JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 69, NO.

20, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2017.03.563

THE PRESENT AND FUTURE

REVIEW TOPIC OF THE WEEK

Achieving a Maximally Tolerated

b-Blocker Dose in Heart Failure Patients
Is There Room for Improvement?

Ankeet S. Bhatt, MD, MBA,a Adam D. DeVore, MD, MHS,a,b,c Tracy A. DeWald, PHARMD, MHS,a,d
Karl Swedberg, MD, PHD,e,f Robert J. Mentz, MDa,b,c

ABSTRACT

Heart failure (HF) is associated with significant morbidity and mortality. Although initially thought to be harmful in HF, beta-
adrenergic blockers (b-blockers) have consistently been shown to reduce mortality and HF hospitalization in chronic HF with
reduced ejection fraction. Proposed mechanisms include neurohormonal blockade and heart rate reduction. A new thera-
peutic agent now exists to target further heart rate lowering in patients who have been stable on a “maximally tolerated
b-blocker dose,” but this definition and how to achieve it are incompletely understood. In this review, the authors summarize
published reports on the mechanisms by which b-blockers improve clinical outcomes. The authors describe differences in
doses achieved in landmark clinical trials and those observed in routine clinical practice. They further discuss reasons for
intolerance and the evidence behind using b-blocker dose and heart rate as therapeutic targets. Finally, the authors
offer recommendations for clinicians actively initiating and up-titrating b-blockers that may aid in achieving maximally
tolerated doses. (J Am Coll Cardiol 2017;69:2542–50) © 2017 by the American College of Cardiology Foundation.

B eta-adrenergic blockade has been a mainstay

of therapy in chronic heart failure (HF) with
reduced ejection fraction (EF) for more than
2 decades. Despite once being thought too dangerous
for use in HF due to negative inotropic effects,
b-blocker therapy has consistently been shown to
reduce mortality and HF-related hospitalizations
(1–6). b-blocker therapy is strongly supported across
major consensus recommendation statements in
patients with reduced EF (7–10). Recent guidelines
recommend consideration of adding a new heart
rate–lowering agent, ivabradine, in patients with
stable chronic HF with EF #35% and sinus rhythm
with resting heart rate $70 beats/min on guideline-
directed medical therapy, “including a beta-blocker
at maximally tolerated dose” (11). These guidelines
recommend initiation and up-titration of b-blockers
to “target doses, as tolerated” before consideration
of ivabradine. Unlike b-blockers, ivabradine has
not been shown to confer a reduction in all-cause
mortality, but does reduce HF hospitalization and
HF-related deaths as compared with placebo (12).
In an era with a new therapeutic option for heart
rate reduction, the question of how to achieve a

Listen to this manuscript’s
audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the aDepartment of Medicine, Duke University Medical Center, Durham, North Carolina; bDivision of Cardiology, Duke
University Medical Center, Durham, North Carolina; cDuke Clinical Research Institute, Durham, North Carolina; dDivision of
Pharmacology, Duke University Medical Center, Durham, North Carolina; eSahlgrenska Academy, University of Gothenburg,
Gothenburg, Sweden; and the fNational Heart and Lung Institute, Imperial College London, London, United Kingdom. Dr. Devore
has received research support from the American Heart Association, Amgen, and Novartis; and has served on an advisory board
for Novartis. Dr. Swedberg has received research support from Servier; and has received honoraria from and consulted for Amgen,
AstraZeneca, Novartis, and Servier. Dr. Mentz has received research support from the National Institutes of Health, Amgen,
AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Medtronic, Novartis, Otsuka, and ResMed; has received honoraria
from HeartWare, Janssen, Luitpold Pharmaceuticals, Novartis, ResMed, and Thoratec/St. Jude; and has served on an advisory
board for Luitpold Pharmaceuticals and Boehringer Ingelheim. All other authors have reported that they have no relationships
relevant to the contents of this paper to disclose.

