European Journal of Internal Medicine 88 (2021) 9–14

Contents lists available at ScienceDirect

European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Review article

The use of β-blockers in patients with heart failure and comorbidities:

Doubts, certainties and unsolved issues
Stefania Paolillo a, b, *, Simona Dell’Aversana a, Immacolata Esposito a, Alessandra Poccia c,
Pasquale Perrone Filardi a, b
a
Department of Advanced Biomedical Sciences, Federico II University of Naples, Italy
b
Mediterranea Cardiocentro, Naples, Italy
c
SDN IRCCS, Naples, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: β-blockers represent a mainstay in the pharmacological approach to patients affected by heart failure with
Heart failure reduced ejection fraction (HFrEF). However, underuse of this class of drugs is still reported, especially in the
β-blocker presence of cardiovascular and non-cardiovascular comorbidities, even if they are not contraindications for
Prognosis
prescription of a β-blocker. The prognostic benefit of β-blockers is relevant in the presence of comorbidities, and
Comorbidities
COPD
achievement of the maximum tolerated dose is an important goal to increase their favorable prognostic role. The
Diabetes aim of the present review is to analyze the available evidence on the use of β-blockers in HFrEF patients with the
Atrial fibrillation most common comorbidities. In particular, we will discuss the role and most appropriate beta-blocker in patients
Erectile dysfunction with pulmonary disease (bisoprolol, metoprolol, nebivolol), diabetes (carvedilol and nebivolol), atrial fibrillation
Peripheral arterial disease (all indicated for rate control, with metoprolol as the first choice followed by bisoprolol, nebivolol, and carve­
dilol), erectile dysfunction (bisoprolol and nebivolol), peripheral arterial disease (nebivolol), and other condi­
tions, in order to clarify the correct use of this class of drugs in the clinical practice.

1. Introduction present with relevant comorbidities, due to a potential negative effect of

these drugs on symptoms, quality of life, and progression of the co­
The use of β-blockers is a mainstay in the pharmacological treatment morbid condition. CV and non-CV comorbidities are highly prevalent in
of patients affected by chronic heart failure (HF) with reduced ejection HF patients and significantly impact disease progression and long-term
fraction (HFrEF) [1]. Four β-blockers are indicated in this setting, car­ prognosis. A recent prospective cohort study [9] reported that in HFrEF
vedilol, bisoprolol, metoprolol, and nebivolol, which differ in their pe­ patients with multiple comorbidities higher doses of β-adrenoceptor
ripheral vascular effects and selectivity for adrenergic receptors, with antagonist were associated with lower rates of all-cause mortality,
being carvedilol a non-selective drug and the remaining three β1-se­ progressive HF, and sudden death (Fig. 1). Thus, optimized pharmaco­
lective agents [1] (Table 1). Randomized clinical trials [2-7] have re­ logical HF treatment is of crucial importance in these patients.
ported a favorable prognostic impact of treatment with β-blockers in The aim of this review is to summarize the current evidence on the
HFrEF, in terms of overall mortality, cardiovascular (CV) mortality, and use of β-blockers in HFrEF patients with specific CV and non-CV
HF hospitalization (HHF), and the most recent European guidelines [1] comorbidities in order to clarify the currently suggested use of this
recommend their use as first-line therapy in patients with reduced sys­ class of drugs in the clinical practice and, when possible, the choice of a
tolic function. Similarly, real-world data have confirmed the positive specific β-blocker according to clinical criteria.
prognostic impact that β-blockers have on treatment of HFrEF, with no
prognostic differences according to selectivity, but with a relevant
prognostic role of achieving the maximum tolerated dose [8]. Some
concerns still exist on the use of β-blockers in HF patients who also

* Corresponding author at: Department of Advanced Biomedical Sciences, Federico II University of Naples, Via Pansini 5 - 80131 Naples, Italy.
E-mail addresses: [email protected] (S. Paolillo), [email protected] (S. Dell’Aversana), [email protected] (I. Esposito),
[email protected] (A. Poccia), [email protected] (P. Perrone Filardi).

https://doi.org/10.1016/j.ejim.2021.03.035
Received 21 December 2020; Received in revised form 12 March 2021; Accepted 15 March 2021
Available online 30 April 2021
0953-6205/© 2021 The Authors. Published by Elsevier B.V. on behalf of European Federation of Internal Medicine. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
S. Paolillo et al. European Journal of Internal Medicine 88 (2021) 9–14

Table 1 Table 2
β-blockers and doses recommended for treatment of HFrEF. Contraindications and cautions for the use of β-blockers. Modified from [1].
AR activity Initial dose (mg/day) Target dose (mg/day) Contraindications
• (True severe) Asthma (COPD is not a contraindication – non-severe asthma is a
Bisoprolol β1-selective 1.25 mg 10 mg
relative contraindication and, in this case, bisoprolol, metoprolol or nebivolol need
Carvedilol β1-β2-α 6.25 mg 50–100 mg
to be preferred)
Metoprolol β1-selective 12.5–25 mg 200 mg
• II-degree or III-degree AV block (in the absence of a permanent pacemaker)
Nebivolol β1-selective 1.25 mg 10 mg
Cautions
AR, adrenergic receptor. • Severe/advanced HF
• Current or recent (<4 weeks) worsening HF, heart block, or heart rate <60 bpm
• Persisting signs of congestion, hypotension (systolic <90 mmHg), raised jugular
1.1. The use of β-blockers in CV and non-CV comorbidities: a practical venous pressure, ascites, peripheral edema (try to relieve congestion and achieve
approach ‘euvolemia’ before starting β-blocker)

