BETA BLOCKERS


















High blood pressure (hypertension)
  • Beta blockers are widely used to treat hypertension
  • A randomized controlled trial that included atenolol is detailed below along with a summary of three Cochrane meta-analyses that looked at beta blockers by class (selective, nonselective +/- alpha blockade)
Atenolol vs Others for Hypertension in Male Veterans, NEJM (1993) [PubMed abstract]
  • The Veterans Affairs Cooperative study enrolled 1292 men with hypertension
Main inclusion criteria
  • Male veteran
  • DBP 95 - 109 mmHg off medications
Baseline characteristics
  • Average age 59 years
  • Average BP 152/99 mmHg
  • Black race - 48%
  • Current smoker - 32%
Randomized treatment groups
  • Group 1 (188 patients) - Hydrochlorothiazide 12.5 - 50 mg once daily
  • Group 2 (176 patients) - Atenolol 25 - 100 mg once daily
  • Group 3 (188 patients) - Captopril 25 - 100 mg/day given in 2 divided doses
  • Group 4 (177 patients) - Clonidine 0.2 - 0.6 mg/day given in 2 divided doses
  • Group 5 (182 patients) - Diltiazem SR 120 - 360 mg/day given in 2 divided doses
  • Group 2 (186 patients) - Prazosin 4 - 20 mg/day given in 2 divided doses
  • Group 2 (186 patients) - Placebo
  • There was a washout period of 4 - 8 weeks before randomization
  • Patients were titrated over a period of 4 - 8 weeks to a DBP < 90 mmHg or until they reached the maximum drug dose
Primary outcome: Attainment of blood pressure goal during titration (DBP < 90 mmHg) and DBP of < 95 mmHg at one year
Results

Average BP reduction at the end of the titration phase (SBP/DBP mmHg)
HCTZ Atenolol Captopril Clonidine Diltiazem Prazosin Placebo
14 / 10 11 / 12 9 / 10 16 / 12 13 / 14 12 / 11 3 / 5
  • Primary outcome: Diltiazem - 59%, Atenolol - 51%, Clonidine - 50%, HCTZ - 46%, Captopril - 42%, Prazosin - 42%, Placebo - 25%
  • All medications were significantly better than placebo for blood pressure reduction
  • The incidence of side effects with atenolol was similar to placebo

Findings: Among men, race and age have an important effect on the response to single-drug therapy for hypertension. In addition to cost and quality of life, these factors should be considered in the initial choice of drug.
Cochrane meta-analyses of beta blockers in hypertension
  • Three separate Cochrane meta-analyses looked at the blood pressure-lowering effects of different classes of beta blockers in patients with hypertension
  • The analyses found the following:
    • Selective beta blockers lowered SBP by 10 mmHg and DBP by 8 mmHg on average (N=7812) [99]
    • Nonselective beta blockers lowered SBP by 10 mmHg and DBP by 7 mmHg on average (N=1264) [100]
    • Carvedilol lowered SBP by 4 mmHg and DBP by 3 mmHg on average (N>1000) [101]
    • Labetalol lowered SBP by 10 mmHg and DBP by 7 mmHg on average (N=110) [101]
Professional recommendations
  • See hypertension guidelines for a review of recommended therapies and treatment goals from various professional organizations
StraightHealthcare analysis
  • Other classes of blood pressure medications have better outcome data than beta blockers and are preferred as first-line agents
  • In practice, beta blockers are still widely prescribed as first-line agents



Overview
  • Beta blockers have consistently been shown to improve outcomes in patients with HFrEF, also called "systolic heart failure"
  • Carvedilol, metoprolol succinate, and bisoprolol have all been shown to be effective in large randomized controlled trials (see below) and are recommended by the AHA. Carvedilol and metoprolol succinate are FDA-approved to treat heart failure.
  • One head-to-head trial has been performed that compared carvedilol to metoprolol tartrate (see COMET trial below)
Carvedilol vs Placebo in HFrEF, NEJM (1996) [PubMed abstract]
  • The US Carvedilol Heart Failure Study enrolled 1094 patients with heart failure
Main inclusion criteria
  • Symptoms of heart failure for ≥ 3 months
  • EF ≤ 35% despite at least 2 months of treatment with diuretics and ACE inhibitors
Main exclusion criteria
  • Major cardiovascular event or major surgery within 3 months
  • Heart valve disease
  • SBP > 160 or < 85
  • DBP > 100
  • Pulse < 68 bpm
  • Receiving calcium channel blocker, alpha agonist or antagonist, or beta agonist or antagonist
Baseline characteristics
  • Average age 58 years
  • NYHA class: II - 53% | III - 44% | IV - 3%
  • Average EF - 22%
  • Average BP - 115/73
  • Medications at enrollment: Digoxin - 90% | Loop diuretic - 95% | ACE inhibitor - 95%
Randomized treatment groups
  • Group 1 (398 patients) - Placebo twice a day
  • Group 2 (696 patients) - Carvedilol 12.5 - 50 mg twice a day (average daily dose achieved was 45 mg)
  • There was a run-in phase where all patients received carvedilol 6.25 mg twice a day for 2 weeks. Patients who tolerated this were randomized to study treatment.
  • Patients with mild or severe heart failure were randomized in a 1:2 ratio
  • Dosage was titrated up over 2 - 10 weeks to a target of 25 - 50 mg twice daily
Primary outcome: Overall mortality
Results

Duration: After a median follow-up of 6.5 months, the study was stopped early due to a clear benefit from carvedilol
Outcome Placebo Carvedilol Comparisons
Primary outcome 7.8% 3.2% HR 0.35, 95%CI [0.20 - 0.61], p<0.001
Hospitalization for cardiovascular causes 19.6% 14.1% HR 0.73, 95%CI [0.55 - 0.97], p=0.036
Decrease in average heart rate 1.4 bpm 12.6 bpm p<0.001
Dizziness 20% 33% N/A
Heart failure 21% 16% N/A
Diarrhea 12% 6% N/A
  • During treatment, there was no significant change in blood pressure in either group