Manuscript received January 26, 2017; revised manuscript received March 7, 2017, accepted March 10, 2017.
JACC VOL. 69, NO. 20, 2017
MAY 23, 2017:2542–50
maximally tolerated b-blocker dose is exceedingly
relevant for clinicians considering active titration of
b-blockers and/or initiation of ivabradine. Despite
decades of experience with the use of b -blockers
and randomized clinical trials (RCTs) enrolling more
than 10,000 patients, optimally defining and
achieving a maximally tolerated b-blocker dose re-
mains a clinical challenge.
In this review, we aim to: 1) provide background on
proposed b-blocker mechanisms of benefit; 2) describe
the current b-blocker doses achieved in practice and
compare them with those achieved in landmark
b-blocker trials; 3) summarize the evidence supporting
b-blocker dose versus heart rate reduction as thera-
peutic targets; and 4) offer an algorithm for clinicians
regarding up-titration of b-blocker therapy.
OVERVIEW OF DATA SOURCES
To identify relevant articles, we searched MEDLINE
(via PubMed) for articles from January 1996 to
September 2014. We used Medical Subject Headings
(MeSH) and key words, focusing on the most relevant
terms. The following search terms were used: (beta
blockers[tiab] OR “adrenergic beta-antagonists”
[pharmacological action] AND “adrenergic beta-
antagonists”[Mesh]) AND (“HF”[Mesh] OR “HF”[tiab]
OR congestive HF) AND (dose OR dosing OR heart rate
OR “dose-response relationship, drug”[Mesh]). We
manually searched for pertinent reviews and studies
to find additional relevant citations missed in our
original search. We imported all citations into an
EndNote X7 (Clarivate Analytics, Philadelphia, Penn-
sylvania) database.
MECHANISMS OF ACTION AND
PATHOPHYSIOLOGY OF HF
HF with reduced EF is a progressive, heterogeneous
disorder with a complex pathophysiology. Existing
evidence on the pathophysiology of HF has been
reviewed previously (13). In brief, the HF phenotype
may, in part, involve interaction between myo-
cardial injury and left ventricular dysfunction, and
compensatory hemodynamic and neurohormonal
mechanisms aimed at maintaining cardiac output
(13–15). Compensatory mechanisms include activa-
tion of the sympathetic nervous system (SNS),
renin-angiotensin-aldosterone system (RAAS), and
vasodilatory molecules (e.g., natriuretic peptides,
prostaglandins, nitric oxide) (14,15). Chronic activa-
tion of adrenergic signaling can lead to adverse bio-
logical effects, accelerated cardiovascular pathology,
and disease progression (14,16). Sympathetic
Bhatt et al. 2543
b-Blockers in Chronic HF
activation may be central to the progression ABBREVIATIONS
of HF. Current guideline-directed medical AND ACRONYMS
therapy targets these compensatory path-
ARNI = angiotensin receptor–
ways and aims to interfere with the neuro- neprilysin inhibitor
endocrine consequences that develop from
COPD = chronic obstructive
their chronic activation (11). Interference pulmonary disease
with these pathways is postulated as one EF = ejection fraction
mechanism of the observed benefits of HF = heart failure
b-blockers (16). RCT = randomized clinical trial
In general, the pharmacological action of
SNS = sympathetic nervous
b-blockers is to attenuate SNS activity. system
Possible mechanisms by which b-blockers
improve outcomes include antiarrhythmic effects,
slowing detrimental remodeling, decreased myocyte
death from catecholamine-induced necrosis, and/or
prevention of other detrimental effects of chronic
SNS activation, such as increased heart rate (16,17). If
general SNS blockade is the key mechanism by which
b-blockers provide clinical benefit in HF, it would be
expected that a class effect would emerge. However,
although selected b -blockers have established a clear
mortality benefit in HF with reduced EF (1–6), others
demonstrated equivocal results (18,19). Principle
characteristics of major b-blocker clinical trials are
listed in Table 1.
Notable differences in b-blockers clinically used in
HF include differences in beta-1 receptor selectivity
and/or affinity, presence of alpha-1 receptor antago-
nism, antioxidant properties, and vasodilating effects
(Table 2). Genetic variants associated with variability
in b-blocker response include polymorphisms in beta-
adrenergic receptors, alpha-adrenergic receptors,
cytochrome P450 2C6, and norepinephrine trans-
porter (NET) (20,21).
Individual variations in b -blocker pharmacology
combined with genetic variance may assist in under-
standing the variable effectiveness of different
b-blockers, and may ultimately enhance our under-
standing of both dose-related clinical benefit and
adverse effects.
WHAT IS A MAXIMALLY TOLERATED DOSE?
Across major b-blocker trials in chronic HF with
reduced EF, doses achieved in trial participants
generally approached target doses. In the CIBIS
(Cardiac Insufficiency Bisoprolol Study) II, bisoprolol
dosing was progressively increased from a 1.25-mg
starting dose to a 10.00-mg daily target dose (1).
Target dose was achieved in 42% of patients, with
>50% of patients receiving at least 75% of the target
dose during the maintenance phase. In the USCS (U.S.
Carvedilol HF Study), study participants were initi-
ated on carvedilol 6.25 mg or 12.5 mg twice daily (2).
2544 Bhatt et al. JACC VOL. 69, NO. 20, 2017

