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LINICAL TRIALS HAVE ESTAB- Main Outcome Measures Prescription and predictors of use of aldosterone an-
lished the incremental ben- tagonists, based on guideline criteria.
efits of aldosterone antago- Results Among 12 565 patients eligible for aldosterone antagonist therapy, 4087
nist therapy in patients with (32.5%) received an aldosterone antagonist at discharge, and treatment increased mod-
heart failure (HF) and reduced left ven- estly from 28% to 34% over the study period. There was also wide variation in aldo-
tricular ejection fraction (LVEF),1-3 such sterone antagonist use among hospitals (0%-90.6%). Aldosterone antagonist use in
that aldosterone antagonists were des- eligible patients was associated with younger age (adjusted odds ratio [OR], 0.85; 95%
ignated as class I, “useful and recom- confidence interval [CI], 0.82-0.88), African American race/ethnicity (adjusted OR,
mended,” within the American Col- 1.17; 95% CI, 1.04-1.32), lower systolic blood pressure (adjusted OR, 0.94; 95% CI,
lege of Cardiology/American Heart 0.92-0.95), history of implantable cardioverter-defibrillator use (adjusted OR, 1.51;
95% CI, 1.34-1.69), depression (adjusted OR, 1.15; 95% CI, 1.01-1.30), alcohol use
Association (ACC/AHA) Chronic HF
(adjusted OR, 1.23; 95% CI, 1.02-1.50), and pacemaker implantation (adjusted OR,
Guidelines.1 Because aldosterone an- 1.21; 95% CI, 1.06-1.38), and with having no history of renal insufficiency (adjusted
tagonists can cause hyperkalemia, guide- OR, 0.85; 95% CI, 0.75-0.96). Applying serum creatinine and potassium appropri-
lines promote safety by specifying that ateness criteria, inappropriate and potentially inappropriate use of aldosterone an-
prior to use, serum creatinine levels tagonist therapy was low and did not change over the 3-year study period.
should be 2.5 mg/dL or less in men and Conclusions Less than one-third of eligible patients hospitalized for HF and partici-
2.0 mg/dL or less in women, and se- pating in a quality improvement registry received HF guideline–recommended aldo-
rum potassium levels should be less than sterone antagonist therapy. Use of aldosterone antagonist therapy among patients
5.0 mEq/L.1 Adoption of aldosterone an- with documented contraindications was low.
tagonists in HF has been mixed; early JAMA. 2009;302(15):1658-1665 www.jama.com
community studies in Canada and the
United States found modest uptake but
also increased use in individuals with program may lead to greater fre- Author Affiliations: Nursing Institute and Kaufman
Center for Heart Failure, Cleveland Clinic, Cleve-
contraindications and increased admis- quency of use of aldosterone antago- land, Ohio (Dr Albert); Baylor Heart and Vascular
sions for hyperkalemia.4,5 nist therapy for appropriate indica- Institute, Baylor University Medical Center, Dallas,
The Get With The Guidelines–HF tions as well as lower use in situations Texas (Dr Yancy); Duke Clinical Research Institute,
Durham, North Carolina (Drs Liang, Hernandez,
(GWTG-HF) program is a national of increased risk. Therefore, the pur- and Peterson and Ms Zhao); TIMI Study Group,
quality improvement program de- pose of this study was to examine con- Brigham and Women’s Hospital, Boston, Massa-
chusetts (Dr Cannon); and Ahmanson-UCLA Cardi-
signed to promote adherence to guide- temporary aldosterone antagonist use omyopathy Center, University of California, Los
line-based recommendations. It is un- among hospitalized patients with HF, Angeles (Dr Fonarow).
Corresponding Author: Nancy M. Albert, PhD, RN,
known whether participation in a temporal trends in use, and appropri- 9500 Euclid Ave, Mail Code J3-4, Cleveland, OH 44195
hospital-based quality improvement ateness of use. (albertn@ccf.org).
1658 JAMA, October 21, 2009—Vol 302, No. 15 (Reprinted) ©2009 American Medical Association. All rights reserved.
interquartile ranges were reported for association between aldosterone an- used to test the trend of aldosterone an-
nonnormally distributed continuous tagonist prescription and patient tagonist use over the 3-year study pe-
variables. groups. Time was divided into six riod. Cochran-Mantel-Haenzel tests
Cochran-Mantel-Haenzel general as- 6-month intervals. Cochran-Mantel- were adjusted for within-hospital clus-
sociation statistics were used to test the Haenzel row mean scores statistics were tering. Multivariable logistic regres-
Table 1. Patient Characteristics by Aldosterone Antagonist Use in Patients Meeting American College of Cardiology/American Heart
Association Heart Failure Guideline Criteria
No. (%)