COPD, chronic obstructive pulmonary disease; AV, atrio-ventricular; HF, heart

In the following section we provide a practical approach to failure.
β-blockers use and single agents’ choice in specific HF-associated con­
ditions (Table 3). From a general point of view, independently from the
comorbid pattern of the patient, β-blockers maintain their prognostic Table 3
role in HFrEF and their prescription should be always considered, Type of β-blocker recommended for patients with HF and comorbid conditions.
carefully assessing the presence of contraindications and cautions Comorbid condition β-blocker
(Table 2), without, however, being unduly concerned by their use.
COPD bisoprolol, metoprolol, nebivolol
Moreover, as already discussed, β-blockers need to be titrated to the Diabetes carvedilol, nebivolol
maximum tolerated dose to achieve their full prognostic benefits. Thus, Atrial fibrillation metoprolol, bisoprolol, nebivolol, carvedilol (in order of
from a practical point of view, treatment with β-blockers can be initiated preference)
at the recommended starting doses (Table 1), proceeding than with dose Erectile dysfunction bisoprolol, nebivolol
Peripheral arterial nebivolol
titration every two weeks, with particular attention to the occurrence of
disease
bradycardia (<60 bpm) or symptomatic hypotension (systolic blood
pressure <90 mmHg) that may limit further dose increase. For β-blocker dose please refer to Table 1.
COPD: chronic obstructive pulmonary disease.

1.2. β-blockers and respiratory comorbidity of HFrEF patients, mainly in terms of recurrent hospitalizations, due to
both rapid impairment of the hemodynamic balance, as a consequence
Patients affected by HF can present a real respiratory comorbidity of COPD exacerbations, and to undertreatment of HF patients and co­
independent from the baseline CV condition, such as asthma or chronic morbid COPD, primarily in terms of use and titration of β-blockers
obstructive pulmonary disease (COPD), or can manifest impairment of leading to poor disease control [12-14]. The prognostic relevance of the
pulmonary function consequent to myocardial enlargement, dysfunc­ administration of β-blockers is independent of the presence of COPD at
tion, and congestive status. As subsequently described, the presence of baseline, and achievement of the maximum tolerated dose has a sig­
these conditions should not limit the use of β-blockers, except in specific nificant prognostic importance even in this setting [15]. Moreover,
cases, although they can influence the choice a specific agent. β1-selective agents (bisoprolol, metoprolol, and nebivolol) should be
With regards to respiratory comorbidities, COPD is not a contrain­ preferred in COPD patients, since these agents are not responsible for
dication to the use of β-blockers; the only contraindication is severe FEV1 worsening compared to placebo nor for exacerbation of respiratory
asthma [1] (Table 2). COPD is highly prevalent in HFrEF patients, being symptoms, and have no impact on the clinical effects of β-agonists [16,
reported in about 30% of cases and, similarly, the prevalence of HF in 17]. Considering the single agents, COPD patients treated with biso­
COPD patients is about 30% [10]. In this setting, however, an epide­ prolol exhibit higher FEV1 values compared to carvedilol and meto­
miological aspect needs to be considered, since diagnosis of COPD is not prolol (carvedilol 1.85 [95% CI 1.67 to 2.03] l/s; metoprolol 1.94 [95%
always supported by pulmonary function tests, which are available in CI 1.73 to 2.14] l/s; bisoprolol 2.0 [95% CI 1.79 to 2.22] l/s; p <0.001)
only about 30% of HF patients [11] and diagnosis is frequently and the switch from carvedilol to a β1-selective agent leads to significant
patient-reported, physician-reported, or based on anamnestic or thera­ improvement of FEV1 [16] (Fig. 2). Moreover, the prescription of a
peutic data. The presence of COPD negatively influences the prognosis

Fig. 1. Kaplan–Meier plots of all-cause mortality, death due to progressive heart failure, and sudden death stratified by bisoprolol equivalent dose of β-blockers.
Escalating doses of beta-adrenoceptor antagonists are protective against all three outcomes. Reproduced with permission from [9].