b-Blockers in Chronic HF MAY 23, 2017:2542–50

T A B L E 1 Characteristics of Major b -Blocker Trials in HF

Study

USCS MERIT-HF CIBIS-II COPERNICUS BEST SENIORS

(N ¼ 1,094) (N ¼ 3,991) (N ¼ 2,647) (N ¼ 2,289) (N ¼ 2,708) (N ¼ 2,128)

b-blocker Carvedilol Metoprolol Succinate Bisoprolol Carvedilol Bucindolol Nebivolol

Mean age, yrs 58 64 61 64 60 76
Starting dose, mg 6.25 b.i.d. 12.5 q.d. 1.25 q.d. 3.125 b.i.d. 3.0 b.i.d. 1.25 q.d.
Target dose, mg 25–50 b.i.d. 200 q.d. 10 q.d. 25 b.i.d. 50–100 b.i.d. 10 q.d.
Mean daily dose achieved, mg 45.0 159.0 7.5 37.0 152.0 7.7
Baseline heart rate, beats/min* 84
12 83
10 80
15 83
13 82
13 79
14
Heart rate reduction, beats/min 12.6 14.0 9.8 NR 9.4 10.3
Baseline SBP, mm Hg* 116
17 130
17 129
19 123
19 117
18 139
20
Titration period, weeks 2–10 1–8 1–15 1–8 1–9 1–16
% Relative effect on all-cause mortality Y 65 Y 34 Y 34 Y 35 Y 10 Y 12
p value <0.001 <0.001 <0.001 <0.001 0.13 0.21

*Values are mean
SD.

Y ¼ reduced; BEST ¼ Beta-Blocker Evaluation of Survival Trial; b.i.d. ¼ twice a day; CIBIS-II ¼ Cardiac Insufficiency Bisoprolol Study II; COPERNICUS ¼ Carvedilol Prospective
Randomized Cumulative Survival; HF ¼ heart failure; MERIT-HF ¼ Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure; q.d. ¼ daily; SBP ¼ systolic
blood pressure; SENIORS ¼ Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure; USCS ¼ U.S. Carvedilol HF Study.

Mean total daily dose was 45
27 mg of carvedilol,
with 80% of patients receiving the target daily dose of
50 mg. An initial run-in period may have excluded
patients demonstrating early intolerance. Similar re-
sults were seen in other major carvedilol trials (3–5).
In MERIT-HF (Metoprolol CR/XL Randomized Inter-
vention Trial in Congestive Heart Failure), dose
titration started at 12.5 mg or 25 mg daily of meto-
prolol succinate, with titration over 8 weeks (6). The
mean daily dose of the study drug was 159 mg daily,
with 87% of patients receiving >100 mg daily and
64% receiving the target dose of 200 mg daily.
Despite achieving high rates of target doses in
early, landmark b-blocker clinical trials, the rates of
target dose achievement in clinical practice and in
subsequent trials are lower (Figure 1). Analysis of the
OPTIMIZE-HF (Organized Program to Initiate Life-
saving Treatment in Hospitalized HF Patients) regis-
try found that the mean b-blocker daily dose
was <50% of target doses, with greater than two-
thirds of patients receiving no up-titration 90 days
post-hospitalization (22). Less than 10% of patients
achieved target doses of b-blocker at discharge (23).
In the COHERE (Coreg [carvedilol] Heart Failure
Registry), 41% of patients reached 25 mg of carvedilol
twice daily, although more than one-half of these
patients were taking <25 mg twice daily at the end of
titration (24). Contemporary clinical trial data suggest
a similar trend, with #50%, #30%, and #25% of pa-
tients at target b-blocker doses in, respectively, the
HF-ACTION (Heart Failure: A Controlled Trial Inves-
tigating Outcomes of Exercise Training) (25), SHIFT
(Systolic Heart failure treatment with the If inhibitor
ivabradine Trial) (12), and CIBIS-ELD (Cardiac Insuf-
ficiency Bisoprolol Study in Elderly) trials (26). Het-
erogeneous studies have shown the routine failure to
achieve target doses in the usual care setting.
REASONS FOR DELAYED INITIATION/
UP-TITRATION OR DISCONTINUATION/
DOWN-TITRATION

