- ACRONYMS AND DEFINITIONS
- A1C - Hemoglobin A1C
- AASLD - American Association for the Study of Liver Disease
- ACG - American College of Gastroenterology
- AHA - American Heart Association
- BP- Blood Pressure
- CAD- Coronary artery disease
- CCB - Calcium channel blocker
- Child-Pugh class - Child-Pugh liver failure classification
- CrCl - Creatinine clearance
- DBP - Diastolic Blood Pressure
- EGD - Esophagogastroduodenoscopy - procedure where the esophagus and stomach are observed with a scope
- EF - Ejection fraction
- ER - Extended release
- FEV1 - Forced expiratory volume over 1 second - measure of airway obstruction performed in pulmonary function tests
- HFpEF - Heart failure with preserved ejection fraction
- HFrEF - Heart failure with reduced ejection fraction
- IR - Immediate release
- NYHA - New York Heart Assoc classification for heart failure
- RCRI - Revised Cardiac Risk Index
- RCT - Randomized controlled trial
- SBP - Systolic Blood Pressure
- SCr - Serum creatinine
- DRUGS IN CLASS
- Selective beta blockers
- Atenolol (Tenormin®)
- Bisoprolol (Zebeta®)
- Metoprolol Succinate (Toprol-XL®)
- Metoprolol Tartrate (Lopressor®)
- Nebivolol (Bystolic®)
- Nonselective beta blockers
- Nadolol (Corgard®)
- Propranolol (Inderal®, Inderal LA®, Innopran XL®)
- Timolol (Blocadren®)
- Nonselective beta blockers with alpha-1 blocking activity
- Carvedilol (Coreg®, Coreg CR®)
- Labetalol (Trandate®)
- Beta blockers with intrinsic sympathomimetic activity (ISA)
- Pindolol (Visken®)
- Combination products with thiazide diuretics
- Corzide® (nadolol + bendroflumethiazide)
- Dutoprol® (metoprolol succinate + HCTZ)
- Inderide® (propranolol + HCTZ)
- Lopressor HCT® (metoprolol + HCTZ)
- Tenoretic® (atenolol + chlorthalidone)
- Ziac® (bisoprolol + HCTZ)
- MECHANISM OF ACTION
- Beta blockers
- Beta receptors are found on the surface of cells throughout the body
- Beta receptors are stimulated by hormones like adrenaline
- There are three main types of receptors that beta blockers block: beta-1, beta-2, and alpha-1 receptors. Beta blockers vary by which of these receptors they inhibit.
- The receptors have the following charcteristics:
- Beta-1 receptors - located mainly in the heart. Blocking beta-1 receptors decreases heart rate, cardiac output, contractility, and cardiac oxygen demand.
- Beta-2 receptors - located on smooth muscle in the lungs, blood vessels, and other organs. Blocking beta-2 receptors inhibits smooth muscle dilation (relaxation).
- Alpha-1 receptors - located on smooth muscles of arteries and veins. Blocking alpha-1 receptors causes vessels to dilate (relax).