10
S. Paolillo et al. European Journal of Internal Medicine 88 (2021) 9–14

impairment in lung diffusion capacity with carvedilol compared to

bisoprolol and nebivolol [23]. These observations are likely related to
the alveolar β2-blockade, which is able to downregulate the active
pumps located on the alveolar surface that are required to pump fluid
out of the alveolar district, thus supporting the hypothesis that
β2-alveolar receptors contribute to alveolar fluid control in humans.
Accordingly, these data support the concept that selective β1-
blockers, in particular bisoprolol as first choice, followed by nebivolol
(no current data is available in this setting for metoprolol), should be
preferred in HFrEF patients with impaired lung diffusion capacity at
baseline, in HFrEF patients prone to congestion, or with frequent
exposure to hypoxia (high altitude, airplanes), and in the presence of
clinical and/or radiological signs of lung fluid accumulation [24].
Fig. 2. Switching between the non-selective beta-blocker carvedilol and β1-
selective blockers results in clear changes in airway function. Forced expiratory 1.3. β-blockers and diabetes mellitus
volume in 1 second (FEV1) in the subgroup of subjects who started the study on
carvedilol (C) and relative differences after the switch to metoprolol and
Diabetes mellitus (DM) is a frequent comorbidity in HFrEF with a
bisoprolol. The last bar on the right shows FEV1 returning to baseline levels on
resumption of carvedilol. *p = 0.02 compared with baseline; §p=ns compared prevalence ranging from 10 to 30% in chronic patients and up to 40% in
with carvedilol at baseline and p = 0.02 compared with bisoprolol. Reproduced hospitalized subjects [25]. A strict bidirectional interaction exists be­
with permission from [16]. tween the two conditions. Patients with DM may develop asymptomatic
myocardial dysfunction or overt HF status more frequently than in the
non-selective agent, such as carvedilol, has been associated with higher general population that is not necessarily related to coronary athero­
rates of HHF over time compared to selective agents, which is related to sclerosis, and HF complicates the management and progression of DM
both exacerbation of COPD symptoms and to lower treatment persis­ over time. In particular, glycemic control over time seems to be the main
tence and compliance vs. selective drugs [18]. A still unsolved issue is predictor of prognosis in these patients [26, 27]. In the last years, some
how to manage the use of β-blockers in case of COPD exacerbation; at concerns have been raised regarding the use of β-blockers in patients
least half of HHF are related to non-CV reasons, and respiratory diseases with DM due to a possible role of these drugs in masking hypoglycemic
contribute to around one-third of them [19]. Only limited data are signs, such as tachycardia, and to a possible direct hypoglycemic effect
available on the optimal use of β-blockers during an acute COPD exac­ of β-blockers. Moreover, a recent observational study [28], together
erbation; a large retrospective study of 35,082 patients with HF, with a post-hoc analysis of the ACCORD study [29], questioned the
ischemic heart disease, or hypertension, hospitalized for an acute COPD long-term prognostic benefit of β-blockers in DM, suggesting increased
exacerbation, showed no correlation between treatment with a β-blocker rates of all-cause death in patients on treatment. These data need further
and in-hospital mortality (OR 0.88, 95% CI 0.71–1.09), 30-day read­ confirmation, even if the prognostic benefit of β-blockers in the context
mission (OR 0.96, 95% CI 0.89–1.03), or need for late mechanical of HFrEF is not challenged since β-blockers are as effective in HF-DM
ventilation (OR 0.98, 95% CI 0.77–1.24) [20]. However, treatment with patients as in the general HF population [30, 31]. Moreover, as re­
non-selective β-blockers, compared to selective agents, was associated ported in the last guidelines of the European Society of Cardiology
with an increased risk of 30-day readmission (OR 1.25, 95% CI (ESC), the treatment benefits strongly support the use of β-blockers in
1.08–1.44). COPD exacerbations should not regularly cause discontin­ patients with HFrEF and DM [1]. The most recent joint guidelines of the
uation of β-blockers [20]. ESC/European Association for the Study of Diabetes (ESC/EASD) [32]
Thus, use of a β-blocker is of prognostic relevance in HF patients with propose that the recommendations for pharmacological treatment of HF
comorbid COPD and should be administered, preferring selective agents, in the general population can be applied to those with HF and comorbid
such as bisoprolol, metoprolol, and nebivolol, starting with low doses, DM. Thus, β-blockers are recommended (class of Recommendation IA)
respectively 1.25 mg od, 12.5–25 mg od, and 1.25 mg od (Table 1), and as first-line therapy for HFrEF to reduce the risk of HHF and death;
aiming to achieve the highest possible dose with close monitoring for similarly, β-blockers are recommended in patients with DM after acute
clinical signs of airway obstruction, and, if needed, instrumental moni­ myocardial infarction and ejection fraction <40% to prevent sudden
toring, especially in complex and elderly patients. cardiac death (class of Recommendation IA) [32]. However, in pre-DM a
Possible impairment of pulmonary function related to the baseline β-blocker/diuretic combination might favor the development of DM
CV condition should also be considered in HF patients: as left ventricular through an effect on insulin sensitivity, and should be avoided for
filling pressure increases, pulmonary congestion and interstitial edema control of hypertension unless required for other reasons [32]. Thus, DM
develop, with a consequent reduction of lung volumes and the occur­ is not a contraindication to β-blockers (Table 2) and β-blockers do not
rence of a spirometry restrictive pattern, together with an impairment of need to be discontinued in patients with DM. In case of uncontrolled
lung diffusing capacity [21]. In decompensated HF, an obstructive-like glycemia, greater attention needs to be given to DM patients being
pattern may develop due to bronchial wall edema [21]. Approxi­ treated with β-blockers, favoring antihyperglycemic agents with a low
mately 90% of pulmonary β-receptors are located in the alveoli and are risk of hypoglycemia. In this context, the recent recommendations on
predominantly of the β2 type (70%). Their stimulation seems to facilitate the use of “new” antidiabetics in DM patients at risk for HF or with an
the removal of alveolar fluid by increasing intracellular sodium trans­ overt HF diagnosis are of utmost importance since these drugs, such as
port. Thus, blockage of these receptors by non-selective β-blockers might SGLT2 inhibitors, have a very low risk of hypoglycemia and will allow
limit the mechanisms of alveolar fluid clearance and impair lung an implementation of use of β-blockers in complex HF-DM patients.
diffusing capacity. Paolillo et al. [22] demonstrated, in 22 healthy males Thus, use of a β-blocker is of prognostic relevance in HF patients with
randomized to treatment with carvedilol or bisoprolol and exposed to comorbid diabetes and should be administered, preferring agents such
rapid saline infusion to over-hydrate the lung and determine interstitial as carvedilol and nebivolol because of their ability to improve insulin
edema, that carvedilol, but not bisoprolol, decreased alveolar-capillary sensitivity, with no negative effects on glycemic control. No specific
membrane diffusion capacity (− 13±7%, p = 0.001) and increased dose recommendations for starting β-blockers exist in the context of DM,
capillary volume (+20±22%, p = 0.016). In HF patients, the same au­ and the currently suggested dose schema for each agent adopted in the
thors reported, in a β-blocker cross-over analysis, that there is greater general HF population can also be applied to HF patients with DM, as
reported by European HF guidelines (1) (Table 1).

