Current Medical Research and Opinion

ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20

Metoprolol in the treatment of cardiovascular

disease: a critical reappraisal

Guido Grassi

To cite this article: Guido Grassi (2018): Metoprolol in the treatment of cardiovascular disease: a
critical reappraisal, Current Medical Research and Opinion, DOI: 10.1080/03007995.2018.1479245

To link to this article: https://doi.org/10.1080/03007995.2018.1479245

Accepted author version posted online: 21

May 2018.

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Metoprolol in the treatment of cardiovascular disease: a critical reappraisal
Guido Grassi1,2
1
Clinica Medica, Dept. Health Science, University Milano-Bicocca, Milano, Italy
2
IRCCS Multimedica, Sesto San Giovanni, Milano, Italy

Corresponding author
Guido Grassi
Clinica Medica, Università Milano Bicocca, Via Pergolesi 33, 20052 Monza, Italy
Email: guido.grassi@unimib.it

Transparency statement

Declaration of funding
Recordati supported the medical writing contribution.

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Declaration of financial/other relationships
The authors have disclosed that they have no significant relationships with or financial interests in any

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commercial companies related to this study or article. Peer reviewers on this manuscript have received an
honorarium from CMRO for their review work, but have no other relevant financial relationships to

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disclose.

Author contributions
GG has critically reviewed literature and contributed to manuscript drafting.
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Acknowledgements
Medical writing and editing was performed by Luca Giacomelli, PhD, and Aashni Shah.
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Abstract

Extensive clinical experience on metoprolol has been gained in different cardiovascular conditions. In this
paper, we discuss the use of metoprolol, with a focus on the extended-release formulation, in clinical
practice in the light of existing evidence and current recommendations. This is a narrative review based on
existing evidence and clinical experience of the Author. Evidence on the use of metoprolol in heart failure,
ischemic artery disease, arterial hypertension and atrial fibrillation is well-established. Metoprolol still
appears a suitable pharmacological option in different cardiovascular conditions. Research on this molecule
is still active and new, promising settings of use are being explored and may provide relevant results in the
years to come.

Keywords: atrial fibrillation, congestive heart failure, essential hypertension, ischemic heart disease,
metoprolol succinate

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Introduction
-adrenergic receptor-blocking agents (-blockers) are among the most widely used class of drugs
in clinical practice. They are competitive inhibitors of catecholamines that bind to adrenergic
receptors. Their first use in clinical practice was in the treatment of essential hypertension and in
the management of angina. Throughout the years, -blockers also became clinically relevant for
the treatment of congestive heart failure and cardiac arrhythmias (mainly atrial fibrillation).
At present, more than 20 molecules belonging to the -blocker class are available for clinical use.
Although all these compounds share the pharmacological blockade of the adrenergic receptors,
each of them is characterized by specific pharmacological properties, including selectivity of action
depending on the adrenergic receptors subtypes, intrinsic sympathomimetic activity (ISA), lipid
solubility, pharmacokinetic profile, and also other ancillary properties [1].
Among different -blockers, metoprolol is a selective 1-blocker, which has an insignificant
membrane-stabilizing effect and does not display partial agonistic activity [2]. It was initially
developed in the mid ‘70s as metoprolol tartrate, a formulation characterized by an immediate

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release, with a pharmacokinetic/pharmacodynamic profile requiring multiple daily

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administrations. After 15 years, a new formulation, namely metoprolol succinate, was developed.
This formulation is characterized by an extended release, allowing a single administration

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throughout a 24-hour period. Table 1 displays current formulations of metoprolol and their
indications.

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A bulk of clinical experience on the use of metoprolol has been gathered throughout the years.
Metoprolol succinate has indications for hypertension, angina pectoris, symptomatic mild-to-
severe chronic heart failure as an adjunct to other heart failure therapy, disturbances of cardiac
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rhythm including, in particular, supraventricular tachycardia, maintenance treatment after
myocardial infarction, functional heart disorders with palpitations and migraine prophylaxis [1].
In this opinion paper, we discuss the use of metoprolol, with a major focus on the succinate,
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extended release formulation, in the treatment of cardiovascular conditions in clinical practice, at

the light of existing evidence and current recommendations.
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Metoprolol in congestive heart failure

