Physician's opinion on Metoprolol in CVD: The master of all trades!

It will not be an overstatement that cardioselective beta-blocker metoprolol has been one of the most researched and at the same time most widely used molecules of its class. Its wide spectrum of indications extends from angina and essential hypertension, for which it was first introduced, to the more serious indications like acute coronary syndromes, heart failure, and tachyarrhythmias (1) where it has proved to be one of the most effective tools at disposal for physicians.

In the following review, we revisit the wide applicability of metoprolol backed by sound trial evidence and provide guideline recommendations for its use in different cardiovascular disorders.

Mechanism and superiority over nonselective beta-blockers.

Metoprolol is a lipophilic cardioselective beta-1-adrenergic receptor inhibitor that competitively blocks beta1-receptors with minimal or no effects on beta-2 receptors at oral doses of less than 100 mg in adults (2). It decreases cardiac output by negative inotropic and chronotropic effects. By counteracting the sympathetic overdrive, it decreases myocardial oxygen demand and prevents arrhythmia triggers.

Unlike non-selective beta-blockers like propranolol, metoprolol is safer for use in patients with peripheral vascular diseases, respiratory conditions, etc. (1).

A bulk of clinical experiences on the use of metoprolol has been gathered throughout the years. Metoprolol has indications for hypertension, angina pectoris, symptomatic mild-to-severe chronic heart failure as an adjunct to other heart failure therapy, disturbances of cardiac rhythm including, in particular, supraventricular tachycardia, maintenance treatment after myocardial infarction, functional heart disorders with palpitations and migraine prophylaxis [3].

Role in myocardial infarction

The rationale for the use of beta-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 (4-6). The pharmacological blockade of cardiac beta-adrenergic receptors exerts several favorable effects after myocardial infarction since it acts on left ventricular remodeling, systolic function, and post-necrotic myocardial inflammatory response (7).

The pivotal METOCARD-CNIC trial investigated the effects of intravenous metoprolol tartrate administration before reperfusion on left ventricular function and clinical events. Smaller infarct size, higher ejection fraction coupled with a trend of reduced incidences of a composite of death, malignant ventricular arrhythmia, cardiogenic shock, atrioventricular block, and reinfarction at 24 hours was observed in the intravenous metoprolol compared with controls (8).

Overall, current evidence suggests that metoprolol does play a role in the treatment of ischemic 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 into long-term benefits, as shown in the pivotal METOCARD-CNIC study (1).

Stable Angina: Beta-blockers are recommended by current European Society of Cardiology (ESC) guidelines on the diagnosis and treatment of stable coronary heart disease as a first-line antianginal drug (9).

Role in heart failure:

The landmark MERIT-HF trial (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure) showed that all-cause mortality was significantly lower with metoprolol succinate compared with the placebo group in patients with chronic heart failure (NYHA class II-IV and left ventricular ejection fraction [LVEF] ≤40%). Further, the metoprolol group showed a reduction in the incidence of sudden deaths and deaths from worsening of heart failure (10).

Is metoprolol better than other beta-blockers?

In a pooled analysis comparing various cardioselective beta-blockers in the setting of heart failure, for all-cause mortality nebivolol was found to be less effective and has a poorer tolerability profile while metoprolol was associated with numerically higher reduction compared to bisoprolol and carvedilol (11).

Is metoprolol's benefit similar in all subclasses of patients?

Interestingly, several sub-analyses of the pivotal MERIT-HF trial have been published to explore the influence of patients' characteristics and concomitant diseases on the efficacy of metoprolol. Overall, the efficacy and safety of metoprolol were not influenced by renal function (12), presence of concomitant atrial fibrillation (13), diabetes (14), hypertension (15), prior infarction (16), age (15), and patient's gender (17).

What is the benefit of early administration?

