JACC: HEART FAILURE VOL. -, NO.

-, 2018
ª 2018 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

STATE-OF-THE-ART REVIEW

Initiation, Continuation, Switching, and

Withdrawal of Heart Failure Medical
Therapies During Hospitalization
Aditi A. Bhagat, MD, MPH,a,* Stephen J. Greene, MD,b,c,* Muthiah Vaduganathan, MD, MPH,d
Gregg C. Fonarow, MD,e Javed Butler, MD, MPH, MBAf

ABSTRACT

Patients with worsening heart failure with reduced ejection fraction (HFrEF) spend a large proportion of time in the
hospital and other health care facilities. The benefits of guideline-directed medical therapy (GDMT) in the outpatient
setting have been shown in large randomized controlled trials. However, the decision to initiate, continue, switch, or
withdraw HFrEF medications in the inpatient setting is often based on multiple factors and subject to significant vari-
ability across providers. Based on available data, in well-selected, treatment-naive patients who are hemodynamically
stable and clinically euvolemic after stabilization during hospitalization for HF, elements of GDMT can be safely initiated.
Inpatient continuation of GDMT for HFrEF appears safe and well-tolerated in most hemodynamically stable patients.
Hospitalization is also a potential time for switching from an angiotensin-converting enzyme inhibitor/angiotensin II
receptor blocker to sacubitril/valsartan therapy in eligible patients, and is the subject of ongoing study. Therapy with-
drawal or need for dose reduction is rarely required, but if needed identifies a particularly at-risk group of patients with
progressive HF. If recurrent intolerance to neurohormonal blockers is observed, these patients should be evaluated for
advanced HF therapies. There is an enduring need for using the teachable moment of HFrEF hospitalization for optimal
initiation, continuation, and switching of GDMT to improve post-discharge patient outcomes and the quality of chronic
HFrEF care. (J Am Coll Cardiol HF 2018;-:-–-) © 2018 by the American College of Cardiology Foundation.

F or patients with heart failure with reduced

ejection fraction (HFrEF), a series of landmark
randomized clinical trials conducted in stable
outpatients identified multiple therapies to improve
therapy (GDMT) remain. Given the persistently high
rates of morbidity and mortality seen in the general
HFrEF population, the hospital setting provides a
key opportunity to readdress medical therapies.
morbidity and mortality (1). Nonetheless, substantial The decision whether to initiate, continue, switch,
gaps in provision of guideline-directed medical withdraw, or withhold initiation of HF medications in

From the aDivision of Cardiology, Stony Brook University, Stony Brook, New York; bDuke Clinical Research Institute, Durham,
North Carolina; cDivision of Cardiology, Duke University School of Medicine, Durham, North Carolina; dBrigham and Women’s
Hospital Heart and Vascular Center and Harvard Medical School, Boston, Massachusetts; eAhmanson-UCLA Cardiomyopathy
Center, University of California Los Angeles, Los Angeles, California; and the fDepartment of Medicine, University of Mississippi,
Jackson, Mississippi. Dr. Greene has received the NHLBI T32 postdoctoral training grant (T32HL069749-14), a Heart Failure Society
of America/Emergency Medicine Foundation Acute Heart Failure Young Investigator Award funded by Novartis; research support
from Novartis and Amgen. Dr. Vaduganathan has received the NHLBI T32 postdoctoral training grant (T32HL007604). Dr.
Fonarow has received personal fees from Novartis, Amgen, Janssen, Medtronic, and St. Jude Medical. Dr. Butler is a principal
investigator of the EMPEROR program (Boehringer Ingelheim); has received research support from the NIH and the European
Union; and has received personal fees from Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb,
Janssen, Novartis, Relypsa, ZS Pharma, Medtronic, Merck, CVRx, G3 Pharmaceuticals, Lutipold, Stealth Peptide, SC Pharma, and
Vifor. All other authors have reported that they have no relationships relevant to the contents of this paper to report. *Drs. Bhagat
and Greene contributed equally to this work and are joint first authors of this paper.

Manuscript received January 17, 2018; revised manuscript received April 28, 2018, accepted April 30, 2018.