Findings: Carvedilol reduces the risk or death as well as the risk of hospitalization for cardiovascular causes in patients with heart failure who are receiving treatment with digoxin, diuretics, and an angiotensin-converting-enzyme inhibitor
MERIT-HF Study - Metoprolol Succinate vs Placebo in HFrEF, JAMA (2000) [PubMed abstract]
  • The MERIT-HF trial enrolled 3991 patients with chronic heart failure
Main inclusion criteria
  • Symptomatic heart failure (NYHA class II - IV) for at least 3 months
  • EF < 40%
  • Resting pulse ≥ 68 bpm
  • Receiving diuretics
  • Receiving ACE inhibitor or ARB or hydralazine + nitrate
Main exclusion criteria
  • Myocardial infarction or unstable angina within 28 days
  • Severe decompensated heart failure
  • Supine SBP < 100
Baseline characteristics
  • Average age 63 years
  • NYHA class: II - 41% | III - 56% | IV - 3.5%
  • Average EF - 28%
  • Medications at enrollment: Digoxin - 63% | Diuretics - 90% | ACE inhibitor - 90% | ARB - 7% | Spironolactone - 7%
Randomized treatment groups
  • Group 1 (1990 patients) - Metoprolol succinate (extended-release) - target dose 200 once daily
  • Group 2 (2001 patients) - Placebo once daily
  • Metoprolol was started at 25 mg once daily (12.5 mg for NYHA class III and IV) and doubled every 2 weeks
Primary outcome: Composite of overall mortality or any hospitalization
Results

Duration: After an average follow-up of 1 year, the study was stopped early due to a clear benefit from metoprolol
Outcome Metoprolol Placebo Comparisons
Primary outcome 32% 38.3% HR 0.81, 95%CI [0.73 - 0.90], p<0.001
Death or heart transplantation 7.5% 11% HR 0.68, 95%CI [0.55 - 0.84]
Drug discontinuation 14% 15.5% HR 0.90, 95%CI [0.76 - 1.05], p=0.18
Worsening heart failure 3.2% 4.2% HR 0.75, 95%CI [0.54 - 1.04], p=0.08

Findings: In this study of patients with symptomatic heart failure, metoprolol CR/XL improved survival, reduced the need for hospitalizations due to worsening heart failure, improved NYHA functional class, and had beneficial effects on patient well-being
CIBIS II Trial - Bisoprolol vs Placebo in HFrEF, Lancet (1999) [PubMed abstract]
  • The CIBIS-II study enrolled 2647 patients with heart failure
Main inclusion criteria
  • Symptomatic heart failure (NYHA class III or IV)
  • EF < 35%
  • Receiving diuretics
  • Receiving ACE inhibitor or other vasodilator if ACE-intolerant
Main exclusion criteria
  • Uncontrolled hypertension
  • Myocardial infarction or unstable angina within previous 3 months
  • PCI or CABG within previous 6 months
  • Resting pulse < 60 bpm
  • SBP < 100 mmHg
Baseline characteristics
  • Average age 61 years
  • NYHA class: III - 93% | IV - 17%
  • Average BP - 130/80
  • Average EF - 27%
  • Medications at enrollment: Digoxin - 52% | Diuretics - 99% | ACE inhibitor - 96%
Randomized treatment groups
  • Group 1 (1320 patients) - Placebo once daily
  • Group 2 (1327 patients) - Bisoprolol - target dose 10 mg once daily
  • Bisoprolol was started at 1.25 mg once daily and the dose was increased by 1.25 mg/week for 3 weeks. 5 mg and 7.5 mg doses were given for 4 weeks each before reaching a target of 10 mg.
Primary outcome: Overall mortality
Results

Duration: After an average follow-up of 1.3 years, the study was stopped early due to a clear benefit from bisoprolol
Outcome Placebo Bisoprolol Comparisons
Primary outcome 17% 12% HR 0.66, 95%CI [0.54 - 0.81], p<0.0001
Hospitalization for heart failure 18% 12% HR 0.64, 95%CI [0.53 - 0.79], p=0.0001
All cause hospitalization 39% 33% HR 0.80, 95%CI [0.71 - 0.91], p=0.0006
Drug discontinuation 15% 15% p=0.98
  • In Group 2, 43% of patients reached the target dose of 10 mg once daily

Findings: Beta-blocker therapy had benefits for survival in stable heart-failure patients. Results should not, however, be extrapolated to patients with severe class IV symptoms and recent instability because safety and efficacy has not been established in these patients.
COMET Trial - Carvedilol vs Metoprolol Tartrate in HFrEF, Lancet (2003) [PubMed abstract]
  • The COMET trial enrolled 3029 patients with heart failure
Main inclusion criteria
  • Symptomatic heart failure (NYHA class II - IV) with at least one cardiovascular admission in past 2 years
  • EF ≤ 35%
  • Receiving ACE inhibitor unless contraindicated
  • Receiving diuretic
Main exclusion criteria
  • Receiving nondihydropyridine calcium channel blocker
  • Myocardial infarction, stroke, unstable angina, or revascularization within previous 2 months
  • SBP > 170 or < 85
  • DBP > 105
  • Resting pulse < 60 bpm
  • History of asthma or COPD
Baseline characteristics
  • Average age 62 years
  • NYHA class: II - 48% | III - 48% | IV - 3%
  • Average BP - 126/77
  • Average EF - 26%
  • Medications at enrollment: Digoxin - 59% | Diuretics - 99% | ACE inhibitor - 92%
Randomized treatment groups
  • Group 1 (1511 patients) - Carvedilol - target dose 25 mg twice a day
  • Group 2 (1518 patients) - Metoprolol tartrate (standard-release) - target dose 50 mg twice a day
  • Carvedilol was started at 6.25 mg twice daily and doubled every 2 weeks to target
  • Metoprolol was started at 12.5 mg twice daily and doubled every 2 weeks to target
Primary outcomes
  • All-cause mortality
  • Composite of all-cause mortality and all-cause hospital admission
Results

