In-Hospital Diuretic Agent Use and Post-Discharge Clinical Outcomes in Patients Hospitalized for Worsening Heart Failure

JACC: HEART FAILURE

VOL.

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

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ISSN 2213-1779/$36.00 http://dx.doi.org/10.1016/j.jchf.2016.02.008

In-Hospital Diuretic Agent Use and Post-Discharge Clinical Outcomes in Patients Hospitalized for Worsening Heart Failure Insights From the EVEREST Trial Alicia Mecklai, MD,a,b Haris Subacius, MA,c Marvin A. Konstam, MD,d Mihai Gheorghiade, MD,c Javed Butler, MPH, MBA, MD,e Andrew P. Ambrosy, MD,f Stuart D. Katz, MD, MSb

ABSTRACT OBJECTIVES The aim of this study was to characterize the association between decongestion therapy and 30-day outcomes in patients hospitalized for heart failure (HF). BACKGROUND Loop diuretic agents are commonly prescribed for the treatment of symptomatic congestion in patients hospitalized for HF, but the association between loop diuretic agent dose response and post-discharge outcomes has not been well characterized. METHODS Cox proportional hazards models were used to estimate the association among average loop diuretic agent dose, congestion status at discharge, and 30-day post-discharge all-cause mortality and HF rehospitalization in 3,037 subjects hospitalized with worsening HF enrolled in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study With Tolvaptan) study. RESULTS In univariate analysis, subjects exposed to high-dose diuretic agents ($160 mg/day) had greater risk for the combined outcome than subjects exposed to low-dose diuretic agents (18.9% vs. 10.0%; hazard ratio: 2.00; 95% confidence interval: 1.64 to 2.46; p < 0.0001). After adjustment for pre-specified covariates of disease severity, the association between diuretic agent dose and outcomes was not significant (hazard ratio: 1.11; 95% confidence interval: 0.89 to 1.38; p ¼ 0.35). Of the 3,011 subjects with clinical assessments of volume status, 2,063 (69%) had little or no congestion at hospital discharge. Congestion status at hospital discharge did not modify the association between diuretic agent exposure and the combined endpoint (p for interaction ¼ 0.84). CONCLUSIONS Short-term diuretic agent exposure during hospital treatment for worsening HF was not an independent predictor of 30-day all-cause mortality and HF rehospitalization in multivariate analysis. Congestion status at discharge did not modify the association between diuretic agent dose and clinical outcomes. (J Am Coll Cardiol HF 2016;-:-–-) © 2016 by the American College of Cardiology Foundation.

From the aWeill Cornell Medical College, New York, New York; bNew York University School of Medicine, New York, New York; c

Northwestern University Feinberg School of Medicine, Chicago, Illinois; dThe CardioVascular Center of Tufts Medical Center and

Tufts Medical Center, Boston, Massachusetts; eStony Brook School of Medicine, Stony Brook, New York; and the fDuke University Medical Center, Durham, North Carolina. The EVEREST program was funded by Otsuka, and database management was provided by the trial sponsor. All authors had direct access to the reported data, and Dr. Subacius conducted the presented post hoc analyses independently of the trial sponsor. This work was supported in part by grant NIH/NCATS UL1 TR000038 from the National Center for Research Resources, National Institutes of Health. Dr. Katz has served as a member of the speakers bureau for Otsuka America Pharmaceuticals. Dr. Konstam has received research support from Otsuka America Pharmaceuticals. Dr. Gheorghiade has served as a consultant for Otsuka America Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received November 3, 2015; revised manuscript received February 17, 2016, accepted February 19, 2016.

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ABBREVIATIONS AND ACRONYMS CI = confidence interval HF = heart failure HR = hazard ratio

C

ongestive

signs

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Short-Term Diuretic Agent Use and Outcomes in ADHF

symptoms

the EVEREST trial was an international, multicenter,

related to excess total body sodium

and

randomized, double-blind, placebo-controlled trial

and water are common in patients

comparing the safety and efficacy of tolvaptan, a

with heart failure (HF) despite the use of

selective vasopressin-2 receptor antagonist, versus

chronic diuretic therapy (1). Current guide-

matching placebo, in addition to standard care, in

lines recommend adjustment of diuretic

4,133 subjects hospitalized for worsening HF. Eligible

agent doses as needed to increase renal sodium and

subjects were $18 years of age with left ventricular

water excretion in patients with clinical evidence of

ejection fractions #40%, 2 or more signs or symptoms

congestion with the goal of achieving a euvolemic

of volume overload (dyspnea, pitting edema, jugular

state (2,3). Factors that may contribute to need for

venous distension), and New York Heart Association

higher diuretic agent doses to maintain clinical euvo-

functional class III or IV symptoms who were hospi-

lemia include excess dietary sodium intake, altered

talized for an exacerbation of chronic systolic HF.

