INTRODUCTION

Coronary artery bypass grafting (CABG) surgery is still the main choice for severe coronary artery diseases^[1]. Classic CABG involves diastolic cardiac arrest under cardiopulmonary bypass (CPB), while off-pump (i.e., on a beating heart) CABG (OPCABG) has become widespread in recent years^[2-4]. OPCABG is recommended in porcelain aorta, which is a contraindication for CPB, low left ventricular ejection fraction (LVEF), persistent angina, and acute myocardial infarction (MI)^[5,6].

As OPCABG involves distal anastomosis in a beating heart, the rate of graft failure is higher than that of on-pump CABG. Additionally, OPCABG requires technical skills and a high level of experience. Therefore, concerns regarding the quality of the anastomosis discourage surgeons from performing OPCABG^[7]. Cardiac movement at the site of the anastomosis is another concern in OPCABG. However, these movements can be minimized using mechanical stabilizers and drug-induced (pharmacological) bradycardia^[8]. Although the latter is a theoretically simple method, it may lead to a variety of side effects and even low cardiac output. For pharmacological bradycardia, beta-blockers (β-blockers), ivabradine, and diltiazem can be used. The choice of drug is of utmost importance to ensure maximum benefit and minimum risk^[9,10].

Atrial fibrillation (AF) accounts for approximately 30% of all CABG cases. In addition, other arrhythmias can be seen in these patients^[11]. Regardless of the type of surgery (i.e., on-pump or off-pump), postoperative arrhythmias are associated with increased morbidity and mortality rates^[12]. Current guidelines recommend the use of β-blockers in the preoperative period, unless contraindicated, to reduce the risk of AF following cardiac surgery^[13]. Previous studies have also shown that β-blockers decrease morbidity and mortality in chronic heart failure and after cardiac surgeries. These agents have several effects, including reducing myocardial contractility, blood pressure and myocardial oxygen demand, and slowing intracardiac conduction, as well as antiarrhythmic effects. Additionally, these agents exert their effects on the peripheral vascular system and airways, and these effects may vary depending on the agent used and the existing disease and comorbidities of the patient^[14].

Ivabradine is the first selective sinus node I(f) channel inhibitor^[15]. It is indicated for the treatment of patients in sinus rhythm or with a heart rate above the target value receiving β-blockers in optimal dose or in those in the maximally tolerated dose of β-blockers^[16]. Ivabradine decreases the tendency to spontaneous diastolic depolarization and slows down the heart rate at rest and during exercise^[17]. However, there are still a limited number of clinical studies investigating the efficacy of ivabradine in the prevention and treatment of postoperative arrhythmias in patients with left ventricular dysfunction or conduction abnormalities undergoing CABG^[18]. Therefore, in the present study, we aimed to evaluate the short-term effects of preoperative ivabradine versus metoprolol on intra- and postoperative AF in patients undergoing OPCABG.

METHODS

Study Design and Study Population

This single-center, retrospective study was conducted between January 1^st, 2018, and February 10^th, 2020. A total of 642 patients who underwent CABG during the study period were screened. Medical records were retrieved from the hospital database and patient files. Of these patients, 274 underwent OPCABG. The inclusion and exclusion criteria are listed in Table 1. Finally, a total of 174 eligible patients who fulfilled the inclusion criteria were included in the study. All patients were informed about the potential benefits and risks of the procedure, and written informed consent was obtained. The study protocol was approved by the local ethics committee with Approval No. 65355327-604.01.02-E.134-28. The study was conducted in accordance with the principles of the Declaration of Helsinki.

Table 1 - Inclusion and exclusion criteria.

Inclusion criteria	Exclusion criteria
·         Elective CABG	·         Emergency CABG
·         ≥18 years of age	·         Receiving any β-blocker in the preoperative period
·         EF >30% or <50%	·         ≥3-vessel CABG
·         <3-vessel CABG	·         <18 age years of age
·         CABG on a beating heart	·         Conversion from OPCABG to conventional CABG
·         Left internal mammary artery harvesting as arterial graft and use of a venous graft	·         Intolerance to metoprolol or ivabradine in the preoperative period (<60 bpm)
·         Stable angina	·         Intolerance to metoprolol or ivabradine in the postoperative period (<60 bpm)
·         No electrocardiographic change (e.g., ST-segment elevation, bundle branch block)	·         Existing preoperative arrhythmia (AF, atrial flutter, second- or third-degree AV block, VF)
·         Not receiving any preoperative antiarrhythmic drug	·         EF <30% or >50%
·         Completion of preoperative medication	·         Use of arterial grafts alone
·         Normal sinus rhythm	·         Use of venous grafts alone
·         Heart rate >60 to <90 bpm	·         Renal failure
	·         Decompensated heart failure (NYHA class IV)
	·         COPD
	·         Known hypersensitivity to metoprolol or ivabradine

AF=atrial fibrillation; AV=atrioventricular; CABG=coronary artery bypass grafting; COPD=chronic obstructive pulmonary disease; EF=ejection fraction; NYHA=New York Heart Association; OPCABG=off-pump coronary artery bypass grafting; VF=ventricular fibrillation

Table 1 - Inclusion and exclusion criteria.