Duration: Average of 4.8 years
Outcome Carvedilol Metoprolol Comparisons
Primary outcome (all-cause mortality) 34% 40% HR 0.83, 95%CI [0.74 - 0.93], p=0.002
Primary outcome (all-cause mortality and any hospitalization) 74% 76% HR 0.94, 95%CI [0.86 - 1.02], p=0.122
Cardiovascular deaths 29% 35% HR 0.80, 95%CI [0.70 - 0.90], p=0.0004
Decrease in pulse (at 4 months) 13.3 bpm 11.7 diff -1.6 bpm, 95%CI [-2.7 to -0.6]
Decrease in SBP (at 4 months) 3.8 mmHg 2.0 mmHg diff -1.8, 95%CI [-3.2 to -0.4]
  • The target dose was achieved in 75% and 78% of patients in Groups 1 and 2, respectively.
  • The incidence of adverse events was similar between groups

Findings: Our results suggest that carvedilol extends survival compared with metoprolol
AHA recommendations
  • All patients with stable heart failure should be prescribed one of the following beta blockers unless contraindicated: carvedilol (Coreg®), extended-release metoprolol succinate (Toprol-XL®), or bisoprolol (Zebeta®)
A "class effect" with beta blockers should not be assumed because of the following:
  • Trials have shown a lack of effectiveness for bucindolol (a beta blocker not available in the U.S.)
  • The COMET trial showed that short-acting metoprolol tartrate was inferior to carvedilol. (It's important to note that the COMET trial used a lower dose of short-acting metoprolol [50 mg twice a day] than what has been used in trials with long-acting metoprolol [up to 200 mg day]).
  • Nebivolol did not have a significant effect on overall mortality in a trial involving elderly patients with heart failure [103]
StraightHealthcare analysis
  • Beta blockers have consistently been shown to improve outcomes in heart failure patients
  • All patients with stable heart failure should receive a beta blocker
  • Carvedilol, extended/sustained-release metoprolol, or bisoprolol may be preferred, but it is difficult to know if they are truly superior to other beta blockers. The COMET trial that compared carvedilol to metoprolol did not use an optimal dose of metoprolol.
  • Of particular note, the widely-prescribed beta blocker atenolol has been shown to improve heart failure symptoms and outcomes in smaller trials, but no large trial has been performed [27,28]






Overview
  • A number of older trials found that beta blockers improved outcomes in acute myocardial infarction. The studies varied by how acutely beta blockers were given (immediately in hospital vs days after heart attack), which beta blocker was used, and how they were administered (IV vs oral vs both).
  • Most of the trials were also performed before antiplatelet therapy, PCI, and fibrinolysis became routine
  • In 2005, the largest trial to evaluate the effects of beta blockers in myocardial infarction was published. It is detailed below.
COMMIT Trial - Metoprolol vs Placebo for Acute MI, Lancet (2005) [PubMed abstract]
  • The COMMIT trial enrolled 45,852 patients with suspected acute myocardial infarction
Main inclusion criteria
  • Symptoms of acute MI within past 24 hours and one of the following: ST elevation, left bundle branch block, or ST depression
Main exclusion criteria
  • Scheduled for PCI
  • SBP < 100
  • Pulse < 50 bpm
  • Heart block
  • Cardiogenic shock
Baseline characteristics
  • Average age 61 years
  • Average time since onset of symptoms - 10.3 hours
  • EKG abnormality at entry: ST elevation - 86.7% | Left bundle branch block - 6.3% | ST depression - 6.9%
  • Received fibrinolysis - 54.3%
  • Taking beta blocker before randomization - 6.5%
Randomized treatment groups
  • Group 1 (22,929 patients) - Metoprolol 5 mg IV up to 3 doses started immediately, followed by metoprolol 50 mg by mouth every 6 hours for 1 day, followed by extended-release metoprolol 200 mg a day for 4 weeks
  • Group 2 (22,923 patients) - Placebo injection and tablets
  • Patients were followed until hospital discharge or Day 28, whichever was sooner
Primary outcomes:
  • Composite of death, reinfarction, or cardiac arrest (including ventricular fibrillation)
  • Death from any cause
Results

Duration: 28 days
Outcome Metoprolol Placebo Comparisons
Primary outcome (death, reinfarction, or cardiac arrest) 9.4% 9.9% OR 0.96, 95%CI [0.90 - 1.01], p=0.10
Primary outcome (overall mortality) 7.7% 7.8% OR 0.99, 95%CI [0.92 - 1.05], p=0.69
Reinfarction 2.0% 2.5% OR 0.82, 95%CI [0.72 - 0.92], p=0.001
Ventricular fibrillation 2.5% 3.0% OR 0.83, 95%CI [0.75 - 0.93], p=0.001
Cardiogenic shock 5.0% 3.9% OR 1.30, 95%CI [1.19 - 1.41], p<0.0001
Heart failure 14.1% 12.7% OR 1.12, 95%CI [1.07 - 1.18], p<0.0001
Persistent hypotension 6.0% 2.9% OR 2.06, 95%CI [1.89 - 2.25], p<0.0001
Bradycardia 5.4% 2.2% OR 2.41, 95%CI [2.19 - 2.65], p<0.0001
  • At discharge, myocardial infarction was confirmed in 95.8% of patients

