Transcript ESC review 2011 - Vasculaire Geneeskunde

BEAUTIfUL:
morBidity-mortality EvAlUaTion of the If inhibitor
ivabradine in patients with coronary disease and left
ventricULar dysfunction
Purpose
To assess whether adding ivabradine to
standard treatment in order to lower heart
rate can reduce cardiovascular dearth and
morbidity in patients with coronary artery
disease (CAD) and left-ventricular (LV) systolic
dysfunction.
Fox et al. Lancet 2008;372:807–816.
BEAUTIfUL: TRIAL DESIGN
Design
Randomized, double-blind, placebo-controlled, parallel-group, multicenter,
multinational trial.
Patients
12,473 patients who were aged ≥55 years old and who had CAD, LV
ejection fraction of <40%, and end-diastolic short-axis internal dimension
of >56 mm. Patients from 781 centers in 33 countries were assessed, and
10,917 were randomized. Exclusion criteria included myocardial infarction
or coronary revascularization in the previous 6 months, or stroke or
cerebral transient ischemic attack in the previous 3 months.
Follow-up and primary endpoint
Patients underwent follow-up visits at 2 weeks, and 1, 3 and 6 months,
and every 6 months thereafter for a median of 19 months. The primary
endpoint was a composite of cardiovascular death, acute myocardial
infarction admission, and new-onset or worsening heart failure admission.
Fox et al. Lancet 2008;372:807–816.
BEAUTIfUL: TRIAL DESIGN
Treatment
Run-in was a period of 14 days without study treatment.
Patients were then randomized to receive ivabradine 5 mg
twice daily or matching placebo.
After 2 weeks, patients with a resting heart rate of ≥60 bpm
received an increased dose of 7.5 mg twice daily. Patients
with a resting heart rate of <50 bpm or with signs or
symptoms of bradycardia received a reduced dose of 5 mg
twice daily if they had been receiving 7.5 mg twice daily, or
were discontinued if they had been receiving 5 mg twice daily.
Appropriate conventional cardiovascular medical treatment
continued throughout study. Beta-blockers were taken by
87% of patients from both treatment groups.
Fox et al. Lancet 2008;372:807–816.
BEAUTIfUL:
Baseline Characteristics
Ivabradine
(n=8576)
Placebo
(n=8502)
All patients
(n=8502)
Mean age (years)
65.3
65.0
65.2
Male (%)
83
83
83
History of hypertension (%)
71
71
71
History of diabetes (years)
37
37
37
Previous myocardial infarction (%)
88
89
88
Heart rate (bpm)
71.5
71.6
71.6
Systolic blood pressure (mm Hg)
128.1
127.9
128.0
Diastolic blood pressure (mm Hg)
77.4
77.5
77.4
LV ejection fraction (%)
32.4
32.3
32.4
Fox et al. Lancet 2008;372:807–816.
BEAUTIfUL: RESULTS
At 12 months, ivabradine lowered resting heart rates versus placebo over baseline
(average reduction, 6.0 bpm), including in patients with baseline heart rate of ≥70
bpm (average reduction, 7.9 bpm).
Primary endpoint
There was no significant difference between the ivabradine and placebo groups in the
occurrence of the primary endpoint (15.4% vs. 15.3%, respectively; hazard ratio [HR],
1.00; p=0.94).
Other results
There was no significant difference in the number of patients who experienced serious
adverse events between ivabradine and placebo patients (22.5% vs. 22.8%,
respectively; p=0.70).
In patients with a baseline heart rate of ≥70 bpm, ivabradine had no impact on the
primary composite outcome (HR, 0.91; p=0.17), cardiovascular death, or admission
for new-onset or worsening heart failure.
However, in comparison with placebo, ivabradine significantly reduced fatal and nonfatal myocardial infarction admissions (HR, 0.64; p=0.001) and coronary
revascularization rates (HR, 0.70; p=0.016).
Fox et al. Lancet 2008;372:807–816.
BEAUTIfUL RESULTS
Kaplan-Meier time-to-event plot for
composite primary endpoint
35
30
Proportion
with
composite
primary
endpoint
(%)
25
20
p=0.94
15
10
Placebo
Ivabradine
5
0
0
0.5
1.0
1.5
2.0
Years
Fox et al. Lancet 2008;372:807–816.
BEAUTIfUL:
Kaplan-Meier time-to-event plot for admission to hospital
for acute myocardial infarction in patients with baseline
heart rate of ≥70 bpm
10
Proportion
admitted to
hospital with
myocardial
infarction
(%)
p=0.001
5
Placebo
Ivabradine
0
0
0.5
1.0
1.5
2.0
Years
Fox et al. Lancet 2008;372:807–816.
BEAUTIfUL: SUMMARY
In patients with coronary artery disease and left-ventricular
systolic dysfunction:
• Ivabradine reduced heart rates by a placebo-corrected 6
bpm at 12 months
• In subgroup analysis, ivabradine did not affect the primary
composite endpoint of cardiovascular death, admission to
hospital for acute myocardial infarction, or admission to
hospital for new-onset or worsening heart failure
• Consequently, ivabradine can be given safely, even in
conjunction with beta-blockers
• Ivabradine, combined with beta blockade, is safe and
improves coronary artery disease outcomes in those with
a baseline heart rate of ≥70 bpm
Fox et al. Lancet 2008;372:807–816.