsmay not apply to younger patients with heart failure, who mayhave fewer risk factors for hyperkalemia than older patients.We analyzed administrative data without direct measures of potassiumor creatinine, adherence to medications, use of nonprescriptiondrugs, and the clinical details surrounding death. Indeed, manyof the patients hospitalized for hyperkalemia may have diedof another illness. The diagnostic coding for hyperkalemia hasnot been validated; moreover, many patients hospitalized forhyperkalemia may have also had volume contraction or renal insufficiencyrelated to spironolactone therapy. In addition, we were unableto identify adverse outcomes that occurred before admission.Although clinicians may have been aware of the potential forspironolactone to cause hyperkalemia, detection bias is an unlikelyexplanation for our findings because electrolytes are routinelymeasured in patients with heart failure when they are admittedto the hospital. Finally, our study was observational in natureand cannot prove causality; however, the relationship betweenthe publication of RALES, the surge in spironolactone use, andthe increase in hyperkalemia-related admissions is temporallycompelling, biologically plausible, and consistent with existingevidence.4,5,6,13,15,28
In conclusion, we found that the publication of RALES was associatedwith an increase in spironolactone use and hyperkalemia-associatedmorbidity and mortality at the population level, most likelybecause of an interaction between spironolactone and ACE inhibitorsthat is accentuated by other medications or coexisting conditions.Much of this harm probably reflects application of the findingsof a landmark clinical trial to patients at increased risk forhyperkalemia, including many who would have been excluded fromthe trial.14 We speculate that iatrogenic hyperkalemia in thissetting can be avoided without withholding spironolactone frompatients for whom it is appropriate. Instead, clinicians shouldconsider other risk factors for hyperkalemia when selectingcandidates for spironolactone therapy, minimize concurrent prescriptionsfor other medications that contribute to hyperkalemia, and closelymonitor renal function and potassium levels.
Supported by a grant from the University of Toronto Dean's Fund;by a New Investigator award from the Canadian Institutes ofHealth Research (CIHR) and by the University of Toronto DrugSafety Research Group (to Dr. Juurlink); by New Investigatorawards from the CIHR (to Drs. Mamdani and Austin); by a fellowshipaward from the CIHR and the Heart and Stroke Foundation of Canada(to Dr. Lee); by a Senior Scientist award from the CIHR (toDr. Laupacis); and by a Career Scientist award from the OntarioMinistry of Health, a grant from the CIHR, and a Canada ResearchChair in Medical Decision Sciences (to Dr. Redelmeier).
We are indebted to Lina Paolucci for assistance with the preparationof the manuscript, and to David Sackett for comments on an earlierdraft of the manuscript.
Source Information
From the Departments of Medicine (D.N.J., D.S.L., A.L., D.A.R.), Pharmacy (M.M.M.), Health Policy, Management, and Evaluation (D.N.J., M.M.M., D.S.L., P.C.A., A.L., D.A.R.), and Public Health Sciences (P.C.A.), University of Toronto; and the Institute for Clinical Evaluative Sciences (D.N.J., M.M.M., D.S.L., A.K., P.C.A., A.L., D.A.R.) — both in Toronto.
Address reprint requests to Dr. Juurlink at Sunnybrook and Women's College Health Sciences Centre, G Wing 106, 2075 Bayview Ave., Toronto, ON M4N 3M5, Canada, or at dnj{at}ices.on.ca.
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Hyperkalemia after the Publication of RALES
Goldfarb D. S., Newsome B. B., Warnock D. G., Witham M. D., Gillespie N. D., Struthers A. D., Cavallari L., Vaitkus P., Groo V., Juurlink D. N., Mamdani M. M., Redelmeier D. A.
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