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Beta-blockers in cardiovascular disease

The receptor pharmacology, agents, dosing and conversion, guideline indications, post-infarction evidence, intravenous use, adverse effects, and contraindications of beta-adrenergic blocking drugs in adult cardiovascular practice.

Beta-adrenergic receptor subtypes and signaling

Beta-adrenergic receptors are G protein–coupled receptors activated by norepinephrine released from sympathetic nerve terminals and by circulating epinephrine. Three subtypes have cardiovascular importance.

Beta-1 receptors predominate in the normal human ventricle. Coupled to the stimulatory G protein (Gs), they activate adenylyl cyclase, raise cyclic adenosine monophosphate (cAMP), and activate protein kinase A. Protein kinase A phosphorylates the L-type calcium channel, phospholamban, the ryanodine receptor, and troponin I. The results are a faster sinus rate (chronotropy), faster atrioventricular conduction (dromotropy), stronger contraction (inotropy), and faster relaxation (lusitropy). Beta-1 receptors on the juxtaglomerular cells of the kidney mediate renin release, which links sympathetic tone to the renin-angiotensin-aldosterone system.

Beta-2 receptors make up a smaller share of cardiac beta-receptors in the normal heart, and their share rises in heart failure as beta-1 receptors are downregulated. They couple to both Gs and the inhibitory G protein (Gi). Outside the heart, beta-2 receptors relax bronchial, vascular, and uterine smooth muscle, mediate hepatic glycogenolysis and potassium uptake into skeletal muscle, and produce tremor. Blockade of these receptors accounts for bronchospasm, cold extremities, impaired recovery from hypoglycemia, and the rise in potassium seen with nonselective agents.

Beta-3 receptors are found in adipose tissue, bladder, and myocardium, where they signal through Gi and endothelial nitric oxide synthase. Conventional beta-blockers have little effect on them at therapeutic doses, although nebivolol's vasodilating action has been attributed in part to beta-3 receptor stimulation.

Desensitization in heart failure. Chronic adrenergic stimulation in heart failure downregulates and uncouples beta-1 receptors and drives calcium overload, myocyte apoptosis, fibrosis, and arrhythmia. Beta-blockade reverses part of this process, but its early negative inotropic effect is the reason therapy starts at a low dose and increases slowly.

How beta-blockade reduces ischemia, arrhythmia, and remodeling

Myocardial oxygen demand. Heart rate, contractility, and wall stress determine myocardial oxygen consumption. Beta-blockers lower all three during exercise and emotional stress. Slowing the heart rate also lengthens diastole, the phase in which the left ventricle is perfused, so subendocardial perfusion improves. These effects raise the ischemic threshold and are the basis of their use in angina.

Arrhythmia and sudden death. Catecholamines increase automaticity, triggered activity from delayed afterdepolarizations, and the dispersion of repolarization in ischemic or scarred myocardium. Beta-blockers counter these effects and slow conduction through the atrioventricular node. In the heart failure trials, sudden death fell by about 40% with bisoprolol and with metoprolol succinate. In the Beta-Blocker Heart Attack Trial (BHAT), sudden death after infarction fell from 4.6% to 3.3%.

Remodeling. In HFrEF, beta-blockers produce dose-dependent improvements in LVEF, fewer heart failure hospitalizations, and lower all-cause mortality, as the 2022 heart failure guideline summarizes. The rise in LVEF appears over 3 to 12 months. The individual-patient analysis of the heart failure trials found that LVEF rose with beta-blockers in sinus rhythm at every baseline LVEF below 50%, but not at 50% or above.

Renin suppression and blood pressure. Lower renin release and lower cardiac output reduce blood pressure. Vasodilating agents add a fall in systemic vascular resistance. Nonvasodilating agents initially raise peripheral resistance through unopposed alpha-adrenergic tone, which partly offsets their antihypertensive effect.

Cardioselectivity, intrinsic sympathomimetic activity, and vasodilating beta-blockers

Beta-blockers are classified by three properties that predict their adverse effects and, in part, their outcome evidence.

Cardioselectivity is a greater affinity for beta-1 than for beta-2 receptors. It is relative and dose-dependent: at higher doses, every "cardioselective" agent blocks beta-2 receptors. The labels for atenolol and esmolol state that selectivity is not absolute. Measured selectivity also depends on the assay. In whole-cell binding studies with cloned human receptors, bisoprolol was the most beta-1–selective agent studied (about 14-fold). Most clinically used beta-blockers showed little beta-1 selectivity, and some, such as timolol, bound beta-2 receptors more avidly. Nebivolol is beta-1 selective at doses of 10 mg or less in extensive metabolizers of cytochrome P450 2D6 (CYP2D6). In poor metabolizers and at higher doses it blocks both receptor subtypes. Genetic loss of CYP2D6 function or a CYP2D6 inhibitor raises metoprolol levels several-fold and reduces its cardioselectivity.

Intrinsic sympathomimetic activity (ISA) is partial agonism. Pindolol and acebutolol occupy the receptor and stimulate it weakly while blocking the full agonist. Resting heart rate falls less, while exercise heart rate falls as with other agents. None of the three mortality-reducing heart failure agents has ISA, and agents with ISA have no heart failure outcome evidence. The theoretical advantage of ISA is less resting bradycardia; in structural heart disease it is an undesirable property.

Vasodilating beta-blockers lower systemic vascular resistance through a second mechanism. Carvedilol and labetalol block alpha-1 receptors, which causes orthostatic hypotension, especially at initiation. Nebivolol produces endothelium-dependent, nitric oxide–mediated vasodilation without alpha-1 blockade at clinical doses.

Membrane-stabilizing activity is a local-anesthetic, sodium channel–blocking effect of propranolol and some other agents. It has no therapeutic role at usual doses, but it contributes to QRS widening, seizures, and lethality in propranolol overdose.

Beta-blocker comparison. Pharmacokinetic values are from US prescribing information. Selectivity data for nebivolol and bisoprolol are from the prescribing information and from whole-cell binding studies with human receptors. ISA, intrinsic sympathomimetic activity.

Lipophilicity, CYP2D6 metabolism, and renal elimination

Lipophilic agents (propranolol, metoprolol, carvedilol, nebivolol) are absorbed almost completely, undergo extensive first-pass hepatic metabolism, and enter the central nervous system. Their oral bioavailability is low and variable, so doses are individualized. Propranolol's label notes that protein-rich food raises its bioavailability by about 50%. Plasma propranolol levels vary widely between patients at the same dose.

Hydrophilic agents (atenolol, nadolol, sotalol) are excreted unchanged by the kidney, have longer half-lives, and accumulate in kidney disease. Atenolol accumulates when creatinine clearance falls below 35 mL/min/1.73 m². The label limits the dose to 50 mg daily at a clearance of 15 to 35 mL/min/1.73 m² and to 25 mg daily below 15. Nadolol's usual dosing interval of 24 hours is lengthened to 24 to 36 hours at a clearance of 31 to 50 mL/min/1.73 m², to 24 to 48 hours at 10 to 30, and to 40 to 60 hours below 10. Atenolol is removed by hemodialysis.

Bisoprolol is eliminated half by the kidney and half by the liver. Its half-life rises about threefold below a creatinine clearance of 40 mL/min, and the label starts such patients, and those with hepatic impairment, at 2.5 mg daily. Nebivolol starts at 2.5 mg daily with a creatinine clearance below 30 mL/min or moderate hepatic impairment, and it is not recommended in severe hepatic impairment.

CYP2D6. Metoprolol, carvedilol, propranolol, nebivolol, and timolol are cleared in part by CYP2D6. CYP2D6 activity is absent in about 8% of White people and about 2% of most other populations. In poor metabolizers, metoprolol levels are several-fold higher and the half-life is 7 to 9 hours. Strong CYP2D6 inhibitors (quinidine, fluoxetine, paroxetine, propafenone) double metoprolol concentrations. Fluoxetine raised d-nebivolol exposure eightfold, yet nebivolol's label does not require dose adjustment in poor metabolizers because its active metabolites contribute to beta-blockade. Unexplained bradycardia or fatigue on a modest dose of metoprolol or carvedilol raises the possibility of an interacting drug or poor metabolism. Bisoprolol or atenolol avoids the interaction.

Central nervous system effects. Lipophilicity was long held to explain vivid dreams, sleep disturbance, and fatigue. In a quantitative review of randomized trials, however, the risks of fatigue and sexual dysfunction did not differ by lipid solubility. In a later meta-analysis of 285 double-blind randomized trials, depression was no more frequent with beta-blockers than with placebo. Unusual dreams, insomnia, and sleep disorders were the psychiatric adverse events possibly related to beta-blocker therapy.

