Metoprolol is used for the management of hypertension, angina, acute myocardial infarction (MI), and heart failure. The drug also has been used for supraventricular and ventricular tachyarrhythmias and prophylaxis of migraine headache.
The choice of a β-adrenergic blocking agent (β-blocker) depends on numerous factors, including pharmacologic properties (e.g., relative β-selectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity, lipophilicity), pharmacokinetics, intended use, and adverse effect profile, as well as the patient's coexisting disease states or conditions, response, and tolerance. While specific pharmacologic properties and other factors may appropriately influence the choice of a β-blocker in individual patients, evidence of clinically important differences among the agents in terms of overall efficacy and/or safety is limited. Patients who do not respond to or cannot tolerate one β-blocker may be successfully treated with a different agent.
In the management of hypertension or chronic stable angina pectoris in patients with chronic obstructive pulmonary disease (COPD) or type 1 diabetes mellitus, many clinicians prefer to use low dosages of a β1-selective adrenergic blocking agent (e.g., atenolol, metoprolol), rather than a nonselective agent (e.g., nadolol, pindolol, propranolol, timolol). However, selectivity of these agents is relative and dose dependent. Some clinicians also will recommend using a β1-selective agent or an agent with intrinsic sympathomimetic activity (ISA) (e.g., pindolol), rather than a nonselective agent, for the management of hypertension or angina pectoris in patients with peripheral vascular disease, but there is no evidence that the choice of β-blocker substantially affects efficacy.
Metoprolol is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Metoprolol's efficacy in the management of hypertension is similar to that of other β-blockers; however, metoprolol may be preferred over a nonselective β-blocker, like propranolol, in hypertensive patients with certain concomitant disease states. Metoprolol may be associated with less risk of bronchospasm than propranolol in patients with bronchitis. Metoprolol's relative cardioselectivity may be advantageous in hypertensive patients with concomitant heart failure controlled by diuretics and cardiac glycosides; however, it remains to be established whether metoprolol is less likely to cause heart failure in these patients than is propranolol. In patients with catecholamine excess (e.g., pheochromocytoma, drug-induced hypoglycemia, or acute withdrawal of adrenergic blocking agents), metoprolol reportedly is less likely to produce impairment of peripheral circulation, heart failure, and hypertensive reactions than is propranolol. Because metoprolol may cause less inhibition of glycogenolysis than does propranolol, metoprolol may be preferred in patients with diabetes mellitus who are receiving insulin or oral antidiabetic agents (e.g., sulfonylurea drugs); however, additional study is required.
In contrast to many other antihypertensive agents, metoprolol lowers blood pressure equally well in the upright or supine position. The drug appears to be safe and effective in the management of hypertension in patients with renal damage. Although metoprolol is apparently more effective in reducing blood pressure in patients with normal or elevated plasma renin concentrations, the drug also lowers blood pressure in patients with low renin hypertension. Tolerance to the antihypertensive effect of metoprolol apparently does not occur during long-term administration.
Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics). Although β-blockers were previously considered a drug of choice for the initial management of hypertension, most current guidelines no longer recommend these drugs as first-line therapy because of the lack of established superiority over other recommended drug classes and at least one study demonstrating that they may be less effective than angiotensin II receptor antagonists in preventing cardiovascular death, MI, or stroke. However, β-blockers may still be considered in hypertensive patients who have a compelling indication (e.g., prior MI, ischemic heart disease, heart failure) for their use or as add-on therapy in those who do not respond adequately to the preferred drug classes. Ultimately, choice of antihypertensive therapy should be individualized, considering the clinical characteristics of the patient (e.g., age, ethnicity/race, comorbid conditions, cardiovascular risk factors) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, costs). Because many patients eventually will need drugs from 2 or more antihypertensive classes, experts generally state that the emphasis should be placed on achieving appropriate blood pressure control rather than on identifying a preferred drug to achieve that control.