11
S. Paolillo et al. European Journal of Internal Medicine 88 (2021) 9–14

1.4. β-blockers and atrial fibrillation multifactorial, and includes atherosclerosis, traumatic injury, hormonal
deficits, medication side effects, and psychogenic influences [41].
Atrial fibrillation (AF) is common in patients affected by HFrEF; data Several pharmacological agents used in HFrEF therapy have been
from the EuroHeart Failure Survey reported that about 20% of patients related to the presence and worsening of ED and, among these,
with HF exhibit AF and that its prevalence reaches 40% in patients with β-blockers have been historically linked to ED. The reasons for this
advanced disease [33, 34]. A bidirectional and complex interaction exits relationship lie in decreased perfusion pressure, especially on effort, due
between these two conditions since HF predisposes to AF, and the to the inotropic and chronotropic negative effects of β-blockers, and in a
presence of AF in HF patients significantly worsens symptoms and possible direct effect on smooth muscle, even if new agents with a vas­
complicates therapeutic management. AF is also related to prognosis of odilating action action action might potentially have a favorable effect
HFrEF; however, it should be considered as a marker of disease severity on ED. Moreover, recent studies have underlined that ED is mostly
rather than an independent prognostic indicator [35]. In the last years, related to the baseline pathological CV condition rather than to phar­
some authors have questioned the use of β-blockers in patients affected macological treatment, which is mostly negligible.
by HFrEF. In 2014, Kotecha et al. performed an individual-patient However, only contrasting data from small studies are available on
meta-analysis of 18,254 patients, of whom 13,946 (76%) were in sinus ED in HFrEF patients. The effect of β-blockers on ED seems to be dose-
rhythm and 3,066 (17%) had AF at baseline [36]. The authors reported dependent and more pronounced with non-selective agents. An anal­
that therapy with a β-blocker was associated with significant reduction ysis of 1007 hypertensive patients on β-blockers [42] showed that ED
in all-cause mortality in patients in sinus rhythm (HR 0.73, 95% CI patients received more active medications and were more frequently
0.67–0.80; p<0.001), but not in patients with AF (HR 0.97, 95% CI treated with carvedilol and less frequently with nebivolol. The evalua­
0.83–1.14; p = 0.73), with a significant p value for interaction according tion of the prevalence and severity of ED considering the individual
to baseline rhythm (p = 0.002). Similar results were obtained for CV β-blocker demonstrated that almost 50% of ED patients treated with
death and hospitalizations, and were confirmed in all subgroups of AF, atenolol, bisoprolol, or nebivolol had mild ED, whereas those treated
considering age, sex, ejection fraction, NYHA class, heart rate, and with carvedilol or metoprolol showed the highest rates of moderate or
baseline medical therapy [36]. These observations are likely related to severe ED [42].
the fact that slower heart rates are not associated with improved survival However, in this setting, patients’ knowledge and prejudice about
in AF [37], even if prospective studies are still not available, and the the side effects of β-blockers should not be underestimated. A study
most recent ESC guidelines for the management of AF refer that the conducted on 96 patients with newly-diagnosed CV disease, not
optimal resting ventricular rate in patients with AF and HF is uncertain, suffering from ED, reported that ED was present in only 1 patient (3.1%)
but a rate of <100–110 bpm is usually recommended [38]. In contrast to in the group without knowledge of ongoing treatment, in 5 patients
the above-mentioned meta-analysis, recent sub-studies of randomized (15.6%) among those who knew that they were receiving a β-blocker,
trials and real-world data reported that β-blockers have a significant and in 10 patients (31.2%) in the group that was informed about the side
prognostic benefit in patients with AF and HF. In particular, a sub-study effects of the drug (p<0.01); sildenafil and placebo were equally effec­
of the AF-CHF trial [39], including 1,376 HF patients, performed a tive in reversing ED [43]. Thus, ED has a substantial psychological
propensity-matched analysis considering treatment or not with component and providing correct information to the patient before
β-blockers and reported that during a median follow-up of 37 months prescription and during follow-up is needed to avoid detrimental con­
there was an association between treatment with β-blockers and lower ditioning about the side effects of β-blockers.
rates of all-cause mortality (HR 0.72, 95% CI 0.54–0.94; p = 0.018), but The use of a β-blocker maintains its prognostic relevance in HF pa­
not hospitalizations (HR 0.88; 95% CI 0.71–1.10; p = 0.223), irre­ tients with comorbid ED and should be administered, preferring agents
spective of the pattern or burden of AF. More recently, a sub-analysis of as bisoprolol and nebivolol and starting at the lowest dose, i.e. 1.25 mg
the MECKI score registry [40] on 958 HFrEF patients with AF described for both agents (Table 1). In symptomatic ED patients, even in presence
that, at 10-year follow-up, patients treated with β-blockers had better of mild ED symptoms, sildenafil can be prescribed, considering a starting
outcomes with no differences between β1-selective drugs (53%) and dose of 50 mg to be taken approximately 1 hour before sexual activity;
β1-β2-blockers (47%), and that survival improved in parallel with starting from effectiveness and toleration, the dose may be increased,
β-blocker dose increase. with caution, to the maximum recommended dose of 100 mg. Consider a
Thus, the question is still open and all patients with HFrEF and AF starting dose of 25 mg in patients >65 years, in patients with severe
should receive guideline-adherent HF therapy. However, prospective renal impairment (creatinine clearance <30 mL/minute), and in pa­
trials are still needed to define the efficacy and prognostic role of long- tients with hepatic impairment (e.g., cirrhosis), because administration
term therapy with β-blockers in HF-AF patients and to determine the of sildenafil in these patients results in higher plasma drug levels.
optimal resting ventricular rate in this setting.
The use of a β-blocker still maintains its importance in HF patients 1.6. β-blockers and peripheral arterial disease
with comorbid AF, and β-blockers represent first-choice drugs to control
heart rate in AF patients with EF <40%. In this context, metoprolol The use of β-blockers in peripheral arterial disease (PAD) is contro­
succinate is the first choice (oral maintenance dose 50–400 mg od), versial due to their impact on vasomotor tone, potentially leading to
followed by bisoprolol (oral maintenance dose 1.25–20 mg od), nebi­ worsening symptoms of intermittent claudication. In 2013, a Cochrane
volol (oral maintenance dose 2.5–10 mg od), and carvedilol (oral intervention review [44] tried to quantify the harmful effects of
maintenance dose 3.125–50 mg bid) [38]. Higher maximum doses of β-blockers in PAD patients in terms of walking and claudication dis­
β-blockers are recommended by AF guidelines for rate control [38] tance; however, the selected trials included only 119 patients and
compared to the maximum doses used in the treatment of HFrEF [1] pooling of trials results was inappropriate since no trials showed a sta­
(Table 1). However, it should be always kept in mind that in HF-AF tistically significant worsening effect of β-blockers on the considered
patients a resting ventricular rate of up to 100-110 bpm might still be outcomes. More recent data from the COPART Registry [45] found that
acceptable [38], and thus such high doses are rarely needed. patients hospitalized for severe PAD and treated with β-blockers at
hospital discharge did not worsen their outcome (overall mortality, CV
1.5. β-blockers and erectile dysfunction mortality or amputation rates) at 1 year compared to patients who were
not treated with β-blockers. In HFrEF, the prognostic benefit of
HF shares several risk factors with erectile dysfunction (ED) and the β-blockers is undisputed and these drugs, as recommended by European
two conditions frequently coexist, with a prevalence of ED in HFrEF of guidelines for PAD [46], are not contraindicated in this setting since
60–90% [41]. The pathophysiological link between HF and ED is they do not alter walking capacity in patients with mild to moderate