Indications for beta-blockers ranked by strength of evidence

Mortality benefit is firmly established in HFrEF and after infarction with reduced ejection fraction. Symptom benefit is established in angina, rate control, and hypertrophic cardiomyopathy. Benefit is absent or uncertain as first-line hypertension therapy and after infarction with preserved ejection fraction.

Indications by strength of evidence. Classes are from the 2022 heart failure, 2025 acute coronary syndrome, 2023 chronic coronary disease, 2023 atrial fibrillation, 2025 high blood pressure, 2024 hypertrophic cardiomyopathy, 2022 aortic disease, and 2017 ventricular arrhythmia guidelines. HFmrEF, heart failure with mildly reduced ejection fraction; ARB, angiotensin receptor blocker; VT, ventricular tachycardia.

Oral dosing by agent and indication

Titration is guided by resting heart rate, blood pressure, symptoms, and, in heart failure, congestion. In angina the label end point is clinical response or "pronounced slowing of the heart rate."

Oral beta-blocker doses for adults. Heart failure start and target doses are from Table 14 of the 2022 AHA/ACC/HFSA guideline; other doses are from US prescribing information.

Evidence-based beta-blockers in HFrEF

Three beta-blockers reduced all-cause mortality in large placebo-controlled trials of chronic HFrEF, each on a background of diuretics and angiotensin-converting enzyme (ACE) inhibitors: bisoprolol, metoprolol succinate, and carvedilol. The 2022 AHA/ACC/HFSA guideline recommends one of these three in every patient with current or previous symptoms of HFrEF to reduce mortality and hospitalization (Class 1). The guideline states that the favorable findings should not be considered a class effect. Other beta-blockers are not included in the recommendation.

The benefit was consistent across ischemic and nonischemic cardiomyopathy, diabetes, sex, age, and racial and ethnic groups. An exception is atrial fibrillation. In an individual-patient meta-analysis of 18,254 patients from ten trials, beta-blockers reduced mortality in sinus rhythm (hazard ratio 0.73) but not in atrial fibrillation (hazard ratio 0.97; 95% confidence interval [CI] 0.83 to 1.14). Beta-blockers remain part of therapy in HFrEF with atrial fibrillation, where they also provide rate control.

Randomized trials that define beta-blocker therapy in heart failure. NYHA, New York Heart Association.

Why the class effect is not assumed. Bucindolol, a nonselective agent with mild vasodilating properties, did not reduce mortality in BEST, a trial of 2,708 patients with advanced heart failure. Metoprolol tartrate at 50 mg twice daily was inferior to carvedilol in COMET. Nebivolol reduced a combined end point of death or cardiovascular admission in SENIORS but not all-cause mortality, and the trial enrolled older patients across a range of ejection fractions.

Choosing among the three agents. No trial has shown one of bisoprolol, carvedilol, or metoprolol succinate to be superior to another at target doses. Selection follows comorbidity. Carvedilol lowers blood pressure more because of alpha-1 blockade, which suits patients with hypertension and limits titration in patients with low blood pressure. Bisoprolol and metoprolol succinate are preferred with reactive airway disease. Bisoprolol avoids CYP2D6 interactions but accumulates in advanced kidney disease. Metoprolol succinate is dosed once daily, and its scored tablets allow half-step titration.

Ivabradine. Ivabradine slows the sinus node through the funny current without negative inotropy. SHIFT enrolled 6,558 patients with LVEF of 35% or less, sinus rhythm, and a resting rate of 70 beats/min or more on background therapy that included a beta-blocker if tolerated. Ivabradine reduced cardiovascular death or heart failure hospitalization (hazard ratio 0.82), mainly by fewer hospitalizations. Only about one-quarter of SHIFT participants were taking target beta-blocker doses. The 2022 guideline therefore reserves ivabradine for patients whose heart rate stays at 70 beats/min or more after beta-blockers are titrated to target or maximally tolerated doses. Ivabradine does not replace a beta-blocker.

The sequencing of all four foundational drug classes, titration schedules for the other classes, and device eligibility are covered on the heart failure with reduced ejection fraction page.

Starting, titrating, and continuing beta-blockers in heart failure

Initiation. A beta-blocker is started at a low dose in a patient who is clinically stable and close to euvolemic. Patients requiring intravenous inotropes, those in shock, and those with marked congestion are not started. Beta-blockers can be started before hospital discharge once the patient is stabilized and no longer needs intravenous inotropic therapy for heart failure, and discharge use is associated with lower 30-day and long-term mortality. Initiation is not delayed until symptoms worsen. The guideline states that benefit extends to patients with mild symptoms or symptoms improved by other therapy.

Titration. The dose is doubled at intervals of at least 2 weeks toward the target, or the highest tolerated dose, as heart rate, blood pressure, and congestion allow. Transient fatigue and modest fluid retention in the first weeks are expected and are managed by adjusting the diuretic. Symptomatic bradycardia or hypotension is managed by first reviewing other nodal and vasodilating drugs (digoxin, amiodarone, nitrates, alpha-blockers) and then reducing the beta-blocker dose. An initial failure of titration does not preclude later attempts, as the metoprolol succinate label states.

Beta-blocker doses for HFrEF from Table 14 of the 2022 AHA/ACC/HFSA guideline. Carvedilol 50 mg twice daily applies to patients weighing more than 85 kg. Metoprolol succinate starts at 12.5 mg in more severe heart failure and 25 mg in NYHA class II.

Dose reached in practice. The 2022 guideline describes the benefits of beta-blockers in HFrEF as dose-dependent, yet most patients in registries remain far from target. In the US CHAMP-HF registry, very few eligible patients received target beta-blocker doses, and the guideline notes that patients with systolic pressure below 110 mm Hg rarely reached them.

During hospitalization for decompensation. A beta-blocker already established is continued during admission for congestion when perfusion is adequate. In OPTIMIZE-HF, discontinuation was associated with higher mortality. The dose is reduced or held for cardiogenic shock, marked hypoperfusion, symptomatic bradycardia, or high-grade atrioventricular block, and in patients with marked volume overload or a marginal low-output state. Dobutamine is less effective in a patient with full beta-blockade, and milrinone, which acts downstream of the receptor, is often chosen when an inotrope is needed.

After the ejection fraction improves. Beta-blockers and target doses are maintained when symptoms or LVEF improve, including in heart failure with improved ejection fraction. The 2022 guideline gives the reason: a lower risk of recurrent ventricular dysfunction and major cardiovascular events.

Contraindications in heart failure. True contraindications are few, and a documented intolerance is revisited later, as the guideline recommends. Reactive airway disease is a caution, not a contraindication, for the beta-1–selective agents.

Target-dose and conversion calculator for heart failure beta-blockers

The calculator expresses a current beta-blocker dose as a percentage of the target dose used in the heart failure outcome trials. It also gives the dose of each evidence-based agent at the same fraction of its target.

Targets: metoprolol succinate 200 mg/day; carvedilol 50 mg/day (100 mg/day above 85 kg); carvedilol extended release 80 mg/day, converted to immediate release by the label table (10, 20, 40, and 80 mg once daily for 3.125, 6.25, 12.5, and 25 mg twice daily); bisoprolol 10 mg/day; nebivolol 10 mg/day (SENIORS). Metoprolol tartrate converts to metoprolol succinate at the same total daily dose. The step shown is the nearest titration step at or below the calculated dose.

Metoprolol succinate versus metoprolol tartrate

Metoprolol tartrate is the immediate-release salt, with a mean elimination half-life of 3 to 4 hours (range about 3 to 7 hours; 7 to 9 hours in poor CYP2D6 metabolizers) and peak-and-trough variation in beta-blockade when given twice daily. Metoprolol succinate is an extended-release formulation that delivers the drug over 24 hours. At steady state, its bioavailability across 50 to 400 mg once daily is about 77% of the same dose given as conventional tablets, and food does not change it. The two are the same molecule. The difference is the release profile, the outcome evidence, and the labeled indications.

Outcome evidence. MERIT-HF tested metoprolol succinate titrated to 200 mg once daily and reduced mortality by about one-third. Metoprolol tartrate has no placebo-controlled mortality trial in HFrEF. In COMET, 3,029 patients received metoprolol tartrate at a target of 50 mg twice daily or carvedilol at 25 mg twice daily. Mortality was higher with metoprolol tartrate (40% vs 34% over a mean of 58 months). The metoprolol dose in COMET (target 100 mg/day of tartrate) was lower than the 200 mg/day target of MERIT-HF, so the trial established that low-dose tartrate is inferior to carvedilol. It did not compare carvedilol with metoprolol succinate. For HFrEF, the 2022 guideline names sustained-release metoprolol succinate, and the 2023 chronic coronary disease guideline prefers metoprolol succinate, carvedilol, or bisoprolol when LVEF is below 50% (Class 1).