ISSN 2213-1779/$36.00 https://doi.org/10.1016/j.jchf.2018.06.011

2 Bhagat et al. JACC: HEART FAILURE VOL. -, NO. -, 2018
In-Hospital Management of Heart Failure Therapies - 2018:-–-

ABBREVIATIONS the hospital-based setting is at the discretion post-discharge use, as 92% of patients continued
AND ACRONYMS of the treating physician and may be driven therapy at 60 to 90 days post-discharge (Figure 2) (7).
by factors such as patient symptoms at pre- Acknowledging potential differences in patient
ACEI = angiotensin-converting
enzyme inhibitor
sentation, blood pressure, heart rate, and characteristics and clinical stability, data from land-
renal function. Despite the central impor- mark randomized controlled trials of beta-blocker
ARB = angiotensin II receptor
blocker tance of these clinical decisions in the therapy among stable outpatients with chronic
ARNI = angiotensin receptor- routine care of hospitalized HF patients, data HFrEF may help contextualize in-hospital initiation
neprilysin inhibitor surrounding in-hospital management of of therapy. MERIT-HF (Metoprolol CR/XL Random-
GDMT = guided-directed chronic HFrEF medications are modest ized Intervention Trial in Congestive Heart Failure)
medical therapy compared to that for the medical manage- randomized patients to either initiation/titration of
HF = heart failure ment in the stable outpatient setting. In this metoprolol controlled release/extended release or
HFrEF = heart failure with review, we discuss the data regarding safety placebo and showed that beta-blocker therapy could
reduce ejection fraction
and logistics surrounding new initiation, be safely tolerated in most patients with low risk of
MI = myocardial infarction continuation, switching, and withdrawal of deterioration. In addition, the trial found risk
MRA = mineralocorticoid HFrEF medical therapy during HF hospitali- of deterioration greatest between 4 and 8 weeks of
receptor antagonist
zation. We focus on beta-blockers, angio- initiation and by week 8 the mortality and hospitali-
tensin-converting enzyme inhibitors (ACEIs)/ zation rates trended in favor of beta-blockade (8).
angiotensin II receptor blockers (ARBs), sacubitril/ Likewise, the COPERNICUS (Carvedilol Prospective
valsartan, and mineralocorticoid receptor antagonists Randomized Cumulative Survival) trial randomized
(MRAs) because these medications form the founda- 2,289 clinically euvolemic patients with severe HF
tion of most GDMT regimens and are applicable to the (i.e., symptoms at rest or with minimal exertion) to
large majority of patients with HFrEF (Table 1). carvedilol or placebo and found clinical benefits on
mortality and hospitalization with beta-blocker ther-
INITIATION OF HF MEDICATIONS
apy over the first 8 weeks of the trial to be consistent
with the long-term trial results (9).
In treatment-naïve patients included in the GWTG-HF
(Get With the Guidelines-Heart Failure) registry, 90% ACEI/ARB. To our knowledge, there are no robust
were initiated on beta-blockers during hospitalization randomized clinical outcome data regarding in-
or at discharge, 87% were initiated on ACEIs/ARBs, hospital ACEI/ARB initiation. Observational data
and 25% were initiated on MRAs (Figure 1) (2). from the GWTG-HF registry found that among 16,052

BETA-BLOCKER. There are no randomized data for

patients, those who were newly started on ACEI/ARB

in-hospital initiation of metoprolol succinate or before discharge had lower mortality and readmission

bisoprolol. In contrast, the IMPACT-HF (Initiation rates up to 1 year (10). A matched-cohort analysis of

Management Predischarge: Process for Assessment of Medicare beneficiaries hospitalized for HF between

Carvedilol Therapy in Heart Failure) trial found that 1998 and 2001 found patients initiated on an ACEI/

carvedilol initiation pre-discharge was feasible ARB had lower 30-day all-cause readmissions (18% vs.

without untoward side effects or prolonged length of 24%) and all-cause mortality (7% vs. 14%), both of

stay, and appeared to improve post-discharge beta- which remained significant 1 year after discharge (11).

blocker use (3). Another small randomized clinical In addition, there was a significantly lower risk of

trial found the strategy of pre-discharge initiation of 30-day HF readmission (7% vs. 15%) (11). Another

low-dose carvedilol coupled with biweekly nursing relevant analysis from the Medicare population spe-

care significantly reduced the need for hospitalization cifically assessed those who also developed acute

and improved functional status at 6 months (4). kidney injury during hospitalization. Overall, 54% of

Likewise, several observational studies from the this subgroup received a discharge prescription for an

OPTIMIZE-HF (Organized Program to Initiate Life- ACEI/ARB and the benefits of ACEI/ARB therapy

saving Treatment in Hospitalized Patients with Heart remained consistent, with significantly lower 30-day

Failure) registry support the relative benefits of in- all-cause readmission, 30-day HF readmission, and

hospital beta-blocker initiation on post-discharge 30-day all-cause mortality, which persisted to 12-

clinical outcomes (5,6). For example, an analysis months post-discharge (12).