T A B L E 2 Pharmacological Properties of b -Blockers Trialed in HF

Reasons behind the discrepancy in dosages achieved
b1 b2 a1 Nitric Oxide in landmark b-blocker trials and later clinical trials or
Generation b-Blocker Antagonism Antagonism Antagonism Production Lipophilic
registries are multifactorial. “Intolerance” may
First Propranolol Yes Yes No No Yes
involve the selective nature of trial enrollment as well
Timolol Yes Yes No No Mild
as provider aversion, therapeutic inertia, real or
Second Metoprolol Yes No No No Yes
Succinate perceived undesired side effects, and clinically sig-
Bisoprolol Yes No No No Mild nificant adverse effects. These factors may result in
Third Carvedilol Yes Yes Yes Yes Yes reluctance to initiate b -blocker therapy, slowed or
Bucindolol Yes Yes No Mild Yes early-terminated up-titration, and down-titration or
Nebivolol Yes No No Yes Yes
permanent discontinuation.
HF ¼ heart failure.
Analyses have shown lower adherence to
evidence-based HF therapies in women and older
JACC VOL. 69, NO. 20, 2017 Bhatt et al. 2545
MAY 23, 2017:2542–50 b-Blockers in Chronic HF

F I G U R E 1 Percentage of Target b -Blocker Dose Achieved in Major Clinical Trials and Registries

USCS (1996)

COMET (2003)

MERIT-HF (1999)
HF-ACTION (2009)*
COPERNICUS (2001)
100%
CIBIS-II (1999)

90%

COHERE (2007)
Mean Daily Dose as Percent of Target Dose (%)

80%
SHIFT (2010)

OPTIMIZE-HF (2008)
CIBIS-ELD (2011)

OPTIMIZE-HF (2008)
70%

CIBIS-ELD (2011)
SHIFT (2010)
60%

SHIFT (2010)
50%

40%

30%

20%

10%

0%
Bisoprolol Carvedilol Metoprolol Succinate
Beta-Blocker

Landmark B-Blocker Trials Registries/Newer Trials

This figure shows the major b-blocker dose achieved in landmark b-blocker clinical trials, as compared to later clinical trials/registry data. Clinical trials
included are those in which the mean daily dose of b-blocker was reported; the authors acknowledge that other principal clinical trials/registries exist,
although those in which the b-blocker dose was unavailable or those completed before the publication of landmark b-blocker trials were excluded.
Landmark b-blocker trials generally had higher mean b-blocker doses when compared with later trial/registry data. Note: OPTIMIZE-HF doses reflect
admission doses. Discharge doses were generally lower than admission doses. *The HF-ACTION trial reports data for all b-blockers in aggregate as
carvedilol equivalents. CIBIS-II ¼ Cardiac Insufficiency Bisoprolol Study II; CIBIS-ELD ¼ Cardiac Insufficiency Bisoprolol Study in Elderly; COHERE ¼ Coreg
(carvedilol) Heart Failure Registry; COMET ¼ Carvedilol or Metoprolol European Trial; COPERNICUS ¼ Carvedilol Prospective Randomized Cumulative
Survival; HF-ACTION ¼ Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training; MERIT-HF ¼ Metoprolol CR/XL Randomized
Intervention Trial in Congestive Heart Failure; OPTIMIZE-HF ¼ Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart
Failure; SHIFT ¼ Systolic Heart Failure Treatment with the If inhibitor Ivabradine Trial; USCS ¼ U.S. Carvedilol HF Study.