Until the results of two landmark trials, namely the Cardiac Insufficiency Bisoprolol Study (CIBIS) II
and the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure were
published (MERIT-HF) at the end of the last century [3,4], the role of -blockers in the
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management of chronic heart failure has been uncertain for a long time [5]. Since then, mounting
evidence supporting the role of -blockers in the treatment of heart failure has been published.
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The physiological mechanisms of -blockers in this setting is based on the blockade of the
sympathetic neural activity, the prevention of catecholamine elevation, the reduction of heart rate
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and the activity against the proapoptotic and cardiotoxic effects of cyclic adenosine
monophosphate-mediated calcium overload [6].
The latest guidelines on the diagnosis and treatment of congestive heart failure issued by the
European Society of Cardiology (ESC) recommend the use of -blockers in patients suffering from
heart failure of both ischemic and non-ischemic origin, for any degree of clinical severity (New
York Heart Association [NYHA] functional class) [7]. Those guidelines also state that -blockers
should be initiated in clinically stable patients at a low dose and gradually up-titrated to the
maximum tolerated dose [7].
With specific reference to metoprolol succinate, the most relevant clinical trial documenting the
therapeutic potential of this molecule in the reduction of cardiovascular mortality in the
decompensated heart failure patient is the MERIT-HF trial (Metoprolol CR/XL Randomized
Intervention Trial in Congestive Heart Failure) [4]. This was a double-blind, placebo-controlled
randomized study on 3991 patients with chronic heart failure (NYHA class II–IV and left ventricular
ejection fraction [LVEF] ≤40%). The target dose of metoprolol was 200 mg once daily added to
standard treatment with ACE inhibitors and diuretics in patients with decreased LVEF and
symptoms of mild-to-severe chronic heart failure and doses were up-titrated over 8 weeks. The
study was prematurely interrupted according to the recommendation of the independent safety
committee because the pre‐specified criteria, for termination of the study for mortality reduction
in the metoprolol group, had been met and exceeded (mean follow-up: 1 year). Remarkably, all-
cause mortality was significantly lower with metoprolol succinate compared with placebo group (-
34%; 145 [7.2%, per patient-year of follow-up] vs 217 deaths [11.0%], risk ratio [RR]: 0.66 [95% CI:
0.53–0.81]; p=0.00009). In addition, metoprolol succinate was superior in the reduction of the
incidence of sudden deaths (-41%; 79 vs 132, RR: 0.59 [95% CI: 0.45–0.78]; p=0.0002) and in
deaths from worsening heart failure (-49%; 30 vs 58, RR: 0.51 [95% CI: 0.33–0.79]; p=0.0023).
Moreover, in the population enrolled in the MERIT-HF trial, metoprolol succinate reduced the
need for hospitalizations due to worsening heart failure by 30%, improved NYHA functional class

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and displayed beneficial effects on patient well-being [5]. In a post-hoc analysis of the same trial,

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heart rate response was investigated in two dosage subgroups: namely, >100 mg of metoprolol CR
once daily (n=1,202) and ≤100 mg daily (n=412) [8]. Overall, heart rate was reduced to a similar

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degree in the two groups, thus suggesting greater sensitivity for beta-blockade in the low-dose
group. The investigators speculated that the increased sensitivity to β1-receptor blockade with
low-dose metoprolol might be due to a downregulation and desensitization of myocardial β1-

receiving high-dose therapy. us

receptors, since patients on low-dose metoprolol presented more advanced HF than those