from OPTIMIZE-HF suggested lower mortality in pa- MRA. Randomized controlled trial data regarding
tients started on beta-blockers compared with those in-hospital initiation of MRA therapy among HFrEF
who were not at 60 to 90 days after discharge (7). patients are limited. The EPHESUS (Eplerenone Post–
Initiation of beta-blockers in the hospital was gener- Acute Myocardial Infarction Heart Failure Efficacy
ally well-tolerated and translated to high rates of and Survival) study randomized patients after an
JACC: HEART FAILURE VOL. -, NO. -, 2018 Bhagat et al. 3
- 2018:-–- In-Hospital Management of Heart Failure Therapies

T A B L E 1 Select Studies of In-Hospital Use of Beta-Blocker, ACEI/ARB/ARNI, and MRA Therapy Among Patients Hospitalized for HF With Reduced Ejection Fraction

Therapy
First Author (Ref. #) Study Design N Key Results

Beta-blocker
Initiation
Gattis et al. (3) Randomized (open-label) clinical trial: 363 At 60 days post-randomization, 91% randomized to pre-discharge
(IMPACT-HF) Carvedilol initiation pre-hospital carvedilol initiation were treated with a beta-blocker, compared
discharge vs. initiation >2 weeks post- with 73% randomized to post-discharge initiation (p < 0.001).
discharge at physician discretion No difference in rates of serious adverse events or index
hospitalization length of stay between groups.
Hernandez et al. (5) Observational: Among patients eligible for 3,001 (subset with At 1 yr post-discharge, beta-blocker initiation associated with lower
(OPTIMIZE-HF registry beta-blockers, in-hospital beta-blocker reduced ejection adjusted risk for all-cause mortality (HR: 0.77; 95% CI: 0.68-
linked to Medicare claims) initiation vs. no initiation fraction) 0.87), all-cause rehospitalization (HR: 0.89; 95% CI: 0.80-
0.99), and mortality or rehospitalization (HR: 0.87; 95% CI:
0.79-0.96).
Continuation or withdrawal
Fonarow et al. (7) Observational: Among patients eligible for 2,373 At 60-90 days post-discharge, beta-blocker continuation
(OPTIMIZE-HF Registry) beta-blockers, in-hospital beta-blocker associated with a lower propensity adjusted risk for mortality
continuation vs. no beta-blocker; (HR: 0.60; 95% CI: 0.37-0.99; p ¼ 0.044) and mortality
beta-blocker withdrawal vs. or rehospitalization (odds ratio: 0.69; 95% CI: 0.52-0.92;
continuation p ¼ 0.012), compared with no beta-blocker.
92% of patients newly initiated on beta-blocker therapy remained
on therapy.
Beta-blocker withdrawal associated with higher adjusted mortality
risk compared with continuation (HR: 2.3; 95% CI: 1.2-4.6;
p ¼ 0.013).
57% of patients with in-hospital beta-blocker discontinuation were
restarted on therapy within 60-90 days.
Angiotensin-converting enzyme
inhibitor or angiotensin II
receptor blocker
Initiation
Sanam et al. (11) Observational: Among patients without 954 (propensity At 30 days post-discharge, ACEI/ARB prescription associated with
(Medicare beneficiaries) prior ACEI/ARB use and without known matched cohort) significantly lower propensity adjusted all-cause readmission
contraindications, discharge ACEI/ARB (HR: 0.74; 95% CI: 0.56-0.97; p ¼ 0.030) and 30-day
prescription vs. no prescription all-cause mortality (HR: 0.56; 95% CI: 0.33-0.98; p ¼ 0.041).
All associations remained significant at 1 yr post-discharge.
Continuation or withdrawal
Gilstrap et al. (10) (GWTG-HF Observational: Among eligible patients, 16,052 At 1-year post-discharge, in-hospital ACEI/ARB withdrawal was
linked to Medicare claims) ACEI/ARB withdrawal vs. continuation associated higher adjusted mortality risk compared with
continuation (HR: 1.35; 95% CI: 1.13-1.61; p < 0.001).
Continued on the next page

