1. BEAUTI f UL: morBidity-mortality EvAlUaTion of the I f 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.

2. 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 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. BEAUTI f UL: TRIAL DESIGN Fox et al. Lancet 2008;372:807–816.

3. 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. BEAUTI f UL: TRIAL DESIGN Fox et al. Lancet 2008;372:807–816.

4. BEAUTI f UL: Baseline Characteristics Mean age (years) Male (%) History of hypertension (%) Heart rate (bpm) 65.3 83 88 Ivabradine (n=8576) 65.2 83 88 All patients (n=8502) Previous myocardial infarction (%) 71.5 71.6 Systolic blood pressure (mm Hg) 128.1 128.0 Diastolic blood pressure (mm Hg) 77.4 71 History of diabetes (years) LV ejection fraction (%) 37 32.4 Placebo (n=8502) 65.0 83 89 71.6 127.9 77.5 71 37 32.3 Fox et al. Lancet 2008;372:807–816.

5. BEAUTI f UL: 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 non- fatal 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.

6. BEAUTI f UL RESULTS Kaplan-Meier time-to-event plot for composite primary endpoint Years Proportion with composite primary endpoint (%) 0 0.51.0 1.52.0 0 5 10 15 20 25 30 35 p=0.94 Placebo Ivabradine Fox et al. Lancet 2008;372:807–816.

7. BEAUTI f UL: Kaplan-Meier time-to-event plot for admission to hospital for acute myocardial infarction in patients with baseline heart rate of ≥70 bpm Years Proportion admitted to hospital with myocardial infarction (%) 00.51.01.52.0 0 5 10 p=0.001 Placebo Fox et al. Lancet 2008;372:807–816. Ivabradine

8. BEAUTI f UL: 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.