Considerations in Initiating Antihypertensive Therapy
Drug therapy generally is reserved for patients who respond inadequately to nondrug therapy (i.e., lifestyle modifications such as diet [including sodium restriction and adequate potassium and calcium intake], regular aerobic physical activity, moderation of alcohol consumption, and weight reduction) or in whom the degree of blood pressure elevation or coexisting risk factors requires more prompt or aggressive therapy; however, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.
While the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended antihypertensive drug therapy in all patients with systolic/diastolic blood pressure of 140/90 mm Hg or higher who fail to respond to lifestyle/behavioral modifications, other experts, including the panel members appointed to the Eighth Joint National Committee (JNC 8 expert panel) currently recommend a higher systolic blood pressure threshold for older individuals (e.g., the JNC 8 expert panel recommends a threshold of 150 mm Hg for patients 60 years of age or older).
In addition, there is some variation in the blood pressure thresholds and treatment goals recommended for patients with diabetes mellitus or chronic kidney disease. In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had blood pressures of 130/80 mm Hg or higher; however, current hypertension management guidelines generally recommend the same blood pressure threshold of 140/90 mm Hg for initiating antihypertensive drug therapy in these individuals as for the general population of patients without these conditions, although a lower goal (e.g., less than 130/80 mm Hg) may still be considered.
Further study is needed to more clearly define optimum blood pressure goals in patients with hypertension; when determining appropriate blood pressure goals, individual risks and benefits should be considered in addition to the evidence from clinical studies.
Antihypertensive drug therapy generally should be initiated gradually and titrated at intervals of approximately 2-4 weeks to achieve the target blood pressure. The goal is to reduce blood pressure to levels below the threshold used for initiating drug therapy. Addition of a second drug should be initiated when use of monotherapy in adequate dosages fails to achieve goal blood pressure. Some experts state that initial antihypertensive therapy with a combination of drugs may be considered in patients with systolic/diastolic blood pressure greater than 20/10 mm Hg above goal blood pressure. Such combined therapy may increase the likelihood of achieving goal blood pressure in a more timely fashion, but also may increase the risk of adverse effects (e.g., orthostatic hypotension) in some patients (e.g., elderly). Initial combined therapy may be particularly useful in patients with markedly high baseline blood pressures and those with additional risk factors.
Initial Drug Therapy
For initial antihypertensive drug therapy, experts currently recommend a thiazide diuretic, calcium-channel blocker, ACE inhibitor, or angiotensin II receptor antagonist. β-Blockers generally are not preferred for initial monotherapy in patients with uncomplicated hypertension, but may be beneficial in patients with a compelling indication (e.g., ischemic heart disease, atrial tachyarrhythmias, history of MI, heart failure) for their use.
Follow-up and Maintenance Therapy
Several strategies are recommended for the titration and combination of antihypertensive drugs; these strategies include maximizing the dosage of the first drug before adding a second drug, adding a second drug before achieving maximum dosage of the initial drug, or initiating therapy with 2 drugs simultaneously (either as separate preparations or as a fixed-dose combination). If goal blood pressure is not achieved with initial monotherapy with one of the recommended antihypertensive drug classes, a second drug from one of the recommended drug classes may be added; if goal blood pressure is still not achieved with optimal dosages of 2 antihypertensive agents, a third drug from one of the recommended drug classes may be added. If more than 3 drugs are required, other antihypertensive drug classes, including β-blockers, may be considered. If the blood pressure goal cannot be achieved with the above recommended strategies, consultation with a hypertension specialist should be considered.
Thus, metoprolol can be used for the management of hypertension as initial monotherapy (not usually preferred, but may be used for a compelling indication) or as a component of a multiple-drug regimen. β-Blockers often are used concurrently with a diuretic because of their additive effects. β-Blockers also have been combined with vasodilators (e.g., hydralazine, minoxidil) to counteract the reflex tachycardia that occurs with vasodilators.