- Nonselective beta blockers
- Nonselective beta blockers block both types of beta receptors (1 and 2)
- Selective beta blockers
- Selective beta blockers block mainly beta-1 receptors
- Beta blockers with alpha-blocking activity
- Nonselective beta blockers that also block alpha-1 receptors
- Beta blockers with intrinsic sympathomimetic activity (ISA)
- Beta blockers with ISA are nonselective beta blockers that block and partially stimulate beta receptors at the same time [11]
- FDA-APPROVED INDICATIONS
- Atenolol (Tenormin®)
- Hypertension
- Angina pectoris due to coronary atherosclerosis
- Acute myocardial infarction (IV)
- Bisoprolol (Zebeta®)
- Hypertension
- Carvedilol (Coreg®, Coreg CR®)
- Hypertension
- Heart failure
- Left ventricular dysfunction following myocardial infarction
- Labetalol (Trandate®)
- Hypertension
- Metoprolol Succinate (Toprol-XL®) Extended-release
- Hypertension
- Heart failure
- Angina pectoris
- Metoprolol Tartrate (Lopressor®) Standard-release
- Hypertension
- Myocardial infarction (IV)
- Angina pectoris
- Nadolol (Corgard®)
- Hypertension
- Angina pectoris
- Nebivolol (Bystolic®)
- Hypertension
- Pindolol (Visken®)
- Hypertension
- Propranolol (Inderal®)
- Hypertension
- Atrial fibrillation
- Angina pectoris due to coronary atherosclerosis
- Myocardial infarction
- Migraine
- Essential tremor
- Hypertrophic subaortic stenosis
- Pheochromocytoma
- Propranolol (Inderal LA®)
- Hypertension
- Angina pectoris due to coronary atherosclerosis
- Migraine
- Hypertrophic subaortic stenosis
- Propranolol (Innopran XL®)
- Hypertension
- Timolol (Blocadren®)
- Hypertension
- Migraine
- Myocardial infarction
- HYPERTENSION
- Overview
- Beta blockers have been used to treat hypertension for many decades. A randomized controlled trial that included atenolol is detailed below, along with a summary of three Cochrane meta-analyses that evaluated the effects of beta blockers by class (selective, nonselective +/- alpha blockade).
- 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 |
|
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.
- STUDY
- 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
- HEART FAILURE WITH REDUCED EJECTION FRACTION (HFrEF)
- Overview
- Beta blockers have consistently been shown to improve outcomes in patients with HFrEF. Carvedilol, metoprolol succinate, and bisoprolol have all proven effective in large, randomized controlled trials and are recommended by the AHA. Only carvedilol and metoprolol succinate are FDA-approved to treat HFrEF.
- Pivotal trials for carvedilol, metoprolol, and bisoprolol are reviewed below, along with a head-to-head trial that compared carvedilol to metoprolol tartrate (COMET trial)
- 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 |
|
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
- 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
- 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 |
|
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.
- 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] |
|
Findings: Our results suggest that carvedilol extends survival compared with metoprolol
- AHA recommendations
- The AHA states that 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 metoprolol tartrate [50 mg twice a day] than what has been used in trials with metoprolol succinate [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]
- Summary
- Beta blockers have consistently been shown to improve outcomes in heart failure patients, and all patients with stable disease should receive one
- Carvedilol, metoprolol succinate, and bisoprolol are preferred because there is insufficient data on other beta blockers. Of particular note, the widely-prescribed beta blocker atenolol has been shown to improve heart failure outcomes in small trials, but no large trial has been performed. [27,28]
- HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFpEF)
- Overview
- Heart failure with preserved ejection fraction (HFpEF) is a syndrome where the signs and symptoms of heart failure are present in patients with a normal ejection fraction
- Beta blockers have not been studied extensively in HFpEF. One small trial that looked at the effects of carvedilol found no benefit. [PMID 22983988]
- AHA recommendations
- ACUTE MYOCARDIAL INFARCTION
- 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 these trials were performed before antiplatelet therapy, PCI, and fibrinolysis became routine treatments.
- In 2005, the enormous COMIT trial (see below) was published that compared metoprolol to placebo in acute MI
- The COMMIT trial enrolled 45,852 patients with suspected acute myocardial infarction
Main inclusion criteria
- Symptoms of acute MI within 24 hours and ≥ 1 of the following:
- ST elevation
- Left bundle branch block
- 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 |
|
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
- Summary
- 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
- STABLE CAD
- AHA recommendations
- The AHA 2012 coronary artery disease guidelines recommend that beta blockers be given for 3 years to all patients with a normal EF after a myocardial infarction or acute coronary syndrome
- Beta blockers should be used indefinitely in all patients with an EF ≤ 40% with heart failure and prior myocardial infarction. Carvedilol, metoprolol succinate, and bisoprolol are the only three beta blockers that should be used [96]
- Summary
- Beta blockers improve outcomes in patients with heart failure. They also help relieve angina.