12
S. Paolillo et al. European Journal of Internal Medicine 88 (2021) 9–14

PAD. In patients with severe PAD, especially in those with severe limb Acknowledgments
ischemia, due to the lack of trials, β-blockers should be used with caution
with a strict control of worsening of symptoms. With regards to which The development of this publication was financially supported by
β-blocker prefer in PAD patients, the vasodilating, Merck Serono S.p.A., Rome, Italy, an affiliate of Merck KGaA, Darm­
endothelium-dependent, NO-releasing properties of nebivolol might be stadt, Germany through an independent medical writing grant. The
beneficial in this context. The Nebivolol or Metoprolol in Arterial views and opinions described in this publication do not necessarily
Occlusive Disease Trial [47] found that both nebivolol and metoprolol in reflect those of the grantor. Medical writing services were provided by
patients with intermittent claudication and arterial hypertension were Content Ed Net.
well tolerated and similar in terms of improvement in maximal walking
distance during a treatment period of ≈1 year. However, nebivolol References
showed an advantage vs. metoprolol with a significant improvement in
pain-free walking distance [+34% (p <0.003) vs. +17% for metoprolol [1] Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al., M.
(p <0.12)]. Authors/Task Force, and R. Document. ESC Guidelines for the diagnosis and treatment
of acute and chronic heart failure: the Task Force for the diagnosis and treatment of
Thus, use of a β-blocker maintains its prognostic relevance in HF acute and chronic heart failure of the European Society of Cardiology (ESC). Developed
patients with comorbid PAD and should be administered, preferring with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J
nebivolol and starting at the lowest dose (1.25 mg), to be up-titrated as Heart Fail 2016;18(8):891–975. https://doi.org/10.1002/ejhf.592. 2016.
[2] A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency
in the general HF population, with focused attention on intermittent Bisoprolol Study (CIBIS). CIBIS Investigators and Committees. Circulation 1994;90
claudication, especially in patients with advanced disease. (4):1765–73. https://doi.org/10.1161/01.cir.90.4.1765.
[3] Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM,
Shusterman NH. The effect of carvedilol on morbidity and mortality in patients
1.7. Other conditions with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med
1996;334(21):1349–55. https://doi.org/10.1056/NEJM199605233342101.
Age. The only β-blocker specifically tested in patients aged more than [4] Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL Randomised
Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353(9169):
75 years is nebivolol [7], and thus this drug might represent a good
2001–7.
choice in older HF patients with normal pulmonary function and lung [5] Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL,
diffusing capacity [24], and in the absence of other comorbid conditions Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL, Carvedilol G.
Prospective Randomized Cumulative Survival Study, Effect of carvedilol on survival
that could direct the choice on a different β-blocker type.
in severe chronic heart failure. N Engl J Med 2001;344(22):1651–8. https://doi.org/
Hyperthyroidism. Non-selective beta blockers, in particular propran­ 10.1056/NEJM200105313442201.
olol, should be prescribed for symptom control in patients with hyper­ [6] The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet
thyroidism because they have a more direct effect on hypermetabolism. 1999;353(9146):9–13.
[7] Flather MD, Shibata MC, Coats AJ, Van Veldhuisen DJ, Parkhomenko A, Borbola J,
However, propranolol is not recommended for the treatment of HFrEF Cohen-Solal A, Dumitrascu D, Ferrari R, Lechat P, Soler-Soler J, Tavazzi L,
and no current specific recommendation exists on the use of one of the Spinarova L, Toman J, Bohm M, Anker SD, Thompson SG, Poole-Wilson PA,
four β-blockers approved for HFrEF in the setting of hyperthyroidism. Investigators S. Randomized trial to determine the effect of nebivolol on mortality
and cardiovascular hospital admission in elderly patients with heart failure
Hepatic cirrhosis. Non-selective beta-blockers are the mainstay of (SENIORS). Eur Heart J 2005;26(3):215–25. https://doi.org/10.1093/eurheartj/
treatment for portal hypertension in the setting of liver cirrhosis. In ehi115.