Patients were divided into two groups. Group I (n=90) received ivabradine 5 mg/day b.i.d. and Group M (n=84) received metoprolol 50 mg/day b.i.d. five days before surgery until postoperative day 10. Intraoperative arrhythmias and hypotension were recorded. Postoperative AF and arrhythmia, mortality and morbidity rates were assessed based on the 30-day postoperative follow-up.

RESULTS

Of a total of 174 patients, 90 were included in Group I, and 84 were included in Group M. There were no statistically significant differences in OPCABG risk factors, such as age, sex, diabetes, smoking, body mass index, and chronic obstructive pulmonary disease, between groups. Mean preoperative LVEF was 39.37±3.40% in Group I and 38.9±4.9% in Group M, indicating no significant difference (P=0.461). The mean baseline heart rate was 79.5±9.2 bpm in Group I and 80±9.3 bpm in Group M, indicating no significant difference (P=0.722). Six patients in Group I and five patients and Group M had previous percutaneous coronary intervention (PCI) (P=0.847). Baseline demographic and clinical characteristics of the patient groups are shown in Table 2.

Table 2 - Baseline demographic and clinical characteristics of the patient groups.

Furthermore, the mean heart rate was significantly lower during distal anastomosis in Group I than in Group M (P<0.001). In Group M, an increased heart rate endangered the quality of anastomosis in seven patients (7.77%); therefore, intravenous metoprolol at a dose of 3.19 was given. However, none of the patients in Group I needed an additional dose.

Pacemakers were needed in 6 patients (6.66%) in Group I and in 3 patients (3.57%) in Group M. In Group I, one of the six patients who needed pacing underwent permanent pacemaker implantation during the follow-up. The need for pacing was abolished in the other three patients on postoperative day 1 and in the remaining two patients on postoperative day 2. In Group M, the three patients requiring pacemaker implantation after surgery no longer needed it as of postoperative day 1. Although there was a trend towards a higher prevalence of the need for a pacemaker in Group I patients, this did not reach statistical significance (Table 3).

Table 3 - Intra- and postoperative data.

There was no significant difference in length of hospital and ICU stay between groups (P=0.28 and P=0.52, respectively). In addition, mortality and morbidity rates were comparable between groups (P=0.49 for both). Two patients in each group developed low cardiac output, leading to mortality (Table 4).

Table 4 - Postoperative morbidity and mortality.

DISCUSSION

Approximately 30% of patients undergoing CABG develop postoperative AF. In addition to AF, arrhythmias can also be seen in these patients^[11]. Regardless of the type of surgery (i.e., on-pump or off-pump), postoperative arrhythmias are associated with increased morbidity and mortality rates^[12]. Patients with postoperative AF are more vulnerable to other complications, including intraoperative MI, congestive heart failure, respiratory failure, prolonged hospital stay and increased healthcare costs^[19]. Postoperative AF has a variable degree of effects from transient complications without serious consequences to severe acute renal injury, hemodynamic instability, heart failure, stroke, and even death^[20].

Meta-analyses and systematic reviews investigating the prevention of postoperative arrhythmias have shown that medical treatment modalities, including β-blockers, sotalol and amiodarone, are effective in the prevention and/or treatment of postoperative AF^[21,22]. The use of β-blockers is difficult and still controversial in patients with conduction abnormalities, severe

There were no significant differences in the mean number of grafts and the mean operation duration between groups (P=0.49 and P=0.40, respectively). In addition, no significant differences in the intraoperative amount of inotropic support and red blood cell transfusion were observed between groups (P=0.87 and P=0.31, respectively). However, the rates of intraoperative arrhythmias and hypotension were not significantly higher in Group M (P=0.317 and P=0.47, respectively). VT/VF was observed in 2 patients in both groups. Postoperative AF occurred in 7 patients (7.7%) in Group I and in 10 patients (11.9%) in Group M. Although there was a trend towards a higher prevalence of AF in Group M patients, this did not reach statistical significance.