By way of indirect comparison, the COPERNICUS and CIBIS II studies addressing the effects of
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carvedilol and bisoprolol in heart failure, respectively [3,9], demonstrated results similar to those
of the MERIT-HF trial. Overall, these findings confirmed the importance of the use of -adrenergic
receptor blockade as a therapeutic benchmark of the decompensated patient. A pooled analysis of
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large-scale trials on the most widely used -blockers, including metoprolol compared the effects of
metoprolol succinate, bisoprolol, carvedilol and nebivolol on total mortality, all-cause mortality or
hospitalization due to cardiovascular causes, all-cause mortality or hospitalization due to HF and
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tolerability in similar patients [10]. To this end, the authors of that pooled analysis compared
stratified subsets of patients enrolled in the MERIT-HF with patients in CIBIS-II (NYHA class III/IV
and ejection fraction [EF] ≤35%) and COPERNICUS (NYHA III/IV and EF <25%) and in patients with
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systolic heart failure in SENIORS-SHF (age ≥70 years and EF ≤35%). Overall, the analysis of total
mortality supports the evidence that nebivolol is less effective and has a poorer tolerability profile
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compared with other agents, while metoprolol was associated with numerically higher reduction
than the other -blockers (Table 2) [10]. Similar findings were reported for the other outcomes.
Interestingly, a number of sub-analyses of the pivotal MERIT-HF trial have been published to
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explore the influence of patients’ characteristics and concomitant diseases on the efficacy of
metoprolol. Overall, the efficacy and safety of metoprolol succinate were not influenced by renal
function [11], presence of concomitant atrial fibrillation [12], diabetes [13], hypertension [14],
prior infarction [15], age [14] and patient’s gender [16].
In the subanalysis in patients with impaired renal function, subjects enrolled in the MERIT-HF trial
were stratified into three subgroups: estimated glomerular filtration rate (eGFR) >60 (n=2,496),
45–60 (n=976), and <45 ml/min per 1.73 m2 (n = 493) [11]. Placebo patients with eGFR <45 ml/min
per 1.73 m2 had significantly higher risk of all-cause mortality than those with eGFR >60 ml/min
per 1.73 m2 (hazard ratio [HR]: 1.90; 95% CI: 1.28–2.81), for the combined endpoint of all-cause
mortality/hospitalization for worsening heart failure (HR: 1.91; 95% CI: 1.44–2.53), and for the risk
of hospitalizations due to heart failure (Figure 1, Panel A). On the other hand, no significant
increase in overall mortality or in the combined endpoint was observed for patients randomized to
metoprolol succinate, compared with placebo recipients (for total mortality, HR: 0.41; 95% CI:
0.25–0.68; p<0.001 for patients with eGFR <45 ml/min per 1.73 m2 and HR: 0.71; 95% CI: 0.54–
0.95; p<0.021 for those with eGFR >60 ml/min; corresponding figure for the combined end point
was HR: 0.44; 95% CI: 0.31–0.63; p<0.0001 and HR: 0.75; 95% CI: 0.62–0.92; p=0.005,
respectively). Metoprolol CR/XL was well tolerated in all subgroups.
In the subanalysis on patients with diabetes, the risk of hospitalization for heart failure was 76%
higher in diabetic subjects compared with non-diabetics (95% CI: 38–123%) [13]. Metoprolol
succinate reduced the risk of hospitalization for heart failure by 37% in diabetics (95% CI: 15–53%),
and by 35% in the non-diabetic group (95% CI: 19–48%) (Figure 1, Panel B). No unexpected safety
issues were reported.
Last, in another post-hoc analysis of the MERIT-HF trial, the effect of metoprolol succinate on
outcome in women (n=898), including 183 with severe heart failure, were evaluated [16].
Treatment with metoprolol in women resulted in a 21% reduction in all-cause mortality and

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hospitalization, as compared with placebo (p=0.044). Metoprolol treatment also reduced the

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incidence of cardiovascular hospitalizations (-29%; p=0.013), and of hospitalizations due to
worsened heart failure (-42%; p=0.021).
Several experiences comparing metoprolol succinate with other -blockers in the treatment of

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heart failure have been published. A detailed description of those experiences goes beyond the
scope of this review; however, three experiences are worth mentioning in our opinion. Using data

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from a National Danish registry, Pasternak et al. investigated the association between metoprolol
and survival, comparing the effectiveness of this molecule with that of carvedilol [17] or bisoprolol
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[18]. Overall, no differences in mortality were reported between these drugs, regardless of
gender, age, LVEF, NYHA class and history of ischemic heart disease. Similar findings were
reported in a Norwegian registry, when metoprolol was compared with carvedilol [19].
The benefit of -blocker therapy in heart failure is also evident in the initial phases of the disease,
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when LVEF is still preserved. Indeed, the double-blind, placebo-controlled Reversal of Ventricular
Remodeling with Toprol-XL (REVERT) study [20] demonstrated the efficacy of metoprolol in
reducing disease progression at echocardiography, with reduction of left ventricular end diastolic
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volume and improvement of ejection fraction, in patients with asymptomatic ventricular diastolic
dysfunction, the clinical precursor of overt heart failure. Furthermore, patients with LVEF <40%,
mild left ventricular dilation, and NYHA class I received metoprolol succinate (200 mg, n=48 or 50
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mg, n=48) or placebo (n=53). At 1 year, in the 200-mg group there was a 14±3 ml/m2 decrease in
end systolic volume index and a 6±1% increase in LEVF (p<0.05 vs baseline and placebo for both
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comparisons). Therefore, metoprolol shows favorable effects on the progression of heart failure
even in the very early and pre-initial stages of the cardiac dysfunction. Moreover, the
improvements of echocardiographic parameters obtained with metoprolol are similar to those
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obtained with carvedilol in both ischemic and non-ischemic cardiomyopathies [21].