particular, propranolol has been historically used in this setting. How­ [8] Paolillo S, Mapelli M, Bonomi A, Corra U, Piepoli M, Veglia F, Salvioni E, Gentile P,
Lagioia R, Metra M, Limongelli G, Sinagra G, Cattadori G, Scardovi AB, Carubelli V,
ever, propranolol is not recommended for the treatment of HFrEF and in Scrutino D, Badagliacca R, Raimondo R, Emdin M, Magri D, Correale M, Parati G,
patients with both HF and hepatic cirrhosis carvedilol is increasingly Caravita S, Spadafora E, Re F, Cicoira M, Frigerio M, Bussotti M, Mina C, Oliva F,
used; it seems to exhibit a greater portal pressure reducing effect than Battaia E, Belardinelli R, Mezzani A, Pastormerlo L, Di Lenarda A, Passino C,
Sciomer S, Iorio A, Zambon E, Guazzi M, Pacileo G, Ricci R, Contini M, Apostolo A,
propranolol and its use is safe in patients with compensated or decom­
Palermo P, Clemenza F, Marchese G, Binno S, Lombardi C, Passantino A, Filardi PP,
pensated cirrhosis [48]. Agostoni P. Prognostic role of beta-blocker selectivity and dosage regimens in heart
failure patients. Insights from the MECKI score database. Eur J Heart Fail 2017;19
(7):904–14. https://doi.org/10.1002/ejhf.775.
2. Conclusions
[9] Straw S, McGinlay M, Relton SD, Koshy AO, Gierula J, Paton MF, Drozd M,
Lowry JE, Cole C, Cubbon RM, Witte KK, Kearney MT. Effect of disease-modifying
β-blockers are disease-modifying drugs that have a significant impact agents and their association with mortality in multi-morbid patients with heart
on the long-term prognosis of patients affected by HFrEF. Accordingly, failure with reduced ejection fraction. ESC Heart Fail 2020. https://doi.org/
10.1002/ehf2.12978.
they are recommended as first-line therapy in the presence of left ven­ [10] Canepa M, Temporelli PL, Rossi A, Rossi A, Gonzini L, Nicolosi GL, et al. Prevalence
tricular dysfunction and need to be titrated to the maximum tolerated and prognostic impact of chronic obstructive pulmonary disease in patients with chronic
dose to achieve their full prognostic benefits . β-blockers are still un­ heart failure: data from the GISSI-HF trial. Cardiology 2017;136(2):128–37. https://
doi.org/10.1159/000448166.
derused in HFrEF patients affected by complex comorbidities, which, [11] Canepa M, Straburzynska-Migaj E, Drozdz J, Fernandez-Vivancos C, Pinilla JMG,
however, do not represent real contraindications to their prescription. Nyolczas N, Temporelli PL, Mebazaa A, Lainscak M, Laroche C, Maggioni AP,
Indeed, the presence of comorbidities should not limit the use of Piepoli MF, Coats AJS, Ferrari R, Tavazzi L, E.-H.H.F.L.-T.R. Investigators.
Characteristics, treatments and 1-year prognosis of hospitalized and ambulatory
β-blockers, and correct knowledge of drug-disease interactions is needed heart failure patients with chronic obstructive pulmonary disease in the European
to guide prescription and titration of β-blockers, and in some cases to Society of Cardiology Heart Failure Long-Term Registry. Eur J Heart Fail 2018;20
direct the choice of a specific agent in the individual patient to promote (1):100–10. https://doi.org/10.1002/ejhf.964.
[12] Staszewsky L, Wong M, Masson S, Barlera S, Carretta E, Maggioni AP, Anand IS,
a personalized and targeted approach to therapy.
Cohn JN, Tognoni G, Latini R, Valsartan I. Heart Failure Trial, Clinical,
neurohormonal, and inflammatory markers and overall prognostic role of chronic
Funding sources obstructive pulmonary disease in patients with heart failure: data from the Val-HeFT
heart failure trial. J Card Fail 2007;13(10):797–804. https://doi.org/10.1016/j.
cardfail.2007.07.012.
No funding has been provided for the research. [13] Canepa M, Franssen FME, Olschewski H, Lainscak M, Bohm M, Tavazzi L,
Rosenkranz S. Diagnostic and therapeutic gaps in patients with heart failure and
Declaration of Competing Interest chronic obstructive pulmonary disease. JACC Heart Fail 2019;7(10):823–33.
https://doi.org/10.1016/j.jchf.2019.05.009.
[14] Pite H, da Cruz MB, Morais-Almeida M. Obstructive lung diseases and beta-blockers:
The authors declare no conflict of interest. where do we stand? Eur J Intern Med 2016;34:e32–3. https://doi.org/10.1016/j.
ejim.2016.04.024.
[15] Ouwerkerk W, Voors AA, Anker SD, Cleland JG, Dickstein K, Filippatos G, van der
Harst P, Hillege HL, Lang CC, Ter Maaten JM, Ng LL, Ponikowski P, Samani NJ, van
Veldhuisen DJ, Zannad F, Metra M, Zwinderman AH. Determinants and clinical

