The Importance of Worsening Heart Failure in Ambulatory Patients

JACC: HEART FAILURE

VOL.

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

-, NO. -, 2016

ISSN 2213-1779/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jchf.2016.03.012

The Importance of Worsening Heart Failure in Ambulatory Patients Definition, Characteristics, and Effects of Amino-Terminal Pro-B Type Natriuretic Peptide Guided Therapy Aditi Mallick, MD,a Parul U. Gandhi, MD,b Hanna K. Gaggin, MD, MPH,a,c Nasrien Ibrahim, MD,a James L. Januzzi, MDa,c ABSTRACT OBJECTIVES The goal of this study was to define and assess the significance of worsening heart failure (WHF) in patients with chronic ambulatory heart failure with reduced ejection fraction (HFrEF). BACKGROUND WHF has been identified as a potentially relevant clinical event in patients with acute heart failure (HF) and is increasingly used as an endpoint in clinical trials. No standardized definition of WHF exists. It remains uncertain how WHF relates to risk for other HF events or how treatment may affect WHF. METHODS A total of 151 symptomatic patients with chronic HFrEF were randomized to standard of care HF management or a goal to lower N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentrations #1,000 pg/ml in addition to standard of care. WHF was prospectively defined as: 1) new or progressive symptoms and/or signs of decompensated HF; and 2) unplanned intensification of diuretic therapy. RESULTS Over a mean follow-up of 10 months, 45 subjects developed WHF. At baseline, patients developing incident WHF had higher ejection fraction (31% vs. 25%; p ¼ 0.03), were more likely to have jugular venous distension and edema (p < 0.02), were less likely to receive angiotensin-converting enzyme inhibitors or received these agents at lower doses (p < 0.04), and also received higher loop diuretic doses (p < 0.001). Occurrence of WHF was strongly associated with subsequent HF hospitalization/cardiovascular death (hazard ratio, landmark analysis: 18.8; 95% confidence interval: 5.7 to 62.5; p < 0.001). NT-proBNP–guided care reduced the incidence of WHF in adjusted analyses (hazard ratio: 0.52; p ¼ 0.06) and improved event-free survival (log-rank test p ¼ 0.04). CONCLUSIONS In chronic HFrEF, WHF was associated with substantial risk for morbidity and mortality. NT-proBNP–guided care reduced risk for WHF. (J Am Coll Cardiol HF 2016;-:-–-) © 2016 by the American College of Cardiology Foundation.

H

eart failure (HF) is a heterogeneous clinical

considerably, as high as 35% by 1 year (2), and this

diagnosis, encompassing a variety of un-

risk essentially doubles with each subsequent hospi-

derlying pathophysiologic processes. Diag-

talization (3). Accordingly, a better understanding of

nosis and treatment of HF have improved (1),

the risk factors for adverse outcomes is needed.

although patients affected by the diagnosis nonethe-

Part of the challenge in the care of patients with HF

less experience considerable morbidity and mortality.

is the fact that the diagnosis is a heterogeneous clinical

Risk

entity, whose manifestations and outcomes remain

for

death

after

HF

hospitalization

rises

From the aCardiology Division, Massachusetts General Hospital, Boston, Massachusetts; bCardiology Division, VA Connecticut Healthcare System, West Haven, and Yale School of Medicine, New Haven, Connecticut; and the cHarvard Clinical Research Institute, Boston, Massachusetts. Dr. Gaggin is supported in part by the Clark Fund for Cardiac Research Innovation; has received grant support from Roche and Portola; consulting income from Roche Diagnostics, American Regent, Amgen, Boston Heart Diagnostics, and Critical Diagnostics; and research payments for Clinical Endpoint Committees for EchoSense. Dr. Ibrahim is supported by the Dennis and Marilyn Barry Fellowship in Cardiovascular Research. Dr. Januzzi has received grants and consulting fees from Roche; grants from Singulex and Prevencio; consulting fees from Critical Diagnostics, Sphingotec, and Philips; was a member of the Data and Safety Monitoring Board of Amgen; received consulting and Clinical Events Committee fees from Novartis, Boeringer Ingelheim, and Janssen; and is supported in part by the Hutter Family Professorship in Medicine in the Field of Cardiology. Drs. Mallick and Gandhi have reported that they have no relationships relevant to the contents of this paper to disclose. John R. Teerlink, MD, served as Guest Editor for this paper. Manuscript received January 25, 2016; revised manuscript received March 16, 2016, accepted March 16, 2016.