Antihypertensive Therapy for Patients with Underlying Cardiovascular or Other Risk Factors
Drug therapy in patients with hypertension and underlying cardiovascular or other risk factors should be carefully individualized based on the underlying disease(s), concomitant drugs, tolerance to drug-induced adverse effects, and blood pressure goal. on Compelling Indications for Drug Classes based on Comorbid Conditions, in Antihypertensive Therapy for Patients with Underlying Cardiovascular and Other Risk Factors under Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.)
Ischemic Heart Disease
The selection of an appropriate antihypertensive agent in patients with ischemic heart disease should be based on individual patient characteristics, but may include a β-blocker, with the addition of other drugs (e.g., ACE inhibitors, thiazide diuretics, calcium-channel blockers) as necessary to achieve blood pressure goals. Because of the demonstrated mortality benefit of β-blockers following MI, these drugs should be administered in all patients who have survived an MI.
While β-blockers as single therapies are not superior to other antihypertensive agents in the reduction of all cardiovascular outcomes, certain β-blockers (bisoprolol, carvedilol, extended-release metoprolol succinate) have been shown to be effective in reducing the incidence of heart failure and associated morbidity and mortality.
(See Uses: Heart Failure.)
Other Special Considerations for Antihypertensive Therapy
In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blockers than to monotherapy with β-blockers, ACE inhibitors, or angiotensin II receptor antagonists. However, such diminished response to a β-blocker is largely eliminated when the drug is administered concomitantly with a thiazide diuretic. In addition, some experts state that when use of β-blockers is indicated in hypertensive patients with underlying cardiovascular or other risk factors, these indications should be applied equally to black hypertensive patients.
For information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.
Chronic Stable Angina
Metoprolol is used for the management of chronic stable angina pectoris. β-Blockers are recommended as the anti-ischemic drugs of choice in most patients with chronic stable angina; despite differences in cardioselectivity, intrinsic sympathomimetic activity, and other clinical factors, all β-blockers appear to be equally effective for this indication. In placebo-controlled studies, metoprolol reduced the frequency of anginal attacks, reduced nitroglycerin consumption, and increased exercise tolerance.
Combination therapy with a β-blocker and a nitrate appears to be more effective than either drug alone because β-blockers attenuate the increased sympathetic tone and reflex tachycardia associated with nitrate therapy while nitrate therapy (e.g., nitroglycerin) counteracts the potential increase in left-ventricular wall tension associated with a decrease in heart rate. Combined therapy with a β-blocker and a dihydropyridine calcium-channel blocker also may be useful because the tendency to develop tachycardia with the calcium-channel blocker is counteracted by the β-blocker. However, caution should be exercised in the concomitant use of β-blockers and the nondihydropyridine calcium-channel blockers verapamil or diltiazem because of the potential for excessive fatigue, bradycardia, or atrioventricular (AV) block. Concomitant use of metoprolol with cardiac glycosides may be beneficial in patients with angina pectoris, especially in those with cardiomegaly, because both drugs reduce myocardial oxygen consumption; however, the potential effect of combined therapy on AV conduction should be considered.
(See Drug Interactions: Cardiovascular Drugs.)