Findings: The use of early beta-blocker therapy in acute MI reduces the risks of reinfarction and ventricular fibrillation, but increases the risk of cardiogenic shock, especially during the first day or so after admission. Consequently, it might generally be prudent to consider starting beta-blocker therapy in hospital only when the haemodynamic condition after MI has stabilised.
AHA recommendations
  • The AHA/ACC recommends that patients without contraindications (see below) receive oral beta blockers within 24 hrs of admission for a heart attack
  • Intravenous beta blockers should be targeted to "specific indications" and avoided in patients with symptomatic heart failure, low blood pressure, or other instability [40]
    • Contraindications to beta blockers include:
      • Symptomatic or decompensated heart failure
      • Marked first degree heart block (PR interval > 0.24s)
      • Second or third degree heart block
      • Low blood pressure
      • High risk for shock - older age (≥ 70 years), worse heart failure (Killip class III), low blood pressure (SBP < 120), faster heart rate (> 110 beats per minute) [91]
      • History of asthma
StraightHealthcare analysis
  • There is no evidence that beta blockers improve outcomes in acute myocardial infarction. The COMMIT trial was an enormous trial that did not find a net benefit with early beta blocker therapy. Given the trial's size, if even the slightest benefit existed, it would have been deemed significant.
  • Many patients will have some degree of heart failure after a heart attack, and long-term beta blocker therapy is likely to be beneficial in these patients
  • If beta blockers are to be given in acute myocardial infarction, they should only be started after the patient is hemodynamically stable






Overview
  • Atrial fibrillation is a common heart arrhythmia that causes a rapid heart rate
  • Atrial fibrillation can be treated in two ways:
    • Rate control - slowing the rapid heart rate produced by the arrhythmia
    • Rhythm control - attempting to convert the arrhythmia back to a normal rhythm or preventing the abnormal rhythm from occurring
Rate control
  • Beta blockers slow the heart rate, therefore they are used to control heart rates in atrial fibrillation
  • There are no large studies that have compared beta blockers to other drugs for rate control in A fib
  • The studies below compared beta blockers to placebo for other outcomes, but they provide some information on the effect of beta blockers on heart rate in A fib
MERIT-HF Trial
  • The MERIT-HF trial is discussed under heart failure above
  • In the MERIT-HF trial, patients with heart failure were randomized to metoprolol or placebo
  • A post-hoc analysis looked at the effects of metoprolol on patients with atrial fibrillation who were enrolled in the study
  • The following effects of metoprolol on heart rates were seen after 3 months of therapy:
    • Metoprolol (average dose 150 mg) reduced the average heart rate by 11 beats per minute in patients with atrial fibrillation
    • Metoprolol (average dose 154 mg) reduced the average heart rate by 13 beats per minute in patients with a normal heart rhythm [47]
JACC Metoprolol study
  • A study published in the Journal of the American College of Cardiology compared metoprolol to placebo for maintaining sinus rhythm in atrial fibrillation
  • The study reported heart rates in patients who relapsed into atrial fibrillation as a secondary endpoint
  • The following effects of metoprolol on heart rates were seen:
    • In the metoprolol group (most common dose 100 mg a day), patients who relapsed into atrial fibrillation had an average heart rate of 98 beats per minute
    • In placebo relapsers, the average heart rate was 107 beats per minute [41]



Overview
  • Beta blockers (excluding sotalol) do not have apparent atrial-stabilizing properties, but they have been shown in small trials to have a modest effect in preventing recurrent atrial fibrillation
Metoprolol vs Placebo to Maintain Sinus Rhythm after Cardioversion, JACC (2000) [PubMed abstract]
  • A trial in the Journal of the American College of Cardiology enrolled 394 patients with a history of persistent A fib who had been successfully cardioverted
Main inclusion criteria
  • History of persistent A fib lasting for at least 3 days and up to 1 year
  • Successful cardioversion with direct current or antiarrhythmic drugs
Main exclusion criteria
  • Maintenance amiodarone within six months of randomization
  • Concomitant antiarrhythmic drugs
  • Paroxysmal A fib
  • Cardiac surgery within 2 months
Baseline characteristics
  • Average age 60 years
  • Average length of atrial fibrillation - 95 days
  • Conversion by direct current - 82.5%
  • History of past cardioversion - 10%
  • Heart failure - 25%
Randomized treatment groups
  • Group 1 (197 patients) - Metoprolol extended-release with a target dose of 200 mg once daily
  • Group 2 (197 patients) - Placebo once daily
  • Metoprolol was started at 100 mg once daily and increased or decreased as tolerated
  • Anticoagulation was recommended before and for 1 month after cardioversion
  • EKGs were obtained at 1 week, 1 month, 3 months, 6 months, and as needed for symptoms of A fib
Primary outcome: Relapse into atrial fibrillation or atrial flutter at 6 months
Results

Duration: 6 months
Outcome Metoprolol Placebo Comparisons
Primary outcome 48.7% 59.9% p=0.005
Median time to relapse 13 days 7.5 days p=0.001
Dizziness / vertigo / nausea 10.2% 3% N/A
Bradycardia 7.1% 0% N/A
  • Metoprolol dose in Group 1: 50 mg once daily - 18.3%, 100 mg once daily - 62%, 200 mg once daily - 16.8%

Findings: The results of this double-blind, placebo-controlled study in patients after cardioversion of persistent atrial fibrillation showed that metoprolol CR/XL was effective in preventing relapse into atrial fibrillation or flutter.
AHA recommendations
  • The AHA/ACC states that beta blockers are not generally considered primary therapy for maintenance of normal heart rhythm (sinus rhythm) in patients with atrial fibrillation
  • They also state that various beta blockers have shown moderate, but consistent efficacy in preventing atrial fibrillation recurrence [57]
  • See AHA atrial fibrillation rhythm control recommendations
StraightHealthcare analysis
  • Beta blockers may help prevent the recurrence of atrial fibrillation, but the effect appears to be very modest
  • Susceptible patients may benefit from a beta blocker if indicated