gastrointestinal absorption of oral diuretic agents,

Key

decreased secretion of loop diuretic agents into the

pressure <90 mm Hg, hemodynamically significant

nephron, comorbid renal insufficiency, and glomer-

primary valvular disease, acute coronary syndrome,

ular and renal tubular changes that limit the increase

serum creatinine $3.5 mg/dl, treatment with hemo-

in fractional sodium excretion in response to loop

filtration or dialysis, end-stage HF (i.e., candidates for

diuretic agents (4,5).

ventricular assist devices or continuous positive

exclusion

criteria

included

systolic

blood

Although loop diuretic agents are the most

intravenous inotropic therapy), or life expectancy

commonly used class of drugs for the treatment of

<6 months. Eligible subjects were randomized within

congestive signs and symptoms (1), the effects of

48 h of admission to receive either 30 mg of oral tol-

diuretic agents on clinical outcomes in patients with

vaptan daily or matching placebo for a minimum of

HF remain uncertain. Several prior studies have

60 days. Concomitant HF medications including

demonstrated an association between higher dose

diuretic agents were administered according to the

diuretic agents and greater risk for adverse clinical

discretion of the treating physician at each partici-

outcomes in both outpatient and inpatient HF pop-

pating site. The clinical trial was conducted in full

ulations (6–9), with putative mechanisms of harm

accordance with the Declaration of Helsinki, with

related to greater risk for arrhythmic death due to

Institutional Review Board or ethics committee

electrolyte depletion, hypovolemia, worsening renal

approval at all study sites. For the current post hoc

function, and/or increased neurohormonal activation

analysis, we included 3,037 subjects who survived

(4,10,11). In contrast, other studies demonstrated that

until hospital discharge with available loop diuretic

higher diuretic agent doses are associated with

agent dose information recorded during the first 72 h

improved survival in hospitalized patients with HF

of hospitalization and recorded clinical signs and

with evidence of hemoconcentration in response to

symptoms of congestion at study entry.

therapy (12–15).

Average daily loop diuretic agent dose (milligrams

Given these divergent data, we hypothesized that

per day) was calculated during the first 72 h of hos-

the relationship between diuretic agent dose and

pitalization as estimates of oral furosemide equiva-

clinical outcomes might differ according to clinical

lents on the basis of relative potency (1 mg

response to diuretic therapy, as evidenced by the

bumetanide ¼ 20 mg torsemide ¼ 40 mg furosemide)

post-treatment volume status of the patient (pres-

and adjusted for the differential bioavailability

ence or absence of clinical signs and symptoms of

related to the route of administration (1 mg intrave-

congestion at hospital discharge). To test this hy-

nous furosemide ¼ 2 mg oral furosemide). For

pothesis, we performed a post hoc analysis to deter-

example, a diuretic agent exposure of furosemide

mine the association between short-term in-hospital

40 mg twice daily by intravenous administration

diuretic agent use and post-discharge 30-day clinical

would be recorded as a total daily dose of 160 mg in

outcomes in patients discharged with and without

oral furosemide equivalents.

signs of persistent congestion in the EVEREST (Effi-

Congestion status was determined by study in-

cacy of Vasopressin Antagonism in Heart Failure:

vestigators at hospital discharge or on hospital day 7

Outcome Study With Tolvaptan) trial.

(whichever occurred earlier) on the basis of the following signs or symptoms: presence of rales on a

METHODS

4-point scale (0 ¼ no rales, 1 ¼ rales at bases, 2 ¼ rales

The rationale, design, and main results of the EVEREST

3 ¼ rales at bases to >50% way up the posterior lung

trial have been previously reported (16,17). In brief,

fields), presence of orthopnea on the basis of a

at bases to 50% way up the posterior lung fields, and

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Short-Term Diuretic Agent Use and Outcomes in ADHF

F I G U R E 1 Average Diuretic Agent Exposure During First 72 Hours of Hospitalization in 3,037 Study Participants

Histogram shows numbers of subjects grouped according to average daily diuretic agent dose.

4-point scale (0 ¼ none, 1 ¼ seldom, 2 ¼ frequent, and ¼

higher

than

this

cutoff

value.