Non-ST-Segment-Elevation Acute Coronary Syndromes
β-Blockers are used as part of the standard therapeutic measures for managing non-ST-segment-elevation acute coronary syndromes (NSTE ACS). Patients with NSTE ACS have either unstable angina or non-ST-segment-elevation MI (NSTEMI); because these conditions are part of a continuum of acute myocardial ischemia and have indistinguishable clinical features upon presentation, the same initial treatment strategies are recommended. The American Heart Association/American College of Cardiology (AHA/ACC) guideline for the management of patients with NSTE ACS recommends an early invasive strategy (angiographic evaluation with the intent to perform revascularization procedures such as percutaneous coronary intervention [PCI] with coronary artery stent implantation or coronary artery bypass grafting [CABG]) or an ischemia-guided strategy (initial medical management followed by cardiac catheterization and revascularization if indicated) in patients with definite or likely NSTE ACS; standard medical therapies for all patients should include a β-blocker, antiplatelet agents (aspirin and/or a P2Y12-receptor antagonist), anticoagulant agents (e.g., low-molecular weight or unfractionated heparin), nitrates (e.g., nitroglycerin), and analgesic agents regardless of the initial management approach. The guideline states that oral β-blocker therapy should be initiated within the first 24 hours in patients who do not have manifestations of heart failure, evidence of a low-output state, increased risk of cardiogenic shock, or any other contraindications to β-blocker therapy; use of IV β-blockers is potentially harmful in patients with risk factors for cardiogenic shock. Continued therapy with a β-blocker proven to reduce mortality (bisoprolol, carvedilol, or metoprolol succinate) is recommended in patients with stabilized heart failure and reduced systolic function.
Acute Myocardial Infarction
Metoprolol tartrate is used orally and IV to reduce the risk of cardiovascular mortality in hemodynamically stable patients with definite or suspected acute MI. The term MI is used when there is evidence of myocardial necrosis in the setting of acute myocardial ischemia. ST-segment-elevation MI (STEMI) is distinguished from NSTEMI based on the presence or absence of ST-segment elevation on ECG. Patients with STEMI typically have complete arterial occlusion; therefore, immediate reperfusion therapy (with primary PCI or thrombolytic agents) is the current standard of care for such patients. Because the clinical presentation of NSTEMI is similar to that of unstable angina, these conditions are considered together in current expert guidelines.
(See Uses: Non-ST-Segment Elevation Acute Coronary Syndromes.)During the early stage of a definite or suspected MI, metoprolol has been initiated with IV doses, followed by continued oral dosing; however, experts currently recommend that early IV use of β-blockers be limited to selected patients.
Because β-blockers can reduce myocardial oxygen demand during the first few hours of an acute MI by reducing heart rate, arterial blood pressure, and/or myocardial contractility, and also have been shown to reduce mortality, early IV therapy with these drugs was routinely recommended following acute MI. Evidence supporting this recommendation was generally based on studies conducted prior to the reperfusion era demonstrating a reduction in mortality and other clinical benefits (i.e., reduced infarct size, incidence of ventricular arrhythmias, chest pain, and cardiac enzyme elevations) with early use of β-blockers during MI. In one double-blind, placebo-controlled study in patients with definite or suspected acute MI, therapy with metoprolol tartrate (initiated IV as soon as possible after arrival to the hospital and continued orally for 3 months) was associated with a 36% reduction in mortality. The mortality benefit of metoprolol was similar between patients who were treated early (no more than 8 hours from the onset of symptoms) and those who initiated treatment at a later time. Patients receiving metoprolol also had substantial reductions in ventricular fibrillation and chest pain.
Studies conducted after the widespread use of reperfusion therapy generally have demonstrated more attenuated benefits with early β-blocker therapy in patients with acute MI; while β-blockers may still confer benefits (e.g., reduction in the risk of reinfarction and ventricular arrhythmias), there is less certainty regarding the drugs' effects on mortality in patients receiving contemporary revascularization and pharmacologic therapies (antiplatelet agents, ACE inhibitors, and lipid-lowering therapies). In addition, early use of β-blockers (particularly when administered IV) has been associated with an increased risk of cardiogenic shock. In the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT), there was no difference in mortality or the combined end point of death, reinfarction, or cardiac arrest between patients receiving early metoprolol therapy (initiated IV for up to 3 doses and continued orally) and those receiving placebo. Although patients who received metoprolol had a lower risk of reinfarction and ventricular fibrillation, these benefits were accompanied by a substantially higher risk of cardiogenic shock, particularly within the first day of treatment. Based on the currently available evidence, the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline for the management of STEMI recommends oral β-blocker therapy in all patients who do not have manifestations of heart failure, evidence of a low-output state, increased risk of cardiogenic shock, or any other contraindications to β-blocker therapy. Such therapy should be initiated within the first 24 hours following acute MI and continued during and after hospitalization. Because of conflicting evidence of benefit and the potential for harm, the guidelines recommend limiting use of IV β-blockers to patients with refractory hypertension or ongoing ischemia.