Stable angina
  • Stable angina is predictable and reproducible cardiac chest pain that occurs with exertion and is relieved with rest
  • Most studies evaluating beta blockers in the treatment of stable angina are small and older
  • We found one meta-analysis that attempted to compare different treatments for stable angina
Beta Blockers vs Nitrates vs CCBs for Stable Angina, JAMA meta-analysis (1999) [PubMed abstract]
  • A JAMA meta-analysis from 1999 evaluated trials that compared beta blockers to nitrates or calcium channel blockers in the treatment of stable angina
When beta blockers were compared to calcium channel blockers, the following results were seen:
  • Compared to calcium channel blockers, beta blockers were associated with 0.31 fewer episodes of angina per week (borderline significant, p=0.05)
  • There was no significant difference in a composite outcome of heart attack or cardiac death
  • There was no significant difference in nitroglycerin use per week
When beta blockers were compared to long-acting nitrates, the following results were seen:
  • There was no significant difference for any outcome [60]
Findings: Beta-Blockers provide similar clinical outcomes and are associated with fewer adverse events than calcium antagonists in randomized trials of patients who have stable angina
AHA recommendations
  • The AHA 2012 CAD guidelines recommend beta blockers as the first-line agent for the treatment of chronic angina
  • If beta blockers are contraindicated or not tolerated, then calcium channel blockers (dihydropyridines and nondihydropyridines) or long-acting nitrates should be used
  • If initial beta blocker therapy does not control symptoms, then a calcium channel blocker or long-acting nitrate should be added to beta blocker therapy [96]
StraightHealthcare analysis
  • Beta blockers are the preferred first-line agent in chronic angina because they improve heart failure outcomes
  • Calcium channel blockers and long-acting nitrates are also effective
  • Nifedipine and diltiazem should be used with caution in patients with heart failure because they may worsen outcomes. Amlodipine has been shown to be safe in heart failure.






Infantile hemangioma
  • Hemangiomas are skin lesions that are caused by an overgrowth of blood vessels. See infantile hemangioma for more
  • Hemangiomas are common in infancy, occurring in up to 10% of infants
  • The majority of hemangiomas resolve and disappear without intervention. Around 12% of hemangiomas will persist and require referral to a specialist.
  • Oral propranolol has been found to stimulate hemangioma resolution by an unknown mechanism. In 2015, a large, randomized controlled trial was published that compared propranolol to placebo.
Propranolol vs Placebo for Infantile Hemangioma, NEJM (2015) [PubMed abstract]
  • A trial in the NEJM enrolled 460 infants with hemangiomas
Main inclusion criteria
  • 35 - 150 days old
  • Proliferating hemangioma with a minimal diameter of 1.5 cm
Main Exclusion criteria
  • Life-threatening, function-threatening, or severely ulcerated hemangiomas
Baseline characteristics
  • Average age 104 days
  • Hemangioma location: Facial - 70% | Nonfacial - 30%
  • Morphologic classification - 90% localized
Randomized treatment groups
  • Group 1 (99 patients) - Propranolol 1 mg/kg/day given in 2 divided doses for 3 months
  • Group 2 (103 patients) - Propranolol 1 mg/kg/day given in 2 divided doses for 6 months
  • Group 3 (101 patients) - Propranolol 3 mg/kg/day given in 2 divided doses for 3 months
  • Group 4 (102 patients) - Propranolol 3 mg/kg/day given in 2 divided doses for 6 months
  • Group 5 (55 patients) - Placebo
  • Propranolol was administered immediately before, during, or after feedings
Primary outcome: Success (complete or nearly complete resolution of the target hemangioma) or failure of trial treatment at week 24 versus baseline according to centralized evaluation
Results

  • p<0.001 vs placebo
Primary outcome at 24 weeks
Pro 1 mg/kg for 3 mon Pro 1 mg/kg for 6 mon Pro 3 mg/kg for 3 mon Pro 3 mg/kg for 6 mon Placebo
8% 49% 12% 60% 4%

Beta blocker associated adverse events
Side effect Pro 3 mg/kg for 6 mon Placebo
Hypotension 0% 2%
Bronchospasm 1% 2%
Bradycardia 0% 0%
Hypoglycemia 1% 0%
Other adverse events
Diarrhea 28% 7%
Sleep disorder 22% 13%
Bronchitis 17% 2%
Vomiting 13% 5%
Bronchiolitis 10% 5%
Cold hands and feet 10% 2%

Findings: This trial showed that propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma
StraightHealthcare analysis
  • In this study, propranolol at a dose of 1 - 3 mg/kg/day for 6 months was clearly effective in facilitating resolution of infantile hemangiomas
  • Surprisingly, propranolol did not increase the risk of significant cardiovascular events. Another study measured the effects of propranolol 2 mg/kg/day on blood pressure in infants aged 1 - 5 months (average age 2.8 months). That study also found that propranolol did not adversely affect blood pressure. [PMID 26391729]
  • Propranolol did increase the risk of other adverse events including diarrhea, sleep disorder, bronchitis, and vomiting






Overview
  • Beta blockers are sometimes given in the perioperative period (shortly before or at the time of surgery and continued for a short period after)
  • A handful of small studies have shown that perioperative beta blocker therapy may improve surgical outcomes
  • A large randomized trial that compared perioperative metoprolol to placebo is detailed below
DIPOM trial - Metoprolol vs Placebo in Major Noncardiac Surgery, BMJ (2006) [PubMed abstract]
  • A trial in the British Medical Journal enrolled 921 diabetics who were scheduled for major noncardiac surgery
Main inclusion criteria
  • Diabetes
  • Age > 39 years
  • Scheduled for major noncardiac surgery defined as surgery expected to last > 1 hour
Main exclusion criteria
  • Taking beta blockers
  • NYHA class IV heart failure
  • Third degree heart block
Baseline characteristics
  • Average age 64 years
  • Heart failure diagnosis - 10%
  • History of coronary artery disease and hypertension - 61%
  • Average duration of diabetes - 11.8 years
  • Type of surgery: Orthopedic - 33% | Intra-abdominal - 27% | Neurological - 8% | Vascular - 7% | Gynecological - 4% | Thoracic - 4%
  • Received general anesthesia - 76%
  • Average duration of surgery - 2.6 hours
Randomized treatment groups
  • Group 1 (462 patients) - Metoprolol extended-release starting the day before, or the day of surgery, and continued until hospital discharge (max of 8 days)
  • Group 2 (459 patients) - Placebo
  • When possible, patients were given a test dose of metoprolol 50 mg the evening before surgery. If tolerated, they were given 100 mg two hours before induction of anesthesia and then 100 mg once daily until discharge or a maximum of 8 days.
  • If oral drug was not feasible, metoprolol 5 mg IV was given before surgery and every 6 hours
  • Study drug was withheld in patients with pulse < 55 bpm or SBP < 100 mmHg
Primary outcome: Composite of all-cause mortality, acute myocardial infarction, unstable angina, or congestive heart failure discovered or aggravated during admission to hospital
Results

