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.

















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.








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  • 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