According to the above-mentioned evidence, at present, metoprolol succinate continues to have a
major role in the treatment of heart failure of any origin. Indeed, in this setting metoprolol
succinate appears to be at least as effective as the other -blockers most used in clinical practice.
Moreover, a number of specific analysis show the efficacy of this molecule also in particular
patients’ subgroups frequently encountered in everyday practice, such as those with poor renal
function, diabetes or women. The use of metoprolol in the early stages of disease should not be
neglected, and deserves further investigation in well-conducted studies.
Metoprolol in ischemic heart disease
The rationale for the use of -blockers after an acute myocardial infarction is multifaceted. Indeed,
acute coronary events are characterized by intense neuro-adrenergic activation, which negatively
affects prognosis due to coronary vasoconstriction and the subsequent possible occurrence of
malignant arrhythmias [22–24]. As it happens in heart failure, the pharmacological blockade of
cardiac -adrenergic receptors exerts a number of favorable effects after a myocardial infarction,
since it acts on left ventricular remodeling, systolic function and post-necrotic myocardial
inflammatory response [25]. Thus, -blockers are recommended by current ESC guidelines on the
diagnosis and treatment of stable coronary heart disease [26]. Furthermore, current ESC
guidelines state that -blockers should be the first-line anti-anginal therapy in stable coronary
artery disease patients who do not present contraindications to this therapy, since these agents –
although evidence on their effect on survival is inconclusive – are effective in controlling exercise-
induced angina, improving exercise capacity and limiting symptomatic and asymptomatic ischemic
episodes [25]. Moreover, the same guidelines point out that metoprolol – as well as carvedilol – is

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safer than nebivolol and bisoprolol in patients with renal impairment [26].

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In a prespecified subgroup analysis of the MERIT-HF trial, patients with congestive heart failure
(CHF) in prior hospitalization for acute myocardial infarction (n=1,926) were randomized to

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metoprolol succinate or placebo [15]. Overall, metoprolol succinate reduced total mortality by
40% (95% CI: 0.20–0.55; p=0.0004), and sudden death by 50% (95% CI: 0.26–0.66; p=0.0004). All-

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cause mortality/hospitalization for worsening CHF (combined endpoint) was reduced by 31% (95%
CI: 0.16–0.44; p<0.0001), and cardiac death/nonfatal acute myocardial infarction by 45% (95% CI:
0.26–0.58; p<0.0001). The authors concluded that in post-myocardial infarction patients with
symptomatic CHF, -blockade continues to exert a profound reduction in mortality and morbidity
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when associated with appropriate management (early and late revascularization, angiotensin-
converting enzyme [ACE] inhibitors, diuretics, aspirin and statins).
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With respect to the acute setting, in which intravenous metoprolol should be administered, the
clinical trial COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) enrolling over
45,000 patients admitted to hospital for an acute myocardial infarction, has provided somehow
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favorable results for metoprolol [27]. More specifically, 45,852 patients admitted to 1,250
hospitals within 24 h of suspected acute myocardial infarction onset were randomly assigned to
metoprolol (up to 15 mg intravenous then 200 mg oral daily; n=22,929) or placebo (n=22,923).
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Treatment was continued until discharge or up to 4 weeks in hospital. In total, 2166 (9.4%)
patients allocated to metoprolol experienced death, reinfarction or cardiac arrest compared with
2261 (9.9%) in the control group. Metoprolol determined a 18% reduction in the risk of
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reinfarction (464 [2.0%] metoprolol vs 568 [2.5%] placebo; OR: 0.82, 95% CI: 0.72–0.92; p=0.001)
and a 17% reduction in the risk of ventricular fibrillation (581 [2.5%] vs 698 [3.0%]; OR: 0.83, 95%
CI: 0.75–0.93; p=0.001) per 1,000 treated. However, these favorable results were counterbalanced
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by 11 more patients per 1,000 developing cardiogenic shock, mainly in the first day after
admission, suggesting starting β-blocker therapy in hospital only when the hemodynamic
condition after MI has stabilized, in order to reduce the risks of reinfarction and ventricular
fibrillation.
Noteworthy, the pivotal METOCARD-CNIC trial investigated the effects of intravenous metoprolol
administration before reperfusion on left ventricular function and clinical events [28,29]. Patients
with Killip class II or less anterior ST-segment-elevation myocardial infarction (STEMI) undergoing
percutaneous coronary intervention within 6 hours since onset of symptoms were randomly
assigned to receive intravenous metoprolol (n=131) or not (control, n=139) before reperfusion
[28]. All patients without contraindications then received oral metoprolol within 24 hours. At
magnetic resonance, mean infarct size was smaller after intravenous metoprolol than controls
(25.6±15.3 vs 32.0±22.2 g; p=0.012). Moreover, LVEF was higher in the intravenous metoprolol
group (adjusted difference, 2.67%; 95% CI: 0.09–5.21; p=0.045). There was a trend to a lower
incidence of a composite of death, malignant ventricular arrhythmia, cardiogenic shock,
atrioventricular block and reinfarction at 24 hours in the intravenous metoprolol compared with
controls (7.1 vs 12.3%; p=0.21).
At the long-term follow-up analysis of the same study (6 months), LVEF was higher after
intravenous metoprolol (48.7±9.9% vs 45.0±11.7%; 95% CI: 0.44–6.55%; p=0.025). The occurrence
of severely depressed LVEF (≤35%) was also lower in patients treated with intravenous metoprolol
(11 vs 27%, p=0.006), as well as the proportion of patients fulfilling class I indications for an
implantable cardioverter-defibrillator (7 vs 20%, p=0.012). At 2 years, the incidence of a pre-
specified composite of death, heart failure admission, reinfarction and malignant arrhythmias was
10.8% in the intravenous metoprolol group versus 18.3% in the control group, with a 45%
reduction with metoprolol (HR: 0.55; 95% CI: 0.26–1.04; p=0.065). Heart failure admission was
also reduced (HR: 0.32; 95% CI: 0.015–0.95; p=0.046).