Labeled indications. Metoprolol succinate is labeled for hypertension, angina, and heart failure. Metoprolol tartrate tablets are labeled for hypertension, angina, and myocardial infarction, and the intravenous tartrate is labeled for early treatment of infarction. In ACS, the short action of the tartrate allows rapid titration during the first days, and conversion to the succinate before discharge simplifies long-term dosing.

Conversion. The label converts immediate-release metoprolol to metoprolol succinate at the same total daily dose: 50 mg twice daily of tartrate becomes 100 mg once daily of succinate. A patient with HFrEF taking metoprolol tartrate is converted to metoprolol succinate, carvedilol, or bisoprolol and titrated toward the target.

Tablet handling. Metoprolol succinate tablets are scored and can be divided, but whole or half tablets are not crushed or chewed, because crushing destroys the extended-release mechanism.

Dose conversion between beta-blockers

No pharmacokinetic study defines exact equivalence between beta-blockers, because their selectivity, ancillary properties, and bioavailability differ. Clinically used conversions rely on two principles: the same fraction of each agent's outcome-trial target dose in heart failure, and the label conversions between formulations of the same drug. After any switch, heart rate and blood pressure are reassessed within 1 to 2 weeks and titration resumes.

Approximate dose correspondence among the evidence-based heart failure beta-blockers at equal fractions of the trial target dose. Carvedilol immediate-release to extended-release conversions are from the carvedilol phosphate prescribing information. Metoprolol succinate also starts at 12.5 mg in severe heart failure.

Same-drug conversions from US labels.

• Metoprolol tartrate to metoprolol succinate: same total daily dose.
• Carvedilol to carvedilol phosphate: 3.125, 6.25, 12.5, and 25 mg twice daily convert to 10, 20, 40, and 80 mg once daily. For older adults and patients at risk of hypotension, a starting dose one step lower (20 mg or 40 mg) may be used when switching from 12.5 mg or 25 mg twice daily.
• Propranolol tablets to propranolol extended-release capsules: not a mg-for-mg substitution, because the extended-release capsule produces lower blood levels; retitration may be necessary.
• Intravenous to oral metoprolol after infarction: three 5-mg intravenous doses at about 2-minute intervals; then 50 mg orally every 6 hours for 48 hours, beginning 15 minutes after the last intravenous dose (25 mg if the full intravenous dose was not tolerated); then 100 mg twice daily.

Switching between agents. Common switches are to carvedilol for uncontrolled hypertension, bisoprolol or metoprolol succinate for bronchospasm or alpha-1–mediated orthostasis, bisoprolol for a CYP2D6 interaction, and nadolol or propranolol for long QT syndrome. The new drug follows the old without a gap that would expose the patient to withdrawal.

Beta-blockers in heart failure with mildly reduced or preserved ejection fraction and with atrial fibrillation

Mildly reduced ejection fraction (41% to 49%). Patients in this range were a small minority of the heart failure trials. In the individual-patient analysis of 11 double-blind trials, among 575 patients in sinus rhythm with LVEF of 40% to 49%, the range that analysis used, death occurred in 7.2% with beta-blockers and 12.4% with placebo (adjusted hazard ratio 0.59; 95% CI 0.34 to 1.03). Cardiovascular death was reduced (hazard ratio 0.48; 95% CI 0.24 to 0.97). The 2022 guideline rates evidence-based beta-blockers, along with angiotensin receptor–neprilysin inhibitors (ARNI), ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists (MRAs), as possibly useful in HFmrEF (Class 2b). After infarction, the individual-patient meta-analysis of mildly reduced ejection fraction described below supports beta-blockade at LVEF of 40% to 49%.

Preserved ejection fraction (50% or more). No randomized trial has shown that beta-blockers reduce events in heart failure with preserved ejection fraction (HFpEF). In the same individual-patient analysis, beta-blockers neither raised LVEF nor improved outcomes in the 244 patients with LVEF of 50% or more. Beta-blockers are used in HFpEF only for another indication: atrial fibrillation, angina, prior infarction, or hypertension not controlled by first-line agents. The 2022 guideline notes that RATE-AF, in older patients with permanent atrial fibrillation and heart failure symptoms (most with preserved LVEF), found similar quality of life with bisoprolol and low-dose digoxin. Dizziness, lethargy, and hypotension were more frequent with bisoprolol.

Chronotropic incompetence in HFpEF. Many patients with HFpEF have chronotropic incompetence, so a beta-blocker continued without a clear indication can worsen exertional symptoms.

Cardiac amyloidosis. The 2022 guideline notes that beta-blockers may worsen heart failure in transthyretin amyloid cardiomyopathy, in which a small, stiff ventricle depends on heart rate for cardiac output. Low doses are used only for rate control when needed.

Heart failure with atrial fibrillation. Beta-blockers in HFrEF with atrial fibrillation provide rate control but did not reduce mortality in the individual-patient meta-analysis. Digoxin is added when rate control is inadequate, and nondihydropyridine calcium channel blockers are avoided with LVEF below 40% (Class 3: Harm in the 2023 atrial fibrillation guideline). Rate-control targets and rhythm-control strategies are covered on the atrial fibrillation page.

Beta-blockers in acute coronary syndromes: early oral and intravenous therapy

Early oral therapy. The 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline recommends starting an oral beta-blocker within 24 hours in patients with ACS without contraindications (Class 1). The dose starts low and is escalated slowly as blood pressure and heart rate allow. The recommendation rests on trials from the prereperfusion and early reperfusion eras showing fewer reinfarctions and ventricular arrhythmias. No adequately powered trial has tested in-hospital beta-blockade in non-ST-elevation ACS (NSTE-ACS) alone.

Contraindications in ACS. The guideline lists acute heart failure (Killip class II to IV), evidence of a low-output state or risk of cardiogenic shock, PR interval longer than 0.24 seconds (0.24 seconds or longer in the intravenous metoprolol label), second- or third-degree atrioventricular block without a pacemaker, severe bradycardia, and active bronchospasm. Patients with an initial contraindication are reassessed after 24 hours. Therapy is discontinued with new or worsening heart failure or signs of shock.

COMMIT and the risk of early shock. COMMIT randomized 45,852 patients within 24 hours of suspected infarction, about half of whom received fibrinolysis, to metoprolol (up to 15 mg intravenously, then 200 mg orally daily) or placebo. Death was not reduced (7.7% vs 7.8%). Per 1,000 patients treated, metoprolol prevented five reinfarctions and five episodes of ventricular fibrillation and caused 11 more cases of cardiogenic shock, mostly on days 0 and 1. The net effect was harmful on the first day in hemodynamically unstable patients and beneficial thereafter in stable patients. The trial is the basis for avoiding intravenous and high-dose early beta-blockade in patients at risk of shock. Risk factors for shock include age above 70 years, systolic pressure below 120 mm Hg, sinus tachycardia above 110 beats/min or heart rate below 60 beats/min, and a longer time since symptom onset.

Intravenous beta-blockers before reperfusion. In hemodynamically stable patients with ST-elevation myocardial infarction (STEMI) without acute heart failure, an intravenous beta-blocker can be given before reperfusion when there are ongoing symptoms or another indication, such as hypertension or tachyarrhythmia. The guideline does not support routine intravenous beta-blockade before primary percutaneous coronary intervention (PCI), because trials of infarct-size reduction have been inconsistent.

Long-term beta-blockade after infarction: the prereperfusion evidence

The recommendation to continue beta-blockers indefinitely after infarction came from trials conducted before primary PCI, potent antiplatelet therapy, high-intensity statins, and routine renin-angiotensin blockade.

Beta-Blocker Heart Attack Trial (BHAT). BHAT randomized 3,837 patients aged 30 to 69 years, 5 to 21 days after infarction, to propranolol 180 or 240 mg/day or placebo. Over an average of 24 months, mortality was 7.2% with propranolol and 9.8% with placebo, and sudden cardiac death was 3.3% vs 4.6%. The trial was stopped 9 months early.

The reperfusion era. A meta-analysis of 60 trials with 102,003 patients separated trials by era. In the prereperfusion era, beta-blockers reduced mortality (incidence rate ratio 0.86). In the reperfusion era, defined by more than half of patients receiving reperfusion or aspirin and statin, they did not (incidence rate ratio 0.98; 95% CI 0.92 to 1.05). In the reperfusion era they reduced reinfarction (incidence rate ratio 0.72; number needed to treat 209) and angina (number needed to treat 26). The cost was more heart failure (incidence rate ratio 1.10), more cardiogenic shock (1.29), and more drug discontinuation. Those prereperfusion trials enrolled patients with large infarcts before LVEF was routinely measured, and many had what would now be classified as reduced ejection fraction.

