**3. Results**

In the entire study population (315 patients), mean age was 62 ± 8 years, and 65.7% of patients were males. Baseline demographics and clinical characteristics of the three treatment groups are displayed in Table 1. There were no differences in age and gender of patients, presence of left ventricular dysfunction or conduction abnormalities between study groups, systolic blood pressure or mean baseline heart rate. Also, there were no differences between groups in mean number of grafts/patient and grafts type, risk score for atrial arrhythmias and mean duration of treatment.

The percentages of patients with previous episodes of atrial fibrillation were similar in the three groups (18.3% in group A, 19.8% in group B, and 19.1% in group C). There were similar proportions of patients with left ventricular dysfunction and conduction abnormalities (first degree atrioventricular block, complete left bundle branch block, bifascicular and trifascicular block) in the three treatment groups.

The primary efficacy and safety, single and composite endpoints in the treatment groups are shown in Table 2. In-hospital postoperative atrial fibrillation or tachyarrhythmias occurred less frequently with combined therapy (metoprolol and ivabradine) than with metoprolol or ivabradine alone used in the postoperative management of patients with coronary artery bypass grafting (7.6% events in group B versus 11.5% events in group A and 17.1% events in group C, p <0.001)**.** The associated relative risk showed a higher protective value for the occurence of postoperative atrial fibrillation in patients with coronary artery bypass grafting treated with combined therapy compared with metoprolol monotherapy (-2.9 vs. -1.8) (Fig. 2).

In group C the frequency of early postoperative third degree atrioventricular block or need for pacing was lower (2.9%) than in group A (13.5%) and in group B (9.4%) (p <0.0001). The frequency of heart failure worsening was lower in patients treated with ivabradine only (1.9%) or ivabradine combined with metoprolol (6.6%) than in patients receiving only metoprolol (11.5%) (p <0.001) (Table 2). The associated relative risks for early postoperative complete atrioventricular block or need for permanent pacing and for postoperative heart failure worsening were lower in ivabradine-treated groups (Fig. 2).


complaints, sleep disturbances, and cold extremities. A composite efficacy and safety endpoint including 30-days mortality, in-hospital atrial fibrillation/arrhythmias, in-hospital atrioventricular block/need for pacing, or in-hospital heart failure worsening was also

No sample size assumptions have been made for this trial. Continuous variable are presented as mean ± standard deviation (SD). Categorical variables are displayed as percentages. To analyze the differences between the treatment groups, the Student *t* test was used for the continuous variables and the chi-square test for the categorical variables For each endpoint, a two-sided 95% confidence interval (CI) was calculated and an overall χ2 test comparing the two treatment groups was used. Also, we performed simple and multivariate, linear and logistic regression analysis and we calculated relative risks and correlation coefficients. For the primary endpoints Kaplan–Meier curves were constructed and log-rank tests were used. All statistical analyses were performed using SYSTAT and

In the entire study population (315 patients), mean age was 62 ± 8 years, and 65.7% of patients were males. Baseline demographics and clinical characteristics of the three treatment groups are displayed in Table 1. There were no differences in age and gender of patients, presence of left ventricular dysfunction or conduction abnormalities between study groups, systolic blood pressure or mean baseline heart rate. Also, there were no differences between groups in mean number of grafts/patient and grafts type, risk score for atrial

The percentages of patients with previous episodes of atrial fibrillation were similar in the three groups (18.3% in group A, 19.8% in group B, and 19.1% in group C). There were similar proportions of patients with left ventricular dysfunction and conduction abnormalities (first degree atrioventricular block, complete left bundle branch block,

The primary efficacy and safety, single and composite endpoints in the treatment groups are shown in Table 2. In-hospital postoperative atrial fibrillation or tachyarrhythmias occurred less frequently with combined therapy (metoprolol and ivabradine) than with metoprolol or ivabradine alone used in the postoperative management of patients with coronary artery bypass grafting (7.6% events in group B versus 11.5% events in group A and 17.1% events in group C, p <0.001)**.** The associated relative risk showed a higher protective value for the occurence of postoperative atrial fibrillation in patients with coronary artery bypass grafting treated with combined therapy compared with metoprolol monotherapy (-2.9 vs. -1.8) (Fig.