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The use of metoprolol in this setting was also investigated in a recent network meta-analysis

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comparing it with carvedilol [30]. In total, 12 randomized controlled trials (n=61,081) were
included. Compared with placebo, both carvedilol and metoprolol reduced composite

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cardiovascular events (RR: 0.63; 95% credible interval [CrI]: 0.41–0.85 for carvedilol; RR: 0.78; 95%
CrI: 0.65–0.93 for metoprolol) and re-infarction (RR: 0.57; 95% CrI: 0.37–0.84 for carvedilol; RR:
0.77; 95% CrI: 0.62–0.91 for metoprolol) in patients with myocardial infarction, with a similar

revascularization and rehospitalization were reported. us

effect of the two molecules. However, no benefits on all-cause death, cardiovascular death,

Overall, current evidence suggests that metoprolol does play a role in the treatment of ischemic
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heart disease, both in the acute setting and in stable patients. In particular, early intravenous
metoprolol before reperfusion may reduce infarct size and increase LVEF; these advantages do
translate in long-term benefits, as shown in the pivotal METOCARD-CNIC study.
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Metoprolol in essential hypertension

Current American guidelines (Joint National Committee VIII) as well as the British guidelines place
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-blockers as a third therapeutic choice for the treatment of hypertension, to be used in clinical
practice when the drugs acting on the renin–angiotensin–aldosterone system (ACE inhibitors and
angiotensin II receptor blockers) and even the calcium channel blockers have proved unable to
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determine a reliable blood pressure control [31–33]. In contrast, the ESH/ESC guidelines do not
rank antihypertensive drugs, but rather consider all classes of antihypertensive drugs available as a
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valid option as the first-line therapy for arterial hypertension [34]. The therapeutic choice in each
individual patient should be formulated according to the characteristics of the patient, the
comorbidities that may be present and his/her own cardiovascular risk profile. To this end, since
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essential hypertension in younger/middle-age is underpinned by high sympathetic nerve activity,

in this age group high resting heart rates and high plasma norepinephrine levels are linked to
premature cardiovascular events [35]. Therefore, antihypertensive agents that increase
sympathetic nerve activity, such as diuretics, calcium blockers, and angiotensin II receptor
blockers, may not be fully appropriate in this younger age group. On the other hand, -blockers
performed well when compared with placebo and other antihypertensive agents regarding in
reducing the risk of death/stroke/myocardial infarction in younger hypertensive subjects, and
therefore may be considered a suitable first-line choice of therapy in this setting.
The use of metoprolol in the treatment of arterial hypertension is supported by a bulk of evidence
and clinical experience, starting from the mid-1970s. The research was initially focused on the
characterization of the hemodynamic effects of metoprolol on 24-hour ambulatory pressure,
organ damage and metabolic profile. Simultaneously, in-depth assessments of the efficacy and
tolerability of the drug versus other commonly used antihypertensive drugs have been published.
Metoprolol was compared with alpha methyldopa and thiazide diuretics, ACE inhibitors and
calcium channel blockers. Overall, the results of these studies have highlighted the efficacy of
metoprolol against the reference drugs under investigation [36]. Over the last decade, the
comparative evaluation of metoprolol in the therapy of essential hypertension was performed
against the new -blockers endowed with vasodilatatory properties mediated by nitric oxide, such
as nebivolol [37]. In Europe, the use of the newer -blockers for the treatment of hypertension is
limited, and probably inferior to the rate of use of the old-generation -blockers in the same
scenario.
At the end of the 1980s, the MAPHY (Metoprolol Atherosclerosis Prevention in Hypertensives) trial
demonstrated the superiority of metoprolol over diuretic therapy for the protection of coronary
events in high-risk cardiovascular hypertensive patients [38]. In that study, hypertensive men (40–
64 years old) with untreated diastolic blood pressure >100 mmHg received metoprolol (n=1,609)

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as initial treatment. Metoprolol was compared with thiazide diuretics (n=1,625) in the reduction of