1660 JAMA, October 21, 2009—Vol 302, No. 15 (Reprinted) ©2009 American Medical Association. All rights reserved.
sure, and had a history of implantable December 2007 (FIGURE). To assess ap- (3.1%) met at least 1 criterion for in-
cardioverter-defibrillator implanta- propriateness of aldosterone antago- appropriate use: 0.5% had a docu-
tion, depression, alcohol use, and pace- nist prescription, different definitions mented contraindication in the medi-
maker implantation. Patients with re- based on guideline specifications were cal record, 2.7% had a serum creatinine
nal insufficiency were less likely to explored. Based on the 3 individual level of 3.0 mg/dL or greater, and 0.07%
receive a prescription for an aldoste- component criteria of the ACC/AHA had a serum potassium level of 6.0
rone antagonist. In contrast, hospital management guidelines, aldosterone mEq/L or greater.
characteristics did not remain associ- antagonist use in patients by LVEF cri- Of patients discharged with aldoste-
ated with aldosterone antagonist pre- teria was 29.5%, by serum creatinine rone antagonist therapy, 194 (2.3%)
scription after adjustment for clinical criteria was 32%, and by serum potas- also received the ACC/AHA guideline–
factors. sium criteria was 31.1%. For each com- proscribed (class III recommenda-
In patients meeting ACC/AHA man- ponent, aldosterone antagonist pre- tion) combination of ACE inhibitor and
agement guidelines criteria, aldoste- scription increased significantly over the ARB therapy. Of 8610 patients dis-
rone antagonist therapy prescription six 6-month intervals (Pⱕ.002 for all). charged home with aldosterone antago-
increased from 27.96% to 34.48% Use of aldosterone antagonists in pa- nists, 640 (7.4%) met at least 1 crite-
(P⬍.001) between January 2005 and tients with LVEF of 35% or less who re- rion for potentially inappropriate use
ceived ACE inhibitor, ARB, or - (Table 4). When evaluating trends over
blocker therapy at discharge was 30.1% time in aldosterone antagonist therapy
Figure. Aldosterone Antagonist Use per
American College of Cardiology/American and increased significantly over time use by appropriateness criteria, there
Heart Association Heart Failure Management (P ⬍ .001). Additionally, aldosterone were no changes in prescription over
Guideline Criteria (N=12 565 Patients) antagonist use remained low in pa- time (P = .67 for inappropriate use,
100 tients with HF and preserved systolic P=.42 for nonguideline inappropriate
use of triple therapy, and P=.49 for po-
Aldosterone Antagonist
80
function and hypertension over 3 years;
Prescriptions, %
1662 JAMA, October 21, 2009—Vol 302, No. 15 (Reprinted) ©2009 American Medical Association. All rights reserved.
mented contraindications were treated. mended.” The wording was subse- nificantly higher in patients also re-
Second, prescription of aldosterone an- quently corrected12,13 but may have in- ceiving other evidence-based HF thera-
tagonist at discharge varies widely fluenced treatment patterns prior to the pies. When European cardiologists were
among clinicians. Third, aldosterone 2009 guidelines update. asked to cite rationale for guideline non-
antagonist use for appropriate indica- Other factors that may have slowed adherence, 3 prominent factors were pa-
tions is less common among patients adoption are (1) published hyperkale- tient compliance, long and complexly
who are elderly, white, have a lower sys- mia rates that may have been an over- written guidelines, and time needed
tolic blood pressure, do not have an im- estimation of harm4 as well as other by cardiologists to implement guide-
plantable cardioverter-defibrillator or published reports of safety con- lines.23
pacemaker, do not have a history of al- cerns14-19 and adequacy in laboratory In our study, aldosterone antagonist–
cohol use or depression, and have a his- monitoring,20,21 (2) poor understand- treated patients were younger than
tory of renal insufficiency. Fourth, in ing of using spironolactone as an aldo- those not treated. When pre- and post–
contrast to prior reports, rates of inap- sterone antagonist rather than as a po- Randomized Aldactone Evaluation
propriate use are infrequent; only 0.5% tassium-sparing diuretic, (3) minimal Study (RALES) study populations were
of patients received therapy when they pharmaceutical company–sponsored compared, patient age was unchanged
had a documented contraindication, drug marketing and drug education to over time in one report4 and was higher
and 2.7% received therapy when they clinicians, (4) the adverse-effect pro- in another.5 There are possible impli-
had a higher than recommended cre- file of spironolactone, (5) evidence for cations of age on appropriateness of
atinine level. use based primarily on a single ran- aldosterone antagonist use. Advanced
Aldosterone antagonist therapy in- domized, multicenter trial initiated be- age is a risk factor for hyperkalemia
creased modestly in the United States, fore -blocker therapy was routinely when drugs are used that interfere with
