In an adult with hypertension, ischemic heart disease or heart failure who is on a short‑acting β‑blocker that fails to control symptoms with once‑daily dosing, is twice‑daily dosing beneficial?

Twice-Daily β-Blocker Dosing: Clinical Benefits and Evidence

For short-acting β-blockers like metoprolol tartrate, atenolol, and propranolol that fail to control symptoms with once-daily dosing, switching to twice-daily dosing is beneficial and necessary to achieve adequate 24-hour coverage, as these agents demonstrate significant loss of effect at the end of a 24-hour dosing interval. 1

The Critical Problem with Once-Daily Dosing of Short-Acting β-Blockers

Atenolol's failure in hypertension trials is specifically attributed to once-daily dosing of an agent that requires twice-daily administration. 2 The ACC/AHA guidelines explicitly note that atenolol, a beta-1-selective blocker, requires twice-daily dosing, yet outcome trials dosed it once daily, which likely explains the lack of mortality benefit observed. 2

Pharmacokinetic Evidence Supporting Twice-Daily Dosing

• Exercise tachycardia suppression studies demonstrate that while several β-blockers maintain some effect 24 hours after dosing, the magnitude of effect is substantially reduced compared to peak levels. 1
• Propranolol and penbutolol show equal reduction of exercise tachycardia at the end of the dosing interval whether given once or twice daily, but the total daily dose must be divided to maintain consistent beta-blockade throughout the day. 1
• Importantly, long half-life agents like atenolol and sotalol were not superior to other β-blockers at 24 hours, contradicting the assumption that pharmacokinetic half-life alone predicts clinical duration of action. 1

Specific Clinical Scenarios Requiring Twice-Daily Dosing

Hypertension Management

For hypertension, metoprolol tartrate specifically requires 100-200 mg daily in divided doses (twice daily), not once-daily administration. 3 The ACC guidelines distinguish this clearly from metoprolol succinate extended-release, which is dosed once daily. 3

• Carvedilol for hypertension requires 12.5-50 mg daily in divided doses (twice daily). 3
• The trough-to-peak ratio for blood pressure response with β-blockers is approximately 65%, meaning significant loss of effect occurs at the end of the dosing interval. 4

Ischemic Heart Disease and Angina

For angina management, the ACC/AHA guidelines specify twice-daily dosing for multiple agents: 2

• Propranolol: 20-80 mg twice daily 2
• Metoprolol (tartrate): 50-200 mg twice daily 2
• Timolol: 10 mg twice daily 2
• Acebutolol: 200-600 mg twice daily 2
• Labetalol: 200-600 mg twice daily 2

Heart Failure Post-Myocardial Infarction

Carvedilol in the CAPRICORN trial was titrated to 25 mg twice daily in post-MI patients with left ventricular dysfunction, achieving a 23% reduction in all-cause mortality and 40% reduction in fatal or non-fatal MI. 4 The mean dosage achieved was 20 mg twice daily, demonstrating that twice-daily dosing is both feasible and necessary for optimal outcomes. 4

The Solution: Switch to Once-Daily Formulations

Rather than continuing twice-daily dosing of short-acting agents, the preferred approach is switching to evidence-based once-daily formulations: 3

• Metoprolol succinate extended-release: 12.5-200 mg once daily for heart failure (target 200 mg) 3
• Bisoprolol: 1.25-10 mg once daily for heart failure (target 10 mg) 3
• Carvedilol must remain twice daily as no extended-release formulation has equivalent evidence 3

Why This Matters for Outcomes

The failure of atenolol in hypertension trials, attributed to once-daily dosing of an agent requiring twice-daily administration, resulted in β-blockers being downgraded from first-line therapy for uncomplicated hypertension. 2, 5 This represents a class-wide consequence of improper dosing of a single agent.

Common Pitfalls to Avoid

• Never assume pharmacokinetic half-life predicts clinical duration of action. Atenolol has a long half-life but still loses clinical effect before 24 hours. 1
• Do not use metoprolol tartrate for heart failure management even with twice-daily dosing, as only metoprolol succinate has demonstrated mortality reduction. 3
• Avoid atenolol entirely for hypertension as it is less effective than placebo in reducing cardiovascular events, regardless of dosing frequency. 6, 5
• Patient adherence is significantly better with once-daily regimens, so switching to appropriate once-daily formulations is preferable to twice-daily dosing when evidence-based options exist. 2

Practical Algorithm for Management

If symptoms are inadequately controlled on once-daily dosing of a short-acting β-blocker:

1. First, verify the patient is on an adequate total daily dose before increasing frequency 3
2. Second, switch to an evidence-based once-daily formulation (metoprolol succinate or bisoprolol) rather than increasing to twice-daily dosing of the short-acting agent 3, 6
3. Third, if carvedilol is indicated (heart failure, post-MI), accept that twice-daily dosing is required and titrate to target doses of 25-50 mg twice daily 3, 4
4. Monitor trough effects by assessing heart rate and blood pressure 12-24 hours after the last dose to ensure adequate coverage 1