adults (27,28). Perceptions of risks and the burden of the post-myocardial infarction population suggests a
multiple medications may lead to provider aversion. discrepancy between prescribing and fill rates. In a
Underuse in older adults is seen even after adjust- study of 846 myocardial infarction patients pre-
ment for comorbidities, EF, and other relevant in- scribed b-blockers, 85% of survivors had filled a pre-
dicators of risk (29). Providers may also be reluctant scription by 30 days post-discharge, but 63% and 61%
to prescribe b-blocker therapy in chronic obstructive were users at 180 and 365 days, respectively (31).
pulmonary disease (COPD), for fear of worsening Trial population selection may also partially explain
pulmonary status. In a registry of more than 20,000 the observed discrepancy. Landmark b-blocker trials
HF patients, b -blockers were prescribed to 66% of generally enrolled a younger cohort (mean age 60 to 65
patients at hospital discharge with COPD and at years) compared with subsequent analyses (mean age
higher rates (75%) in patients without COPD (30). Of 70 to 75 years) (26). Earlier trial populations also
note, this survey was taken before widespread generally had a higher mean resting heart rate, repre-
adoption of b-blockers, and more current evidence is senting greater room for up-titration without inducing
needed. These data suggest that HF patients at the clinically significant and dose-limiting bradycardia.
highest cardiac risk may consistently receive lower Reasons for intolerability have varied greatly
doses (28). In addition, fill patterns in HF have not across prior analyses, but include: 1) worsening HF
been evaluated on a large scale, but experience from symptoms; 2) bradycardia; 3) hypotension and/or
2546 Bhatt et al. JACC VOL. 69, NO. 20, 2017

b-Blockers in Chronic HF MAY 23, 2017:2542–50

orthostasis; and 4) fatigue. Dizziness and bradycardia converting enzyme inhibitor/angiotensin receptor
are the most commonly cited. In 1 small study of blocker therapy to ARNI may have on the maximally
87 patients with chronic HF, 40% of patients could not tolerated b-blocker dose.
tolerate targeted doses of b -blockers using a titration
A DOSE RELATIONSHIP OR A
scheme similar to that used in the COPERNICUS
HEART RATE REDUCTION RELATIONSHIP?
(Carvedilol Prospective Randomized Cumulative
Survival) trial. Dizziness was the most common
EVIDENCE FOR A DOSE RELATIONSHIP. Conflicting evi-
reason for discontinuation (41%), with bradycardia/
dence exists on whether clinicians should target b-blocker
arrhythmia second (16%) (32).
dose, heart rate reduction, or both, in chronic HF. Ana-
Tolerability may be affected by the specific
lyses examining b-blocker dose and clinical outcomes are
b-blocker chosen. In the CIBIS-ELD trial, the principal
listed in Table 3. The MOCHA (Multicenter Oral Carvedilol
reason for restricted titration was an undesirable
HF Assessment) study was the first trial of its kind to
reduction in heart rate #60 beats/min, seen at higher
demonstrate an overall positive dose-response of carve-
rates in bisoprolol versus carvedilol (26). The same
dilol on left ventricular EF and mortality rates (37). A
study found higher rates of reductions in spirometry
dose-response relationship was found exclusively in
parameters in patients receiving carvedilol. Car-
nonischemic cardiomyopathy. Although there was an
dioselective b-blockers may be preferable in patients
overall dose response, crude mortality rates were actually
with reactive airway disease of chronic obstruction
higher in the 12.5-mg twice-daily group as compared with
(33), although data are conflicting (30).
the 6.25-mg twice-daily group. Large reductions in mor-
Intolerance is influenced by implementation prac-
tality rates were only observed when the dose
tices. Patients who had specifically trained nurses
reached $25 mg twice daily. Low event rates and a small
actively managing up-titration reached higher doses
sample size limit the generalizability of these conclusions.
with lower intolerance (34). This strategy simulated
Recent evidence from the chronic HF trial HF-ACTION
the controlled up-titration environments of landmark
(Heart Failure: A Controlled Trial Investigating Out-
b-blocker trials. Similar success rates were not seen
comes of Exercise Training) showed a dose response
when patients were simply sent clinical reminders
with respect to all-cause death or hospitalization, but not
advocating b -blocker use (34). Furthermore, intoler-
cardiovascular-specific endpoints (25). The dose-
ance may not be a class effect. In a retrospective
response relationship was seen until 50 mg of carvedi-
analysis by Butler et al. (35), 80% of patients intol-
lol daily equivalents, after which increasing dose no
erant to one b -blocker were successfully treated
longer correlated with improved outcomes. Of note,
with another. In-class switching resulted in a final
there was no b-blocker randomization in this clinical
b-blocker tolerance rate of 90%.
trial, placing the observed results at risk for bias, con-
Predictors for intolerability vary across trials. Large
founding, and statistical chance. A follow-up analysis
retrospective data suggest higher serum creatinine
showed that although higher b-blocker dose and lower
and more severe chronic HF (lower EF, higher N-
heart rate were both associated with lower CV mortality
terminal pro–B-type natriuretic peptide) may predict
in unadjusted analysis, only b-blocker dose was associ-
intolerance (29,34). No specific predictors emerged
ated with lower all-cause death or hospitalization after
after multivariate analysis in these studies. In
multivariate adjustment (38). The effect of b-blocker
another small prospective analysis, serum creatinine
dose on outcomes was not modified by heart rate.
was the only significant factor predicting b-blocker
Similar results were seen with bisoprolol (39). A CIBIS II
intolerance (32).
trial analysis found the effect of permanent treatment
The development of new therapeutic targets,
withdrawal of bisoprolol on outcomes may also be dose-
particularly the angiotensin receptor–neprilysin
dependent. Higher mortality rates were seen after
inhibitor (ARNI) sacubitril/valsartan, may also affect
withdrawal in the high-dose group, despite patients
the ability to successfully up-titrate b-blockers. The
being younger and with fewer comorbidities than
use of ARNI resulted in a 3.2
0.4 mm Hg reduction in
those on lower bisoprolol doses (40).
mean systolic blood pressure as compared with ena-
Overall, there is emerging evidence for a relation-
lapril in the PARADIGM-HF (Prospective Comparison
ship between b-blocker dose and clinical outcomes in
of ARNI With ACEI to Determine Impact on Global
major clinical trials. The effect of dose on outcomes is
Mortality and Morbidity in Heart Failure) clinical trial
not modified by heart rate in these analyses.
(36). The mean daily dose of b -blockers at follow-up in
the treatment versus active comparator arms has not EVIDENCE FOR A HEART RATE REDUCTION
been published; therefore, it is currently difficult to RELATIONSHIP. Epidemiological and clinical studies
quantify the impact that switching from angiotensin- suggest an association between high resting heart
JACC VOL. 69, NO. 20, 2017 Bhatt et al. 2547
MAY 23, 2017:2542–50 b-Blockers in Chronic HF