Differences

in

venous

selected clinical characteristics between groups on

distension $6 cm (yes or no), or presence of pedal or

the basis of average daily loop diuretic agent dose

sacral edema (yes or no). Congestion status at hospi-

were assessed with parametric or nonparametric

tal discharge was determined as a cumulative sum-

tests for independent samples for continuous vari-

med

EVEREST

ables as appropriate for the variable distribution

publication. The revised score added rales and sacral

and chi-square tests for categorical variables. The

edema to the previous congestion score on the basis

primary outcome endpoint for this post hoc analysis

of orthopnea, jugular venous pressure, and pedal

was the 30-day combined endpoint of all-cause

edema; little or no congestion at discharge was

mortality and rehospitalization for HF as deter-

defined as a summed score of #1 (18).

mined

STATISTICAL

are reported as

committee. To address our hypothesis that the

mean  SD for continuous variables with normal

association between short-term diuretic agent expo-

distributions,

sure and 30-day outcomes would differ by discharge

3

continuous),

score

presence

adapted

from

a

of

previous

ANALYSIS. Values

median

jugular

(interquartile

range)

for

by

an

independent

event

adjudication

continuous variables not normally distributed, and

congestion status (effect modification), the statistical

percentages for categorical variables. Average daily

plan was designed to first test the associations

loop diuretic agent dose was expressed as a cate-

between average daily loop diuretic agent dose and

gorical variable (low dose, <160 mg/day; high

discharge

dose, $160 mg/day) on the basis of a commonly used

endpoint separately and then test for interaction

clinical definition to differentiate “low-dose” from

between these 2 predictor variables. Univariate log-

“high-dose”

empirical

rank tests were used to evaluate time to event

observation that a significant association between

associations with the combined endpoint, and Cox

diuretic agent dose and outcome events was present

proportional hazards regression was used to calculate

only in subjects treated with diuretic agent doses

the hazard ratios (HRs) and their 95% confidence

diuretic

agents

and

the

congestion

status

on

the

combined

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Short-Term Diuretic Agent Use and Outcomes in ADHF

pre-selected covariates of disease severity that were

T A B L E 1 Demographic and Clinical Characteristics at Study Entry of 3,037 Subjects

Grouped by Average Loop Diuretic Agent Dose During First 72 Hours of Hospitalization

used in previous EVEREST multivariate analyses

(Low Dose, <160 mg/day; High Dose, $160 mg/day)

(15,18): study drug assignment, age, sex, geographic region, left ventricular ejection fraction, medical

Average Loop Diuretic Agent Dose

comorbidities (diabetes, hypertension, and chronic

Low (<160 mg/day) (n ¼ 2,171)

High ($160 mg/day) (n ¼ 866)

p Value

Age (yrs)

65.8  11.6

66.1  12.2

0.453

Male

1,579 (72.7)

671 (77.5)

0.007

White

1,905 (87.7)

650 (75.1)

derived from the abbreviated MDRD [Modification of

Black

105 (4.8)

131 (15.1)

Diet in Renal Disease] equation [19]), serum albumin

Hispanic

114 (5.3)

61 (7)

(milligrams per deciliter), systolic blood pressure

Asian

7 (0.3)

1 (0.1)

(millimeters of mercury), QRS duration (millisec-

Other

47 (2.2)

23 (2.7)

Variable

kidney disease), history of ventricular arrhythmias,

Demographics

per milliliter), serum blood urea nitrogen (milligrams

<0.001

Race

1,118 (51.5)

96 (11.1)

Western Europe

209 (9.6)

103 (11.9)

North America

473 (21.8)

481 (55.5)

South America

371 (17.1)

186 (21.5)

per deciliter), estimated glomerular filtration rate (milliliters per minute per 1.73 square meters,

onds), New York Heart Association class, presence of <0.001

Region Eastern Europe

serum sodium, B-type natriuretic peptide (picograms

an automatic implantable cardioverter-defibrillator, baseline medication use (beta-adrenergic receptor blocker, angiotensin-converting enzyme inhibitors or angiotensin

receptor

blockers,

mineralocorticoid

receptor antagonists, digoxin, and positive inotropic

Baseline laboratory values and clinical characteristics Left ventricular ejection fraction (%) QRS duration (ms)

28.5  7.8

25.4  8.1

<0.001

121 (95–147)

127 (103–153)

<0.001 <0.001

agents), and the presence of atrial flutter or fibrillation

on

baseline

electrocardiography.

Estimated

effect sizes are reported as HRs and 95% CIs.

Weight (kg)

81.8  18

86.6  20

Height (cm)

169.9  9.3

170.9  9.5

0.007

Body mass index (kg/m2)

28.3  5.3

29.5  5.9

<0.001

All statistical analyses were performed using SAS

Atrial fibrillation/flutter

674 (31.1)

216 (24.9)

0.001

version 9.4 (SAS Institute, Cary, North Carolina) at a

2,052 (94.5)

798 (92.1)

0.014

conventional 2-tailed 5% significance level.