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Worsening Heart Failure in Ambulatory Patients

ABBREVIATIONS

difficult to predict. This challenge is particu-

patients were eligible if they were >21 years of age and

AND ACRONYMS

larly germane in the present era of HF care, in

had experienced a decompensated HF event within 6

which increased focus on optimization of

months before enrollment. Patients were excluded if

chronic HF care and simultaneous prevention

they had severe renal disease, inoperable aortic

of HF hospitalization represents a major

valvular heart disease, life expectancy <1 year due to

effort.

causes other than HF, cardiac transplantation or

ACE = angiotensin-converting enzyme

CI = confidence interval CV = cardiovascular

Emerging

impending

HFrEF = heart failure with reduced ejection fraction

HR = hazard ratio hsTnT = highly sensitive troponin T

risk

tools for

HF

for

identifying

events

include

revascularization indicated or expected within 6

implantable hemodynamic monitoring, as

months, severe pulmonary disease, or coronary

well as serial measurement of prognostic bio-

revascularization (percutaneous coronary interven-

markers (4,5); however, clinical history and

tion or coronary artery bypass graft) within the pre-

physical examination remain highly valuable

vious 3 months.

for such prognostication. In this manner,

After enrollment, patients were randomized to

fraction

recent attention has focused on the phenom-

receive either standard HF management (with a goal of

NT-proBNP = N-terminal

enon of worsening heart failure (WHF), which

minimizing HF symptoms and achieving maximal

pro–B-type natriuretic peptide

may signal HF deterioration and unfavorable

dosages of therapies with proven mortality benefit

sST2 = soluble ST2

prognosis (6). WHF is increasingly being used

in HF) or standard HF management plus treatment

WHF = worsening heart failure

as an accepted inclusion criterion (7) and

adjustments to reduce NT-proBNP concentrations

endpoint in clinical trials (8) as an indirect

#1,000 pg/ml. To achieve this goal, patients received

predictor of HF outcomes such as hospitalization or

up-titration of guideline-directed medical therapy

death.

according to clinical judgement (both arms) with or

LVEF = left ventricular ejection

Despite growing use of WHF to include subjects in

without supplemental testing for NT-proBNP; in the

trials or as an endpoint, most studies have generally

context of a therapy change, repeated office visits were

relied on clinician judgment to define the presence or

made within 4 weeks. At entry to the study, patients

absence of WHF, leading to substantial subjectivity;

underwent a 2-dimensional echocardiogram (10),

to our knowledge, no standardized definition of WHF

which was repeated in study completers at a mean of

has been accepted. Furthermore, the importance of

10 months from enrollment; both the technician

WHF in the ambulatory population with heart failure

performing the echocardiogram as well as the staff

and reduced ejection fraction (HFrEF) remains poorly

member interpreting the study were blinded to study

defined, as much of the data regarding WHF have

arm or NT-proBNP values.

focused on those with hospitalized HF. Finally,

The primary endpoint of the PROTECT study was

treatment strategies that might favorably influence

total cardiovascular (CV) events (including WHF) over

incidence of WHF are not defined.

a 1-year period.

In the PROTECT (Pro-BNP Outpatient Tailored Chronic HF Therapy) study, WHF was strictly and prospectively defined, and it was used as an endpoint for the trial (9). This approach provides an opportunity to examine protocol-defined WHF in a contemporary cohort of patients with HFrEF. The hypothesis of the present study was that WHF would be associated with significant subsequent adverse outcomes and that HF management guided by N-terminal pro–B-type natriuretic peptide (NT-proBNP) would reduce WHF.