T A B L E 3 Major Analyses of b -Blocker Dose and Outcomes

Outcomes

Study, First Author, Dose Studied AC Death or CV Death or

Year (Ref. #) b-Blocker (mg/Day) AC Death AC Hosp AC Hosp CV Death CV Hosp

MOCHA, Bristow Carvedilol Low: 12.5, Low: RR: 0.36; NA NA NA NA

et al., 1996 (37) moderate: 25, 95% CI: 0.13–0.998
high: 50 vs.
placebo
Moderate: RR: 0.42;
95% CI: 0.16–1.10
High: RR: 0.07; 95% CI:
0.01–0.51
p < 0.001 for linear trend
HF-ACTION, Fiuzat Varied, reported 0–200 HR: 0.97; 95% CI: NA HR: 0.96; 95% CI: NA NA
et al., 2012 (25) as “carvedilol 0.92-1.03, for each 0.93–0.99 for
equivalents” 10-mg increase in each 10-mg
b-blocker dose increase in
b-blocker dose
HF-ACTION, Fiuzat Varied, reported High: $25 vs. HR: 0.94; NA HR: 0.87; HR: 0.93; HR: 0.93;
et al., 2016 (38) as “carvedilol low: <25 95% CI: 95% CI: 95% CI: 95% CI:
equivalents” 0.75–1.17 0.77–0.99 0.71–1.23 0.81–1.06
CIBIS II, Simon et al., Bisoprolol Moderate: 5–7.5 and Moderate: RH 0.49; Moderate: RH 0.62; NA Moderate: RH: 0.44; NA
2003 (40) high: 10 vs. 95% CI: 0.32–0.75 95% CI: 0.48–0.79 95% CI: 0.27–0.71
low: 1.25–3.75 High: RH: 0.30; High: RH: 0.38; High: RH: 0.26;
95% CI: 0.19–0.46 95% CI: 0.30–0.48 95% CI: 0.16–0.43

