Beta Blocker Trails

in Heart failure
INTRODUCTION

● Beta -blockers traditionally considered contraindicated in patients with heart failure

● Substantial reduction in mortality (∼30%) and morbidity

● Improvement in symptoms and patient’s well-being

Which BB are beneficial in HF

● 3 BB- Bisoprolol, Carvedilol and Metoprolol succinate -conclusively shown to reduce mortality
and morbidity in patients with systolic heart failure

● Not all beta-blockers equally effective in heart failure –Bucindolol and nebivolol

● Atenolol – absence of RCTs

BETA BLOCKERS AND IMPORTANT
TRIALS
● CARVEDILOL ● US CARVEDILOL STUDY, COPERNICUS,CAPRICORN

● BISOPROLOL ● CIBIS II

● METOPROLOL ● MERIT HF

● BUCINDOLOL ● BEST

● NEBIVOLOL ● SENIORS
 Metoprolol in Dilated Cardiomyopathy
(MDC) trial
● First Placebo controlled multicenter trial with a beta-­blocking agent Metoprolol
● 383 patients with IDC (LVEF<40%)
● 90% were NYHA class II-IlI
● Randomized to metoprolol or Placebo
● Target doses: 50-75 mg po bid
● Follow-up: One year
● Primary endpoint: Death or need for transplant
● Secondary endpoint: EF
Death or Transplant
Change In Ejection Fraction
Change in Functional Status
Metoprolol CR/XL Randomized Intervention
Trial in Congestive Heart Failure (MERIT-­HF)
● Hypothesis: To determine the effects on mortality of once-daily dosing of metoprolol succinate
controlled release/extended release (CR/XL) when added to standard therapy for heart failure.
● Study Design : Randomized, double-blind, placebo-controlled.
● Patients Enrolled: 3,991
● NYHA Class: 41% Class II; 55% Class III, 3.5% Class IV
● Mean Patient Age: 64
● Female: 23%
● Mean Ejection Fraction: 28%
Primary and secondary end point
US Carvedilol study

● Study Design : Double-blind, placebo-controlled

● Patients Enrolled: 1,094
● NYHA Class: I=(53%), III=(44%), IV=(3%)
● Mean Follow Up: 6.5 months (1 day - 15 months)
● Mean Patient Age: 58
● Female: 24 %
● Mean Ejection Fraction: 23%
● Carvedilol 6.25 to 50 mg BID (average 45)
Inclusion and exclusion criteria
● Symptoms of CHF at least 3 months
● Left ventricular ejection fraction < 0.35%
● Baseline treatment with digoxin,
diuretics, and ACE inhibitor encouraged
● Heart rate < 68
● Systolic blood pressure > 160 mmHg or < 85
mmHg
● Diastolic blood pressure > 100 mmHg
● Calcium channel blockers, alpha or beta blockers,
amiodarone
● Recent cardiovascular event or procedure (3
months)
● Uncorrected, primary valvular disease
● Myocarditis
● Sustained ventricular tachycardia or heart block
not treated or controlled with antiarrhythmic
therapy or pacemaker.
● Other co-morbid condition limiting survival
● Mortality in placebo group was 7.8% versus 3.2% in carvedilol group. (65% risk reduction; p
<0.001).
● Carvedilol associated with a 27% reduction in risk of hospitalization for cardiovascular causes
(19.6% versus 14.1%; p = 0.036).
● Carvedilol also reduced combined risk of hospitalization or death (p < 0.001).
● 2289 patients
● Heart failure at rest or on minimal exertion, who were clinically euvolemic, and who had an ejection fraction of less
than 25 percent.
● Double-blind fashion.
● we randomly assigned 1133 patients to placebo and 1156 patients to treatment with carvedilol for a mean period of
10.4 months .
● carvedilol 3.125 mg bd to 25 mg bd significantly reduced total death (HR 0.65, 0.52-0.81,
p=0.0014)
 CAPRICORN Trail