582 (26.8)

299 (34.5)

<0.001

Dyspnea Jugular venous pressure >10 cm

Assumptions of proportional hazards were verified.

Rales

1,810 (83.4)

710 (82)

0.359

Edema

1,790 (82.5)

704 (81.3)

0.452

Systolic blood pressure (mm Hg)

122.6  19.8

117.7  18.7

<0.001

Diastolic blood pressure (mm Hg)

74.4  12.6

69.7  12.5

<0.001

80.6  16

79.3  15.2

0.035

EXPOSURE. Average daily diuretic agent dose dur-

Heart rate (beats/min)

877 (40.4)

407 (47)

0.001

3.8 (3.5–4.1)

3.6 (3.3–3.9)

<0.001

wide range in the 3,037 subjects with available loop

633 (266–1,411)

928 (423–1,851)

<0.001

diuretic

Albumin (g/dl) N-terminal pro–B-type natriuretic peptide (pg/ml)

BASELINE CHARACTERISTICS BY DIURETIC AGENT

ing the first 72 h of hospitalization varied over a

New York Heart Association class IV B-type natriuretic peptide (pg/ml)

RESULTS

4,148 (1,978–8,952) 5,411 (2,377–10,464)

0.011

agent

dosing

data (Figure

1).

Table

1

describes the baseline characteristics grouped by the average daily diuretic agent dose during the first

Blood urea nitrogen (mg/dl)

25 (19–32)

29 (21–40)

<0.001

Creatinine (mg/dl)

1.2 (1–1.5)

1.3 (1.1–1.8)

<0.001

72 h of hospitalization (low dose [<160 mg] or high

Hematocrit (%) Hemoglobin (gm/dl) Estimated glomerular filtration rate (ml/min) Serum sodium (mEq/l)

43 (38–46)

41 (37–45)

<0.001

dose [$160 mg]). Mean age and sex distribution

13.7 (12.3–15)

13 (11.6–14.4)

<0.001

were comparable with the full EVEREST trial popu-

57 (43–71)

50 (34–65)

<0.001

lation. High average daily diuretic agent dose was

140 (138–143)

140 (137–142)

<0.001

Continued on the next page

associated with clinical markers of more severe disease, including lower left ventricular ejection fraction, more severe New York Heart Association symptoms, lower systolic blood pressure, lower

con-

estimated glomerular filtration rate, higher blood

structed for patients with low and high average daily

urea nitrogen levels, and higher B-type natriuretic

loop diuretic agent doses. Associations between

peptide levels (p # 0.001 for all vs. low average daily

average daily loop dose and the combined endpoint

diuretic agent dose). Subjects receiving the high

were also assessed using multivariate Cox propor-

average daily diuretic agent dose had greater fre-

tional hazard models to estimate the independent

quency of comorbidities, including diabetes melli-

association of average loop diuretic agent dose

tus, chronic kidney disease, and chronic lung disease

and

Multi-

(p < 0.001 for all vs. low average daily diuretic

variate regression models were adjusted for other

agent dose). Average diuretic agent dose differed

intervals

the

(CIs).

Kaplan-Meier

combined

outcome

curves

were

endpoint.

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Short-Term Diuretic Agent Use and Outcomes in ADHF

by geographic region. A majority of subjects enrolled in

North

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America

received

high

average

daily

T A B L E 1 Continued

Average Loop Diuretic Agent Dose

diuretic agent doses, whereas a majority of the subjects in the Eastern European sites received low average daily diuretic agent doses. The natural logarithm of the average daily diuretic agent dose

Variable

Low (<160 mg/day) (n ¼ 2,171)

High ($160 mg/day) (n ¼ 866)

p Value

Medical history

did not differ in subjects treated with placebo com-

Previous HF hospitalization

1,656 (76.8)

695 (80.3)

0.033

pared with that in subjects treated with tolvaptan

Coronary artery disease

1,512 (69.7)

610 (70.5)

0.660

(untransformed mean values: 89.4 mg [95% CI: 85.6

History of myocardial infraction

1,071 (49.4)

455 (52.5)

0.118

to 93.3 mg] vs. 87.8 mg [95% CI: 83.9 to 91.8 mg],

Hypertension

1,564 (72)

650 (75.1)

respectively; p ¼ 0.55).