acute myocardial infraction (MI) with left ventricular significant difference between 30-day all-cause mor-
dysfunction (ejection fraction < 40%) and found tality/HF hospitalization rates. Moreover, there was
initiation of eplerenone 3-14 days after MI reduced no significant difference in the natriuretic peptide
the risk of cardiovascular events (13). Although this trajectory at 96 h between treatment arms (17).
trial focused on use after acute MI, early MRA use in Regarding associations with clinical outcomes,
acute HF exacerbations may play a role in reducing observational data have shown mixed results
sudden cardiac death and arrhythmia (14). In a pro- regarding comparative effectiveness of in-hospital
spective single-blinded trial of patients hospitalized MRA initiation (18–21). For example, a study of 946
for HF (15), spironolactone was associated with patients found the 46% of patients discharged on
greater congestion relief and reductions in natriuretic spironolactone to have lower rates of all-cause and
peptides at day 3 (15). Another randomized controlled cardiovascular death (19). In contrast, an analysis of
trial conducted among 116 patients hospitalized for Medicare patients found that when compared with
HF found that those who were initiated on spi- those not receiving therapy, prescription of MRA
ronolactone versus placebo had a reduced rate of therapy at discharge was not associated with a dif-
arrhythmias (16). Most recently, the ATHENA-HF ference in mortality and cardiovascular readmissions,
(Aldosterone Targeted Neurohormonal Combined but was associated with a lower rate of HF read-
with Natriuresis Therapy in Heart Failure) trial missions (21). Speculating as to why the reliable
compared initiation of high-dose spironolactone 100 benefits of MRA therapy in randomized trials differ
mg daily plus usual care versus usual care alone from the inconsistent results in observational studies,
among patients hospitalized for HF and found no residual confounding and the potential for MRA
4 Bhagat et al. JACC: HEART FAILURE VOL. -, NO. -, 2018
In-Hospital Management of Heart Failure Therapies - 2018:-–-

T A B L E 1 Continued

Therapy
First Author (Ref. #) Study Design N Key Results

Angiotensin receptor-neprilysin
inhibitor
Initiation
Velazquez et al. (32) Randomized clinical trial: Eligible patients 882 Trial ongoing and results not yet available.
(PIONEER-HF) randomized to in-hospital initiation of
sacubitril/valsartan vs. enalapril with
12-week follow-up.
Mineralocorticoid receptor antagonist
Initiation
Ferreira et al. (15) Nonrandomized clinical trial, single-blind 100 Spironolactone not associated with excess in-hospital worsening
(patients): Patients not receiving renal function or hyperkalemia.
background MRA therapy and meeting Greater proportions of patients receiving spironolactone were free
other study criteria assigned short of congestion at day 3: less edema, rales, jugular venous
in-hospital course of spironolactone pressure and orthopnea (all p < 0.05).
50-100 mg/d plus standard care vs.
standard care alone.
Butler J et al. (17) Randomized clinical trial: High-dose 360 Spironolactone not associated with excess in-hospital worsening
(ATHENA-HF) spironolactone 100 mg/d for 4 days renal function or hyperkalemia.
plus standard care vs. standard care Spironolactone therapy did decrease NT-proBNP level or improve
alone. Overall, 11% of patients on clinical markers of congestion compared with standard care.
spironolactone at baseline.
Lam et al. (20) (Medicare Observational: Among patients without 648 (propensity At 30 days post-discharge, MRA therapy not associated with
beneficiaries) MRA use at admission and without matched cohort) propensity adjusted risk of all-cause readmission
known contraindications, discharge (HR: 0.92; 95% CI: 0.64-1.32; p ¼ 0.650), all-cause mortality
MRA prescription vs. no prescription (HR: 0.84; 95% CI: 0.38-1.88; p ¼ 0.678), or HF readmission
(HR: 0.74; 95% CI: 0.41-1.31; p ¼ 0.301).
Associations remained consistent at 1-yr follow-up.
Prescription at discharge
Hamaguchi et al. (19) Observational: Use of spironolactone at 946 Over mean post-discharge follow-up of 2.2 yrs, discharge use of
(JCARE-CARD registry) discharge vs. no use at discharge spironolactone associated with lower adjusted risk of all-cause
(HR: 0.62; 95% CI: 0.41-0.93; p ¼ 0.020) and cardiovascular
death (HR: 0.52; 95% CI: 0.32-0.87; p ¼ 0.013).
Spironolactone not associated with adjusted risk of all-cause
hospitalization (HR: 0.79; 95% CI: 0.59-1.05; p ¼ 0.101).
Hernandez et al. (21) Observational: Among patients eligible for 5,887 At 3 years post-discharge, MRA therapy not associated with
(GWTG-HF linked to Medicare therapy, discharge MRA prescription vs. adjusted risk of mortality (HR: 1.04; 95% CI: 0.96-1.14;
claims) no prescription p ¼ 0.32) or cardiovascular rehospitalization (HR: 1.00;
95% CI: 0.91-1.09; p ¼ 0.94).
At 3 years, MRA therapy associated with lower adjusted risk of
HF rehospitalization (HR: 0.87; 95% CI: 0.77-0.98; p ¼ 0.02).
MRA therapy associated with higher adjusted risk of hospitalization
for hyperkalemia at 30 days (HR: 2.54; 95% CI: 1.51-4.29;
p < 0.001) and 1 yr (HR: 1.50; 95% CI: 1.23-1.84; p < 0.001).
Curtis et al. (22) (GWTG-HF linked Observational: Among patients eligible for 2,086 Within 90 days post-discharge, 79% of patients with a discharge
to Medicare claims) therapy, discharge MRA prescription vs. prescription filled a prescription for therapy, compared with
no prescription 13% without a discharge prescription (p < 0.001).
8% of patients with a discharge prescription discontinued therapy
within 1 yr.

ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin II receptor blocker; ARNI ¼ angiotensin receptor neprilysin inhibitor; ATHENA-HF ¼ Aldosterone Targeted Neurohormonal Combined With
Natriuresis Therapy in Heart Failure trial; CI ¼ confidence interval; GWTG-HF ¼ Get With the Guidelines-Heart Failure; HF ¼ heart failure; HR ¼ hazard ratio; IMPACT-HF ¼ Initiation Management Pre-
discharge: Process for Assessment of Carvedilol Therapy in Heart Failure trial; MRA ¼ mineralocorticoid receptor antagonist; NT-proBNP ¼ N-terminal pro-B-type natriuretic peptide; OPTIMIZE-HF ¼
Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure registry; PIONEER-HF ¼ Comparison of Sacubitril/valsartan Versus Enalapril on Effect on NT-proBNP in Patients
Stabilized From an Acute Heart Failure Episode trial.

therapy to be selectively prescribed to higher-risk discharge prescription filling a prescription within 90

patients may be likely explanations. days (22). Among patients who filled a prescription
Despite limited randomized data regarding clinical within 90 days, most remained on therapy at 1 year
effects of in-hospital MRA initiation, observational with only an 8% discontinuation rate. In contrast,
data support the hospitalization as a tool to increase only 13% of eligible patients without a discharge
downstream long-term MRA use. For instance, prescription initiated therapy as outpatients (22).
GWTG-HF data found discharge prescription for MRA Although these relationships may be seen with other
therapy to be strongly correlated with continued HFrEF therapies, the particularly low rates of MRA
post-discharge adherence with 79% of patients with a use among eligible patients in routine practice
JACC: HEART FAILURE VOL. -, NO. -, 2018 Bhagat et al. 5
- 2018:-–- In-Hospital Management of Heart Failure Therapies

F I G U R E 1 Medication Utilization at Admission, During Hospitalization, and at Discharge

Analysis from the Get With the Guidelines Heart Failure Registry: Proportion of patients on guideline-directed medical therapies at admission
(purple bars), during hospitalization (red bars), and at discharge (yellow bars) with associated upper and lower boundaries of 95% confi-
dence intervals in patients hospitalized for heart failure. ACE-I ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin II receptor
blocker. Adapted with permission from Krantz et al. (2).

highlight in-hospital initiation as a particularly valu- among those discharged with a beta-blocker as
able strategy for consideration (23). compared with those discharged without such ther-
apy (6% vs. 11%).
CONTINUATION VERSUS WITHDRAWAL OF
HF MEDICATIONS ACEI/ARB. The OPTIMIZE-HF registry found the in-
hospital discontinuation rate for ACEI/ARB to be
The GWTG-HF registry showed that continuation 28%, as compared to 7% for beta-blockers (25). In an
rates of medications during hospitalization for HF analysis from the GWTG-HF registry, continuation of
were 92% for beta-blockers, 89% for ACEI/ARB, and ACEI/ARB among patients hospitalized for HFrEF was
72% for MRA (2). associated with significantly lower 30-day, 90-day,
and 1-year mortality and 30-day readmission, as
BETA-BLOCKER. Continuation of beta-blockers
compared to those who were discontinued (Figure 3)
during an acute HF exacerbation in the inpatient
(10). In African American patients with HFrEF, ACEI/
setting has been consistently associated with
ARB dose reduction or discontinuation occurred more
improved clinical outcomes (6,24). Data from
frequently than for beta-blockers (17% vs. 7%). Pa-
OPTIMIZE-HF showed that among 2,373 patients
tients who were discontinued versus continued on
eligible for beta-blockers at discharge, 1,350 were
ACEI/ARB had an associated greater median length of
previously on therapy and continued and 79 patients
stay at 5.5 days versus 3.0 days and a shorter time to
were withdrawn from previous therapy (7). Those
HF readmission; however, this trend did not meet
who continued on therapy had a significantly lower
statistical significance (26).
risk of post-discharge death and death/rehospitali-
zation compared with patients on no beta-blocker. In MRA. Continuation of spironolactone as an inpatient
contrast, withdrawal of beta-blocker was associated has not been well elucidated in clinical trials or
with substantially higher risk-adjusted mortality observational studies. Perhaps the most informative
compared with those who continued on beta- work in this area comes from an analysis of the
blockers. OPTIMIZE-HF also found a statistically sig- COACH (Co-ordinating Study Evaluating Outcomes of
nificant benefit of beta-blocker use (i.e., initiation or Advising and Counseling in Heart Failure) biomarker
continuation) at discharge, showing that death from study, which found patients who were initiated or
any cause at 60 to 90 days was significantly lower continued on spironolactone had a lower 30-day
6 Bhagat et al. JACC: HEART FAILURE VOL. -, NO. -, 2018
In-Hospital Management of Heart Failure Therapies - 2018:-–-