AC ¼ all-cause; CI ¼ confidence interval; CIBIS-II ¼ Cardiac Insufficiency Bisoprolol Study II; CV ¼ cardiovascular; HF-ACTION ¼ Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training;
Hosp ¼ hospitalization; HR ¼ hazard ratio; MOCHA ¼ Multicenter Oral Carvedilol HF Assessment; NA ¼ not assessed; RH ¼ relative hazard; RR ¼ relative risk.

rate and increased risk of cardiovascular events and
hospitalization (12,41–44). Secondary analyses sug-
gest the magnitude of heart rate reduction is an
important indicator of effect on left ventricular
function and mortality (39,45). However, other
studies have not confirmed this relationship (46,47).
A meta-analysis of 23 RCTs showed an 18% reduction
in death for every heart rate reduction of 5 beats/min
(48). No relationship between b-blocker dose and all-
cause mortality was observed. Another analysis of
654 ambulatory HF patients found b -blocker use
and heart rate both predicted mortality, although
b-blocker dose did not (49). Interestingly, a mortality
rate nadir was seen in the group with heart rates
between 58 and 64 beats/min, with a trend toward
harm when the heart rate was reduced significantly
lower. None of these analyses included patients with
HF device therapies, which is particularly relevant
because pacing at lower rates may have clinical
advantages in HF (as long as consistent right ventricle
pacing is avoided), although this has not been vali-
dated in large trials (50).
A REVISED MODEL FOR INITIATION AND
UP-TITRATION
In accordance with guideline recommendations, in
most cases, b-blockers should be up-titrated to reach
maximally tolerated doses whenever possible. There
are specific specialized populations, including some
patients with Stage D HF, where uncertainty still
exists regarding the role of b-blockers and the desir-
ability and/or efficacy of up-titration; despite this, the
overall evidence suggests that patients who tolerate
any dose of a b-blocker are likely to receive overall
benefit as compared with nonuse.
Achieving a maximally tolerated dose will require
aggressive up-titration in the appropriate clinical
setting with accompanying strategies to overcome
barriers to up-titration. It will further require a
balancing of the known benefits of b-blockers with
unintended consequences, which include the need to
reduce doses of other vasoactive peptides and the
development of unwanted or intolerable adverse ef-
fects. The European Society of Cardiology provides
guidelines for the initiation and up-titration of
b-blockers in HF (10), suggesting low initial doses
with dose doubling no earlier than every 2 weeks.
These guidelines also suggest strategies for intoler-
ance, such as decreasing the diuretic agent dose in
symptomatic hypotension or reviewing the need for
other atrioventricular nodal blockers in bradycardia.
On the basis of existing published reports, with the
need for further validation, additional strategies
may aid clinicians in reaching target doses. A clinical
algorithm for achieving a maximally tolerated
b-blocker dose is presented in the Central Illustration.
b-Blocker selection may be an important initial
consideration. Patients with reactive airway disease
may benefit from the use of cardioselective b-blockers.
2548 Bhatt et al. JACC VOL. 69, NO. 20, 2017

b-Blockers in Chronic HF MAY 23, 2017:2542–50

C E NT R AL IL L U STR AT IO N Clinical Algorithm for Up-Titration of b-Blockers

Patient with HF and left ventricular ejection fraction (LVEF) < 40%

Does patient have contradictions to β-blockers?

(Cardiogenic shock, symptomatic bradycardia, 2nd degree/3rd degree heart block)

N Y
Regularly
Initiate and uptitrate β-blocker assess
(Double dose no more frequently than every 2 weeks; use specialized nurse facilitators) patient
eligibility

Metoprolol XL Carvedilol Bisoprolol

β-blocker therapy
Initial dose: 12.5–25 mg daily Initial: 6.25–12.5 mg twice daily Initial: 1.25 mg daily not appropriate
Target dose: 200 mg daily Target: 25 mg twice daily Target: 10 mg daily until conditions
no longer persist

Is patient intolerant of increased dose?

(Worsening HF, bradycardia, hypotension, fatigue)

N Y Regularly
assess
Achieve a maximally tolerated dose Strategies to increase tolerance: patient
tolerance
Decrease diuretic dose if volume depleted
Does patient have LVEF ≤ 35%,
sinus rhythm and heart rate ≥ 70 bpm? In-class switching

Y Minimize other AVN blockers

Consider initiation of ivabradine Reduce calcium channel blocker dose

Bhatt, A.S. et al. J Am Coll Cardiol. 2017;69(20):2542–50.