In group C the frequency of early postoperative third degree atrioventricular block or need for pacing was lower (2.9%) than in group A (13.5%) and in group B (9.4%) (p <0.0001). The frequency of heart failure worsening was lower in patients treated with ivabradine only (1.9%) or ivabradine combined with metoprolol (6.6%) than in patients receiving only metoprolol (11.5%) (p <0.001) (Table 2). The associated relative risks for early postoperative complete atrioventricular block or need for permanent pacing and for postoperative heart

SPSS software. A *p* value <0.05 defined the statistical significance.

bifascicular and trifascicular block) in the three treatment groups.

failure worsening were lower in ivabradine-treated groups (Fig. 2).

arrhythmias and mean duration of treatment.

defined.

**3. Results** 

2).

**2.6 Statistical analyses** 

Note. Parameters are expressed as mean values (standard deviation) or percentages. All p values for comparisons between groups were non-significant.

Table 1. Baseline demographics and clinical characteristics of study population by treatment group


Table 2. Composite and single efficacy and safety endpoints by treatment group

The rates of 30-day mortality were lower in the combined therapy group (2.8%) versus metoprolol or ivabradine monotherapy groups (3.8% in each monotherapy group).

Note. AV, atrioventricular.

Fig. 2. The relative risks of ivabradine and combined therapy with ivabradine and metoprolol versus metoprolol monotherapy for early postoperative atrial fibrillation, complete atrioventricular block/need for pacing and postoperative heart failure worsening.

The overall quality of life was better in ivabradine groups. Ivabradine-treated patients had shortened hospital stay (the mean duration of hospital stay in the group A was 10.2 ± 6.3 days, compared to 8.5 ± 6.8 days in group B and 8.2 ± 6.4 days in group C), and reduced immobilization duration in the immediate postoperative period (2.0 ± 3 days in group A, 1.1 ± 3 days in group B and 1.1 ± 3 days in group C) (Table 2).

The cumulative incidence of non-cardiac side effects (sleep disturbances, gastrointestinal symptoms, and skin reactions) was similar in ivabradine (2.9%), metoprolol (2.9%) or combined ivabradine or metoprolol therapy (2.8%) groups (Table 2).

For the composite efficacy endpoint of 30-day mortality and in-hospital atrial fibrillation/arrhythmias the rates were 10.4% in the combined therapy group, 15.4% in the metoprolol group and 21.0% in the ivabradine monotherapy group. For the composite efficacy and safety endpoint of 30-day mortality, in-hospital atrial fibrillation/arrhythmias, in-hospital atrioventricular block/need for pacing, or in-hospital heart failure worsening, the rates were 25.7% in the ivabradine group, 26.4% in the ivabradine plus metoprolol group and 40.4% in the metoprolol group respectively (p = 0.0002) (Table 2), thus showing ivabradine therapy was superior to metoprolol therapy in terms of these composite endopoints. Kaplan Meier curves generated for primary endpoints also showed the superior efficacy and safety in ivabradine groups, either ivabradine monotherapy or combined ivabradine and metoprolol therapy (Fig. 3). Log-rank tests were highly significant from Days 4-5 of treatment period to Day 30.

Note. AVB, atrioventricular block, HF, heart failure.

Fig. 3. Kaplan-Meier curves for the composite endpoint of 30-days mortality, in-hospital atrial fibrillation/arrhythmias, in-hospital atrioventricular block/need for pacing, or inhospital heart failure worsening in the three treatment groups: ivabradine alone versus combined ivabradine plus metoprolol and metoprolol alone

The associated relative risks for the composite efficacy and safety endpoint of 30-day mortality, in-hospital atrial fibrillation/arrhythmias, in-hospital atrioventricular block/need for pacing, or in-hospital heart failure worsening in ivabradine-treated groups (with or without metoprolol) versus metoprolol-treated group in a subgroups analysis according to age, preoperative conduction abnormalities, NYHA class, previous episodes of atrial fibrillation and grafts number and type are shown in Table 3 and illustrated in Fig. 4. Ivabradine therapy (alone or associated to metoprolol) remained superior to metoprolol therapy in terms of the composite efficacy and safety endpoint of of 30-day mortality, inhospital atrial fibrillation/arrhythmias, in-hospital atrioventricular block/need for pacing, or in-hospital heart failure worsening.