13
S. Paolillo et al. European Journal of Internal Medicine 88 (2021) 9–14

outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart [34] Martin-Perez M, Ruigomez A, Michel A, Garcia Rodriguez LA. Incidence and risk
failure: a prospective European study. Eur Heart J 2017;38(24):1883–90. https:// factors for atrial fibrillation in patients with newly diagnosed heart failure.
doi.org/10.1093/eurheartj/ehx026. J Cardiovasc Med (Hagerstown) 2016;17(8):608–15. https://doi.org/10.2459/
[16] Jabbour A, Macdonald PS, Keogh AM, Kotlyar E, Mellemkjaer S, Coleman CF, JCM.0000000000000403.
Elsik M, Krum H, Hayward CS. Differences between beta-blockers in patients with [35] Paolillo S, Agostoni P, Masarone D, Corra U, Passino C, Scrutinio D, Correale M,
chronic heart failure and chronic obstructive pulmonary disease: a randomized Cattadori G, Metra M, Girola D, Piepoli MF, Salvioni E, Giovannardi M, Iorio A,
crossover trial. J Am Coll Cardiol 2010;55(17):1780–7. https://doi.org/10.1016/j. Emdin M, Raimondo R, Re F, Cicoira M, Belardinelli R, Guazzi M, Clemenza F,
jacc.2010.01.024. Parati G, Scardovi AB, Di Lenarda A, La Gioia R, Frigerio M, Lombardi C,
[17] Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blockers for chronic Gargiulo P, Sinagra G, Pacileo G, Perrone-Filardi P, Limongelli G. C. Metabolic
obstructive pulmonary disease. Cochrane Datab Syst Rev 2005;(4):CD003566. Exercise test data combined with, and G. Kidney Indexes Score Research, Prognostic
https://doi.org/10.1002/14651858.CD003566.pub2. role of atrial fibrillation in patients affected by chronic heart failure. Data from the
[18] Sessa M, Mascolo A, Mortensen RN, Andersen MP, Rosano GMC, Capuano A, MECKI score research group. Eur J Intern Med 2015;26(7):515–20. https://doi.org/
Rossi F, Gislason G, Enghusen-Poulsen H, Torp-Pedersen C. Relationship between 10.1016/j.ejim.2015.04.023.
heart failure, concurrent chronic obstructive pulmonary disease and beta-blocker [36] Kotecha D, Holmes J, Krum H, Altman DG, Manzano L, Cleland JG, Lip GY,
use: a Danish nationwide cohort study. Eur J Heart Fail 2018;20(3):548–56. Coats AJ, Andersson B, Kirchhof P, von Lueder TG, Wedel H, Rosano G,
https://doi.org/10.1002/ejhf.1045. Shibata MC, Rigby A, Flather MD, G. Beta-Blockers in Heart Failure Collaborative.
[19] Maggioni AP, Orso F, Calabria S, Rossi E, Cinconze E, Baldasseroni S, Martini N, Efficacy of beta blockers in patients with heart failure plus atrial fibrillation: an
Observatory A. The real-world evidence of heart failure: findings from 41 413 individual-patient data meta-analysis. Lancet 2014;384(9961):2235–43. https://
patients of the ARNO database. Eur J Heart Fail 2016;18(4):402–10. https://doi. doi.org/10.1016/S0140-6736(14)61373-8.
org/10.1002/ejhf.471. [37] Cullington D, Goode KM, Zhang J, Cleland JG, Clark AL. Is heart rate important for
[20] Stefan MS, Rothberg MB, Priya A, Pekow PS, Au DH, Lindenauer PK. Association patients with heart failure in atrial fibrillation? JACC Heart Fail 2014;2(3):213–20.
between beta-blocker therapy and outcomes in patients hospitalised with acute https://doi.org/10.1016/j.jchf.2014.01.005.
exacerbations of chronic obstructive lung disease with underlying ischaemic heart [38] Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomstrom-Lundqvist C,
disease, heart failure or hypertension. Thorax 2012;67(11):977–84. https://doi. Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM,
org/10.1136/thoraxjnl-2012-201945. La Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN,
[21] Magnussen H, Canepa M, Zambito PE, Brusasco V, Meinertz T, Rosenkranz S. What Valgimigli M, Van Gelder IC, Van Putte BP, Watkins CL, Group ESCSD. 2020 ESC
can we learn from pulmonary function testing in heart failure? Eur J Heart Fail Guidelines for the diagnosis and management of atrial fibrillation developed in
2017;19(10):1222–9. https://doi.org/10.1002/ejhf.946. collaboration with the European Association of Cardio-Thoracic Surgery (EACTS).
[22] Paolillo S, Pellegrino R, Salvioni E, Contini M, Iorio A, Bovis F, et al. Role of Eur Heart J 2020. https://doi.org/10.1093/eurheartj/ehaa612.
alveolar beta2-adrenergic receptors on lung fluid clearance and exercise [39] Cadrin-Tourigny J, Shohoudi A, Roy D, Talajic M, Tadros R, Mondesert B, et al.
ventilation in healthy humans. PLoS ONE 2013;8(4):e61877. https://doi.org/ Decreased mortality with beta-blockers in patients with heart failure and coexisting atrial
10.1371/journal.pone.0061877. fibrillation: an AF-CHF substudy. JACC Heart Fail 2017;5(2):99–106. https://doi.
[23] Contini M, Apostolo A, Cattadori G, Paolillo S, Iorio A, Bertella E, Salvioni E, org/10.1016/j.jchf.2016.10.015.
Alimento M, Farina S, Palermo P, Loguercio M, Mantegazza V, Karsten M, [40] Campodonico J, Piepoli M, Clemenza F, Bonomi A, Paolillo S, Salvioni E, Corra U,
Sciomer S, Magri D, Fiorentini C, Agostoni P. Multiparametric comparison of Binno S, Veglia F, Lagioia R, Sinagra G, Cattadori G, Scardovi AB, Metra M,
CARvedilol, vs. NEbivolol, vs. BIsoprolol in moderate heart failure: the CARNEBI trial. Senni M, Scrutinio D, Raimondo R, Emdin M, Magri D, Parati G, Re F, Cicoira M,
Int J Cardiol 2013;168(3):2134–40. https://doi.org/10.1016/j.ijcard.2013.01.277. Mina C, Limongelli G, Correale M, Frigerio M, Bussotti M, Perna E, Battaia E,
[24] Sinagra G, Corra U, Contini M, Magri D, Paolillo S, Perrone Filardi P, Sciomer S, Guazzi M, Badagliacca R, Di Lenarda A, Maggioni A, Passino C, Sciomer S,