- There is no conclusive evidence that beta blockers improve outcomes in patients who have CAD without heart failure
- ATRIAL FIBRILLATION
- Overview
- Atrial fibrillation is a common heart arrhythmia that can cause 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 conduction through the AV node, and therefore, they can be used to control heart rates in A fib
- The RATE-AF study detailed below compared the effects of bisoprolol to digoxin on heart rate in patients with permanent A fib. The other two studies compared beta blockers to placebo for various outcomes, and differences in heart rates between groups are shown.
- STUDY
- In the RATE-AF study, 160 patients with permanent A fib were randomized to digoxin or bisoprolol for 6 months
- The baseline average resting heart rate was around 100 bpm in both groups
- The following effects on heart rate were seen after 6 months of therapy:
- Bisoprolol (average dose 3.2 mg/day) reduced the average resting heart rate to 74.8 bpm
- Digoxin (average dose 161 mcg/day) reduced average resting heart rate to 76.9 bpm
- STUDY
- In the MERIT-HF study, 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 (metoprolol minus placebo) in patients with atrial fibrillation
- Metoprolol (average dose 154 mg) reduced the average heart rate by 13 beats per minute (metoprolol minus placebo) in patients with a normal heart rhythm [47]
- 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]
- AHA recommendations
- ATRIAL FIBRILLATION | Rhythm control
- Overview
- Beta blockers (excluding sotalol) do not have apparent atrial-stabilizing properties, but the small trial detailed below did find a modest effect for metoprolol in preventing recurrent A fib
- 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 |
|
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
- Summary
- The trial above found that metoprolol had a modest effect in preventing recurrent A fib in patients who had undergone successful cardioversion. Antiarrhythmics and catheter ablation are more effective for rhythm control and are preferred.
- STABLE ANGINA
- Overview
- 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
- STUDY
- 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]
- CIRRHOSIS
- Overview
- Cirrhosis of the liver can lead to esophageal varices which are dilated blood vessels that develop in the lining of the esophagus. Esophageal varices can bleed and lead to life-threatening hemorrhage.
- Nonselective beta blockers (propranolol, nadolol) are often prescribed to patients with esophageal varices
- Nonselective beta blockers cause the blood vessels leading to the liver to constrict (B-2 receptor effect), therefore decreasing blood flow to the liver and helping to relieve congestion
- ACG and AASLD recommendations
- Patients with cirrhosis and no varices
- Beta blockers have not been proven to prevent varices
- Routine beta blockers are not recommended
- Patients with cirrhosis and small varices (defined as < 5 mm in diameter) that have not bled
- Beta blockers may help slow variceal growth, although this is not conclusive
- In patients with increased risk of hemorrhage (Child B/C or presence of red wale marks on varices), nonselective beta blockers should be used
- In patients without increased risk of hemorrhage, beta blockers may be used, but their long-term benefit is not proven
- For patients placed on beta blockers, follow-up EGD is not necessary
- Patients with cirrhosis and medium to large (defined as > 5 mm in diameter) varices that have not bled
- Nonselective beta blockers significantly reduce the risk of first variceal bleeding
- In patients with increased risk of hemorrhage (Child B/C or presence of red wale marks on varices), nonselective beta blockers should be used or endoscopic variceal ligation should be performed
- In patients without increased risk of hemorrhage, beta blockers are preferred
- For patients placed on beta blockers, they should be adjusted to maximum tolerated dose, and follow-up EGD is unnecessary
- Patients with cirrhosis and varices that have bled
- Beta blockers should be prescribed and repeat endoscopic variceal ligation should be performed
- Beta blockers should be titrated to the maximum tolerated dose [67]
- MIGRAINE PREVENTION
- Certain beta blockers (propranolol, atenolol, metoprolol, timolol) are used to prevent migraine headaches
- See migraine prevention for more
- PERIOPERATIVE BETA BLOCKERS
- Overview
- Beta blockers have cardioprotective effects, and studies have looked at initiating them just prior to surgery to improve surgical outcomes. Results from these studies have been mixed. A large randomized trial that compared perioperative metoprolol to placebo in diabetics is detailed below, along with recommendations from the AHA.