METHODS

PROTOCOL DEFINITION OF WHF. Online Table 1

details the PROTECT protocol definition of WHF, which was defined as: 1) new or progressive symptoms/signs of decompensated HF (including significant weight gain, worsening dyspnea or fatigue, newly elevated jugular venous pressure, new cardiac S3 gallop rhythm, the development of pulmonary rales, hepatic congestion, cool extremities, or lower extremity edema); and 2) unplanned intensification of oral or intravenous decongestive therapy with loop diuretic agents or the addition of a thiazide diuretic agent to loop diuresis.

All study procedures were approved by the local

STATISTICAL ANALYSES. Baseline patient charac-

institutional review board. Informed consent was

teristics were assessed and analyzed as a function of

obtained from participants.

the presence or absence of subsequent incident WHF

PROTECT STUDY DESIGN. The design and results of

after enrollment. These factors included demographic

the PROTECT study have been published previously

characteristics, background medical history, physical

(5,9). PROTECT was a prospective, randomized,

examination at baseline, and drug therapy at base-

single-center trial of 151 patients with New York Heart

line. As before, we expressed dosages of angiotensin-

Association functional class II to IV systolic HF (left

converting enzyme (ACE) inhibitors in “lisinopril

ventricular ejection fraction [LVEF] #40%). In brief,

total daily equivalents,” dosages of beta-blockers in

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Worsening Heart Failure in Ambulatory Patients

equivalents,”

care on WHF then considered. First, total burden of

dosages of mineralocorticoid receptor antagonists in

succinate

total

daily

WHF was considered as a function of treatment allo-

“spironolactone total daily equivalents,” and dosages

cation, with logistic regression expressing reduction

of loop diuretic agents in “furosemide total daily

in total WHF events in odds ratios (ORs) and 95% CIs.

equivalents” (5,11). Results of diagnostic testing at

After this assessment, Cox proportional hazards

enrollment, including LVEF, renal function (esti-

analysis was used to evaluate the effects of NT-

mated glomerular filtration rate determined by using

proBNP–guided therapy on the occurrence of WHF.

the Modification of Diet in Renal Disease equation), as

Lastly, Kaplan-Meier curves were constructed to

well as concentrations of several prognostic bio-

evaluate the effects of NT-proBNP versus standard of

markers (including NT-proBNP, soluble ST2 [sST2],

care (SOC) management relative to the time-to-first

highly sensitive troponin T [hsTnT] [4], and galectin-

WHF event and compared by using the log-rank test.

3 [12]), were also considered. Dichotomous variables

All statistics were performed by using Stata version

were compared by using chi-square tests, and

13.0 software (Stata Corp., College Station, Texas); all

continuous variables were compared by using the

p values are 2-sided, with values <0.05 considered

Student t test or Mann-Whitney U test as appropriate.

significant.

Univariate

followed

by

multivariable

logistic

regression analyses were used to identify baseline

RESULTS

predictors of the occurrence of subsequent WHF; all baseline characteristics, medical history, medica-

PATIENT CHARACTERISTICS IN THOSE WITH WHF

tions, and echocardiographic data were considered

VERSUS WITHOUT WHF. Of the 151 study subjects,

for the univariate model, with a retention p value of

the baseline factors of demographic characteristics,

0.05 used to identify candidates for inclusion in the

medical history, medication use, medication doses at

multivariable model. Biomarkers were considered for

baseline, treatment allocation, laboratory results for

this model, both as log-transformed continuous var-

various biomarkers, and, when available, echocardio-

iables as well as dichotomous variables, using previ-

graphic data were compared across those with and

ously described thresholds (4,5,12) of 1,000 pg/ml and

without WHF (Table 1). These data show that patients

2,000 pg/ml for NT-proBNP, 14 ng/ml for hsTnT, 35

who went on to subsequently develop WHF were

ng/ml for sST2, and 17.8 ng/ml for galectin-3.