Duration: Median 18 months
Outcome Metoprolol Placebo Comparisons
Primary outcome (at 30 days postop) 6% 5% p>0.05
Primary outcome (median of 18 months) 21% 20% HR 1.06, 95%CI [0.80 - 1.41] p=0.66
Overall mortality (median of 18 months) 16% 16% HR 1.03, 95%CI [0.74 - 1.42]
Bradycardia or hypotension 32% 18% p<0.05
Average duration of study treatment 4.6 days 4.9 days N/A

Findings: Perioperative metoprolol did not significantly affect mortality and cardiac morbidity in these patients with diabetes. Confidence intervals, however, were wide, and the issue needs reassessment.
AHA recommendations
Vascular surgery - (ex. aortic and other major vascular surgery, peripheral vascular surgery)
  • Patients already receiving beta blockers should continue them
  • Patients with documented heart disease or ischemia should "probably" receive perioperative beta blockers
  • In patients with one or more high-risk cardiac factors (see below), perioperative beta blockers are "reasonable"
Intermediate risk surgery - (ex. intrathoracic surgery, carotid endarterectomy, head/neck surgery, orthopedic)
  • Patients already receiving beta blockers should continue them
  • In patients with documented heart disease or ischemia, perioperative beta blockers are "reasonable"
  • In patients with one or more high-risk cardiac factors (see below) or documented heart disease, perioperative beta blockers are "reasonable"
High-risk cardiac factors defined as:
  • Ischemic heart disease
  • Heart failure
  • Cerebrovascular disease
  • Diabetes
  • Kidney disease (defined as serum creatinine > 2 mg/dl)
StraightHealthcare analysis
  • There is no good evidence that routine perioperative beta blockers improve surgical outcome in any type of surgery


Slow heart rate (bradycardia)

Worsening heart failure
Overview
  • While beta blockers improve outcomes in patients with heart failure, they can also make symptoms of heart failure worse, particularly when they are first started or the dose is increased
  • Beta blockers should not be given to patients who are in active, decompensated heart failure [13]
The AHA recommends that beta blockers be held in the following heart failure patients:
  • Patients in Intensive Care Units (ICU)
  • Patients with evidence of fluid overload or volume depletion
  • Patients recently treated with positive inotropic agents [18]

Worsening of asthma or chronic obstructive pulmonary disease (COPD)
Overview
  • Beta-2 receptors are located on airways in the lungs
  • Blocking beta-2 receptors in the lungs can inhibit airways from relaxing and may worsen asthma or COPD symptoms
  • Nonselective beta blockers block beta-2 receptors
  • Selective beta blockers also have a small degree of beta-2 blockade
  • All beta blockers state in the package insert that they should not be taken by patients with COPD or asthma
  • Despite this, many patients with COPD or asthma have received beta blockers over the years
  • A number of small studies have also measured the effects of beta blockers in patients with asthma and COPD
STUDY
Cardioselective beta-blockers for reversible airway disease, Cochrane meta-analysis (2002) [PubMed abstract]
  • A Cochrane meta-analysis evaluated trials in which patients with COPD or asthma were given selective beta blockers and pulmonary function tests were analyzed
  • The following results were seen when beta blockers were compared to placebo:
  • Single dose trials
    • Patients were given one dose of beta blockers and tests were performed
    • FEV₁ values decreased an average of 9.14% with beta blockers
    • Beta blockers significantly increased the FEV₁ response to inhalers (beta agonists) by 6.6%
    • Beta blockers had no significant effect on patient-reported symptoms
  • Longer trials
    • Patients received beta blockers for 3 days to 4 weeks
    • Beta blockers had no significant effect on FEV₁
    • Beta blockers had no significant effect on patient-reported symptoms [93]
STUDY
Effect of beta blockers in treatment of COPD: a retrospective cohort study, BMJ (2011) [PubMed abstract]
  • A cohort study in the British Medical Journal looked at 5977 patients > 50 years old with COPD
  • Patients information was derived from several medical databases
  • Patients were divided into 2 cohorts:
    • 1. Patients who had been prescribed beta blockers
    • 2. Patients who had not been prescribed beta blockers
  • After an average follow-up of 4.35 years, the following was seen when patients taking beta blockers were compared to nonusers:
    • Patients taking beta blockers had a relative risk reduction of 22% for overall mortality
    • Beta blockers did not increase the risk of hospital admission for COPD
    • In patients where pulmonary function tests were available, beta blockers had no significant effect
    • Beta blockers did not increase the risk of a need for oral steroids
    • 88% of the beta blockers prescribed were selective beta blockers
    • When selective beta blockers were compared to nonselective beta blockers, no significant difference was seen for all-cause mortality [75]
STUDY
Beta-blockers may reduce mortality and risk of exacerbations in patients with COPD, Arch Intern Med (2010) [PubMed abstract]
  • A cohort study in the Archives of Internal Medicine looked at 2230 patients > 45 years old with COPD
  • Patients information was derived from a large medical database
  • Patients were divided into 2 cohorts:
    • 1. Patients who had been prescribed beta blockers
    • 2. Patients who had not been prescribed beta blockers
  • After an average follow-up of 7.2 years, the following was seen when patients taking beta blockers were compared to nonusers:
    • Patients taking beta blockers had a relative risk reduction of 36% for overall mortality
    • Patients taking beta blockers had a relative risk reduction of 32% for COPD exacerbations
    • Nonselective beta blockers showed similar risk reductions to selective beta blockers [76]
Summary
  • Beta blockers have historically been contraindicated in patients with asthma and COPD
  • The available evidence does not support this contraindication
  • Beta blockers may actually be beneficial in these patients
  • If a patient with COPD or asthma is to start a beta blocker, they should start at a low dose and titrate slowly while monitoring respiratory symptoms
  • Selective beta blockers may be preferred in these patients, although this is not conclusive