Hyperlipidemia

916 (42.5)

536 (62)

0.091 <0.001

Peripheral vascular disease

422 (19.5)

202 (23.4)

0.016

ASSOCIATION BETWEEN SHORT-TERM DIURETIC

History of coronary artery bypass graft

352 (16.2)

261 (30.1)

<0.001

AGENT EXPOSURE AND 30-DAY COMBINED ENDPOINT.

History of percutaneous coronary intervention

301 (13.9)

214 (24.7)

<0.001

Implantable cardioverter-defibrillator in situ

249 (11.5)

184 (21.2)

<0.001

There were 380 events (12.5%; 67 deaths, 340 rehospitalizations, and 27 patients with both) in the study population over a follow-up duration of 30 days.

Permanent pacemaker in situ

276 (12.7)

216 (24.9)

<0.001

Figure 2 demonstrates the number of 30-day com-

Diabetes mellitus

742 (34.2)

416 (48)

<0.001

Chronic kidney disease

446 (20.6)

355 (41)

<0.001

182 (8.4)

119 (13.7)

<0.001

bined outcome events according to categories of short-term diuretic agent exposure. Among patients with average diuretic agent dose <160 mg/day, there

Chronic obstructive lung disease Baseline medication use Aspirin

1,233 (57)

503 (58.2)

0.547

was no association between diuretic agent dose and

Clopidogrel

160 (7.4)

96 (11.1)

0.001

30-day risk for the combined outcome event (HR for

Angiotensin converting-enzyme inhibitor or angiotensin receptor blocker

1,874 (86.6)

706 (81.6)

0.001

Mineralocorticoid receptor antagonist

1,227 (56.7)

414 (47.9)

<0.001

a significant association between diuretic agent dose

Beta-adrenergic receptor blocker

1,527 (70.5)

621 (71.8)

0.490

and 30-day risk for the combined outcome event

Calcium-channel blocker

224 (10.3)

111 (12.8)

0.049

Digoxin

1,073 (49.6)

391 (45.2)

0.030

Nitrates

829 (38.3)

338 (39.1)

0.689

log-linear analysis of diuretic agent dose: 1.09; 95% CI: 0.90 to 1.33; p ¼ 0.37). However, among those with average diuretic agent doses $160 mg/day, there was

(HR for log-linear analysis of diuretic agent dose: 1.22; 95% CI: 1.05 to 1.42; p ¼ 0.001). Univariate analysis

Lipid-lowering agents

685 (31.6)

417 (48.2)

demonstrated that those subjects exposed to the

<0.001

Statins

655 (30.3)

399 (46.1)

<0.001

high-dose diuretic agents had greater risk for the

Amiodarone

358 (16.5)

181 (20.9)

0.004

30-day combined endpoint compared with those

Dobutamine

59 (2.7)

36 (4.2)

0.040

exposed to low-dose diuretic agents (18.9% vs. 10.0%;

Milrinone

5 (0.23)

15 (1.7)

<0.001

HR: 2.00; 95% CI: 1.64 to 2.46; p < 0.0001) (Figure 3). After adjustment for pre-specified covariates of disease severity in multivariate analysis, diuretic agent dose was no longer associated with increased

Values are mean  SD, n (%), or median (interquartile range). p values for comparisons between the 2 groups are reported. Subjects treated with average loop diuretic agent doses $160 mg/day had clinical characteristics consistent with more severe HF and had a higher frequency of comorbid medical conditions compared with those treated with average loop diuretic agent doses <160 mg/day. HF ¼ heart failure.

risk for the combined endpoint (HR: 1.11; 95% CI: 0.89 to 1.38; p ¼ 0.35) (Table 2). Study treatment allocation (tolvaptan vs. placebo) did not modify the association between diuretic agent dose and outcomes (p for interaction ¼ 0.26). INTERACTION

BETWEEN

SHORT-TERM

DIURETIC

summed score) yielded comparable findings (p for interaction ¼ 0.13).

DISCUSSION

AGENT EXPOSURE AND DISCHARGE CONGESTION STATUS. Of the 3,011 patients with information on

The EVEREST trial provides a unique data resource

discharge congestion status, 2,063 (69%) had little or

with detailed information on in-hospital diuretic

no

Discharge

agent use, serial clinical assessments of congestion

congestion status (little or no congestion vs. persis-

status at study entry and hospital discharge, and

tent congestion) did not modify the effect of diuretic

adjudicated clinical outcomes in a large contempo-

agent exposure on the combined endpoint (Table 3)

rary cohort of patients hospitalized for worsening

congestion

at

hospital

discharge.