largely similar to those who did not in terms of age,

To better understand the prognostic importance of

race, and baseline systolic blood pressure, among

WHF, we then considered the composite outcome of

other characteristics. Those developing WHF were

HF hospitalization or CV death relative to the pres-

more likely to have higher LVEF (31% vs. 25%;

ence or absence of incident WHF after enrollment. To

p ¼ 0.03), jugular venous distension (51% vs. 29%;

do so, univariate regression was used to identify

p ¼ 0.01), and peripheral edema (49% vs. 24%;

candidate baseline predictors of HF hospitalization/

p ¼ 0.002) on physical examination. Therapeutically,

CV death subsequent to enrollment. Dichotomous

those developing incident WHF later in the study were

clinical variables were entered into the model as such

less likely to be taking ACE inhibitors (53% vs. 72%;

and included demographic characteristics and medi-

p ¼ 0.03) at baseline and, if they were taking these

cal history. Use of guideline-directed medical therapy

drugs, they were on lower dosages (2.5 mg vs. 5 mg;

was entered both dichotomously as well as relative to

p ¼ 0.03). In addition, patients who eventually devel-

the log-transformed doses used. As described earlier,

oped WHF were also more likely to be taking a loop

to better explore the predictive relationship between

diuretic agent at baseline (100% vs. 88%; p ¼ 0.01)

biomarker concentrations, we log-transformed each

and at higher dosages (60 mg vs. 40 mg; p < 0.001)

biomarker concentration, as well as biomarkers

(Table 2). Overall, those developing WHF were less

expressed in dichotomous fashion. Multivariable Cox

likely to receive guideline-directed medical therapies

proportional hazards analysis was then performed,

or received them at lower doses, and were more likely

including univariate predictors with a retention p

to receive loop diuretic agents at higher doses or to

value of <0.05 along with WHF, with hazard ratios

have thiazide diuretic agents added. Data were not

(HRs) and 95% confidence intervals (CIs) for HF

available regarding intravenous medication use.

hospitalization/CV

death

landmarked

after

the

WHF event.

Those who developed WHF also had worse renal function at baseline (estimated glomerular filtration

Treatment strategies were next considered as a

rate 50.2 ml/min/m2 vs. 63.7 ml/min/m 2; p < 0.001)

function of subsequent WHF. The effect of HF drug

and higher concentrations of known prognostic

therapy on the likelihood of developing WHF was first

markers, including NT-proBNP, hsTnT, sST2, and

assessed and the effects of NT-proBNP–guided HF

galectin-3 (all p < 0.05) (Table 1).

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T A B L E 1 Baseline Characteristics as a Function of the Presence or Absence of

T A B L E 2 Medications at Baseline and Final Visits as a Function

WHF After Enrollment

of the Presence or Absence of WHF During the Trial WHF (n ¼ 45)

No WHF (n ¼ 106)

p Value

Age, yrs

66  13

62  14

0.19

Male

37 (82)

90 (85)

0.68

ACE inhibitor

White race

41 (91)

90 (85)

0.30

ACE inhibitor dose, mg/d

31 [23–36]

25 [20–33]

0.03

ARB

0.10

ARB dose, mg/d

Baseline LVEF, % NYHA functional class, %

WHF (n ¼ 45)

15 (33)

53 (50)

Beta-blocker

III

21 (47)

42 (40)

Beta-blocker dose, mg/d

IV

9 (20)

11 (10)

27 (60)

49 (46)

0.12

Medical history

0.27 0.62 0.66 0.70

93 (88)

0.01

60 [40–80]

40 [20–50]

<0.001

Myocardial infarction

19 (42)

39 (37)

0.53

ACE inhibitor

Atrial fibrillation

22 (49)

39 (37)

0.17

ACE inhibitor dose, mg/d

Ventricular tachycardia

15 (33)

29 (27)

0.46

ARB

Diabetes mellitus

20 (44)

43 (41)

0.66

ARB dose, mg/d

Emphysema

11 (24)

20 (19)

0.44

Beta-blocker

2 (4)

9 (8)

0.38

Beta-blocker dose, mg/d

27.7 [24.0–32.6]

27.9 [24.3–32.4]

0.89

Loop diuretic dose, mg/d

MRA dose, mg/d

71 [64–80]

71 [64–80]

0.65

Loop diuretic agent

108 [100–116]

110 [98–120]