Abruptly stopping beta blockers

Depression

Sexual dysfunction

Fatigue

Low blood pressure (hypotension)

Masking symptoms of low blood sugar
Overview
  • Beta blockers may mask some symptoms of low blood sugar (rapid heart rate, sweating, dizziness) in diabetics
  • In clinical trials, this has not led to significant problems [80,81]
Summary
  • Diabetics should be aware that beta blockers may mask the symptoms of low blood sugar
  • Patients who have uncontrolled blood sugars and/or frequent low blood sugars may want to check blood sugars more frequently while taking a beta blocker
  • See hypoglycemia for more

Increased blood sugar
Overview
  • Beta receptors in the pancreas are involved in insulin release. Beta blockers may interfere with this mechanism and inhibit insulin release.
  • The effects of beta blockers on blood sugar levels in several studies are detailed below. The GEMINI study was a head-to-head comparison of metoprolol and carvedilol that was specifically designed to compare their effects on blood sugars.
STUDY
Hypertension and antihypertensive therapy as risk factors for type 2 DM, NEJM (2000) [PubMed abstract]
  • The ARC study was a cohort study where 3804 adults with hypertension and no diabetes at baseline were followed for 6 years
  • Patients were divided into cohorts based on the type of blood pressure medication they received over the 6 years
  • When compared to no treatment, the following risks for diabetes were seen:
    • Beta blockers: HR 1.28, 95%CI (1.04 - 1.57)
    • ACE inhibitors: HR 0.98, 95%CI (0.72 - 1.34)
    • Calcium channel antagonists: HR 1.17, 95%CI (0.83 - 1.66)
    • Thiazide diuretics: HR 0.91, 95%CI (0.73 - 1.13) [83]
  • Findings: Concern about the risk of diabetes should not discourage physicians from prescribing thiazide diuretics to nondiabetic adults who have hypertension. The use of beta-blockers appears to increase the risk of diabetes, but this adverse effect must be weighed against the proven benefits of beta-blockers in reducing the risk of cardiovascular events.
STUDY
Metabolic effects of carvedilol vs metoprolol in patients with type 2 DM and hypertension, JAMA (2004) [PubMed abstract]
  • The GEMINI study enrolled 1235 diabetics with hypertension
  • Main inclusion criteria: type 2 diabetes; SBP > 130 ≤ 179 and DBP > 80 ≤ 109 (after washout period); taking ACE inhibitor or ARB; HgA1C 6.5% - 8.5%
  • Main exclusion criteria: CHF; myocardial infarction or stroke within 3 months; bradycardia; second or third degree heart block; stage 3 or higher kidney disease
  • Baseline characteristics: average age 61 years; average HgA1C - 7.2%; average BP - 149/87
  • Patients were randomized in a 2:3 ratio to one of two groups:
    • Group 1 (498 patients) - Carvedilol 6.25 - 25 mg twice a day
    • Group 2 (737 patients) - Metoprolol tartrate 50 - 200 mg twice a day
    • All other BP meds except ACE inhibitors and ARBs were discontinued over a 2 - 4 week washout period
    • Patients were treated to a target SBP of < 135 and a target DBP of < 85
    • HCTZ 12.5 mg followed by calcium channel blocker could be added if needed
    • After achieving target BP, patients were treated for 5 months with maintenance therapy
  • Primary outcome: Difference in change from baseline HgA1C between groups following 5 months of maintenance therapy
  • After 5 months of maintenance therapy, the following was seen:
    • Primary outcome (average increase in A1C): Group 1 - 0.02%, Group 2 - 0.15% (diff 0.13%, 95%CI [-0.22 to -0.04], p=0.004)
    • Insulin sensitivity improved with carvedilol (HOMA-IR -9.1%, p=0.004) but not with metoprolol (HOMA-IR -2.0%, p=0.48) [102]
  • Findings: Both beta-blockers were well tolerated; use of carvedilol in the presence of RAS blockade did not affect glycemic control and improved some components of the metabolic syndrome relative to metoprolol in participants with DM and hypertension. The effects of the 2 beta-blockers on clinical outcomes need to be compared in long-term clinical trials.
Summary
  • Beta blockers appear to have a slight negative effect on blood sugar control
  • Diabetics who are starting beta blockers should be aware that beta blockers may cause their blood sugars to increase slightly
  • In patients with heart failure, the benefits of beta blockers outweigh their small effect on blood sugars
  • Nondiabetics who are at high risk for diabetes may want to avoid beta blockers if they don't have other indications for their use (ex. heart failure)
  • In the GEMINI study, carvedilol did not have a negative effect on blood sugars where metoprolol did. Carvedilol may therefore be preferred in diabetics who need a beta blocker.