● Randomized, placebo-controlled trial

● Designed to test the long-term efficacy of carvedilol on morbidity and mortality in patients
with left ventricular (LV) dysfunction after myocardial infarction (MI) already treated with
angiotensin-converting enzyme (ACE) inhibitors.
● Patients Enrolled: 1,959
● Mean Follow Up: average 1.3 years
● Mean Patient Age: mean 63
● Female: 27
● Mean Ejection Fraction: Mean 32.9% in carvedilol group; mean 32.7% in placebo group
● Carvedilol (starting dose of 6.25 mg twice a day, uptitrated to a maximum of 25 mg twice a day)
versus placebo
● Age ≥18 years
● Stable definite MI within 3-21 days of
randomization
● LV ejection fraction of ≤40% by
echocardiography
● Radionuclide or contrast ventriculography,
or wall motion-score index of 1.3 or less;
● Receipt of concurrent treatment of ACE
inhibitors for at least 48 hours with a stable
dose for more than 24 hours, unless there
was a proven intolerance of ACE inhibitors
● Continuing requirement for intravenous
diuretics or inotropes
● Uncontrolled heart failure
● Unstable angina
● Hypotension (systolic blood pressure <90
mm Hg); uncontrolled hypertension;
● Bradycardia (heart rate <60 beats per minute);
● Unstable insulin-dependent diabetes mellitus;
● Continuing indication for β-blockers for any
clinical indication other than heart failure;
● Ongoing therapy with inhaled β2-agonists or
steroids
● A total of 1,959 patients were randomized to carvedilol (n=975) or placebo (n=984).
● The primary endpoint of all-cause mortality or hospital admissions was similar between arms
(35% vs. 37%, hazard ratio [HR] 0.92, p=0.296).
● Although the coprimary endpoint of all-cause mortality was lower in the carvedilol arm than
in the placebo arm (12% vs. 15%, HR 0.77, p=0.031), this did not satisfy statistical
significance for the revised co primary endpoint.
● Sudden death and hospital admissions from heart failure were similar between arms, but
cardiovascular mortality was lower in the carvedilol arm (11% vs. 14% for placebo, HR 0.75,
p=0.024), as was all-cause mortality or nonfatal MI (14% vs. 20%, HR 0.71, p=0.002).
● Bisoprolol vs. placebo for mortality in heart failure.
● Hypothesis : To test benefits of β-blockade (bisoprolol) in patients with heart failure.
● Study Design:Double blind ,Placebo controlled Randomised trail
● Patients Enrolled: 2,647
● Mean Follow Up: 1.4 years
● Female: 0
● Bisoprolol 1.25 mg. qd, titrated to 10 mg qd. over 6 months, vs placebo
● Inclusion Criteria :
1. Ambulatory NYHA Class III or IV patients with dyspnea on exertion, orthopnea or paroxysmal nocturnal
dyspnea
2. Between 18 and 80 years of age
3. Stable on ACE I and diuretics
4. LVEF less than or equal to 35%
Principal Findings:

● Bisoprolol reduced all cause mortality by 32% (11.8% vs 17.3%, p=0.002). Sudden death was
reduced by 45% (3.6% vs 6.4%, p=0.001).
● Hospitalizations for heart failure was reduced by 30% (11.9% bisoprolol vs 17.6% placebo, p <
0.001), and all cause hospitalizations were reduced by 15% (33.6% vs 39.6%, p=0.002).
● The number of patients needed to treat for 1 year to save one life was 25
● CIBIS-II was the first randomized controlled trial with sufficient power to address all cause
mortality as a primary objective. The mortality benefit of low-dose beta blockade in congestive
heart failure is encouraging.
● Study Design:Double blind Randomised Trial
● Patients Enrolled: 2708
● Treatment with either bucindolol (1354 patients) or placebo (1354 patients) and followed for the
primary end point of death from any cause.
● Inclusion Criteria : Age 18 years old ,NYHA III or IV due to primary or secondary dilated
cardiomyopathy and LVEF < 35 %
● Exclusion Criteria : Reversible cause of heart failure
○ uncorrected primary valvular disease,
○ untreated thyroid disease,
○ obstructive or hypertrophic cardiomyopathy,
○ pericardial disease, amyloidosis,
○ active myocarditis, a malfunctioning artificial heart valve, or a history of myocardial infarction within
the previous six months.
● There was no significant difference in mortality between the two groups (unadjusted p=0.16).
● No significant overall survival benefit.
● 2128 patients
● Age ≥70 years with a history of heart failure (hospital admission for heart failure within the
previous year or known EF ≤35%)
● Initial dose - 1.25 mg od - increased - target of 10 mg od
● Avg follow-up - 21 months
● Nebivolol reduced the composite end point of all-cause mortality and cardiovascular
hospitalization (HR=0.86; 95% CI, 0.74-0.99; P=.039) but did not reduce the total mortality rate
Major Placebo controlled trial of beta
blocker in Heart Failure
Among the BB,which is most effective

● Carvedilol and metoprolol - similar hemodynamics and heart rate effects

● COMET trial - carvedilol is superior in extending survival
● 3029 patients
● Inclusion criteria : NYHA functional class II to IV HF,
○ Left ventricular ejection fraction ≤35%,
○ At least one cardiovascular hospitalization during the previous two years,
○ Receiving stable HF treatment with ACEI for at least four weeks unless contraindicated
○ Receiving treatment with diuretics (≥40 mg of furosemide or equivalent) for at least two weeks.

Exclusion Criteria :

○ Patients with a contraindication to a beta-blocker,

○ Uncontrolled hypertension
○ Major valvular disease,
○ Major vascular event or ventricular arrhythmia within the previous two months were excluded.
● Treatment with carvedilol (target dose 25 mg bd) and metoprolol (metoprolol tartrate, target dose 50 mg bd)
● Of 3,029 patients, 1,511 were assigned to treatment with carvedilol and 1,518 to metoprolol.
● The mean study duration was 58 months.
● The all-cause mortality was 34% for carvedilol and 40% for metoprolol (hazard ratio 0·83 [95%
CI 0·74–0·93], p=0·0017)
● Results suggested that carvedilol extends survival compared with metoprolol.
Thank you