0.76

Final medications

MRA

Loop diuretic dose, mg/d Thiazide added

0.01

103 (97) 50 [25–100]

45 (100)

0.053

31 (29)

42 (93) 50 [25–150]

Loop diuretic agent 0.60

23 (51)

0.94 0.22

43 (41)

54 (51)

Jugular venous distension

16 (15) 37.5 [12.5–75]

0 [0–12.5]

55 (52)

Systolic blood pressure, mm Hg

7 (16) 25 [0–50]

20 (44)

31 (69)

Heart rate, beats/min

0.03 0.03

0 [0–25]

25 (56)

BMI, kg/m2

76 (72) 5 [0–10]

MRA dose, mg/d

Coronary artery disease

Examination

24 (53) 2.5 [0–7.5]

MRA

Hypertension

Smoker, current

p Value

Baseline medications

II

Ischemic cardiomyopathy

No WHF (n ¼ 106)

26 (58)

76 (72)

2.5 [0–5]

5 [0–10]

0.03 0.009

7 (16)

19 (18)

0.88

25 [0–37.5]

37.5 [6.25–75]

0.62

44 (98)

102 (96)

0.99

50 [25–100]

50 [50–100]

0.02 0.72

23 (51)

58 (55)

6.25 [0–25]

12.5 [0–25]

0.38

44 (98)

93 (88)

0.07

80 [40–80]

40 [20–60]

<0.001

5 (11)

3 (3)

0.05

Pulmonary rales

8 (18)

11 (10)

0.21

Values are n (%) or median [interquartile range].

S3 gallop

16 (36)

27 (25)

0.21

Edema

22 (49)

25 (24)

0.002

ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; MRA ¼ mineralocorticoid receptor antagonist; WHF ¼ worsening heart failure.

50.2 [39.3–62.4]

63.7 [51.2–73.1]

Laboratory results eGFR, ml/min/1.73 m2 NT-proBNP, pg/ml

<0.001

2,380 [1,213–10,415] 1,112 [424–2,328] <0.001

enrollment to worsening HF event was 128 days

NT-proBNP > 1,000 pg/ml

37 (82)

58 (55)

0.001

(interquartile range: 57 to 194 days) with a range of

NT-proBNP > 2,000 pg/ml

74 (70)

19 (42)

0.001

42 [27–53]

20 [12–35]

6 to 521 days. Variables of interest, including baseline

40 (89)

72 (69)

45 [35–67]

33 [24–44]

<0.001

34 (76)

48 (45)

<0.001

data, and time in response for each biomarker

25 [17–31]

19 [14–25]

0.002

assessed, were analyzed to identify predictors of

31 (35)

58 (55)

0.11

subsequent WHF (Table 3). In univariate logistic

Baseline LVEF, %

31 [25–36]

26 [20–35]

0.04

Baseline LVEDVi

78 [64–98]

84 [70–108]

0.13

Baseline LVESVi

53 [42–72]

64 [46–87]

0.07

hsTnT, ng/ml hsTnT >14 ng/ml sST2, ng/ml sST2 >35 ng/ml Galectin-3, ng/ml Galectin-3 >17.8 ng/ml

<0.001 0.009

Baseline echocardiogram

demographic characteristics, medications, medication doses, treatment allocation, echocardiographic

regression analyses, multiple potential predictors were

identified;

however,

after

adjustment

in

multivariable logistic regression analyses, only logtransformed sST2 (HR: 4.6; 95% CI: 2.4 to 8.8;

Values are mean  SD, n (%), or median [interquartile range].

p < 0.001) and higher baseline LVEF (HR: 3.1; 95%

BMI ¼ body mass index; eGFR ¼ estimated glomerular filtration rate; hsTnT ¼ high sensitivity troponin T; LVEDVi ¼ left ventricular end-diastolic volume index; LVEF ¼ left ventricular ejection fraction; LVESVi ¼ left ventricular end-systolic volume index; NT-proBNP ¼ N-terminal pro–Btype natriuretic peptide; NYHA ¼ New York Heart Association; sST2 ¼ soluble ST2; WHF ¼ worsening heart failure.