Although the efficacy of metoprolol tartrate following administration of the drug for longer than 3 months has not been conclusively established, the benefits of long-term β-blocker therapy for secondary prevention have been well established in numerous clinical studies. Patients with MI complicated by heart failure, left ventricular dysfunction, or ventricular arrhythmias appear to derive the most benefit from long-term β-blocker therapy. Data from studies using other β-blockers suggest that treatment should be continued for at least 1-3 years if not indefinitely after infarction unless contraindicated. Several large, randomized studies have demonstrated that long-term therapy with a β-blocker can reduce the rates of reinfarction and mortality (e.g., sudden or nonsudden cardiac death) following acute MI. It is estimated that such therapy could result in a relative reduction in mortality of about 25% annually for years 1-3 after infarction, with high-risk patients exhibiting the greatest potential benefit; the benefit of continued therapy may persist for at least several years beyond this period, although less substantially. Therefore, metoprolol, like other β-blockers, can be used for secondary prevention following acute MI to reduce the risk of reinfarction and mortality. The AHA/ACCF secondary prevention guideline recommends β-blocker therapy in all patients with left ventricular systolic dysfunction (ejection fraction of 40% or less) and a prior MI; use of a β-blocker with proven mortality benefit (bisoprolol, carvedilol, or metoprolol succinate) is recommended. Although the benefits of long-term β-blockade in post-MI patients with normal left ventricular function are less well established, the guideline recommends continued β-blocker therapy for at least 3 years in such patients. Further studies are needed to establish the optimal duration of β-blocker therapy for secondary prevention of MI.
β-Blockers, including metoprolol, have been used to slow ventricular rate in patients with supraventricular tachycardia (SVT). The American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guideline for the management of adult patients with supraventricular tachycardia recommends the use of β-blockers in the treatment of various SVTs (e.g., atrial flutter, junctional tachycardia, focal atrial tachycardia, AV nodal reentrant tachycardia [AVNRT]); in general, an IV β-blocker is recommended for acute treatment, while an oral β-blocker is recommended for ongoing management of these arrhythmias. Vagal maneuvers and/or IV adenosine are considered first-line interventions for the acute treatment of SVT and should be attempted prior to other therapies when clinically indicated; if such measures are ineffective or not feasible, an IV β-blocker may be considered in hemodynamically stable patients. Although evidence of efficacy is limited, experts state that the overall safety of β-adrenergic blockers warrants their use in patients with SVT. Patients should be closely monitored for hypotension and bradycardia during administration of these drugs.
Atrial Fibrillation and Flutter
β-Blockers, including metoprolol, have been used to slow rapid ventricular response in patients with atrial fibrillation or atrial flutter. IV β-blockers (e.g., esmolol, propranolol, metoprolol) are recommended as one of several drug therapy options for ventricular rate control in patients with nonpreexcited atrial fibrillation or flutter; an oral β-blocker may be used for ongoing rate control in such patients. Choice of a specific β-blocker should be individualized based on the patient's clinical condition.
IV β-blockers may be used for the acute treatment of patients with hemodynamically stable focal atrial tachycardia (i.e., regular SVT arising from a localized atrial site), and an oral β-blocker may be used for ongoing management.