Reduced ejection fraction after infarction. CAPRICORN randomized 1,959 patients with infarction and LVEF of 40% or less, treated with ACE inhibitors and contemporary therapy, to carvedilol or placebo. The primary composite of death or cardiovascular admission was not reduced (35% vs 37%; hazard ratio 0.92), but all-cause mortality fell from 15% to 12% (hazard ratio 0.77). Long-term beta-blockade after infarction with reduced ejection fraction is established. The 2023 chronic coronary disease guideline recommends it with LVEF of 40% or less (Class 1) and prefers the evidence-based agents when LVEF is below 50% (Class 1).

Contemporary trials of beta-blockers after infarction with preserved ejection fraction

Five randomized trials published between 2018 and 2025 (REDUCE-AMI, REBOOT, BETAMI, DANBLOCK, and CAPITAL-RCT) tested routine beta-blockade after infarction in patients without reduced ejection fraction, and two (ABYSS and SMART-DECISION) tested stopping it. All were open-label, which affects end points that depend on a decision to hospitalize.

Randomized trials of beta-blocker initiation or withdrawal after infarction without reduced ejection fraction. CAPITAL-RCT, a smaller Japanese trial of carvedilol in 801 patients after primary PCI with LVEF ≥40%, found no difference in its composite end point at 3 years (6.8% vs 7.9%).

REDUCE-AMI. Enrollment required coronary angiography during the index admission and LVEF of 50% or more. Death from any cause (3.9% vs 4.1%), infarction (4.5% vs 4.7%), and heart failure hospitalization (0.8% vs 0.9%) were similar, as were hospitalizations for bradycardia, atrioventricular block, hypotension, syncope, or pacemaker implantation (3.4% vs 3.2%).

REBOOT. The largest of these trials enrolled patients with LVEF above 40% after invasive management of infarction with or without ST elevation. Death (hazard ratio 1.06), reinfarction (1.01), and heart failure hospitalization (0.89) were each unchanged. A prespecified analysis by sex found harm in women. Among 1,627 women, the primary outcome occurred at 30.4 vs 21.0 events per 1,000 patient-years with and without a beta-blocker (hazard ratio 1.45; 95% CI 1.04 to 2.03). In men the hazard ratio was 0.94 (P for interaction 0.026). The excess in women was mainly driven by mortality and was most evident with preserved LVEF and higher beta-blocker doses.

BETAMI-DANBLOCK. The Norwegian BETAMI and Danish DANBLOCK trials were analyzed together, and they included patients with LVEF of 40% or more. The reduction in the composite was driven by fewer myocardial infarctions (5.0% vs 6.7%; hazard ratio 0.73; 95% CI 0.59 to 0.92). All-cause death (4.2% vs 4.4%), unplanned revascularization, stroke, heart failure, and malignant ventricular arrhythmia did not differ.

ABYSS. The trial tested stopping, not starting. Patients were a median of 2.9 years from their last infarction. Interruption did not meet the noninferiority margin of 3 percentage points: the risk difference was 2.8 percentage points (95% CI less than 0.1 to 5.5). The excess was carried by hospitalization for cardiovascular reasons, an end point susceptible to open-label bias, while rates of death, infarction, and stroke were similar. Interruption did not improve quality of life on the EQ-5D questionnaire. Blood pressure and heart rate rose after interruption. In a secondary analysis, interruption raised heart rate by about 10 to 13 beats/min in a dose-dependent fashion, and higher heart rate was associated with death, infarction, or stroke.

SMART-DECISION. The trial also tested stopping after at least 1 year of therapy, in a population that was 12.8% women, and found discontinuation noninferior for death, infarction, or heart failure hospitalization. Its end point did not include hospitalization for other cardiovascular reasons.

Interpreting the post-infarction trials by ejection fraction, sex, and time

Ejection fraction of 50% or more. An individual-patient meta-analysis pooled 17,801 patients with LVEF of 50% or more from REBOOT (7,459), REDUCE-AMI (4,967), BETAMI (2,441), DANBLOCK (2,277), and CAPITAL-RCT (657), all without another indication for beta-blockade. Over a median of 3.6 years, death, infarction, or heart failure occurred in 8.1% with a beta-blocker and 8.3% without (hazard ratio 0.97; 95% CI 0.87 to 1.07). All-cause death (hazard ratio 1.04), infarction (0.89; 95% CI 0.77 to 1.03), and heart failure (0.87) were not significantly changed. In contemporary practice, routine long-term beta-blockade after infarction with LVEF of 50% or more and no other indication has not been shown to reduce events.

Mildly reduced ejection fraction (40% to 49%). An individual-patient meta-analysis included 1,885 patients with infarction, LVEF of 40% to 49%, and no history or signs of heart failure, drawn from REBOOT (979), BETAMI (422), DANBLOCK (430), and CAPITAL-RCT (54). Beta-blockade was associated with fewer deaths, infarctions, or heart failure events: 32.6 vs 43.0 per 1,000 patient-years (hazard ratio 0.75; 95% CI 0.58 to 0.97), without heterogeneity between trials. Together with the heart failure data in this range, the result supports beta-blockade after infarction when LVEF is 40% to 49%.

Time since infarction and stopping therapy. The pooled individual-patient analysis of ABYSS and SMART-DECISION included 6,238 patients a median of 3.6 years after infarction, with LVEF of 40% or more and no heart failure. The primary end point of death, infarction, stroke, or cardiovascular hospitalization occurred in 17.2% after discontinuation and 15.9% with continuation (hazard ratio 1.09; 95% CI 0.97 to 1.24). Discontinuation met the prespecified noninferiority margin of 1.25. Death, infarction, or heart failure hospitalization was the same in both groups (6.5% vs 6.4%; hazard ratio 1.01). The authors noted that interpretation of the primary end point is limited because it is dominated by hospitalization.

Sex. The excess risk in women in REBOOT was a prespecified subgroup finding that has not been tested prospectively.

Indications that persist regardless of LVEF. Angina, atrial fibrillation or other arrhythmias requiring rate or rhythm control, hypertension not controlled by first-line drugs, ventricular arrhythmia, and residual ischemia are independent indications.

US guideline positions. The 2025 ACS guideline retained early oral beta-blockade (Class 1) and states that the optimal duration in patients with preserved LVEF is unclear and remains under study. The 2023 chronic coronary disease guideline states that reassessing the indication for long-term (more than 1 year) use may be reasonable (Class 2b) for patients who started a beta-blocker after infarction and have no angina, arrhythmia, or uncontrolled hypertension and no current or previous LVEF of 50% or less. It also states that without previous infarction or LVEF of 50% or less, and without another primary indication, beta-blocker therapy does not reduce major adverse cardiovascular events (Class 3: No Benefit). Both guidelines were written before REBOOT, BETAMI-DANBLOCK, SMART-DECISION, and the individual-patient meta-analyses. The 2023 European Society of Cardiology ACS guideline differs: it states that routine beta-blockade after ACS should be considered regardless of LVEF (Class IIa).

When therapy is stopped. A beta-blocker started after infarction is not stopped abruptly. The dose is reduced over 1 to 2 weeks, as the metoprolol succinate label specifies for patients with ischemic heart disease, and heart rate, blood pressure, and angina are reassessed. Recurrent angina or rapid atrial fibrillation identifies an indication that was masked by the drug. Beta-blocker decisions across chronic coronary disease, including the guideline recommendations, are covered on the chronic coronary disease page.

Beta-blockers for angina and chronic coronary disease

The 2023 chronic coronary disease guideline recommends a beta-blocker, a calcium channel blocker, or a long-acting nitrate for relief of angina (Class 1). Beta-blockers relieve exertional angina by lowering myocardial oxygen demand at each workload. The dose is titrated to a resting heart rate of about 55 to 60 beats/min and to blunting of the exercise rate response. A beta-blocker is preferred after recent infarction, with LVEF of 50% or less, with tachyarrhythmias, or with a high resting heart rate.

Agents. Any beta-blocker without intrinsic sympathomimetic activity is effective for angina. Agents with ISA lower the resting rate less and are less suitable for angina. In the United States, metoprolol (succinate and tartrate), atenolol, propranolol, and nadolol carry angina labeling. Carvedilol and bisoprolol are used for angina under their heart failure and hypertension labels.