WHF AND OUTCOMES. Patients with WHF had a

CI: 1.1 to 8.7; p ¼ 0.03) retained significance. significantly higher rate of subsequent HF hospitalization than those without (53% vs. 1%; p < 0.001) and a significantly higher rate of composite outcome of HF hospitalization or cardiovascular death (56% vs.

WHF IN THE PROTECT STUDY. Among the 151 pa-

6%; p < 0.001) (Table 4). Thus, of 45 patients with

tients in the study, 45 (29.8%) had WHF, and the

WHF, 25 subsequently had a HF hospitalization or

average number of WHF events per patient was 0.56,

died after WHF as defined according to the PROTECT

with a range of 0 to 6. Of those with WHF, the ma-

protocol, whereas of the 106 patients without WHF,

jority (80%) had 1 to 2 events. The median time from

only 6 had an HF hospitalization or death.

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Multivariate Cox proportional hazards models for the composite of CV death and worsening HF as the

T A B L E 3 Univariate and Multivariable Predictors of WHF

Univariate

outcome were constructed by using stepwise selec-

p Value

NYHA functional class IV

2.7 (1.2–6.2)

0.02

Peripheral edema

2.6 (1.5–4.8)

0.001

tion from baseline variables (Table 5), highlighting the predictive power of baseline NT-proBNP (HR: 1.9; 95% CI: 1.3 to 2.8; p < 0.001) for this outcome, as well as spironolactone usage, ACE inhibitor usage, and baseline New York Heart Association functional class.

Multivariable

OR (95% CI)

Laboratory results Log-eGFR

0.38 (0.16–0.90)

0.03

1.5 (1.2–1.8)

<.001

Log–NT-proBNP, pg/ml

addition of the incident WHF; in this model, land-

NT-proBNP >1,000 pg/ml

2.7 (1.2–5.8)

0.01

marked incident WHF powerfully predicted risk for

NT-proBNP >2,000 pg/ml

1.9 (1.0–3.6)

0.04

subsequent HF hospitalization/CV death (HR, land-

Log-hsTnT

2.0 (1.4–3.0)

<.001

mark analysis: 18.8; 95% CI: 5.7 to 62.5; p < 0.001).

hsTnT >14 ng/ml

2.6 (1.0–6.7)

0.04

Log-sST2

4.8 (2.6–8.8)

<.001

sST2 >35 ng/ml

3.3 (1.6–6.7)

<.001

AND WHF. Among

patients treated with biomarker-guided therapy,

Log-galectin-3

1.7 (1.00–2.8)

0.05

WHF occurred in 23% of patients compared with 37%

Galectin-3 >17.8 ng/ml

1.7 (0.89–3.2)

0.11

2.8 (0.96–8.0)

0.06

of patients in the SOC arm; considering frequency of total WHF events, NT-proBNP–guided care was associated with near-significant reduction of total WHF events, compared with SOC (HR: 0.50; 95% CI: 0.25 to

4.6 (2.4–8.8) <0.001

Baseline echocardiogram Baseline LVEF, %

3.1 (1.1–8.7)

CI ¼ confidence interval; OR ¼ odds ratio; other abbreviations as in Table 1.

1.0; p ¼ 0.06). Using first incident WHF as the dependent

variable,

NT-proBNP–guided

therapy

significantly reduced the occurrence of WHF (HR:

HF (8), standardized research criteria for the defini-

0.52; 95% CI: 0.28 to 0.96; p ¼ 0.04) in Cox propor-

tion of WHF are lacking; recent research has called for

tional hazards analyses. Lastly, Kaplan-Meier analysis

standardized endpoints in clinical trials of HF (1,13),

found that NT-proBNP–guided care significantly

and our data define and validate the endpoint of

improved the probability of survival without WHF

WHF. In this regard, given strong links to consequent

(p ¼ 0.03) (Figure 1).