from 21.3% in 2001 in Medicare ben- used, (6) selection of other HF add-on the renin-angiotensin-aldosterone sys-
eficiaries after hospitalization for HF5 drug therapies when patients remain tem,24 but it is unknown if less use of
to 28% in the first half of 2005 and 34% symptomatic, and (7) clinicians’ plans aldosterone antagonists in older pa-
in the second half of 2007 among adult for initiating therapy after hospital dis- tients in this study represents a dispar-
patients hospitalized with HF. Simi- charge once ACE inhibitor or ARB and ity that needs to be overcome or a safety
larly, investigators from the Registry to -blocker therapies are optimized. measure. After spironolactone initia-
Improve the Use of Evidence-Based HF Slow adoption by hospitals could be tion, hyperkalemia occurrence did not
Therapies in the Outpatient Setting attributable to lack of monitoring al- differ by age 20 except in 1 single-
(IMPROVE-HF) found that 36% of pa- dosterone antagonist use, since it is not center study report,15 and patients who
tients in an ambulatory cardiology prac- a HF performance measure selected by received laboratory monitoring were
tice who met usage criteria and were The Joint Commission/Centers for not older than those who did not.21
without documented contraindica- Medicare and Medicaid Services or the Moreover, the mean age at spironolac-
tions were prescribed an aldosterone ACC/AHA. Admitting and discharge or- tone initiation was lower than mean age
antagonist.10 In the EuroHeart Failure der sets, algorithms, and other tools de- at the time of hyperkalemia (67 vs 73
Survey II (EHFS II) of 3580 hospital- veloped to aid in the provision of qual- years), suggesting that decreased cre-
ized patients with acute HF from 133 ity care may be focused on core atinine clearance with age contributes
centers in 30 European countries, in performance measures. Other factors to hyperkalemia.17 Thus, age may be a
2004-2005 the rate of aldosterone an- that may have slowed adoption by hos- surrogate of renal function in patients
tagonist use at hospital discharge was pitals are physician specialty, con- receiving multiple therapies targeting
48%.11 Although prescription of aldo- cerns that hyperkalemia and an in- the renin-angiotensin-aldosterone
sterone antagonists increased over time creased creatinine level would extend system. After drug dose stabilization,
based on this GWTG-HF report, use hospital length of stay, or lack of time hyperkalemia monitoring may need
was less than expected on the basis of to start aldosterone antagonist therapy to be based on patient age and base-
clinical trial evidence demonstrating owing to a short length of stay for HF. line renal function rather than on a set
substantial reductions in all-cause mor- However, when aldosterone antago- schedule.
tality and all-cause hospitalization and nists were assessed for use in patients A high proportion of patients in
also less than the European use rate. with left ventricular systolic dysfunc- GWTG-HF hospitals had normal po-
Slow adoption of aldosterone antago- tion by length of stay, prescription at tassium and creatinine levels com-
nists in patients meeting HF manage- discharge was not associated with hos- pared with previous observational re-
ment guideline criteria may be attrib- pital length of stay.22 ports using similar data collection
utable to wording in the original version Moreover, slow adoption may be at- methods, 5,14-17 reflecting clinician
of the 2005 guidelines stating that al- tributable simply to nonadherence to knowledge of safety recommenda-
dosterone antagonist therapy “should evidence-based practice. In this study, tions for hyperkalemia and renal dys-
be considered” rather than “is recom- use of aldosterone antagonists was sig- function. Appropriateness of aldoste-
©2009 American Medical Association. All rights reserved. (Reprinted) JAMA, October 21, 2009—Vol 302, No. 15 1663
rone antagonist therapy may reflect the benefits after in-hospital therapy ini- sated work as of June 2008); currently serving on the
US Food and Drug Administration cardiovascular de-
influence of evidence-based, guideline- tiation are unknown. In clinical prac- vice panel and study section for the National Institutes
driven therapy or participation in a per- tice, clinicians may use a definition of of Health; and holding an editorial position with the
American Journal of Cardiology and serving on sev-
formance improvement program; how- moderate-to-severe HF different from eral other editorial boards. Dr Hernandez reported re-
ever, our analyses were not designed to that used in this study, which would al- ceiving research grants from GlaxoSmithKline, Johnson
determine either circumstance. It is ter findings. Lastly, these findings may & Johnson (Scios Inc), Medtronic, Merck, and Roche
Diagnostics; and serving on the speakers bureau for
plausible that well-refereed guideline not apply to practices that differed in or receiving honoraria within the past 5 years from
statements inform clinical practice and patient characteristics or care patterns AstraZeneca, Medtronic, Novartis, Sanofi-Aventis, and
