BETA BLOCKERS



















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.







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 the bisoprolol group, 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 the carvedilol and metoprolol groups, respectively
  • The incidence of adverse events was similar between groups

Findings: Our results suggest that carvedilol extends survival compared with metoprolol









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.
















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.














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








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.




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 Cochrane meta-analysis found no ill effects of beta blockers in patients with COPD or asthma. Two other observational studies also found no ill effects, and in addition, a potential beneficial effect was observed. These findings prompted a randomized controlled trial of metoprolol in patients with COPD. All 4 studies are detailed below.
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]
STUDY
BLOCK COPD Trial - Metoprolol vs Placebo to Prevent COPD Exacerbations, NEJM (2019) [PubMed abstract]
  • Design: Randomized, placebo-controlled trial (N=532 | length = 350 days) in patients with moderate-to-severe COPD and no indication for a beta blocker
  • Treatment: Metoprolol 25 - 100 mg once daily vs Placebo
  • Primary outcome: Median time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol
  • Results:
    • Primary outcome: Metoprolol - 202 days, Placebo - 222 days (p=0.66)
  • Findings: Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol.
Summary
  • Beta blockers have historically been contraindicated in patients with asthma and COPD. Despite this, many patients with COPD and asthma have received beta blockers. Observational studies have not identified any adverse effects in patients with COPD or asthma who received beta blockers for other indications. The BLOCK COPD trial did not find any benefit of metoprolol in patients with COPD who did not have an indication for beta blockers.
  • Patients with COPD or asthma who have an indication for a beta blocker are likely to tolerate them. The beta blocker should be started at a low dose and titrated slowly while monitoring respiratory symptoms. A selective beta blocker may be preferred.
  • Patients with COPD who do not have an indication for beta blockers should avoid them

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)



All beta blockers

  • Clonidine (Catapres®)
    • Abruptly stopping clonidine in patients taking beta blockers can lead to severe rebound hypertension
    • When clonidine and beta blockers are taken together and clonidine is to be stopped, it is recommended that the beta blocker be withdrawn first, and then clonidine can be tapered over 2 - 4 days.
  • Medications that slow the heart rate - All beta blockers slow the heart rate. When they are taken with other medications that slow the heart rate, the effect may be potentiated.
  • Sulfonylureas (glimepiride, glipizide, Glucotrol®, etc.) - beta blockers may potentiate the effect of sulfonylureas. The significance of this effect is unclear. [95]

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