While evidence is more limited, IV metoprolol also has been used in patients with multifocal atrial tachycardia (rapid, irregular rhythm with at least 3 distinct P-wave morphologies) to control ventricular rate and convert to normal sinus rhythm.Multifocal atrial tachycardia is commonly associated with an underlying condition (e.g., pulmonary, coronary, or valvular heart disease) and is generally not responsive to antiarrhythmic drug therapy. Antiarrhythmic drug therapy usually is reserved for patients who do not respond to initial attempts at correcting or managing potential precipitating factors (e.g., exacerbation of COPD or congestive heart failure, electrolyte and/or ventilatory disturbances, infection, theophylline toxicity) or in whom a precipitating factor cannot be identified. Therapy with IV metoprolol has been associated with slowing of atrial and ventricular rates and conversion to sinus rhythm in many patients with this arrhythmia; therefore, some experts state that IV metoprolol may be useful for the acute treatment of patients with multifocal atrial tachycardia who do not have respiratory decompensation, sinus node dysfunction, or AV block. Metoprolol also may be useful orally for chronic suppression of symptomatic multifocal atrial tachycardia.
Paroxysmal Supraventricular Tachycardia
IV β-blockers may be used for the acute treatment of hemodynamically stable patients with paroxysmal supraventricular tachycardia (PSVT), including AVNRT, that is uncontrolled or unconverted by vagal maneuvers and adenosine; an oral β-blocker may be used for the ongoing management of such patients who are not candidates for, or prefer not to undergo, catheter ablation.
β-Blockers are considered one of several drug therapy options for the treatment of junctional tachycardia (i.e., nonreentrant SVT originating from the AV junction), a rapid, occasionally irregular, narrow-complex tachycardia. While evidence is limited, there is some data indicating that β-blocking agents (specifically propranolol) are modestly effective in terminating and/or reducing the incidence of junctional tachycardia.
β-Blockers have been used in patients with cardiac arrest precipitated by ventricular fibrillation or pulseless ventricular tachycardia. However, AHA states that routine administration of β-adrenergic blocking agents after cardiac arrest is potentially harmful (e.g., may worsen hemodynamic instability, exacerbate heart failure, or cause bradyarrhythmias) and is therefore not recommended.
Polymorphic Ventricular Tachycardia
β-Blockers may be useful in the management of certain forms of polymorphic ventricular tachycardia (e.g., associated with acute ischemia).
Metoprolol is used (usually in conjunction with other heart failure therapies) in the management of mild to moderately severe (New York Heart Association [NYHA] class II or III) heart failure of ischemic, hypertensive, or cardiomyopathic origin. In clinical studies, metoprolol (as extended-release metoprolol succinate) increased survival and reduced the risk of hospitalization in patients with chronic heart failure. Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure. Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart-failure related hospitalizations. Experts recommend that all asymptomatic patients with reduced left ventricular ejection fraction (LVEF) (ACCF/AHA stage B heart failure) receive therapy with an ACE inhibitor and a β-blocker to prevent symptomatic heart failure and to reduce morbidity and mortality. In patients with prior or current symptoms of heart failure and reduced LVEF (ACCF/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality. While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction, some evidence indicates that therapy with an ARNI may be more effective than ACE inhibitor therapy in reducing cardiovascular death and heart failure-related hospitalization in such patients. ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure with reduced LVEF (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.
Because of favorable effects on survival and disease progression, therapy with a clinical trial-proven β-blocker (bisoprolol, carvedilol, extended-release metoprolol succinate) should be initiated as soon as the patient is diagnosed with heart failure and reduced LVEF. While bisoprolol, carvedilol, and extended-release metoprolol have been effective in reducing the risk of death in patients with chronic heart failure, these positive findings should not be considered indicative of a β-blocker class effect. Even when symptoms are mild or improve with other therapies, β-blocker therapy should not be delayed until symptoms return or the disease progresses. Despite concerns about β-blockade potentially masking some signs of hypoglycemia, patients with diabetes mellitus may be particularly likely to experience a reduction in morbidity and mortality with the use of β-blockers. If a patient cannot tolerate a β-blocker or if increasing the β-blocker dosage is ineffective, ivabradine should be considered an alternative or additional treatment option. Some evidence suggests that ivabradine is effective in reducing hospitalizations related to heart failure, but unlike β-blockers, ivabradine has not been shown to reduce cardiovascular mortality.