HF hospitalization or cardiovascular death, the PRO-

DISCUSSION

patient phenotype, which may be leveraged for

The principal findings of the present study illustrate

TECT study definition of WHF identifies a high-risk future clinical trial design for HF therapeutics. Although the benchmark outcome measure of HF

that WHF (identified by using the protocol definition

hospitalization/CV death will likely continue to

as given in the PROTECT study) is both common and

represent a gold standard, addition of WHF as a

predictive of poor outcomes (particularly subsequent

relevant high-risk CV event may allow for minimizing

HF hospitalization) among patients with chronic

of sample size. Second, on a clinical level, given the

HFrEF. In addition, elevated sST2 serum concentra-

importance of HF hospitalization as a sentinel event

tions and higher baseline LVEF were independent

in the care of patients with chronic HF, our results

predictors of WHF. Although data are not available

may help clinicians to immediately identify patients

regarding use of intravenous rescue diuretic therapy,

likely to benefit from closer follow-up intervals, more

patients who developed WHF were less likely to be

frequent screening, and additional ancillary services,

taking ACE inhibitors at high doses and more likely to

such as home telemonitoring. Because studies of

be taking higher doses of oral loop and thiazide

home monitoring and treatment approaches have

diuretic agents at follow-up, despite similar blood pressure readings. Finally, outpatient management guided by reduction of NT-proBNP seemed to reduce

T A B L E 4 WHF and Cardiovascular Outcomes

the risk of WHF. Our results are novel in 3 ways. First, the PROTECT

WHF (n ¼ 45)

No WHF (n ¼ 106)

4 (9%)

6 (6%)

0.49

p Value

study protocol definition of WHF (incorporating fac-

Cardiovascular death

tors from history, physical examination, laboratory

Heart failure hospitalization

24 (53%)

1 (1%)

<0.001

test results, and therapeutic intervention) provides

Composite*

25 (56%)

6 (6%)

<0.001

useful possibilities relative to clinical trial design of treatments for HF care. Although utilized as an inclusion criterion (7) and endpoint in clinical trials of

p Value

Characteristic

The model was further refined with subsequent

NT-proBNP–GUIDED THERAPY

OR (95% CI)

Values are n (%). *Cardiovascular death or heart failure hospitalization. WHF ¼ worsening heart failure.

0.03

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shifted from hospitals to ambulatory centers; with the

T A B L E 5 Optimal Model Selecting From Baseline Variables to Predict

greater focus on natriuretic peptide–guided care, such

Composite of Heart Failure Hospitalization and CV Death

data are important. Hazard Ratio (95% CI) p Value

Model 1: Stepwise model without WHF <0.001

Interestingly, elevated concentrations of sST2 (a biomarker believed to play a pivotal role in

Baseline NT-proBNP (log-transformed)

1.9 (1.3–2.8)

Baseline spironolactone dose (log-transformed)

1.5 (1.1–2.0)

0.01

myocardial fibrosis and left ventricular remodeling

Baseline NYHA functional class

2.1 (1.1–4.1)

0.02

[15]) were associated with increased risk of devel-

0.38 (0.15–0.95)

0.04

oping WHF. This outcome is in accordance with pre-

1.5 (0.99–2.3)

0.06

deleterious left ventricular remodeling (4) and con-

1.7 (1.2–2.5)

0.005

firms that some biomarkers may be more useful than others to more objectively risk-stratify patients with

Prescribed ACE inhibitors at baseline

viously reported data that sST2 may be predictive of

Model 2: Stepwise model with WHF Baseline NT-proBNP (log-transformed) Baseline spironolactone dose (log-transformed) NYHA functional class

1.9 (0.88–4.2)

0.10

Prescribed ACE inhibitors at baseline

0.44 (0.15–1.3)

0.15

Occurrence of worsening heart failure

18.8 (5.7–62.5)

<0.001

Model 1 is the stepwise model without WHF considered; Model 2 is the stepwise model including WHF. In this analysis adjusted for baseline variables, WHF was a powerful predictor of heart failure–subsequent hospitalization/cardiovascular (CV) death.

HF. Because sST2 has been shown to predict a broad range of adverse HF outcomes independently of NT-proBNP or other biomarkers, its role for more broad use in HF monitoring and treatment programs deserves further attention.