F I G U R E 2 Post-Discharge Survival by Beta-Blocker Treatment Groups

Kaplan-Meier survival curve of patients newly started, continued, withdrawn, and not treated with beta-blocker therapy. Reproduced with
permission from Fonarow et al. (7).

mortality (18). However, regardless of whether MRA available regarding the use and safety among pa-
therapy is newly initiated or continued during the tients hospitalized for HF (27). Subsequent analyses
hospitalization, data strongly support the association of PARADIGM-HF have suggested that patients
between MRA use at discharge and higher rates of recently hospitalized for HFrEF are just as likely to
post-discharge use (22). benefit from sacubitril/valsartan as more stable
HFrEF patients with remote or no prior hospitaliza-
SWITCHING tions (28). Consistent safety and efficacy of angio-
tensin receptor-neprilysin inhibitor (ARNI) even in
BETA-BLOCKER. Specific beta-blockers (carvedilol, patients with recent HF hospitalization suggests
metoprolol succinate, and bisoprolol) have been well- clinical benefit with in-hospital switching among
studied and proven to improve clinical outcomes in stable, clinically euvolemic patients. Similarly, the
patients with chronic HFrEF. Currently, there are no benefits of ARNI therapy appear consistent across a
published studies in hospitalized patients for HFrEF spectrum of risk in the PARADIGM-HF trials; higher-
regarding transition from non–evidence-based beta- risk patients identified in this study may be analo-
blockers, such as atenolol, to evidence-based beta- gous to stable patients hospitalized for HF (29).
blockers. However, clinical experience suggests that Furthermore, there appears to be important clinical
transitioning from non–evidence-based beta-blockers benefits of ARNI early after initiation and after HF
to evidence-based beta-blockers is generally well hospitalization. In patients who experienced hospi-
tolerated in clinically stable hospitalized patients. talization for HF in PARADIGM-HF, sacubitril/valsar-
ACEI/ARB TO ANGIOTENSIN RECEPTOR-NEPRILYSIN tan appears to reduce 30-day all-cause readmissions
INHIBITOR. Although the PARADIGM-HF (Prospective compared with enalapril (28).
Comparison of ARNI With an ACEInhibitor to Deter- Unfortunately, the uptake and use of sacubitril/
mine Impact on Global Mortality and Morbidity in valsartan has been sluggish; an analysis of the GWTG-
Heart Failure) trial showed that sacubitril/valsartan HF registry found that only 2.3% of hospitalized
was superior to enalapril in reducing cardiovascular patients were discharged with ARNI therapy (30).
events in stable patients with HFrEF, limited data are As evidenced by numerous trials for beta-blockers,
JACC: HEART FAILURE VOL. -, NO. -, 2018 Bhagat et al. 7
- 2018:-–- In-Hospital Management of Heart Failure Therapies

ACEI/ARBs, and MRAs, postponing the initiation of

F I G U R E 3 Post-Discharge Outcomes by ACEI Treatment Groups
optimal medical therapy in the hospital-based setting
often leads to failure to initiate medication in the
outpatient setting. Failure of ARNI prescription at
discharge and therefore potential lack of optimal use
in the outpatient setting may be directly attributed to
28,484 deaths per year in the United States (31). As
with all other GDMT for HFrEF, data from chronic
HFrEF trials have been readily extrapolated as best
practice for treatment and optimization of medical
therapy during hospitalization for HF. Nonetheless,
to provide more specific data, the PIONEER-HF
(Comparison of Sacubitril/Valsartan Versus Enalapril
on Effect on NT-proBNP in Patients Stabilized From
an Acute Heart Failure Episode) study is a multicenter
randomized double-blind controlled trial currently
underway to evaluate the effect of in-hospital initia-
tion of sacubitril/valsartan on changes in N-terminal
pro-B-type natriuretic peptide (NT-proBNP) and
safety and tolerability (32). Likewise, the LIFE
(Entresto in Advanced Heart Failure) (NCT02816736)
trial aims to evaluate the safety and efficacy of
sacubitril/valsartan in New York Heart Association
functional class IV HFrEF patients and will be inclu-
sive of patients hospitalized for HF.