In individualizing the decision to use a β-blocker, clinicians should consider that clinical studies establishing the effects of these drugs on morbidity and mortality excluded patients who were hospitalized or had unstable symptoms and enrolled few patients with current or recent NYHA class IV symptoms. The efficacy of β-blockers in such patients is not known, and they may be at particular risk of deterioration following initiation of therapy with β-blockers.
In a large, randomized, double-blind, placebo-controlled study (Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure [MERIT-HF]) in patients with mild to severe (NYHA class II-IV) heart failure and a left ventricular ejection fraction of 0.4 or less, therapy with metoprolol succinate (as extended-release tablets) 12.5-25 mg daily as the tartrate (initial dosage depending on NYHA class, with dosage increased over 8 weeks to a target daily dosage of 200 mg daily) in addition to optimal standard therapy (principally ACE inhibitors and diuretics) was associated with a reduction in all-cause mortality of 34% (mortality rates of 7.2 and 11% with metoprolol and placebo, respectively). The MERIT-HF trial was terminated early because of the favorable effects of metoprolol on overall mortality; the mean follow-up period was 1 year. Sudden deaths and deaths from worsening heart failure also were reduced with metoprolol therapy. In addition to improved survival, metoprolol therapy improved NYHA class, reduced hospitalizations due to worsening heart failure, and resulted in beneficial effects on patient well-being (as determined by quality-of-life measurements); the composite end point of overall mortality and hospitalization for any cause was reduced by 19%. Metoprolol therapy appeared to be well tolerated, with 64% of patients achieving the target dosage of 200 mg daily and 87% tolerating a daily dosage of 100 mg; the mean daily dosage of metoprolol as the tartrate was 159 mg.
The beneficial effects of β-blockers in the management of heart failure are thought to result principally from inhibition of the effects of the sympathetic nervous system. Although the specific effects on the heart and circulation that are responsible for progression of heart failure remain to be established, sympathetic activity can increase ventricular volumes and pressure secondary to peripheral vasoconstriction and by impairing sodium excretion by the kidneys. Other sympathetic effects (e.g., induction of cardiac hypertrophy, arrhythmogenic activity) also may be involved. Collective experience indicates that long-term therapy with β-blockers, like that with ACE inhibitors, can reduce heart failure symptoms and improve clinical status in patients with chronic heart failure and also can decrease the risk of death as well as the combined risk of death and hospitalization. These beneficial effects were demonstrated in patients already receiving an ACE inhibitor, suggesting that combined inhibition of the renin-angiotensin system and sympathetic nervous system can produce additive effects.
β-Blockers should not be used in patients with acutely decompensated heart failure requiring IV inotropic therapy
(see Cautions: Precautions and Contraindications)and those with substantial fluid retention requiring intensive diuresis. In the absence of hemodynamic instability or contraindications, it has been recommended that patients with heart failure and a reduced ejection fraction who are hospitalized for a symptomatic exacerbation continue to receive maintenance treatment with standard oral therapy (e.g., β-blocker, ACE inhibitor). Withholding of, or reduction in, β-blocker therapy may be considered in patients hospitalized after recent initiation or increase in β-blocker therapy. Initiation of β-blocker therapy in hospitalized patients is recommended once the patient's condition is stabilized (i.e., after optimization of volume status and successful discontinuance of IV diuretics, vasodilators, and inotropic agents). Caution should be used when initiating β-blockers in patients who have required inotrope therapy during their hospitalization.
Metoprolol has been used for the prophylaxis of migraine headache. When used prophylactically, metoprolol can prevent migraine or reduce the number of attacks in some patients. Results of comparative studies suggest that metoprolol may be comparable to propranolol for this indication. However, the US Headache Consortium states that the quality of evidence for metoprolol is not as compelling as it is for propranolol for this indication. Metoprolol is not recommended for the treatment of a migraine attack that has already started. For further information on management and classification of migraine headache, .