- 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 2014 recommendations
- Beta blockers should be continued in patients undergoing surgery who have been on beta blockers chronically
- In patients with intermediate- or high-risk myocardial ischemia noted in preoperative risk stratification tests, it may be reasonable to begin perioperative beta blockers
- In patients with 3 or more RCRI risk factors (see below) it may be reasonable to begin beta blockers before surgery
- In patients with a compelling long-term indication for beta-blocker therapy but no other RCRI risk factors, initiating beta blockers in the perioperative setting as an approach to reduce perioperative risk is of uncertain benefit
- In patients in whom beta-blocker therapy is initiated, it may be reasonable to begin perioperative beta blockers long enough in advance to assess safety and tolerability, preferably more than 1 day before surgery
- Beta-blocker therapy should not be started on the day of surgery
- It is reasonable for the management of beta blockers after surgery to be guided by clinical circumstances, independent of when the agent was started [105]
- RCRI risk factors
- Intraperitoneal, intrathoracic, or suprainguinal vascular surgery
- History of ischemic heart disease
- History of CHF
- History of cerebrovascular disease
- Preoperative treatment with insulin
- Preoperative creatinine > 2 mg/dl
- SIDE EFFECTS
- Slow heart rate (bradycardia)
- Beta blockers slow the heart rate, and this can lead to syncope and heart failure in some people. Patients with first-degree AV block, sinus node dysfunction, and/or conduction disorders (e.g. Wolff-Parkinson-White) are at increased risk.
- Three Cochrane meta-analyses that evaluated the effect of beta blockers on hypertension found the following effects of beta blockers on heart rate:
- Selective beta blockers lowered the average heart rate by 11 bpm [99]
- Nonselective beta blockers lowered the average heart rate by 12 bpm [100]
- Carvedilol and labetalol lowered the average heart rate by 5 bpm [101]
- In the COMET heart failure trial detailed above, carvedilol and metoprolol lowered the average heart by 13 bpm and 12 bpm, respectively
- Beta blocker may need to be reduced or stopped if the resting heart rate is below 55 beats per minute [13]
- Worsening heart failure
- 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)
- 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
- 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
- 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
- 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
- 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
- All beta blocker package inserts warn against abruptly stopping the drugs. Cases of chest pain, heart attack, and heart arrhythmias have been reported when beta blockers are stopped suddenly. Patients with documented heart disease are at greatest risk, but it's important to note that patients taking beta blockers for other reasons may also have undocumented CAD.
- Beta blockers should be tapered over 1 - 2 weeks when discontinuing, and patients should monitor for signs and symptoms of heart disease. If chest pain or abnormal heart rate occurs, beta blockers should be restarted immediately. [13]
- Depression
- Beta blockers have been reported to cause depression in some patients. Several large reviews have looked at the association of beta blockers with depression in randomized placebo-controlled trials. These studies have found no significant difference in the incidence of depression between beta blockers and placebo. [PMID 33719510, PMID 12117400]
- Sexual dysfunction
- Sexual dysfunction has been reported in patients receiving beta blockers
- A meta-analysis of beta blocker trials found that beta blockers were associated with a slight increase in the risk of sexual dysfunction when compared to placebo. The risk equated to about 1 additional case of sexual dysfunction for every 199 patients treated for a year. [78]
- Fatigue
- Beta blockers have been reported to cause fatigue in some patients
- A meta-analysis of trials found that beta blockers increased the relative risk of fatigue by 15% when compared to placebo (14 trials)
- The risk equated to about 1 additional case for every 55 patients treated with a beta blocker for a year [78]
- Low blood pressure (hypotension)
- Like most blood pressure medications, beta blockers may cause low blood pressure and the symptoms that accompany it
- The incidence of low blood pressure and its symptoms has ranged from 6 - 10% in trials [13,79]
- Hypoglycemia
- Beta blockers may mask symptoms of hypoglycemia (e.g. rapid heart rate, sweating, and dizziness) and prevent its correction by endogenous catecholamines. In clinical trials, this has not led to significant problems. [80,81]
- Diabetics and patients with risk factors for hypoglycemia (e.g. fasting, infection, vomiting) may want to check blood sugars more frequently while taking beta blockers. See hypoglycemia for more.