Thoratec Corporation; Dr Hernandez has made de-
when incorporated into a program de- from GWTG-HF hospitals. tailed listings of financial disclosures available online
signed to improve quality yield more at http://www.dcri.duke.edu/research/coi.jsp. Dr
CONCLUSIONS Peterson reported serving as the principal investigator
appropriate application of evidence- for the American Heart Assocation Get With The Guide-
based care. Ongoing monitoring of pro- Aldosterone antagonist usage in eli- lines data analytic center at the Duke Clinical Research
Institute; receiving a research grant from BMS/Sanofi;
cesses of care may influence discon- gible patients with HF increased only and previously serving on an advisory board for Pfizer
tinuation or nonuse of aldosterone modestly from 2005 through 2007 and and as a consultant for Eli Lilly; Dr Peterson has made
antagonist therapy based on abnormal detailed listings of financial disclosures available on-
remained at less than 35% penetra- line at http://www.dcri.duke.edu/research/coi.jsp. Dr
laboratory findings, because GWTG-HF tion. Importantly, inappropriate use was Cannon reported receiving research grants/support from
provides opportunities to evaluate care low. These data confirm that in the con- Accumetrics, AstraZeneca, Bristol-Myers Squibb/
Sanofi Partnership, GlaxoSmithKline, Intekrin, Merck,
outcomes and continually improve per- text of a hospital-based performance im- Merck/Schering-Plough Partnership, Novartis, and Tak-
formance. provement program, aldosterone an- eda; and serving as a clinical advisor with equity in Au-
tomedics Medical Systems. Dr Fonarow reported re-
This study has several limitations. The tagonist therapy can be used according ceiving research grants or other research support from
data are dependent on the accuracy and to guidelines with little inappropriate GlaxoSmithKline, Pfizer, and the National Institutes of
Health; receiving honoraria from Amgen, AstraZen-
completeness of data abstraction from use. Given the substantial morbidity eca, Boston Scientific/Guidant, GlaxoSmithKline,
medical chart review. Contraindica- and mortality risk faced by patients hos- Medtronic, Merck, Novartis, Pfizer, Schering-Plough,
tions and intolerance of aldosterone an- and St Jude Medical; serving as a consultant for
pitalized with HF and the established ARCA, Boston Scientific/Guidant, DebioPharm,
tagonist and other core HF drug thera- efficacy of aldosterone antagonist pre- GlaxoSmithKline, Medtronic, Merck, Novartis, Pfizer,
pies were abstracted as recorded in the scription in HF, a stronger uptake of al- Relypsa, Scios, and St Jude Medical; and serving as chair
of the American Heart Association Get With The Guide-
medical record. As such, a proportion dosterone antagonist therapy indi- lines Steering Committee;. Dr Fonarow holds the Eliot
of patients reported to be eligible for al- cated by evidence-based guidelines may Corday Chair of Cardiovascular Medicine at UCLA and
is also supported by the Ahmanson Foundation (Los An-
dosterone antagonist therapy but not be warranted. geles, California). No other authors reported disclo-
treated may have had undocumented sures.
Author Contributions: Drs Albert and Fonarow had Funding/Support: The Get With The Guidelines–
contraindications or intolerances. The full access to all of the data in the study and take re- Heart Failure program is sponsored by the American
database does not track specific aldo- sponsibility for the integrity of the data and the ac- Heart Association and receives funding in part from
sterone antagonist agent or dosage, curacy of the data analysis. GlaxoSmithKline and Medtronic.
Study concept and design: Albert, Yancy, Cannon, Role of the Sponsors: GlaxoSmithKline and Medtronic
which may have influenced rates of Fonarow. had no role in the design and conduct of the study;
hyperkalemia and renal dysfunction. Acquisition of data: Albert, Fonarow. the collection, management, analysis, and interpre-
Analysis and interpretation of data: Albert, Liang, Zhao, tation of the data; or the preparation, review, or ap-
Data on physician specialty or type of Hernandez, Peterson, Fonarow. proval of the manuscript.
inpatient service were not collected. Drafting of the manuscript: Albert, Fonarow. Disclaimer: Dr Peterson, a contributing editor for
Critical revision of the manuscript for important in- JAMA, was not involved in the editorial review of or
GWTG-HF hospitals are self-selected; tellectual content: Albert, Yancy, Liang, Zhao, the decision to publish this article.
our analysis could overrepresent high- Hernandez, Peterson, Cannon, Fonarow.
Statistical analysis: Liang, Zhao, Peterson.
performing hospitals or hospitals with Obtained funding: Peterson, Cannon, Fonarow. REFERENCES
cardiologists specializing in care of HF. Administrative, technical, or material support: Albert,
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©2009 American Medical Association. All rights reserved. (Reprinted) JAMA, October 21, 2009—Vol 302, No. 15 1665