Abbreviations as in Tables 1 to 3.

STUDY

been generally disappointing (14), identifying patients most likely to benefit would be expected to be useful. WHF seems amenable to reduction with different treatment strategies, and such patients might therefore be ideal for more intensive surveillance. In this regard, third, no previous data have evaluated the effect of NT-proBNP–guided care on WHF;

we

showed

that NT-proBNP–guided care

reduced WHF events by 50% and prolonged WHF-free survival. Given the importance of HF hospitalization to patients and health care systems alike, the 50% reduction in burden and frequency of WHF associated with NT-proBNP care is of substantial significance, particularly because HF care is increasingly being

LIMITATIONS. Limitations

of

this

study

include the fact it is small, with the potential for type I or II error, and was performed at a single tertiary care urban medical center. Nonetheless, results of the study are significant and consistent throughout. Our results should be validated in other, prospectively designed studies using the PROTECT study definition of WHF. Of note, most events in this study were HF readmissions (i.e., that an episode of WHF was mostly predictive of the need for a subsequent hospital admission). The relationship between WHF and cardiovascular

mortality

could

not

be

adequately

assessed in this study due to the small number of events. In terms of the statistical analysis, hierarchical modeling was not performed because only 22 patients experienced >1 WHF event. Moreover, the number of events was a categorical/descriptive vari-

F I G U R E 1 WHF-Free Survival According to Treatment Arm

able (none, exactly 1, or >1) with the 3 categories all being mutually exclusive on the basis of approximately equal follow-up; thus, the data were analyzed independently. Lastly, we lack data regarding use of intravenous loop diuretic agents used as rescue therapy for those with WHF; outpatient intravenous diuretic therapy was not in substantial use in our institution at the time of the trial, however. The strengths of this study include its well-defined cohort and its strictly defined definition for WHF. Our findings support the central finding of the PROTECT trial that biomarker-guided therapy is superior to SOC for management of chronic outpatient HFrEF. Our results also lend further understanding to the observation that biomarker-guided therapy may improve

N-terminal pro–B-type natriuretic peptide (NT-proBNP)–guided

quality of life (16), possibly by leading to a more sta-

care was associated with improved time to first worsening heart

ble HF phenotype, with better functional capacity,

failure (WHF) event compared with standard of care (SOC).

and may foster more significant reverse left ventricular remodeling (10,17).

JACC: HEART FAILURE VOL.

-, NO. -, 2016

Mallick et al.

- 2016:-–-

Worsening Heart Failure in Ambulatory Patients

CONCLUSIONS

PERSPECTIVES

WHF is both common and morbid in patients with ambulatory chronic HFrEF. WHF can serve as a useful intermediate outcome, predictive of existing, harder outcomes of HF hospitalization, and CV death. Although recent data have focused on the importance of WHF in acute HF syndromes, our study is the first, to our knowledge, to specifically examine this question in patients with chronic ambulatory HF. Treatment strategies affecting WHF such as NT-proBNP– guided care seem to reduce risk for other events in parallel. Further studies are needed to corroborate and extend these findings.

COMPETENCY IN MEDICAL KNOWLEDGE: For clinicians, this research defines the sentinel event of WHF as a combination of symptoms, signs, and therapeutic response. The results indicate that the phenomenon of WHF may be useful for identifying patients at higher risk for HF hospitalization or death. In this vein, better characterization of WHF may be advantageous for delivery systems and stewards of population health management by helping to identify patients likely to benefit from closer follow-up intervals, more frequent screenings, and additional ancillary services. TRANSLATIONAL OUTLOOK: For investigators, defining WHF allows for standardization of language and a benchmark

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

James L. Januzzi, Cardiology Division, Massachusetts General Hospital, 32 Fruit Street, Yawkey 5984, Boston, Massachusetts 02114. E-mail: jjanuzzi@mgh.

against which novel diagnostics, pharmacotherapies, and device therapies can be compared. In addition, the independent predictors of WHF included the biomarker sST2, which further supports its important role as a risk predictor in HF.

harvard.edu.

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A PP END IX For a supplemental table, please see the online version of this article.

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