SAFETY

A significant number of patients hospitalized for

HFrEF have worsening hemodynamics and/or wors-
ening renal function. These characteristics and
others may lead to clinical reluctance of initiating
or continuing hemodynamically active therapies
(33,34).
BETA-BLOCKER. The IMPACT-HF trial found low
rates of worsening HF (0.5%), hypotension (1.6%),
and bradycardia (1.6%) requiring discontinuation in
patients started on beta-blockers during hospitaliza-
tion. Rates of discontinuation did not appear
different between treatment and control groups.
Further, length of stay in the hospital was the same
between both groups (w5 days) (3). The ESCAPE
(Evaluation Study of Congestive Heart Failure and
Pulmonary Artery Catheterization) trial found that
beta-blockers were commonly discontinued for res-
piratory rate >24 breaths/min, heart rate >100 beats/
min, lower EF, diabetes mellitus, and systolic blood
pressure <100 mm Hg during hospitalization (24).
OPTIMIZE-HF found beta-blocker therapy was not
ACEI Initiation, Continuation, Discontinuation, and Never Initiated rates for 1-year mor-
prescribed at discharge due to symptomatic brady- tality (A), 1-year readmission (B), and 1-year mortality/readmission (C). Adapted with
cardia (1%), reactive airway disease (3%), symptom- permission from Gilstrap et al. (10). ACE-I ¼ angiotensin-converting enzyme inhibitor.
atic hypotension (3%), second- or third-degree heart
8 Bhagat et al. JACC: HEART FAILURE VOL. -, NO. -, 2018
In-Hospital Management of Heart Failure Therapies - 2018:-–-

C E N T R A L IL L U ST R A T I O N Key Elements Related to Initiation, Switching, Continuation, and

Withdrawal of GDMT During Hospitalization for HF

Bhagat, A.A. et al. J Am Coll Cardiol HF. 2018;-(-):-–-.

ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin II receptor blockers; ARNI ¼ angiotensin receptor neprilysin inhibitor;
GDMT ¼ guideline-directed medical therapies; HF ¼ heart failure; MRA ¼ mineralocorticoid receptor antagonist.

block (0.4%), allergy (0.2%), and other reasons (4%) hyperkalemia (10). Another analysis among African
(35). The COPERNICUS trial showed that patients American patients found that ACEI/ARB medications
randomized to carvedilol therapy were more likely to were reduced or discontinued because of acute
report dizziness, hypotension, edema, and brady- kidney injury (57%), hypotension (23%), and hyper-
cardia and required medication withdrawal, but this kalemia (10%); serum creatinine and systolic blood
was limited to a small number of cases (9). However, pressure at admission were significant independent
safety data on risk of worsening HF was reassuring, predictors of in-hospital dose reduction or discon-
with rates of worsening HF early after therapy initi- tinuation (26). However, this study also found that
ation numerically higher among patients receiving despite renal dysfunction cited as the most frequent
placebo (9). reason for de-escalation of ACEI/ARB therapy, 24% of
ACEI/ARB. In the inpatient setting, reasons for patients had no significant in-hospital rise in creati-
discontinuation of ACEI/ARBs in the GWTG-HF nine level (i.e., did not meet criteria for an acute
registry were primarily renal dysfunction and kidney injury) and medication changes were made
JACC: HEART FAILURE VOL. -, NO. -, 2018 Bhagat et al. 9
- 2018:-–- In-Hospital Management of Heart Failure Therapies