Kidney disease
Atenolol (Tenormin®)
  • CrCl 15 - 35 ml/min - Maximum dose 50 mg a day
  • CrCl < 15 ml/min - Maximum dose 25 mg a day
Bisoprolol (Zebeta®)
  • CrCl < 40 ml/min - the initial dose should be 2.5 mg a day
  • Dosage increases should be done with caution
Carvedilol (Coreg®)
  • Carvedilol levels are increased in patients with moderate to severe kidney disease
  • Manufacturer makes no specific dosage recommendations
Labetalol (Trandate®)
  • Manufacturer makes no specific dosage recommendations
Metoprolol (Toprol®, Lopressor®)
  • No dosage adjustment necessary in kidney disease
Nadolol (Corgard®)
  • CrCl > 50 ml/min - dosage interval is 24 hours
  • CrCl 31 - 50 ml/min - dosage interval is 24 - 36 hours
  • CrCl 10 - 30 ml/min - dosage interval is 24 - 48 hours
  • CrCl < 10 ml/min - dosage interval is 40 - 60 hours
Nebivolol (Bystolic®)
  • CrCl < 30 ml/min - recommended starting dose is 2.5 mg once a day; titrate slowly as needed
Pindolol (Visken®)
  • For patients with significant kidney disease, drug clearance is decreased
  • Caution should be used in these patients
  • Manufacturer makes no specific dosage recommendations
Propranolol (Inderal®)
  • For patients with significant kidney disease, drug clearance is decreased
  • Caution should be used in these patients
  • Manufacturer makes no specific dosage recommendations
Timolol (Blocadren®)
  • Timolol is excreted by the kidneys. Use caution in kidney disease.
  • Manufacturer makes no specific dosage recommendations

Liver disease
Atenolol (Tenormin®)
  • Manufacturer makes no specific dosage recommendations
  • Atenolol undergoes little or no liver metabolism
Bisoprolol (Zebeta®)
  • For patients with significant liver disease, the initial dose should be 2.5 mg a day
  • Dosage increases should be done with caution
Carvedilol (Coreg®)
  • Carvedilol is contraindicated in patients with severe hepatic impairment (Child-Pugh > B)
Labetalol (Trandate®)
  • Labetalol should be used with caution
  • Manufacturer makes no specific dosage recommendations
Metoprolol (Toprol®, Lopressor®)
  • Metoprolol should be used with caution
  • Start therapy at lower doses
  • Manufacturer makes no specific dosage recommendations
Nadolol (Corgard®)
  • Nadolol is not metabolized by the liver, and it is excreted unchanged by the kidneys
  • Manufacturer makes no specific dosage recommendations
  • Liver disease by itself would not be expected to affect nadolol clearance
Nebivolol (Bystolic®)
  • In patients with moderate liver disease, the recommended starting dose is 2.5 mg once a day; titrate slowly as needed
  • Nebivolol is not recommended in patients with severe liver disease (Child-Pugh > B)
Pindolol (Visken®)
  • Pindolol levels are increased in patients with significant liver disease
  • Caution should be used in these patients
  • Manufacturer makes no specific dosage recommendations
Propranolol (Inderal®)
  • Propranolol levels are increased in patients with significant liver disease
  • Caution should be used in these patients
  • Manufacturer makes no specific dosage recommendations
Timolol (Blocadren®)
  • Timolol is partially metabolized by the liver. Use caution in liver disease.
  • Manufacturer makes no specific dosage recommendations

Asthma and COPD

Heart block

Black patients
Overview
  • Beta blockers appear to be less effective at lowering blood pressure in black patients when compared to other medications [88,89]
STUDY
Systematic review: antihypertensive drug therapy in black patients, Ann Intern Med (2004) [PubMed abstract]
  • A meta-analysis of trials using beta blockers in African-American patients found the following:
    • Beta blockers did not significantly lower systolic blood pressure (SBP) when compared to placebo
    • Beta blockers lowered diastolic blood pressure (DBP) an average of 5.43 mmHg when compared to placebo
  • Compare to:
    • Diuretics - average SBP reduction of 11.81 mmHg / DBP reduction of 8.06 mmHg
    • Calcium channel blockers - average SBP reduction 12.10 mmHg / DBP 9.40 mmHg [88]
Summary
  • Despite their inferior blood pressure effects, beta blockers are effective in improving significant clinical outcomes in African-Americans [89]

Sick sinus syndrome

Intraoperative floppy iris syndrome (carvedilol and labetalol)

Hyperthyroidism

Prinzmetal's angina (variant angina)



Drug interactions

All beta blockers

Carvedilol (Coreg®)
  • Cyclosporine (Neoral®) - carvedilol can increase cyclosporine levels [13]
  • CYP2D6 inhibitors - may increase carvedilol levels
  • CYP2D6 poor metabolizers - poor CYP2D6 metabolizers may have increased blood levels of carvedilol

Labetalol (Trandate®)
  • Cimetidine (Tagamet®) - cimetidine may increase labetalol levels [86]

Metoprolol (Toprol®, Lopressor®)
  • CYP2D6 inhibitors - may increase metoprolol levels
  • CYP2D6 poor metabolizers - poor CYP2D6 metabolizers may have increased blood levels of metoprolol

Nebivolol (Bystolic®)

Pindolol (Visken®)
  • Thioridazine (Mellaril®) - thioridazine may increase pindolol levels and vice versa [85]

Propranolol (Inderal®)

Timolol (Blocadren®)

  • Reference: Manufacturer's PI
Beta blocker metabolism and clearance
Drug CYP1A2 CYP2C9 CYP2C19 CYP2D6 P-glycoprotein OCT2
Carvedilol - Substrate - Substrate Substrate and inhibitor -
Metoprolol - - - Substrate - -
Nebivolol - - - Substrate - -
Pindolol - - - - - Substrate
Propranolol Substrate - Substrate Substrate Substrate and inhibitor -
Timolol - - Minor substrate Major substrate - -
Atenolol Not well defined
Bisoprolol Not well defined
Labetalol Mainly metabolized through glucuronidation
Nadolol Not well defined

Medications that slow the heart rate

Overview
  • All beta blockers slow the heart rate. When they are taken with other medications that slow the heart rate, bradycardia (< 50 beats per minute) may occur.

Common medications that slow the heart rate