- Increased blood sugar
- 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
- 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
- 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.
- CONTRAINDICATIONS
- All beta blockers
- Sinus bradycardia
- Second and third degree heart block
- Cardiogenic shock
- Overt heart failure
- Sick sinus syndrome (unless a permanent pacemaker is in place)
- Nebivolol (Bystolic®) and Carvedilol (Coreg®, Coreg CR®)
- Patients with severe hepatic impairment (Child-Pugh > B)
- Nonselective beta blockers
- Asthma and COPD
- See worsening of asthma and COPD for a discussion
- PRECAUTIONS
- 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®, Coreg® CR)
- Carvedilol levels are increased 40 - 50% in patients with moderate to severe kidney disease. Changes in mean peak plasma levels are less pronounced, approximately 12% to 26% higher. Manufacturer makes no specific recommendation.
- Labetalol (Trandate®)
- Manufacturer makes no specific dosage recommendations
- Metoprolol (Toprol®, Lopressor®)
- No dosage adjustment is 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®)
- Poor renal function has only minor effects on pindolol clearance
- CrCL < 20 ml/min: clearance is significantly reduced. Use caution.
- Propranolol (Inderal®)
- Use caution. Clearance is decreased.
- Propranolol (Inderal® LA)
- Use caution. Clearance is decreased.
- Propranolol (Innopran® XL)
- Exposure is increased. Start with 80 mg once daily and monitor for marked bradycardia and hypotension.
- Timolol (Blocadren®)
- Clearance is decreased. Use caution.
- 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®)
- Blood levels are likely to be increased. Start therapy at lower doses and increase gradually.
- Nadolol (Corgard®)
- Nadolol is not metabolized by the liver and is excreted unchanged by the kidneys. Liver disease by itself would not be expected to affect nadolol clearance.
- Nebivolol (Bystolic®)
- Child-Pugh B: recommended starting dose is 2.5 mg once a day; titrate slowly as needed
- Child-Pugh C: not recommended
- Pindolol (Visken®)
- Poor hepatic function may cause blood levels of pindolol to increase substantially. Use caution.
- Propranolol (Inderal®)
- Propranolol is extensively metabolized by the liver. Use caution. Clearance is decreased.
- Propranolol (Inderal® LA)
- Propranolol is extensively metabolized by the liver. Use caution. Clearance is decreased.
- Propranolol (Innopran® XL)
- Exposure is increased. Start with 80 mg once daily and monitor for marked bradycardia and hypotension.
- Timolol (Blocadren®)
- Clearance is decreased. Use caution.
- Asthma and COPD
- See Worsening of asthma/COPD above for a discussion
- Heart block
- Beta blockers are contraindicated in second and third degree heart block
- Black patients
- Beta blockers appear to be less effective at lowering blood pressure in black patients when compared to other medications [88,89]
- STUDY
- 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
- Because beta blockers slow conduction through the AV node, they should not be taken by patients with sick sinus syndrome
- Intraoperative floppy iris syndrome (carvedilol and labetalol)
- Intraoperative Floppy Iris Syndrome (IFIS) is a syndrome where the iris (colored part of the eye) becomes floppy and flaccid
- IFIS can complicate eye surgery, particularly cataract surgery
- In 2005, it was discovered that alpha blockers are associated with an increased risk of IFIS
- Carvedilol and labetalol block alpha receptors and may increase the risk of IFIS
- Patients taking carvedilol and labetalol should inform their ophthalmologist that they are taking these medications
- Stopping alpha blockers before surgery does not appear to have a benefit
- Hyperthyroidism
- Beta blockers may mask the symptoms of hyperthyroidism (rapid heart rate, anxiety, tremor, palpitations, etc.). Because of this, they are also often used to treat symptoms of hyperthyroidism
- Prinzmetal's angina (variant angina)
- Beta blockers can theoretically make Prinzmetal's angina worse, although this has not been proven. Use caution when prescribing beta blockers to patients with Prinzmetal's angina. [40]
- Pheochromocytoma
- If beta blockers are used in the setting of pheochromocytoma, they should be given in combination with an alpha blocker, and only after the alpha blocker has been initiated. Administration of beta blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle.