over concern for worsening renal function rather than expected to be unable or unwilling to comply with
its actual occurrence (26). appropriate post-discharge clinical and laboratory
MRA. Although the precise reasons for poor use of monitoring are not candidates for inpatient initiation
MRA therapy by time of hospital discharge among or escalation of MRA therapy. In addition, caution
eligible patients are unclear, likely barriers include should be used when initiating ACEI/ARB therapy in
perceived risks of hyperkalemia and worsening renal hypovolemic patients (such as patients who are “over-
function. An analysis from the EPHESUS trial found diuresed”) because renin-angiotensin-aldosterone
that estimated glomerular filtration rate was system activation is high and ACEI/ARB may cause
decreased at 24-month follow-up in patients taking excessive blood pressure lowering. Likewise, careful
eplerenone as opposed to placebo (36). Whereas attention is required when initiating or up-titrating
MRA-associated adverse effects of hyperkalemia and beta-blocker therapy among patients with relative
worsening renal function are well recognized, more bradycardia or compensatory tachycardia, as presence
contemporary evidence supports a relatively sound of the former may increase risk for symptomatic
safety profile for in-hospital use of MRA therapy. bradycardia (at rest or with exertion) while the latter
Most notably, despite use of high doses of 100 mg may be compensatory in the setting of severely
daily, the ATHENA-HF trial found spironolactone to reduced stroke volume.
be well-tolerated among patients hospitalized with Limited data from observational studies and small
HF with no significant change in potassium level or randomized clinical trials suggest that inpatient
renal function, as compared with usual care (17). continuation of foundational therapies (beta-
blockers, ACEI/ARBs, and MRAs) is safe and well-
OPTIMIZATION OF GDMT DURING tolerated in most hemodynamically stable patients.
HOSPITALIZATION FOR HF It is important to recognize that observational studies
assessing changes in medical therapy are subject to
Decisions to initiate, continue, switch, or withdraw significant patient selection and confounding. None-
HFrEF medications in the inpatient setting are com- theless, although unable to definitively prove cau-
plex, often based on multiple factors, and subject to sality, such data clearly identify tolerance of GDMT to
significant variability across providers. However, be (at minimum) a very strong marker of a more
although randomized clinical trial data and safety favorable post-discharge clinical course. Patients
data regarding in-hospital use of GDMT are modest, should be counseled and educated with respect to the
clinical treatment guidelines, hospital performance importance, treatment benefits, and anticipated side
measures, and ongoing quality improvement initia- effect profiles of these therapies during hospitaliza-
tives all strongly emphasize prescription of these tion. Early post-discharge follow-up with close
medications by time of hospital discharge (1,2,37). monitoring of hemodynamics, renal function, elec-
We provide a conceptual framework regarding trolytes, and symptoms in the weeks after initiation
inpatient decision-making to optimize GDMT in HFrEF of these therapies is required, especially in treat-
patients (Central Illustration). After stabilization ment-naïve patients. Therapy withdrawal or need for
during hospitalization for HFrEF, in well-selected dose reduction identifies a particularly at-risk group
treatment-naïve patients who are hemodynamically of patients with progressive HF. If recurrent intoler-
stable (e.g., not requiring inotropes or vasopressors) ance to neurohormonal antagonists is observed, these
and clinically euvolemic (e.g., being transitioned to patients should be evaluated for advanced HF
oral diuretic therapy), guideline-directed medications therapies.
can be safely initiated (38). Moreover, in the presence Pre-discharge switching to sacubitril/valsartan
of close monitoring, multiple guideline medications may be a mechanism to improve overall use of ARNI.
can generally be safely initiated or up-titrated during a Most patients hospitalized for worsening chronic
single hospitalization. For example, in the EPHESUS HFrEF are admitted on either ACEI or ARBs. In
trial, low rates of prior MI (27%) and HF (15%) in the appropriately selected patients who were tolerating
context of high rates of ACEI/ARB (87%) and beta- ACEI/ARB, pre-discharge transition to sacubitril/val-
blocker (75%) at study baseline (3 to 14 days after MI) sartan should be considered. ACEI must be stopped at
suggest many patients were initiated on 1 or both least 36 h before the first dose of sacubitril/valsartan
therapies during the index hospitalization (before and ARNI should not be considered in patients who
randomization), with additional benefits to those have had prior angioedema or hypersensitivity to
further randomized to eplerenone (39). Nonetheless, ACEI/ARB. Depending on the degree of clinical sta-
some important considerations should be noted dur- bility, dose of prior ACEI/ARB, and systemic blood
ing inpatient management of these therapies. Patients pressures, sacubitril/valsartan can be initiated at
10 Bhagat et al. JACC: HEART FAILURE VOL. -, NO. -, 2018
In-Hospital Management of Heart Failure Therapies - 2018:-–-

24 mg/26 mg twice daily or 49 mg/51 mg twice daily. settings allows frequent provider engagement and
Close outpatient follow-up is required for serial patient education regarding these therapies. As such,
monitoring of symptoms, side effects, electrolytes, the inpatient setting affords an important opportu-
renal function, and hemodynamics. The dose of nity to initiate, switch, or continue GDMT that may
sacubitril/valsartan can be doubled every 2 to 4 weeks improve long-term post-discharge prognosis in this
depending on clinical tolerance, but more gradual up- high-risk cohort. There is an enduring need for data to
titration strategies in the early post-discharge period guide these inpatient decisions regarding new initia-
may optimize dosing (40). tion of novel and established therapies.
In the stable outpatient setting, the robust clinical
benefits of GDMT are well established. Hospitaliza- ADDRESS FOR CORRESPONDENCE: Dr. Javed Butler,
tion for HF identifies patients at high risk for pro- Department of Medicine, University of Mississippi,
gressive HF and thus represents an important L650, 2500 North State Street, Jackson, Mis-
opportunity to revisit and optimize GDMT. Significant sissippi 39216. E-mail: [email protected]. Twitter:
time spent in the inpatient and post-acute care @JavedButler1.

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