In patients with chronic coronary artery disease (CAD), when are beta‑blockers indicated and what are the recommended agents, starting doses, titration targets, and alternatives?

Beta-Blocker Use in Coronary Artery Disease

Beta-blockers are mandatory only for CAD patients with LVEF ≤40% or heart failure, using specifically metoprolol succinate, carvedilol, or bisoprolol titrated to target doses; for all other CAD patients without prior MI, reduced ejection fraction, angina, arrhythmias, or uncontrolled hypertension, beta-blockers provide no mortality benefit and should not be routinely prescribed.

Absolute Indications for Beta-Blockers (Class 1 Recommendations)

Reduced Left Ventricular Function

• Beta-blocker therapy is required in all CAD patients with LVEF ≤40% with or without prior MI to reduce cardiovascular death and major adverse cardiovascular events 1
• Only three beta-blockers have proven mortality reduction: sustained-release metoprolol succinate, carvedilol, or bisoprolol 1
• These specific agents must be titrated to target doses rather than using other beta-blockers 1

Heart Failure with Reduced Ejection Fraction

• Beta-blockers are essential components of treatment for patients with LVEF <50% due to efficacy in relieving angina and reducing morbidity and mortality 1
• The European Society of Cardiology reinforces this as a Class 1 recommendation for LV dysfunction or systolic heart failure 1

Conditional Indications (Class 2a-2b)

Symptomatic Angina Control

• Beta-blockers are recommended as initial treatment alongside calcium channel blockers for most patients with chronic coronary syndrome experiencing anginal symptoms 1
• Target resting heart rate should be 55-60 beats per minute when using beta-blockers for antianginal purposes 1, 2
• Beta-blockers reduce myocardial oxygen consumption by decreasing heart rate and contractility, improving exercise capacity 3, 4

Post-MI Patients with Preserved LVEF

• For patients initiated on beta-blockers after MI who have no history of LVEF ≤50%, angina, arrhythmias, or uncontrolled hypertension, reassessment of long-term use (>1 year) may be reasonable (Class 2b) 1
• The European Society of Cardiology suggests long-term beta-blocker treatment should be considered after STEMI (Class 2a) 1
• Recent evidence questions beta-blocker benefit in post-ACS patients with preserved LVEF, with ongoing European trials investigating this 1

When Beta-Blockers Are NOT Beneficial (Class 3: No Benefit)

In CAD patients without previous MI or LVEF ≤50%, beta-blocker therapy does not reduce major adverse cardiovascular events in the absence of another primary indication 1

This represents a critical paradigm shift from historical practice, as the 2023 ACC/AHA guidelines explicitly state no benefit for stable CAD with preserved function 1.

Specific Agent Selection and Dosing

Evidence-Based Beta-Blockers for CAD with Reduced LVEF

• Metoprolol succinate (extended-release): Reduced all-cause mortality by 34% in MERIT-HF 5
• Bisoprolol: Associated with 34% mortality benefit in CIBIS-II 5
• Carvedilol: Demonstrated 35% mortality reduction in COPERNICUS trial 5

Alternative Agents for Angina Control

• Atenolol and immediate-release metoprolol have shown benefit in acute MI but lack the mortality data of the three preferred agents 5
• Propranolol and timolol demonstrated mortality reduction in older post-MI trials but are not preferred in current guidelines 5

Clinical Algorithm for Beta-Blocker Initiation

Step 1: Assess LVEF and Heart Failure Status

• If LVEF ≤40%: Initiate metoprolol succinate, carvedilol, or bisoprolol immediately (Class 1) 1
• If LVEF 41-49%: Consider beta-blocker if symptomatic angina, arrhythmias, or hypertension present 1
• If LVEF ≥50% without prior MI: Beta-blockers not indicated for MACE reduction 1

Step 2: Evaluate Symptomatic Indications

• Angina present: Beta-blockers or calcium channel blockers as first-line therapy 1
• Arrhythmias: Beta-blockers reduce arrhythmic death and cardiac arrest 5
• Uncontrolled hypertension: Beta-blockers appropriate with or without RAS blocker or CCB 3

Step 3: Screen for Contraindications

• Absolute contraindications: Severe bradycardia, high-grade AV block, marked sinus node dysfunction, acute heart failure exacerbations 5
• Vasospastic angina component: Beta-blockers contraindicated as they can precipitate spasm by unopposed α-mediated vasoconstriction 2
• Severe peripheral artery disease or critical limb ischemia: Avoid beta-blockers 2

Step 4: Titrate to Target Doses

• Titration to target doses is specifically recommended for metoprolol succinate, carvedilol, or bisoprolol in patients with LVEF <50% 1
• Target heart rate of 55-60 bpm for antianginal effect 1, 2

Alternative Antianginal Strategies

When Beta-Blockers Are Ineffective or Contraindicated

• Calcium channel blockers are recommended for ischemic symptoms when beta-blockers are not successful or contraindicated 1
• Non-dihydropyridine CCBs (diltiazem or verapamil) can substitute for beta-blockers in microvascular disease 2
• Ivabradine may offer superior benefits in coronary microvascular disease compared to bisoprolol, despite similar heart rate reduction 2

Add-On Therapy for Refractory Symptoms

• Long-acting nitrates, nicorandil, ranolazine, or trimetazidine can be added to beta-blockers or CCBs 1
• Ivabradine is not recommended as add-on therapy in patients with LVEF >40% and no clinical heart failure 1

Critical Caveats and Common Pitfalls

Avoid Extrapolating Class Effects

• Beneficial effects of beta-blockers cannot always be extrapolated as a class effect; patient selection and drug preparations should follow trial guidelines 5
• Only metoprolol succinate, carvedilol, and bisoprolol have proven mortality reduction in heart failure 1

Reassess Long-Term Use in Stable Patients

• For post-MI patients with preserved LVEF who remain stable without angina, arrhythmias, or hypertension beyond 1 year, consider discontinuation 1
• This represents a departure from historical "indefinite" beta-blocker recommendations 5

Hemodynamic Considerations

• Beta-blockers should be used at low doses only in patients with low blood pressure 3
• Not suitable for patients with heart rate <50 bpm unless pacemaker support is available 3
• Use with caution in hemodynamically unstable patients 4

Drug Interactions and Combinations

• Combination of ivabradine with non-dihydropyridine CCB or strong CYP3A4 inhibitors is not recommended 1
• Short-acting dihydropyridine calcium channel antagonists should be avoided 1

Evidence Quality and Guideline Divergence

The 2023 ACC/AHA guidelines 1 and 2024 ESC guidelines 1 show substantial agreement on beta-blocker indications, with both emphasizing:

• Strong evidence (Class 1) for reduced LVEF
• Weak or no evidence for preserved LVEF without other indications
• Preference for specific agents with mortality data

The recommendation for beta-blockers in stable CAD with preserved function has shifted from historical Class 1 to current Class 3 (no benefit), reflecting modern evidence in the era of contemporary antiplatelet therapy, statins, and percutaneous interventions 6.