This figure is a guide for clinicians considering initiation and/or up-titration of b-blockers. It is based on current American College of Cardiology/American Heart
Association and European Society of Cardiology guidelines, and offers strategies for overcoming known barriers to up-titration, including reduction of other agents
(diuretic agents, AVN-blockers, and consideration of in-class switching). The figure also shows an algorithm for when consideration of ivabradine may be appropriate.
ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; AVN ¼ atrioventricular nodal; BB ¼ beta-blocker; b.i.d. ¼ twice daily;
bpm ¼ beats per minute; CCB ¼ calcium-channel blocker; HF ¼ heart failure; LVEF ¼ left ventricular ejection fraction; QD ¼ daily.

Consequently, patients at risk for dose-limiting When in-class switching occurred, initial halving of
bradycardia may benefit from agents other than the new b -blocker dose led to lower rates of side
bisoprolol. HF patients with comorbid peripheral effects (51). Precision medicine initiatives may
vascular disease or Raynaud disease may benefit from ultimately allow for more personalized b-blocker
carvedilol, given its positive effects on vascular tone. choice on the basis of individual genetic variations
In cases of intolerance refractory to dose reduc- that may predict superior responses.
tion, efforts should be made to switch to another Active up-titration should be done under the su-
evidence-based b -blocker, given the discussed pervision of a nurse facilitator or clinical provider. A
improvement in adherence rates with in-class RCT of 169 patients found that nurse facilitators
switching (35). Other crossover studies, including a allowed for maintenance of b -blocker therapy in 67% of
secondary analysis from COMET (Carvedilol or patients, far higher than in the group receiving pro-
Metoprolol European Trial), showed similar findings. vider education and computerized reminders and/or
JACC VOL. 69, NO. 20, 2017 Bhatt et al. 2549
MAY 23, 2017:2542–50 b-Blockers in Chronic HF

patient letters (34). Similar results were seen in a Eu-
ropean study group using a clinic staffed by specialized
nurses and pharmacists, increasing the proportion of
patients on $50% of target b-blocker dose from 18% to
57% over a median follow-up of 112 days (52). Under-
standing that cost considerations may limit the feasi-
bility of this intervention across all HF patients,
specialized facilitators should be considered in high-
risk HF populations wherever possible, as these
groups tend to have lower b -blocker utilization rates.
Further investigation should
mentation models allowing for shared decision-
making between providers and patients and/or
families. These models may have favorable cost-
effectiveness profiles and allow for more rapid up-
titration than can be achieved by physicians alone.
Self-monitoring and self-titration schemes, including
telemonitoring, have been effective and safe in other
chronic cardiovascular diseases, such as hypertension
and diabetes (53–55). Such strategies should be eval-
uated in chronic HF and may be particularly useful in
patients with transportation barriers.
CONCLUSIONS
clinical aversion, differences in the enrollment and
titration strategies, and dose-limiting adverse ef-
fects. Defining a maximally tolerated b -blocker dose
continues to remain a challenge for clinicians. The
data we have presented seek to summarize the
complex interactions between heart rate, b -blocker
dose, and clinical outcomes. Our review offers stra-
tegies for achieving a maximally tolerated b -blocker
dose and suggestions for new implementation ap-
proaches that have been successful in other chronic
evaluate imple- diseases.
The development of new pharmacological targets
for patients with HF and high resting heart rate
has increased the relevance of this topic to clinicians
and researchers. It is particularly relevant to those
considering up-titration of b-blockers and/or the
proper time to initiate ivabradine. Implementing
high-quality HF care requires aggressive medication
titration and optimization of all interactions with
the medical system. Ultimately, a maximally toler-
ated b-blocker dose will be determined through a
longitudinal patient-physician interaction. In this
case, there is still room for doctoring.

Dose differences observed in earlier landmark ADDRESS FOR CORRESPONDENCE: Dr. Robert J.
b-blocker RCTs and newer clinical trials and registry Mentz, Duke Clinical Research Institute, PO Box
data are significant. Our review finds that the 17969, Durham, North Carolina 27715. E-mail: robert.
observed discrepancy is likely a combination of mentz@duke.edu.

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KEY WORDS beta-antagonists, chronic
heart failure, dosing, heart rate