(p for interaction ¼ 0.84). A sensitivity analysis with a

symptoms of HF. Two salient findings are evident

more stringent definition of discharge decongestion

from the current post hoc analysis of the EVEREST

status (score <1 and inclusion of dyspnea score in the

data: 1) higher average diuretic agent doses during

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F I G U R E 2 Percentage of Subjects With Combined 30-Day Outcome Event (All-Cause Mortality and Heart Failure Rehospitalization)

Grouped by Average Diuretic Agent Dose During First 72 Hours of Hospitalization

Error bars indicate 95% confidence intervals for the estimates in each diuretic agent dose group. A significant association between diuretic agent dose and 30-day risk for the combined outcome event was present only among those subjects treated with average diuretic agent doses $160 mg/day.

the first 3 days of hospitalization were not associated

outcomes after hospital discharge. Prior observa-

with increased risk for the 30-day combined endpoint

tional studies have reported an association between

of all-cause mortality or rehospitalization for HF

increased diuretic agent dose and increased mortality

when adjusting for other known covariates of disease

risk in patients hospitalized with worsening HF

severity, and 2) the relationship between short-term

symptoms (8,9). In these reports, increased diuretic

diuretic agent exposure and 30-day combined out-

agent dose was associated with markers of increased

comes did not vary according to clinically determined

disease severity, but diuretic agent dose remained an

congestion status at hospital discharge.

independent predictor of mortality in multivariate

Consensus guideline statements recommend titra-

models with adjustment for potential confounding

tion of diuretic agent dose to achieve euvolemia in

factors. In the EVEREST study population, we found

patients with HF and signs and symptoms of

that diuretic agent dose was associated with markers

congestion in both ambulatory and acute care settings

of increased disease severity and all-cause mortality

(2). This recommendation is based on expert opinion,

or HF rehospitalization at 30 days in univariate

because there are few prospective controlled trials to

analysis, but not in the multivariate model with

support the clinical benefits and safety of diuretic

adjustment for numerous known prognostic cova-

agent use for optimization of volume status in pa-

riates used in previous analyses of the EVEREST

tients with HF (20). The impetus for the current post

database. Our multivariate analysis indicates that

hoc analysis was the ongoing concern that diuretic

short-term exposure to higher diuretic agent doses

agents used for short-term relief of congestive signs

during hospitalization is a marker of more severe

and symptoms during hospitalization for worsening

disease and is not independently associated with

HF might also be conferring increased risk for adverse

greater risk for adverse outcomes. The discrepancy

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F I G U R E 3 Kaplan-Meier Curves for 30-Day Combined Endpoint of All-Cause Mortality and Heart Failure Rehospitalization by

Groups on the Basis of Diuretic Agent Exposure

Subjects with high average daily diuretic agent doses ($160 mg/day; dashed line) had significantly greater risk for the combined endpoint compared with those with low average daily diuretic agent doses (<160 mg/day; solid line). After adjustment for pre-specified covariates of disease severity in multivariate analysis, diuretic agent dose was no longer associated with increased risk for the combined endpoint (Table 2) (hazard ratio: 1.11; 95% confidence interval: 0.89 to 1.38; p ¼ 0.35).

between the results of our multivariate analysis and

post–hospital discharge adverse events in hospital-

those of past studies could be attributable to differ-

ized patients with HF randomly assigned to lower

ences in the methods used to calculate diuretic agent

versus higher doses of diuretic agents (24).

exposure, differences in follow-up duration, and the

To our knowledge, the present post hoc analysis of

number of potential confounder variables incorpo-

the EVEREST database is the first to specifically test

rated into multivariate models. Differences in inter-

the hypothesis that the relationship between short-

national patterns of diuretic agent use and global

term diuretic agent exposure during HF hospitaliza-

regional heterogeneity in health care systems, stan-

tion and 30-day clinical outcomes might differ

dards of care, and event rates in the EVEREST popu-

according to the clinically assessed congestion status

lation may have also contributed to the divergent

at hospital discharge. Our findings indicate that the

findings of the present analysis versus prior studies of

relationship between diuretic agent dose and out-

U.S. populations (21,22). The results of our multivar-

comes is not modified by the presence or absence of

iate analysis are concordant with a report from the

persistent congestion on the basis of clinical assess-

ALARM-HF (Acute Heart Failure Global Survey of

ment at hospital discharge. Two prior post hoc ana-

Standard Treatment) international registry, which

lyses of the placebo arm of the EVEREST cohort

reported no association between in-hospital diuretic

reported on the association between measures of

agent dose and 30-day mortality in a propensity-

discharge congestion status (on the basis of a com-

matched analysis (23). The lack of association

posite clinical congestion score and the presence of

between diuretic agent dose and mortality or HF

hemoconcentration) and mortality, but neither of

rehospitalizations in our multivariate analysis is

these reports provided information on diuretic

also consistent with the findings of the prospective

agent dose (15,18). Our finding of lack of effect

DOSE (Diuretic Optimization Strategies Evaluation)

modification on the basis of clinical assessment of

trial, which reported no difference in the risk for

discharge congestion status is consistent with prior

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Short-Term Diuretic Agent Use and Outcomes in ADHF