Combinations. A dihydropyridine calcium channel blocker is a rational partner for a beta-blocker, because the beta-blocker blunts the dihydropyridine's reflex tachycardia and the dihydropyridine offsets the beta-blocker's rise in peripheral resistance. Verapamil or diltiazem with a beta-blocker adds negative chronotropic, dromotropic, and inotropic effects and risks high-grade atrioventricular block, especially in older adults and with conduction disease. The combination is used only with electrocardiographic follow-up and preserved ventricular function. Long-acting nitrates and ranolazine add antianginal effect without further slowing the heart.

Vasospastic angina. Beta-blockers alone are avoided in vasospastic angina, because unopposed alpha-adrenergic tone can intensify spasm; calcium channel blockers and nitrates are the treatment.

Microvascular angina. In angina with nonobstructive coronary arteries and coronary microvascular dysfunction, beta-blockers are among the drugs used for symptom relief, alongside calcium channel blockers and nitrates.

No mortality benefit in stable disease without infarction. In chronic coronary disease without prior infarction or reduced ejection fraction, beta-blockers relieve symptoms but do not reduce major adverse cardiovascular events (Class 3: No Benefit).

Rate control in atrial fibrillation and flutter

Beta-blockers and nondihydropyridine calcium channel blockers are the recommended first-line drugs for acute and long-term rate control in atrial fibrillation (Class 1 in the 2023 ACC/AHA/ACCP/HRS guideline). Beta-blockers are preferred in coronary disease, HFrEF, thyrotoxicosis, and the hyperadrenergic states of postoperative and critical illness, and they control the exercise heart rate better than digoxin. Verapamil and diltiazem are avoided with LVEF below 40% (Class 3: Harm), which leaves beta-blockers, digoxin, and amiodarone in reduced ejection fraction.

Acute rate control. In hemodynamically stable patients, intravenous metoprolol (2.5 to 5 mg over 2 minutes, up to three doses) or esmolol (500 µg/kg over 1 minute, then 50 µg/kg/min titrated to a maximum of 200 µg/kg/min) is recommended (Class 1). Intravenous diltiazem lowers the rate faster than metoprolol in several emergency department comparisons. Instability attributable to the arrhythmia is treated with synchronized cardioversion, not nodal blockade.

Long-term rate control. Oral doses for rate control are metoprolol tartrate 25 to 200 mg twice daily, metoprolol succinate 50 to 400 mg daily, carvedilol 3.125 to 25 mg twice daily, bisoprolol 2.5 to 10 mg daily, and atenolol 25 to 100 mg daily. A resting rate below 100 to 110 beats/min is the usual target (Class 2a), with stricter control when tachycardia-mediated cardiomyopathy is suspected. Beta-blockers combined with digoxin control both resting and exercise rates.

Pre-excitation. Beta-blockers, verapamil, diltiazem, digoxin, and intravenous amiodarone are avoided in pre-excited atrial fibrillation (Class 3: Harm in the 2015 ACC/AHA/HRS supraventricular tachycardia guideline), because slowing the atrioventricular node can accelerate conduction over the accessory pathway and precipitate ventricular fibrillation.

Rate-control targets, digoxin, atrioventricular node ablation, and rhythm control are covered on the atrial fibrillation page.

Beta-blockers for supraventricular and ventricular arrhythmias

Supraventricular tachycardia. Beta-blockers slow or block conduction through the atrioventricular node. Intravenous metoprolol or esmolol terminates or controls atrioventricular nodal reentrant and orthodromic reciprocating tachycardia when vagal maneuvers and adenosine fail. Oral beta-blockers are used for ongoing suppression in patients without pre-excitation who decline or are not candidates for ablation. Focal atrial tachycardia and inappropriate sinus tachycardia respond in part to beta-blockade.

Ventricular premature beats and nonsustained ventricular tachycardia. In structurally normal hearts, symptomatic premature ventricular complexes and outflow tract ventricular tachycardia respond to beta-blockers or nondihydropyridine calcium channel blockers, and catheter ablation is an alternative. In structural heart disease, beta-blockers are the foundation of antiarrhythmic therapy and are continued with amiodarone, sotalol, or mexiletine when these are added.

Sustained ventricular tachycardia and electrical storm. Beta-blockers reduce recurrent ventricular arrhythmias and defibrillator shocks. In ischemic heart disease with recurrent arrhythmia despite a beta-blocker, amiodarone or sotalol is added (Class 1 in the 2017 AHA/ACC/HRS ventricular arrhythmia guideline). In electrical storm, intravenous beta-blockade reduces the sympathetic drive that sustains the storm. In a small randomized trial of defibrillator recipients with storm treated with intravenous amiodarone, propranolol produced fewer arrhythmic events than metoprolol. Intravenous beta-blockers are reasonable for polymorphic ventricular tachycardia due to ischemia (Class 2a).

Inherited arrhythmia syndromes. In catecholaminergic polymorphic ventricular tachycardia, a beta-blocker is recommended (Class 1), preferably nadolol, with flecainide added when arrhythmias persist. Long QT syndrome is described below.

Beta-blockers in hypertension and why they are not first line

The 2025 AHA/ACC high blood pressure guideline lists thiazide-type diuretics, ACE inhibitors, ARBs, and dihydropyridine calcium channel blockers as first-line drugs. Beta-blockers are not first-line for uncomplicated hypertension. They are used when another indication exists: angina, prior infarction, HFrEF, atrial fibrillation rate control, aortic aneurysm or dissection, and some arrhythmias. In resistant hypertension, a mineralocorticoid receptor antagonist is the recommended added drug. When it is not tolerated or is contraindicated, the guideline considers adding a beta-blocker reasonable (Class 2a). The same class applies to amiloride, an alpha-blocker, a central sympatholytic, a dual endothelin receptor antagonist, and a direct vasodilator.

LIFE. LIFE randomized 9,193 patients aged 55 to 80 years with hypertension and electrocardiographic left ventricular hypertrophy to losartan-based or atenolol-based treatment. Blood pressure fell by 30.2/16.6 mm Hg with losartan and 29.1/16.8 mm Hg with atenolol. The primary composite of cardiovascular death, infarction, or stroke occurred at 23.8 vs 27.9 per 1,000 patient-years (relative risk 0.87; 95% CI 0.77 to 0.98), driven by fewer strokes with losartan (relative risk 0.75). Infarction did not differ, and new-onset diabetes was less frequent with losartan.

ASCOT-BPLA. ASCOT-BPLA randomized 19,257 patients with hypertension and at least three other risk factors to amlodipine with perindopril as needed or atenolol with bendroflumethiazide as needed. The trial was stopped early after a median of 5.5 years. The primary end point of nonfatal infarction and fatal coronary disease was not significantly reduced (hazard ratio 0.90; 95% CI 0.79 to 1.02). Stroke (hazard ratio 0.77), total cardiovascular events and procedures (0.84), all-cause mortality (0.89), and new diabetes (0.70) were all lower with the amlodipine-based regimen.

Meta-analyses. In a meta-analysis of 13 randomized trials with 105,951 patients, stroke was 16% more frequent with beta-blockers than with other antihypertensive drugs (95% CI 4% to 30%). Compared with placebo, the stroke reduction was 19%, about half that expected from previous hypertension trials. Most patients in these trials took atenolol, and no outcome trials exist for vasodilating beta-blockers in hypertension.

Proposed explanations. The shortfall has been linked to several factors: a smaller fall in central aortic pressure than in brachial pressure with atenolol, incomplete 24-hour coverage with once-daily atenolol, and the rise in peripheral resistance and adverse metabolic effects of nonvasodilating agents. Vasodilating agents (carvedilol, labetalol, nebivolol) have more favorable hemodynamics, but no outcome trial has tested them against first-line drugs.

Settings that call for a beta-blocker. A beta-blocker is part of the antihypertensive regimen with a coexisting indication, with hypertension in pregnancy (labetalol), and with hydralazine or minoxidil, which are used only with a beta-blocker and a loop diuretic.

Blood pressure targets, first-line combinations, and resistant hypertension are covered on the hypertension page.

Intravenous beta-blockers: esmolol, metoprolol, and labetalol

Intravenous beta-blockers are used for rapid rate control, acute aortic syndromes, hypertensive emergencies, perioperative tachycardia and hypertension, electrical storm, and selected patients with ACS. Continuous arterial pressure and electrocardiographic monitoring accompany their use.

Intravenous beta-blockers. Esmolol, metoprolol, and labetalol doses are from US prescribing information. The weight-based labetalol regimen is from Table 26 of the 2025 AHA/ACC high blood pressure guideline, which a 2026 correction amended to give the bolus at 10-minute intervals (the original text said every 2 minutes).