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cardiovascular events. Overall, the risk for coronary events was lower in patients on metoprolol
than in patients on diuretics (111 vs 144 cases, p=0.001, corresponding to 14.3 vs 18.8 cases/1000

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patient years; RR: 0.76, 95% CI: 0.58–0.98).
Moreover, over the years the potential differences in clinical efficacy, cardio-metabolic effects,
organ protection and tolerability among the different -blockers have been the subject of a large

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amount of well-conducted research. A meta-analysis of 13 large clinical trials involving >90,000
participants has highlighted the superiority of lipophilic -blockers (including metoprolol)
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compared with hydrophilic compounds in terms of cardiovascular, coronary and cerebrovascular
protection [39]. Lipophilic β-blockers significantly reduced the risk of cardiovascular mortality
(odds ratio [OR]: 0.72, 95% CI: 0.54–0.97) compared with hydrophilic β-blockers, and also
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displayed a trend to reduced all-cause mortality and coronary artery disease. In this line, the
differences between -blockers may also affect the metabolic profile, considering that metoprolol
is metabolically neutral compared with other drugs of the same class, which can often worsen the
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glycemic and insulin profile, with negative consequences on the cardio-metabolic risk of the
patient [40].
As previously mentioned, the 2013 ESH/ESC guidelines on the diagnosis and treatment of
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hypertension recommend the use of a combination therapy at low doses, as first therapeutic
approach especially in high-risk patients, to obtain an optimal pressure control and to reduce the
potential side effects of the two drugs [34]. Moreover, the use of a fixed-dose combined
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treatment translates into higher rates of adherence and compliance to therapy, which is known to
be inversely proportional to the number and extent of side effects [41], and to affect prognosis as
well as the cardiovascular risk profile [42].
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In this line, well-grounded evidence supports the antihypertensive efficacy of the combination
metoprolol/felodipine. In this combination, the presence of a -blocker allows to overcome the
reflex tachycardia induced by the calcium antagonist [43]. On the other hand, felodipine enhances
peripheral vasodilatation and therefore reduces peripheral vascular resistance. These combined
effects provide the background for the -blocker/calcium antagonist combination
metoprolol/felodipine as one of most frequently used and recommended therapeutic
combinations for hypertension [34]. The effectiveness and tolerability of this combination is also
supported by the results of the M-FACT (Metoprolol Succinate-Felodipine Antihypertension
Combination Trial) [43]. M-FACT was a multicenter, randomized, placebo-controlled, unbalanced
factorial study that comprised a 4- to 5-week single-blind placebo, 9-week, double-blind treatment
phase, and a 2-week double-blind, down-titration period. Patients (n=1092) were randomized to
one out of 16 treatment groups: extended release (ER) metoprolol succinate (25, 100 or 400 mg),
ER felodipine (2.5, 10 or 20 mg), ER felodipine/ER metoprolol succinate (2.5/25, 2.5/100, 2.5/400,
10/25, 10/100, 10/400, 20/25, 20/100 or 20/400 mg), or placebo. Overall, monotherapy with
metoprolol succinate induced dose-related reductions in sitting systolic/diastolic blood pressure
(mean: 8.1/7.7 to 9.7/11.1 mmHg) as did ER felodipine (mean: 7.7/7.7 to 14.0/11.8 mmHg) and
the combinations reflected additive effects (mean: 13.8/11.0 to 19.8/15.2 mmHg). The decline in
the placebo group was 2.1/4.0 mmHg. All combinations were more effective than monotherapies.
Another large clinical study investigating the tolerability profile and the efficacy of the
combination, supports the above-mentioned conclusion [44]. It was a double-blind trial on 947
patients with essential hypertension aged 20–70 years, who were randomly assigned to
felodipine+metoprolol 5+50 mg (F+M), or enalapril 10 mg (E) or placebo. The blood pressure
reductions after F+M (18/14 mmHg) and E (12/9 mmHg) were significantly greater than after
placebo (7/7 mmHg), and the reduction after F+M was significantly greater than after E; all active
treatments also determined improvements in health-related quality of life. Lastly, a recently

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published meta-analysis evaluating 208 clinical trials for over 90,000 patients identifies the

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combination metoprolol/felodipine as one of the most effective treatments, allowing for blood
pressure control in a large fraction of treated hypertensive patients (mean reductions: systolic

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blood pressure -20.8 mmHg, diastolic blood pressure -14.7 mmHg) [45].