- Anaphylactic reactions
- Patients with a history of severe anaphylactic reactions may be more reactive to allergens while taking beta blockers. Beta blockers may also reduce the effectiveness of epinephrine used to treat these reactions.
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- All beta blockers
- Catecholamine depleting drugs - concomitant use of catecholamine-depleting drugs (e.g. reserpine, monoamine oxidase (MAO) inhibitors) with beta blockers may increase the risk of hypotension and bradycardia
- Clonidine (Catapres®) - abruptly stopping clonidine in patients taking beta blockers can lead to severe rebound hypertension. When clonidine and a beta blocker are taken together, and clonidine is to be discontinued, it is recommended that the beta blocker be stopped several days before clonidine is withdrawn. Clonidine can then 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 heart rate-slowing medications, the effect may be potentiated, and bradycardia can occur.
- Common medications that slow the heart rate
- Amiodarone (Cordarone®)
- Calcium channel blockers (diltiazem and verapamil)
- Clonidine (Catapres®)
- Digoxin (Lanoxin®)
- Fingolimod (Gilenya®)
- Ivabradine (Corlanor®)
- Siponimod (Mayzent®)
- 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 - metoprolol is a CYP2D6 sensitive substrate. CYP2D6 strong inhibitors have been shown to double metoprolol concentrations. The effects of moderate and weak inhibitors have not been studied, but they also likely increase exposure. Use caution when combining CYP2D6 inhibitors with metoprolol. Higher plasma concentrations of metoprolol decrease its cardioselectivity.
- CYP2D6 poor metabolizers - poor CYP2D6 metabolizers may have increased metoprolol exposure. Use caution.
- Nebivolol (Bystolic®)
- CYP2D6 inhibitors - may increase nebivolol levels
- Pindolol (Visken®)
- Thioridazine (Mellaril®) - thioridazine may increase pindolol levels and vice versa [85]
- Propranolol (Inderal®)
- Bile Acid Sequestrants (Questran, etc®) - bile acid sequestrants may decrease the absorption of propranolol [87]
- CYP2D6 substrates and inhibitors - may increase propranolol levels
- CYP1A2 substrates / inhibitors / inducers - may increase or decrease propranolol levels
- CYP2C19 substrates and inhibitors - may increase propranolol levels
- Rizatriptan (Maxalt®) - propranolol increases rizatriptan levels. See rizatriptan for dosing recommendations.
- Warfarin (Coumadin®) - propranolol may increase warfarin levels
- Zileuton (Zyflo®) - zileuton has been shown to increase blood levels of propranolol
- Timolol (Blocadren®)
- CYP2D6 strong inhibitors - timolol is a CYP2D6 sensitive substrate. CYP2D6 inhibitors may increase timolol exposure.
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 |
- DOSING
- LONG-TERM SAFETY
- Beta blockers have been in use since the 1960s
- They have been prescribed to millions of people and their safety has been evaluated in numerous trials
- Beta blockers have consistently been shown to be safe in long-term use
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- 92 - PMID 10351980
- 93 - PMID 12519582
- 94 - Zileuton PI
- 95 - Glimepiride PI
- 96 - PMID 23166211 AHA GL on stable CAD
- 97 - PMID 25693013 - hemangioma study
- 98 - PMID 17431033 - Timolol metabolism
- 99 - PMID 26961574 - selective BB effects
- 100 - PMID 24585007 - nonselective BB effects
- 101 - PMID 26306578 - alpha/beta blockers BB effects
- 102 - PMID 15536109 - GEMINI study
- 103 - PMID 23741058 - AHA 2013 Heart Failure GL
- 104 - PMID 28455343 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure, Circulation (2017)
- 105 - PMID 25085961 - 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery, Circulation (2014)