Esmolol. Esmolol is hydrolyzed by red blood cell esterases, independent of hepatic and renal function, with an elimination half-life of about 9 minutes. Substantial recovery from beta-blockade occurs 10 to 20 minutes after the infusion stops, which makes esmolol the agent of choice when tolerance is uncertain. The acid metabolite is renally excreted, and its half-life rises about 12-fold, to 48 hours, in end-stage kidney disease, but the metabolite has negligible pharmacologic activity. Infusion site reactions range from irritation to thrombophlebitis, necrosis, and blistering, particularly with extravasation, and infusion into small veins is avoided. In aortic dissection, esmolol is titrated to a heart rate of 60 to 80 beats/min before a vasodilator is added.

Labetalol. The ratio of alpha- to beta-blockade is about 1:3 after oral and 1:7 after intravenous labetalol, so the intravenous drug is predominantly a beta-blocker that lowers pressure with little reflex tachycardia. With a half-life of about 5.5 hours, its effect lasts hours, and the label notes that steady state is not reached during the usual infusion period. Its role in hypertensive emergencies, stroke, and preeclampsia, with organ-specific blood pressure targets, is covered on the hypertensive emergency and hypertension in pregnancy pages.

Hypertrophic cardiomyopathy, long QT syndrome, and aortic disease

Hypertrophic cardiomyopathy. In symptomatic hypertrophic cardiomyopathy, obstructive or nonobstructive, nonvasodilating beta-blockers titrated to effect or to the maximally tolerated dose are first-line therapy (Class 1 in the 2024 AHA/ACC guideline). Slowing the heart lengthens diastolic filling, lowers myocardial oxygen demand, and blunts the exercise-induced rise in the outflow gradient. Vasodilating agents lower afterload and can worsen obstruction. When beta-blockers are ineffective or not tolerated, verapamil or diltiazem is substituted. When symptoms persist, a cardiac myosin inhibitor, disopyramide with an atrioventricular nodal blocker, or septal reduction therapy follows (each Class 1). In MAPLE-HCM, a double-blind trial in 175 adults with symptomatic obstructive disease, monotherapy with the cardiac myosin inhibitor aficamten raised peak oxygen uptake at 24 weeks by 1.1 mL/kg/min. Metoprolol monotherapy lowered it by 1.2 mL/kg/min (between-group difference 2.3 mL/kg/min; 95% CI 1.5 to 3.1). Aficamten also improved NYHA class, symptom scores, and the outflow tract gradient more than metoprolol. The 2024 guideline, which names beta-blockers as first-line therapy, predates the trial.

Long QT syndrome. The 2017 AHA/ACC/HRS guideline recommends a beta-blocker in long QT syndrome with a resting QTc above 470 ms (Class 1). A beta-blocker is reasonable in asymptomatic patients with a QTc of 470 ms or less (Class 2a). The agents are not interchangeable. In genotype cohorts, patients with type 1 and type 2 long QT syndrome taking metoprolol had more breakthrough events than those taking propranolol or nadolol, and nadolol was the agent that reduced risk in type 2. Nonselective nadolol or propranolol is therefore preferred. Doses are titrated to the maximally tolerated level. Syncope or cardiac arrest despite beta-blockade leads to defibrillator implantation or left cardiac sympathetic denervation, as covered on the long QT syndrome page.

Marfan syndrome and heritable aortopathy. The 2022 ACC/AHA aortic disease guideline recommends either a beta-blocker or an ARB at maximally tolerated doses to reduce the rate of aortic dilation in Marfan syndrome (Class 1). The combination of both is reasonable (Class 2a). In the Marfan Treatment Trialists' individual-patient meta-analysis, ARBs about halved the annual increase in aortic root Z score, and the effect of beta-blockers was similar to that of ARBs. Beta-blockers are continued through pregnancy and the postpartum period in women with heritable aortopathy.

Acute aortic syndromes. In acute aortic dissection, intravenous beta-blockers are given first (Class 1) to lower heart rate and the rate of rise of aortic pressure (dP/dt). The targets are a heart rate of 60 to 80 beats/min and a systolic pressure below 120 mm Hg, or the lowest pressure that maintains organ perfusion. A vasodilator given before beta-blockade causes reflex tachycardia that raises aortic wall stress. When beta-blockers are contraindicated, intravenous diltiazem or verapamil is reasonable (Class 2a). Long-term oral beta-blockade continues after the acute phase and after repair.

Perioperative beta-blockade and the POISE trial

POISE randomized 8,351 patients with or at risk of atherosclerotic disease undergoing noncardiac surgery to extended-release metoprolol succinate or placebo. The drug was started 2 to 4 hours before surgery at high fixed doses and continued for 30 days. Metoprolol reduced the primary composite of cardiovascular death, nonfatal infarction, and nonfatal cardiac arrest (5.8% vs 6.9%; hazard ratio 0.84) and myocardial infarction (4.2% vs 5.7%). It increased death (3.1% vs 2.3%; hazard ratio 1.33) and stroke (1.0% vs 0.5%; hazard ratio 2.17). Hypotension and bradycardia from a high dose started without titration in beta-blocker–naive patients are the accepted explanation.

The 2024 AHA/ACC perioperative guideline does not support starting beta-blockers solely to reduce perioperative cardiac risk. It recommends continuing beta-blockers in patients who take them for long-term indications and recommends against starting them on the day of surgery. The 2025 AHA/ACC high blood pressure guideline states the same positions with classes: chronic beta-blockade is continued through major surgery (Class 1), abrupt preoperative withdrawal is potentially harmful (Class 3: Harm), and starting a beta-blocker on the day of surgery in a patient not already taking one is harmful (Class 3: Harm). When initiation before surgery is needed for another indication, it begins at least 7 days beforehand. This timing is based on an observational study in which initiation less than 7 days before surgery was associated with higher mortality than initiation more than 31 days before. The metoprolol succinate label likewise warns against initiation of high-dose extended-release metoprolol before noncardiac surgery and against routine withdrawal of chronic beta-blocker therapy. Perioperative risk assessment as a whole is covered on the perioperative cardiovascular evaluation page.

Adverse effects of beta-blockers

Adverse effects of beta-blockers, from US prescribing information and the trials cited in the text. MRA, mineralocorticoid receptor antagonist.

Depression, fatigue, and sexual dysfunction in randomized trials. Concern about these symptoms is a common reason for underuse. A quantitative review of 15 placebo-controlled trials of beta-blockers in infarction, heart failure, and hypertension included more than 35,000 patients. Beta-blockers did not significantly increase depressive symptoms (6 per 1,000 patients per year; 95% CI −7 to 19). They increased fatigue by 18 per 1,000 per year (one additional report for every 57 patients treated for a year) and sexual dysfunction by 5 per 1,000 per year (one for every 199). Fatigue was more frequent with early-generation agents.

Bradycardia and conduction block. Symptomatic bradycardia is the most common dose-limiting effect. Beta-blockers act on the sinus and atrioventricular nodes, not on the His-Purkinje system. A wide-QRS escape rhythm in a patient taking only a beta-blocker indicates intrinsic His-Purkinje disease, which will not resolve when the drug is stopped.

Hypotension. Dizziness and lightheadedness, rarely syncope, can occur within the first hour after carvedilol is started or increased, and the label advises patients to avoid driving or hazardous tasks during that period.

Intraoperative floppy iris syndrome. Carvedilol and labetalol carry the alpha-1 blocker warning for intraoperative floppy iris syndrome during cataract surgery, and the ophthalmologist is informed before surgery.

Diabetes, hypoglycemia awareness, and metabolic effects

Beta-blockers reduce cardiovascular events in patients with diabetes who have a standard indication, and diabetes is not a contraindication. In HFrEF, the benefit of beta-blockers was observed in patients with and without diabetes.

Hypoglycemia. Beta-blockade masks the tremor, palpitations, and tachycardia that warn of hypoglycemia, while sweating, which is cholinergic, is preserved. Nonselective agents also blunt beta-2–mediated hepatic glycogenolysis and can delay recovery from insulin-induced hypoglycemia. The labels for nadolol and other agents warn of hypoglycemia during fasting or vomiting. Patients taking insulin or sulfonylureas are taught that sweating, hunger, and confusion may be the only warnings.

Glycemic and lipid effects. Nonvasodilating beta-blockers modestly worsen glycemic control and are associated with new-onset diabetes, which was more frequent in the atenolol arms of LIFE and ASCOT-BPLA. Carvedilol and nebivolol have neutral or more favorable metabolic effects in comparative studies.

Contraindications and cautions in beta-blocker therapy

Contraindications in US labels. The labels for most oral beta-blockers list severe sinus bradycardia, second- or third-degree atrioventricular block and sick sinus syndrome without a functioning pacemaker, cardiogenic shock, and decompensated heart failure. The metoprolol tartrate label adds systolic pressure below 100 mm Hg. The carvedilol label adds bronchial asthma or related bronchospastic conditions, citing deaths from status asthmaticus after single doses, and severe hepatic impairment.