Metoprolol in atrial fibrillation

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The use of metoprolol as an antiarrhythmic drug has been investigated in animal as well as in
human studies. The comparison between metoprolol and the classical antiarrhythmic drugs, such
as propafenone, amiodarone and flecainide, is frequently proposed in clinical studies. Given the
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evidence reported, current ESC guidelines recommend metoprolol succinate – as well as other -
blockers – for heart rate control [46].
Resting tachycardia is frequent in clinical practice; moreover, a high resting heart rate (>85 bpm)
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negatively affects the clinical course of any cardiovascular disease (heart failure, post myocardial
infarction and probably also arterial hypertension) and is also associated with increased
cardiovascular morbidity and mortality [47,48]. therefore, the reduction of resting heart rate is a
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primary goal of the therapeutic intervention.

The efficacy of metoprolol in the reduction of heart rate in patients with inappropriate sinus
tachycardia was shown in one small study on 20 patients in which metoprolol potentiated the
pt

negative chronotropic effect of ivabradine, which did not allow to achieve this therapeutic goal
when administered alone [49].
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The main cause of atrial fibrillation is essential hypertension, which is associated with 50–65% of
all cases of this arrhythmia [50]. High blood pressure state may favor the development of atrial
fibrillation through different mechanisms, the most important of which are the increase in the size
Ac

of the right atrium, the development of left ventricular hypertrophy, the adrenergic hyper-tone
and the activation of the renin–angiotensin–aldosterone system [50]. The association between
arterial hypertension and atrial fibrillation is of particular clinical relevance as it triplicates the risk
of stroke compared with patients with atrial fibrillation alone and normal blood pressure values
[50]. In this setting, metoprolol acts by reducing the sympathetic activation at the atrial level and
by simultaneously inhibiting the pro-arrhythmogenic (and profibrotic) effects of angiotensin II at
the same site [51]. A recent monocentric prospective randomized clinical study on 173 patients
with a recent episode of paroxysmal or persistent atrial fibrillation has shown the long-term
efficacy of the flecainide/metoprolol combination in the prevention of relapses of paroxysmal or
persistent atrial fibrillation, with a reduction of about 40% compared with flecainidine
monotherapy [52]. Other studies have reported the favorable effects of metoprolol in
preoperative prevention of peri- or post-operative atrial fibrillation (major thoracic surgery,
coronary artery bypass surgery and cardiac surgery) [12,53–57]. In a double-blind randomized
trial, metoprolol (n=73) showed a higher efficacy in the prevention of atrial fibrillation episodes
following coronary bypass surgery as compared with amiodarone, with 92% of patients achieving
normal rhythm [55]. These findings corroborate those of previous studies. In a post-hoc analysis of
the pivotal MERIT-HF trial on 556 patients with atrial fibrillation, mean metoprolol dose in patients
in atrial fibrillation (154 mg) and sinus rhythm (158 mg) was similar, as well as decrease in heart
rate (14.8 and 13.7 bpm) [12]. On follow-up, new atrial fibrillation was observed in 85 patients on
placebo and 47 patients on metoprolol (RR: 0.53; 95% CI: 0.37–0.76; p=0.0005), revealing a risk
reduction of 48%. In another double-blind, controlled, randomized study, 394 patients with a
history of persistent atrial fibrillation were assigned to metoprolol succinate or placebo after
successful conversion to sinus rhythm [57]. In the metoprolol group, 96 patients (48.7%) showed a
relapse of atrial fibrillation, versus 118 patients (59.9%) in the placebo group (p=0.005). This lower
incidence of relapse was consistent regardless of several characteristics, including age, HF/prior

t
major cardiovascular events, and duration of atrial fibrillation (Figure 2). Moreover, heart rate in

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patients after a relapse into atrial fibrillation was significantly lower in the metoprolol group
(98±23 beats/min vs 107±27 beats/min).

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Conclusions

in several cardiovascular conditions.

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Despite being on the market for many years, metoprolol still remains a relevant therapeutic option

This molecule undoubtedly has a role in the management of patients with heart failure, also at the
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light of current ESC guidelines. Interestingly, a bulk of evidence from clinical trials and –
importantly – from field-practice scenarios shows that metoprolol succinate can be considered at
least as effective as other β-blockers used in clinical practice. Moreover, the efficacy and safety
M

profile are not influenced by patient’s characteristics, as reported in several studies.