Badagliacca R, Agostoni P. Choosing among beta-blockers in heart failure patients Pacileo G, Mapelli M, Vignati C, Lombardi C, Filardi PP, Agostoni P, M.S.R. Group.
according to beta-receptors’ location and functions in the cardiopulmonary system. Dose-dependent efficacy of beta-blocker in patients with chronic heart failure and
Pharmacol Res 2020;156:104785. https://doi.org/10.1016/j.phrs.2020.104785. atrial fibrillation. Int J Cardiol 2018;273:141–6. https://doi.org/10.1016/j.
[25] Solang L, Malmberg K, Ryden L. Diabetes mellitus and congestive heart failure. ijcard.2018.08.012.
Further knowledge needed. Eur Heart J 1999;20(11):789–95. https://doi.org/ [41] Schwarz ER, Rastogi S, Kapur V, Sulemanjee N, Rodriguez JJ. Erectile dysfunction
10.1053/euhj.1998.1472. in heart failure patients. J Am Coll Cardiol 2006;48(6):1111–9. https://doi.org/
[26] Pastormerlo LE, Mammini C, Giannoni A, Valleggi A, Prontera C, Gabutti A, 10.1016/j.jacc.2006.05.052.
Poletti R, Padeletti L, Emdin M, Passino C. Glycosylated haemoglobin is associated [42] Cordero A, Bertomeu-Martinez V, Mazon P, Facila L, Bertomeu-Gonzalez V,
with neurohormonal activation and poor outcome in chronic heart failure patients Conthe P, Gonzalez-Juanatey JR. Erectile dysfunction in high-risk hypertensive
with mild left ventricular systolic dysfunction. J Cardiovasc Med (Hagerstown) patients treated with beta-blockade agents. Cardiovasc Ther 2010;28(1):15–22.
2015;16(6):423–30. https://doi.org/10.2459/JCM.0000000000000159. https://doi.org/10.1111/j.1755-5922.2009.00123.x.
[27] Paolillo S, Salvioni E, Perrone Filardi P, Bonomi A, Sinagra G, Gentile P, et al., M.s. [43] Silvestri A, Galetta P, Cerquetani E, Marazzi G, Patrizi R, Fini M, Rosano GM.
r. group. Long-term prognostic role of diabetes mellitus and glycemic control in heart Report of erectile dysfunction after therapy with beta-blockers is related to patient
failure patients with reduced ejection fraction: insights from the MECKI Score database. knowledge of side effects and is reversed by placebo. Eur Heart J 2003;24(21):
Int J Cardiol 2020;317:103–10. https://doi.org/10.1016/j.ijcard.2020.04.079. 1928–32. https://doi.org/10.1016/j.ehj.2003.08.016.
[28] Tsujimoto, T., T. Sugiyama, M.F. Shapiro, M. Noda, and H. Kajio, Risk of [44] Pavastu SCV, Mendoca DA, Da Silva A. Beta blockers for peripheral arterial disease.
cardiovascular events in patients with diabetes mellitus on beta-blockers. Hypertension, Cochrane Database Syst Rev 2013;2013(9):CD005508.
2017. 70(1): p. 103–10. 10.1161/HYPERTENSIONAHA.117.09259. [45] Mirault T, Galloula A, Cambou JP, Lacroix P, Aboyans V, Boulon C, et al. Impact of
[29] Tsujimoto T, Kajio H, Shapiro MF, Sugiyama T. Risk of all-cause mortality in betablockers on general and local outcome in patients hospitalized for lower extremity
diabetic patients taking beta-blockers. Mayo Clin Proc 2018;93(4):409–18. https:// peripheral artery disease: the COPART Registry. Medicine (Blatimore) 2017;96:
doi.org/10.1016/j.mayocp.2017.11.019. e5916.
[30] Erdmann E, Lechat P, Verkenne P, Wiemann H. Results from post-hoc analyses of [46] Aboyans V, Ricco JB, Bartelink MEL, Björck M, Brodmann M, Cohnert T, et al., ESC
the CIBIS II trial: effect of bisoprolol in high-risk patient groups with chronic heart Scientific Document Group. 2017 ESC Guidelines on the Diagnosis and Treatment of
failure. Eur J Heart Fail 2001;3(4):469–79. https://doi.org/10.1016/s1388-9842 Peripheral Arterial Diseases, in collaboration with the European Society for Vascular
(01)00174-x. Surgery (ESVS): document covering atherosclerotic disease of extracranial carotid and
[31] Bobbio M, Ferrua S, Opasich C, Porcu M, Lucci D, Scherillo M, Tavazzi L, vertebral, mesenteric, renal, upper and lower extremity arteriesEndorsed by: the
Maggioni AP, Investigators B-U. Survival and hospitalization in heart failure European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of
patients with or without diabetes treated with beta-blockers. J Card Fail 2003;9(3): Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the
192–202. https://doi.org/10.1054/jcaf.2003.31. European Society for Vascular Surgery (ESVS). Eur Heart J 2018 Mar 1;39(9):
[32] Grant PJ, Cosentino F. The 2019 ESC Guidelines on diabetes, pre-diabetes, and 763–816. https://doi.org/10.1093/eurheartj/ehx095.
cardiovascular diseases developed in collaboration with the EASD: new features and the [47] Espinola-Klein C, Weisser G, Jagodzinski A, Savvidis S, Warnholtz A, Ostad MA,
‘Ten Commandments’ of the 2019 Guidelines are discussed by Professor Peter J. Grant et al. Beta-blockers in patients with intermittent claudication and arterial
and Professor Francesco Cosentino, the Task Force chairmen. Eur Heart J 2019;40(39): hypertension: results from the nebivolol or metoprolol in arterial occlu- sive
3215–7. https://doi.org/10.1093/eurheartj/ehz687. disease trial. Hypertension 2011;58:148–54.
[33] Maisel WH, Stevenson LW. Atrial fibrillation in heart failure: epidemiology, [48] Rodrigues SG, Mendoza YP, Bosch J. Beta-blockers in cirrhosis: evidence-based
pathophysiology, and rationale for therapy. Am J Cardiol 2003;91(6A). https:// indications and limitations. JHEP Rep 2019 Dec 20;2(1):100063. https://doi.org/
doi.org/10.1016/s0002-9149(02)03373-8. 2D–8D. 10.1016/j.jhepr.2019.12.001.

14