Cautions.

• Reactive airway disease: beta-1–selective agents at the lowest effective dose, with a beta-2 agonist available.
• Peripheral artery disease and Raynaud phenomenon: not a contraindication (see below).
• Diabetes treated with insulin or sulfonylureas: masked hypoglycemia.
• Pheochromocytoma: an alpha-blocker is started first.
• Thyrotoxicosis: beta-blockade masks tachycardia, and abrupt withdrawal may precipitate thyroid storm.
• History of severe anaphylaxis: patients may react more strongly to repeated allergen exposure and may be unresponsive to the usual doses of epinephrine.
• Vasospastic (Prinzmetal) angina: unopposed alpha-mediated vasospasm.
• Pregnancy: atenolol is avoided because of fetal growth restriction.
• Pre-excited atrial fibrillation: atrioventricular nodal blockade accelerates accessory pathway conduction.

Beta-blocker withdrawal syndrome and tapering

Long-term beta-blockade upregulates beta-receptors. When the drug is stopped abruptly, the larger receptor population meets normal catecholamine levels, and heart rate, blood pressure, and myocardial oxygen demand rise sharply. In patients with coronary disease this produces exacerbation of angina and, in some cases, myocardial infarction and ventricular arrhythmia, as the labels state. The carvedilol label notes that infarction and ventricular arrhythmia may occur with or without preceding exacerbation of angina.

Tapering. The metoprolol succinate label specifies gradual dose reduction over 1 to 2 weeks with monitoring in patients with ischemic heart disease. The bisoprolol label advises tapering over approximately 1 week even in patients without overt coronary disease. The propranolol label specifies several weeks and the acebutolol label about 2 weeks. If angina worsens or acute coronary ischemia develops during the taper, the beta-blocker is reinstated promptly.

Unplanned interruption. Withdrawal occurs with nonadherence, interrupted supply, perioperative fasting, and discontinuation for a minor adverse effect.

Clonidine. When clonidine and a beta-blocker are taken together and both are to be stopped, the beta-blocker is withdrawn several days before the gradual withdrawal of clonidine, because unopposed alpha stimulation during clonidine withdrawal intensifies rebound hypertension. When clonidine is replaced by a beta-blocker, the beta-blocker is started several days after clonidine has been stopped.

Asthma, chronic obstructive pulmonary disease, and peripheral artery disease

Asthma. Nonselective beta-blockers can provoke severe and occasionally fatal bronchospasm in asthma. In a meta-analysis of randomized, placebo-controlled trials of acute beta-blocker exposure in asthma, beta-1–selective agents lowered forced expiratory volume in 1 second (FEV1) by a mean of 6.9%, with a fall of 20% or more in one in eight patients and symptoms in one in 33. They attenuated the response to a beta-2 agonist by about 10%. Nonselective agents lowered FEV1 by 10.2%, with a fall of 20% or more in one in nine patients and symptoms in one in 13, and attenuated the response to a beta-2 agonist by 20%. Risk rose with dose. When a compelling indication exists in a patient with asthma, a highly beta-1–selective agent is started at a low dose under observation with a short-acting beta-2 agonist available. Nonselective agents, including carvedilol, are avoided.

Chronic obstructive pulmonary disease (COPD). Beta-1–selective agents are well tolerated in COPD and are used for cardiac indications. COPD is not a reason to withhold a beta-blocker from a patient with HFrEF or recent infarction. In patients with COPD without a cardiac indication, routine beta-blockade does not prevent exacerbations. In BLOCK-COPD, among 532 patients with moderate to severe COPD, metoprolol succinate did not delay the first exacerbation (hazard ratio 1.05) and increased exacerbations leading to hospitalization (hazard ratio 1.91; 95% CI 1.29 to 2.83). The trial was stopped early. In BICS, among 515 analyzed patients at high risk of exacerbation, bisoprolol up to 5 mg daily did not reduce exacerbations (2.03 vs 2.01 per year; incidence rate ratio 0.97) and did not increase serious adverse events.

Peripheral artery disease. The belief that beta-blockers worsen claudication came from case reports and from the vasoconstriction caused by nonselective agents. In a meta-analysis of randomized trials in mild to moderate peripheral artery disease, beta-blockers did not impair pain-free walking distance (pooled effect size −0.24; 95% CI −0.62 to 0.14). Beta-blockers are not contraindicated in peripheral artery disease and are used when coronary disease, heart failure, or arrhythmia requires them.

Drug interactions of beta-blockers

Clinically important beta-blocker interactions, from US prescribing information.

Pheochromocytoma, cocaine, and other states of unopposed alpha stimulation

When catecholamine levels are very high, blocking vasodilating beta-2 receptors leaves alpha-1–mediated vasoconstriction unopposed. Blood pressure can rise and coronary spasm can intensify.

Pheochromocytoma and paraganglioma. Beta-blockade without prior alpha-blockade can precipitate a hypertensive crisis. An alpha-blocker is started first, as the metoprolol label states, and a beta-blocker is added only after adequate alpha-blockade to control tachycardia. Labetalol is predominantly a beta-blocker (alpha-to-beta ratio about 1:3 orally), and its label reports paradoxical hypertensive responses in a few patients with pheochromocytoma.

Cocaine and methamphetamine. The concern rests on animal studies, catheterization studies showing that propranolol increased cocaine-induced coronary vasoconstriction, and case reports. The 2014 AHA/ACC NSTE-ACS guideline gives a Class 3: Harm recommendation against beta-blockers in patients with ACS and signs of acute intoxication (euphoria, tachycardia, or hypertension). Benzodiazepines are first-line for the hyperadrenergic state, followed by nitrates and calcium channel blockers for hypertension and spasm. The 2008 AHA statement on cocaine-associated chest pain allows a combined alpha- and beta-blocker such as labetalol for hypertension or tachycardia after a vasodilator has been given. Observational data on patients with cocaine-associated chest pain who received beta-blockers are reassuring but cannot settle the question. The recommendation is limited to patients with signs of acute intoxication. A beta-blocker indicated for another reason, such as HFrEF, is started once intoxication has resolved.

Other hyperadrenergic states. Clonidine withdrawal, monoamine oxidase inhibitor reactions, and autonomic dysreflexia share the same physiology. Severe hypertension in these states is treated with phentolamine or another vasodilator, and in clonidine withdrawal, reinstating clonidine is the most direct treatment.

Beta-blocker overdose

Beta-blocker poisoning produces bradycardia, atrioventricular block, hypotension, and cardiogenic shock, often with hypoglycemia, and, with propranolol, QRS widening, seizures, and coma from sodium channel blockade. Sotalol overdose adds QT prolongation and torsades. Hypotension after an overdose can temporarily reduce renal function, and the label describes an initial slow elimination phase with a half-life of about 30 hours, compared with a mean of 12 hours at therapeutic doses. Sotalol is not protein bound, and hemodialysis lowers its plasma concentration. Atenolol can be removed by hemodialysis.

The 2023 AHA focused update on poisoning considers high-dose insulin therapy reasonable in beta-blocker poisoning with shock (Class 2a), because insulin improves inotropy in toxin-induced cardiogenic shock. Glucagon, which raises cAMP independent of the beta-receptor, improves contractility in some case series and not others. Treatment also includes atropine, vasopressors, cardiac pacing, and, for shock refractory to these measures, venoarterial extracorporeal membrane oxygenation. Treatment continues for a period consistent with the half-life of the ingested agent; the carvedilol label specifies antidote treatment long enough to cover its 7- to 10-hour half-life. Detailed antidote dosing is covered on the cardiovascular toxicology page.

Older adults, kidney and liver disease, pregnancy, and lactation

Older adults. Beta-blockers reduce mortality in HFrEF in older patients, and SENIORS enrolled patients aged 70 years and older. Bradycardia, orthostatic hypotension, falls, fatigue, conduction disease, and concurrent nodal drugs are more frequent, so doses start low and orthostatic blood pressure is measured during titration. The half-lives of propranolol and pindolol are longer in older adults, and the bioavailability of acebutolol is about doubled, so the acebutolol label advises avoiding doses above 800 mg/day. Beta-blockers prescribed after infarction with preserved ejection fraction and no other indication are candidates for deprescribing in older adults with fatigue or falls, using the taper described above.