The use of metoprolol in ischemic heart disease is also well established. This molecule has proven
ed

to have a role in the acute setting, namely in the treatment of myocardial infarction and early
post-infarction phases. In these patients, the early use of metoprolol results in more favorable
long-term outcomes. Moreover, metoprolol can be effective in the treatment of stable coronary
pt

artery disease.
The use of metoprolol succinate in the treatment of hypertension is supported by a large amount
of published evidence and clinical experience, which date back to more than 40 years ago.
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According to current ESC/ESH guidelines, fixed-combination therapy should be preferred in

patients not effectively controlled by monotherapy, or who are at high cardiovascular risk. In this
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line, the fixed-dose combination of metoprolol and felodipine is supported by a strong

pharmacological rationale, and allows to enhance the therapeutic effects of both drugs while at
the same time reducing the potential side effects of each molecule.
Last, metoprolol succinate is recommended, as well as other β-blockers, in the reduction of heart
rate in patients with atrial fibrillation. Moreover, prevention of relapses of post-operative atrial
fibrillation can be an additional setting for the use of metoprolol.
In conclusion, metoprolol, especially in its extended-release formulation of metoprolol succinate,
continues to deserve a primary role as a suitable pharmacological option in different
cardiovascular conditions. Research on this molecule is still ongoing, promising settings of use are
being explored and may provide relevant results in the years to come.
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Report. 2017;7:14941. us
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after conversion from persistent atrial fibrillation: a randomized, double-blind, placebo-controlled
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Tables and figures

Table 1. Current formulations of metoprolol.

ACTIVE SUBSTANCE PHARMACEUTICAL FORM THERAPEUTIC INDICATIONS*

metoprolol succinate Controlled release tablets, u.i.d. Hypertension#

(23.75 mg, Angina pectoris
47.5 mg, 95 mg and Chronic heart failure§
190 mg). Disturbances of cardiac rhythm
Maintenance treatment after
myocardial infarction
Functional heart disorders with
palpitations

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Migraine prophylaxis

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metoprolol tartrate (50 Tablets, b.i.d. Hypertension#
mg, 100 mg) Angina pectoris

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Disturbances of cardiac rhythm
Maintenance treatment after

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myocardial infarction
Functional heart disorders with
palpitations
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Migraine prophylaxis
Hyperthyroidism
metoprolol tartrate Prolonged release tablets, u.i.d. Same indications as for metoprolol
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(200 mg) tartrate (50 mg, 100 mg)

metoprolol tartrate (1 Solution for injection 1 mg/mL Disturbances of cardiac rhythm

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mg/mL) (5 mL ampoule) Confirmed or suspected myocardial

infarction
* Therapeutic indications may differ among countries
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# to reduce blood pressure and to reduce the risk of cardiovascular and coronary mortality (including sudden death),
and morbidity.
§ Symptomatic mild to severe chronic heart failure as an adjunct to other heart failure therapy: to increase survival,
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reduce hospitalisation, improve left ventricular function, improve New York Heart Association (NYHA) functional class
and improve Quality of Life.
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 Table 2. Yearly risk and risk reduction for all-cause mortality in CIBIS-II (bisoprolol vs placebo),
COPERNICUS (carvedilol vs placebo) and SENIORS-SHF (nebivolol vs placebo) compared with the
respective stratified subsets from MERIT-HF (metoprolol succinate vs placebo) (elaborated from
[9]).
Trial Beta- Yearly Yearly Reduction Stratified Yearly mortality Yearly Reduction
blocker mortality mortality (active cohort of (No./pat. yrs %) mortality (metoprolol
(No./pat. yrs (No./pat. treatment the with (No./pat. yrs vs placebo)
%) with active yrs %) vs MERIT-HF metoprolol in %) with in the
treatment with placebo) trial the stratified placebo in stratified
placebo cohort of the stratified cohort of
MERIT-HF trial cohort the the MERIT-
MERIT-HF HF trial
trial
CIBIS-II Bisoprolol 8.8 13.2 -34%* Metoprolol 8.6 14.8 -42%*
COPERNICUS Carvedilol 12.8 19.7 -35%* Metoprolol 11.7 19.1 -39%*
SENIORS- Nebivolol 9.7 11.3 -16% Metoprolol 10.1 14.8 -32%*

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SHF

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* p<0.05 vs placebo

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Figure 1. Total number of hospitalizations due to worsening of heart failure in the MERIT-HF trial,
according to renal function (Panel A) and the presence of diabetes (Panel B) [10,12].

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Figure 2. Proportion of patients with a relapse of AF in different subgroups after treatment with
metoprolol succinate or placebo (N=394; number of patients in each subgroup are not reported
here for the sake of clarity, please refer to the original source) [56].

Atrial fibrillation ≥30 days 58.2%

49.1%

Atrial fibrillation <30 days 53.8%

40.7%

Organic heart disease* 68.7%

56.0%

No organic heart disease* 55.4%

44.3%

Heart failure 67.7%

52.9%

No heart failure 57.4%

47.3%

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68.7%
Age > 65 years
51.2%

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Age ≤65 years 53.5%
40.0%

Placebo Metoprolol

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*Heart disease: either a history of cardiac failure, angina pectoris, history of myocardial infarction, or valvular heart
disease.
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