T A B L E 2 Multivariate Analysis of the Association Between Average Diuretic Agent Dose

and Other Pre-Selected Predictor Variables and the 30-Day Combined Primary Endpoint

but the optimal clinical application of the score or its individual components has not been determined. Persistent clinical or subclinical volume overload is

Predictor Variable

HR

95% CI

p Value

Average diuretic agent dose $160 mg/day

1.11

0.89–1.38

0.354

Tolvaptan study treatment

1.13

0.92–1.38

0.251

frequently present at hospital discharge and may contribute to the high rate of post–hospital discharge events (25). It is also possible that our negative

Eastern European region

0.35

0.24–0.51

<0.0001

Western European region

1.18

0.85–1.63

0.334

finding could be attributable to beta error, as the

South American region

0.79

0.56–1.11

0.171

power for detection of a significant interaction is

Male

0.91

0.70–1.18

0.481

limited by the sample size and event rates. Future

History of diabetes

1.19

0.95–1.48

0.131

trials to compare the clinical utility of physical

History of hypertension

1.19

0.93–1.53

0.168

assessment versus alternate measures for assessment

History of CKD

1.19

0.90–1.56

0.217

History of CAD

0.84

0.56–1.26

0.393

and management of optimal volume status (hemo-

History of COPD

0.99

0.72–1.35

0.936

concentration, direct blood volume measurement,

History of ICD

1.17

0.89–1.54

0.265

thoracic or total body water content, and/or data

NYHA functional class IV

1.33

1.08–1.64

0.009

derived from implantable hemodynamic monitors)

Atrial fibrillation

1.35

1.05–1.73

0.021

are needed to define the therapeutic strategies asso-

Ischemic cardiomyopathy

1.31

0.89–1.93

0.167

ciated with best clinical outcomes (25,30,31).

Prior heart failure hospitalization

1.12

0.85–1.47

0.420

Strengths of the present analysis include the

RAS inhibition (ACE inhibitor or ARB)

0.70

0.54–0.90

0.005

detailed characterization of loop diuretic agent

Beta-adrenergic receptor blocker

0.84

0.67–1.06

0.149

Mineralocorticoid receptor antagonist

0.87

0.69–1.09

0.213

exposure during hospitalization, extensive characterization of clinical and biochemical markers of dis-

Digoxin

1.09

0.88–1.36

0.429

Positive inotrope

0.92

0.59–1.41

0.694

B-type natriuretic peptide

1.30

1.15–1.47

<0.0001

Age

0.995

0.98–1.01

0.325

ease severity for inclusion in the multivariate analysis,

and

prospectively

adjudicated

clinical

outcomes.

Left ventricular ejection fraction

0.994

0.98–1.01

0.403

Systolic blood pressure

0.992

0.99–0.999

0.020

Serum sodium

0.987

0.97–1.01

0.263

Blood urea nitrogen

1.73

1.18–2.53

0.005

Our analysis is based on short-term exposure to

STUDY LIMITATIONS. There are several caveats to

consider in the interpretation of the presented data.

Estimated GFR

1.01

1.00–1.02

0.021

diuretic agents in a hospital setting and therefore is

Serum albumin

0.96

0.75–1.23

0.726

not generalizable to long-term diuretic agent use in

QRS duration

1.002

0.999–1.01

0.267

ambulatory HF populations. Diuretic agent dose in-

ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; CAD ¼ coronary artery disease; CI ¼ confidence interval; CKD ¼ chronic kidney disease; COPD ¼ chronic obstructive pulmonary disease; GFR ¼ glomerular filtration rate; HR ¼ hazard ratio; ICD ¼ implantable cardioverter-defibrillator; NYHA ¼ New York Heart Association; RAS ¼ renin-angiotensin system.

formation was available in approximately 75% of the subjects enrolled in the EVEREST study. Although the demographics of our subset with diuretic agent dose information were comparable with those of the overall EVEREST study population, selection bias in the study sample and the entry criteria for EVEREST

reports demonstrating that physical assessment un-

may limit the generalizability of our findings.