Kidney disease. Atenolol, nadolol, sotalol, and acebutolol's active metabolite are renally eliminated and need dose or interval adjustment. Bisoprolol is half renally cleared and starts at 2.5 mg below a creatinine clearance of 40 mL/min. Metoprolol, carvedilol, propranolol, and labetalol need no renal adjustment, although propranolol levels can rise in chronic kidney disease because of reduced first-pass metabolism. Nonselective agents add to the risk of hyperkalemia.

Liver disease. High-extraction agents (propranolol, metoprolol, carvedilol, labetalol) have higher bioavailability in cirrhosis. Carvedilol is contraindicated in severe hepatic impairment, and nebivolol is not recommended in severe impairment. Nonselective beta-blockers (propranolol, nadolol, carvedilol) are used in cirrhosis to prevent variceal bleeding by lowering portal pressure.

Pregnancy. Beta-blockers are used in pregnancy for hypertension, arrhythmia, hypertrophic cardiomyopathy, aortopathy, long QT syndrome, and HFrEF. Labetalol and extended-release nifedipine are the preferred antihypertensives for chronic hypertension in pregnancy (Class 1 in the 2025 AHA/ACC high blood pressure guideline). Metoprolol is the beta-blocker most commonly continued in pregnant women with cardiomyopathy, according to the 2022 heart failure guideline. Atenolol is avoided because of its association with fetal growth restriction. In long QT syndrome and heritable aortopathy, beta-blockers are continued through pregnancy and the postpartum period.

Lactation. Metoprolol is the preferred beta-blocker during breastfeeding in the 2022 heart failure guideline, with monitoring of the infant's heart rate.

Exercise, chronotropic incompetence, and athletes

Exercise capacity. Beta-blockers lower peak heart rate and reduce maximal exercise capacity modestly in healthy people. In patients with angina, exercise capacity increases, because beta-blockade raises the workload at which ischemia appears. In HFrEF, exercise capacity is maintained or improves over months. On cardiopulmonary exercise testing, patients tolerating beta-blockers can have better survival than untreated patients at the same peak oxygen consumption (VO2). The 2022 heart failure guideline cites a peak VO2 of 12 mL/kg/min or less as the more appropriate threshold for transplant listing in patients taking beta-blockers.

Chronotropic incompetence. Chronotropic incompetence, an inadequate heart rate response to exercise, limits exercise in HFpEF and older adults. Beta-blockers, nondihydropyridine calcium channel blockers, digoxin, and amiodarone produce it, and the usual thresholds based on heart rate reserve are adjusted downward in patients taking beta-blockers. In a patient with exertional intolerance, the beta-blocker indication is reviewed before the symptom is attributed to the heart or lungs.

Exercise testing. Beta-blockade lowers peak heart rate and can reduce the sensitivity of exercise electrocardiography and stress imaging for ischemia, because the target heart rate is often not reached. The test protocol specifies whether the drug is withheld, which depends on the clinical question: diagnosis, or ischemia on treatment. Exercise training prescriptions in cardiac rehabilitation use perceived exertion or a heart rate range measured on the drug.

Athletes and doping. The World Anti-Doping Agency Prohibited List bans beta-blockers in competition in a small group of precision and breath-hold sports: archery, automobile racing, billiards, darts, golf, mini-golf, shooting, and the underwater disciplines of freediving, spearfishing, and target shooting. In archery, shooting, and these underwater disciplines they are also prohibited out of competition. An athlete in these sports who needs a beta-blocker for a cardiac indication applies for a therapeutic use exemption.

Septic shock and critical illness

Sustained tachycardia in septic shock is associated with mortality, and adrenergic stress contributes to myocardial injury and metabolic derangement. Short-acting beta-1–selective agents have been tested to control the heart rate once fluid resuscitation and vasopressors are established.

Esmolol. In a single-center, open-label trial, 154 patients in septic shock with heart rate of 95 beats/min or more on high-dose norepinephrine were assigned to esmolol titrated to 80 to 94 beats/min or to standard care. Norepinephrine and fluid requirements fell, and 28-day mortality was 49.4% with esmolol and 80.5% with standard care (adjusted hazard ratio 0.39). The very high control-group mortality and single-center design limit generalization.

Landiolol. STRESS-L randomized 126 adults in 40 UK intensive care units with heart rate of 95 beats/min or more and septic shock on norepinephrine for more than 24 hours to landiolol or standard care. Organ failure scores did not improve (mean Sequential Organ Failure Assessment [SOFA] score 8.8 vs 8.1). Mortality at 28 days was 37.1% with landiolol vs 25.4% with standard care, and at 90 days 43.5% vs 28.6%. These differences were not significant, and the trial was stopped early for possible harm.

Beta-blockade for heart rate control in septic shock is therefore not established. Sinus tachycardia in sepsis is treated through its causes: hypovolemia, fever, pain, and catecholamine dose. In critically ill patients with atrial fibrillation in whom other agents fail or cannot be used, intravenous amiodarone is an option for rate control (Class 2b in the 2023 atrial fibrillation guideline).

Noncardiac uses of beta-blockers

Beta-blockers prescribed for other conditions bear on interactions, bradycardia, and the choice of agent when a cardiac indication arises.

• Essential tremor: propranolol is labeled for familial or hereditary essential tremor.
• Migraine prophylaxis: propranolol and timolol are labeled for migraine prevention, and metoprolol is used.
• Performance anxiety: propranolol is used off label to blunt adrenergic symptoms such as tremor and palpitations.
• Thyrotoxicosis: beta-blockade controls adrenergic symptoms until the thyroid disorder is treated, and abrupt withdrawal may precipitate thyroid storm.
• Portal hypertension: propranolol, nadolol, and carvedilol prevent variceal bleeding.
• Glaucoma: timolol and betaxolol eye drops reduce aqueous humor production. Systemic absorption through the nasolacrimal duct bypasses first-pass metabolism and can cause bradycardia, atrioventricular block, and bronchospasm. Eye drops are part of the medication history in unexplained bradycardia.
• Cancer: no beta-blocker has an approved indication for the treatment of cancer in adults. Preemptive carvedilol or nebivolol to prevent cardiomyopathy from anthracyclines or trastuzumab has been tested in small trials, and the 2022 heart failure guideline describes the findings as conflicting. In established cancer therapy–related cardiomyopathy, beta-blockers and ACE inhibitors improve ventricular function.

Sources of error in beta-blocker prescribing

• Metoprolol tartrate prescribed for HFrEF: it has no placebo-controlled mortality evidence, and at 50 mg twice daily it was inferior to carvedilol in COMET. Metoprolol succinate (same total daily dose), carvedilol, or bisoprolol is used.
• Atenolol, nebivolol, or another agent assumed to share the heart failure mortality benefit: the benefit is established for bisoprolol, carvedilol, and metoprolol succinate only.
• A beta-blocker started in a congested or hypoperfused patient: initiation waits for near-euvolemia and stability, while an established beta-blocker is usually continued during admission for congestion.
• Titration abandoned after one episode of fatigue or fluid retention: these early effects are expected, and initial difficulty with titration does not preclude later attempts, as the metoprolol succinate label states.
• Intravenous metoprolol given early in ACS to a patient with Killip class II or higher, systolic pressure below 120 mm Hg, or tachycardia from low output: COMMIT showed excess cardiogenic shock on the first day.
• Routine indefinite beta-blockade after infarction with LVEF of 50% or more and no other indication: contemporary trials show no reduction in death, reinfarction, or heart failure, and REBOOT suggested harm in women, particularly at higher doses.
• Beta-blockade withheld after infarction with LVEF of 40% to 49%: an individual-patient meta-analysis showed fewer deaths, infarctions, and heart failure events in this range.
• A beta-blocker stopped abruptly in a patient with coronary disease, during surgery, or for a minor adverse effect: rebound angina, infarction, and arrhythmia can follow; the drug is tapered over 1 to 2 weeks.
• Verapamil or diltiazem added to a beta-blocker in an older patient or with conduction disease, without an ECG: complete heart block and asystole can occur.
• Metoprolol for long QT syndrome: breakthrough events are more frequent than with nadolol or propranolol.
• COPD treated as a contraindication in a patient with HFrEF or recent infarction: a beta-1–selective agent at a low dose is used with monitoring.
• Unexplained bradycardia on a modest dose of metoprolol attributed to the dose alone: CYP2D6 inhibitors such as fluoxetine or paroxetine, poor CYP2D6 metabolism, and timolol eye drops are reviewed first.
• Wide-QRS escape rhythm attributed to a beta-blocker: beta-blockers act on the sinus and atrioventricular nodes, and the finding indicates His-Purkinje disease.
• A nonvasodilating beta-blocker replaced by carvedilol in obstructive hypertrophic cardiomyopathy: alpha-1 blockade lowers afterload and worsens the outflow gradient.

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