The benefit of beta-blocker therapy in heart failure is also evident in the initial phases of the disease, as shown by the REVERT study (18). This study showed that metoprolol reduces disease progression with a reduction in left ventricular end-diastolic volume and improvement of ejection fraction, as observed in echocardiography, in patients with asymptomatic ventricular diastolic dysfunction, the clinical precursor of overt heart failure. Therefore, metoprolol shows favorable effects on the progression of heart failure even in the very early and pre-initial stages of cardiac dysfunction.

What do the guidelines say?

The latest guidelines on the diagnosis and treatment of congestive heart failure issued by the ESC recommend the use of beta-blockers in patients suffering from heart failure of both ischemic and non-ischemic origin, for any degree of clinical severity (NYHA functional class) (19).

Role in essential hypertension: sole agent and in combination therapy?

Beta-blockers performed well when compared with placebo and other antihypertensive agents in reducing the risk of death/stroke/myocardial infarction in young hypertensive subjects, and therefore may be considered a suitable first-line choice of therapy in this setting (1).

A meta-analysis of 13 large clinical trials involving >90,000 participants has highlighted the superiority of lipophilic beta-blockers like metoprolol compared with hydrophilic compounds in terms of cardiovascular, coronary, and cerebrovascular protection (20). In this regard, differences between beta-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 glycemic and insulin profile, with negative consequences on the cardio-metabolic risk of the patient (21).

For patients in whom effective blood pressure control necessitates the use of combination therapy, well-grounded evidence supports the antihypertensive efficacy of the combination of metoprolol with calcium channel blocker, felodipine (1). The presence of a beta-blocker allows overcoming the reflex tachycardia induced by the calcium antagonist and felodipine enhances peripheral vasodilatation and therefore reduces peripheral vascular resistance (22).

What do the guidelines say?

The ESH/ESC guidelines do not rank antihypertensive drugs, but rather consider all classes of antihypertensive drugs available including metoprolol as the first-line therapy for arterial hypertension (23). The choice depends on the patient's profile. For example, beta-blockers alone, or in combination are a suitable first-line option for young patients with arterial hypertension (1).

Role in tachyarrhythmias:

Sinus tachycardia:

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 negative chronotropic effect of ivabradine, which did not allow to achieve this therapeutic goal when administered (24).

Atrial Fibrillation:

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. Metoprolol also counterbalances one of the most important risk factors for AF i.e. hypertension (25).

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. They confirmed that recurrence of symptomatic atrial fibrillation is lower in combined therapy of metoprolol plus flecainide compared with flecainide alone at 1-year follow-up (26).

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. 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 major cardiovascular events, and duration of atrial fibrillation (27).

Given the aforementioned evidence, the ESC guidelines recommend metoprolol succinate – as well as other beta-blockers – for heart rate control in AF (28).

Recommended dosing regimens

1. For Myocardial infarction: Intravenous metoprolol tartrates up to three 5-mg boluses given 2 minutes apart (8).

For angina (29): The recommended initial dose is one tablet 50 mg/25mg once daily. If necessary, the dose may be increased to two tablets once daily.

2. For heart failure (29): The recommended starting dose of Metoprolol Succinate extended-release tablets is 25 mg once daily for two weeks in patients with NYHA Class II heart failure and 12.5 mg once daily in patients with more severe heart failure. Double the dose every two weeks to the highest dosage level tolerated by the patient or up to 200 mg of Metoprolol Succinate extended-release tablets.

3. For hypertension (29): The usual initial dosage is 25 mg to 100 mg daily in a single dose. The dosage may be increased at weekly (or longer) intervals until optimum blood pressure reduction is achieved.

Take away message for physicians

Metoprolol is one of the most commonly prescribed drugs today while dealing with various cardiovascular etiologies. Given its wide spectrum of indications and better safety profile, the drug continues to deserve a primary role in the management of heart failure, acute coronary syndromes, stable angina, hypertension, and atrial fibrillation. Research on this molecule is still ongoing with promising settings of use being explored and may provide relevant results in the years to come.

References:

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29. https://www.ciplamed.com/content/metolar-am-tablets