derestimates the degree of intravascular volume

Renal function was relatively well preserved in the

overload in patients with HF (25–29). The empirically

EVEREST study population, so the relationship

derived congestion score used in this analysis was

between diuretic agent dose and outcomes in patients

adapted from a previous EVEREST post hoc analysis,

with more severe comorbid chronic kidney disease

T A B L E 3 Combined 30-Day Outcome Events in 3,011 Subjects Grouped by Discharge Congestion Status and Average Diuretic Agent Dose

Discharge Congestion Status

Little or no congestion Persistent congestion

Average Diuretic Agent Dose

n

Events

%

Univariate HR* (95% CI)

p Value

Multivariate HR*

p Value

Low (<160 mg/day)

1535

134

8.7

1.85 (1.40–2.43)

<0.001

1.06 (0.80–1.42)

0.67

High ($160 mg/day)

528

82

15.5 1.93 (1.41–2.63)

<0.001

1.15 (0.84–1.59)

0.38

Low (<160 mg/day)

615

81

13.2

High ($160 mg/day)

332

79

23.8

Discharge congestion status (little or no congestion vs. persistent congestion) did not modify the effect of diuretic agent exposure on the combined endpoint (p for interaction ¼ 0.84). *HR for comparison of high versus low average daily diuretic agent dose in subjects with little or no congestion or persistent congestion. Abbreviations as in Table 2.

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Short-Term Diuretic Agent Use and Outcomes in ADHF

cannot be determined from our analysis. Moreover,

not independently associated with risk for the com-

our analysis did not include information on change in

bined endpoint of all-cause mortality and HF reho-

renal function, electrolytes, or other blood bio-

spitalization over 30 days. Clinically determined

markers, so it does not provide insight into potential

congestion status at hospital discharge did not

mechanisms linking diuretic agent dose and out-

modify the association between average diuretic

comes. Investigator assessment of congestion was not

agent dose and 30-day outcomes. These findings

centrally adjudicated in the EVEREST study and

support current consensus guideline recommenda-

therefore may be subject to interobserver variability.

tions. Additional work is needed to define the optimal

However, the fidelity of the reported signs of

techniques for assessment of euvolemia and deter-

congestion in the EVEREST database is supported by

mine the best strategies to improve post-discharge

the observation that subjects enrolled in EVEREST

outcomes in patients hospitalized with worsening

with hemoconcentration, a proposed biomarker of

symptoms.

effective decongestion therapy, had decreased signs and symptoms of congestion compared with subjects

REPRINT REQUEST AND CORRESPONDENCE: Dr.

without hemoconcentration (15). Our outcomes anal-

Stuart D. Katz, Leon H. Charney Division of Cardiol-

ysis was limited to 30 days post-discharge, as we

ogy, New York University Langone Medical Center,

considered this interval to be a biologically plausible

530 First Avenue, Skirball 9R, New York, New

time span for assessment of the health effects of

York 10016. E-mail: [email protected].

short-term diuretic agent exposure and also a clinically relevant time span for hospital-based treatment

PERSPECTIVES

programs targeting improved post-discharge outcomes. Post-discharge diuretic agent dose and other

COMPETENCY IN MEDICAL KNOWLEDGE: Loop diuretic

post-discharge medical therapies may have influ-

agents are commonly used to reduce congestive signs and

enced the 30-day outcomes. Finally, the post hoc

symptoms in patients hospitalized for worsening HF, but limited

nature of the analysis does not permit causal infer-

data are available to guide clinicians with regard to the selection

ence related to the observed associations, as unmea-

of the optimal loop diuretic agent dose, assessment of the clin-

sured confounders related to the complex medical

ical response to diuretic therapy, and safety of loop diuretic

decision-making

agents in clinical practice.

process

for

determination

of

diuretic agent dose might have contributed to our findings. Further work is needed to characterize the

TRANSLATIONAL OUTLOOK: Our analysis demonstrates that

association between diuretic agent exposure during

use of high-dose loop diuretic agents is a marker of more

hospitalization, congestion status at discharge, and

advanced HF but not an independent predictor of adverse out-

post-discharge treatment on longer term clinical

comes in patients hospitalized with worsening HF. These data are

outcomes and health care resources utilization.

in agreement with the findings of a randomized study of lower dose versus higher dose loop diuretic agents in hospitalized

CONCLUSIONS

patients with HF and support current HF treatment consensus

This post hoc analysis of the EVEREST study database demonstrates that higher short-term diuretic agent

guideline recommendations to adjust the dose of loop diuretic agents as needed to achieve euvolemia.

exposure during hospitalization for worsening HF is

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KEY WORDS acute heart failure, loop

heart failure. N Engl J Med 2011;364:797–805.

diuretic agents, outcomes