Six of the seven patients in Group I returned to normal sinus rhythm with antiarrhythmic drugs, while the other patient returned to normal sinus rhythm following cardioversion. Normal sinus rhythm was restored with antiarrhythmic drugs in five patients and following cardioversion in two patients in Group M. The three remaining patients in Group M were discharged with AF without signs of hemodynamic instability. Two of these patients returned to normal sinus rhythm during follow-up, while the other patient was followed up with AF in the outpatient setting. The intra- and postoperative data of the patients are presented in Table 3.

left ventricular dysfunction, or active bronchospasm; therefore, other antiarrhythmics must be used for patients undergoing cardiac surgery. Ivabradine, the first selective sinus node I(f) channel inhibitor, slows the heartbeat without affecting myocardial contractility and has protective effects on low LVEF^[23]. It has been shown to be effective in the treatment of stable coronary artery disease, left ventricular systolic dysfunction, and chronic heart failure^[24].

OPCABG has morbidity and mortality rates comparable to those of conventional CABG in high-risk patients^[4-7]. In a review including 16,900 patients, there were no significant differences in morbidity and mortality rates between patients undergoing OPCABG and those undergoing conventional CABG; however, OPCABG exerted a more protective effect against infection and renal dysfunction^[25]. OPCABG is recommended in porcelain aorta, which is a contraindication for CPB, LVEF, persistent angina, and acute MI^[5,6]. However, challenges of the technique are debated, including epicardial instability during distal anastomosis due to the nature of the distal anastomosis site. Mechanical stabilizers are used to avoid epicardial instability and to maintain local stabilization. The use of mechanical stabilizers has been shown to be associated with a significant increase in anastomotic patency rates^[26-28]. However, these devices cannot always be actively utilized or may remain limited in certain settings. In such cases, pharmacological bradycardia offers technical simplicity during anastomosis in OPCABG.

Currently, several medical agents are available to induce pharmacological bradycardia, including β-blockers (i.e., esmolol, metoprolol tartrate, metoprolol succinate, propranolol, atenolol, and nadolol), diltiazem, verapamil, digoxin, amiodarone, flecainide, ibutilide, and ivabradine^[29]. Theoretically, these agents may also be helpful in reducing cardiac displacement. In clinical practice, β-blockers are commonly used in the treatment of cardiovascular disease. In general, CABG is required in patients with previous MI and impaired LVEF; therefore, medications that reduce cardiac oxygen demand and prevent intra- and postoperative arrhythmias are of vital importance. In addition, the agent to be used must be free from deleterious effects, without affecting myocardial contractility, blood pressure, and ventricular repolarization. Of note, medications with potential respiratory side effects, such as β-blockers, must be avoided following OPCABG^[30]. Thus, medications with lower arrhythmia burden and higher surgical comfort during OPCABG should be selected.

In a study, Iliuta et al.^[18] divided cardiac surgery patients into three groups as follows: metoprolol 100 mg/day, n=176; metoprolol 50 mg/day + ivabradine 5 mg b.i.d., n=179; and ivabradine 5 mg b.i.d., n=172. All patients were followed for postoperative AF and arrhythmias for 30 days. The rate of third-degree AV block and pacing was significantly higher in the metoprolol alone group (12.5%), while this rate was the lowest in the ivabradine alone group (2.91%) (P<0.0001). However, postoperative AF and arrhythmias during hospitalization were less frequently seen in the group receiving the combined treatment (metoprolol + ivabradine) than in the monotherapy groups (P<0.001). The associated relative risk indicated a higher protective value against postoperative AF with the combined treatment than with metoprolol alone (-2.9 vs. -1.8). Based on the 30-day follow-up outcomes, ivabradine monotherapy showed superiority over metoprolol monotherapy. In our study, the rate of postoperative AF was not significantly lower in Group I (n=7, 7.7%) than in Group M (n=10, 11.9%) (P=0.36). However, there was not a significantly higher number of patients in Group I who needed pacing in our study (P=0.49). This can be attributed to the lower LVEF of the patient population included in our study. In addition, we administered premedication for five days before surgery, while Iliuta et al.^[18] used premedication for only two days.

In a multicenter study, Koester et al.^[31] investigated the efficacy of additional ivabradine 5 mg/day b.i.d. to β-blocker in patients with stable angina. Patients were followed for four months, and, at the end of follow-up, the mean heart rate decreased from 84.3±14.6 bpm to 72.0±9.9 bpm (P<0.001). None of the patients developed bradycardia, and the treatment was well tolerated in more than 90% of patients. In another study, Werdan et al.^[32] examined the addition of ivabradine (5 mg/day b.i.d.) in patients with chronic stable angina despite the use of β-blockers following PCI and assessed symptoms and heart rhythm at one and four months. Mean heart rate was 83.1±11 bpm at baseline, 69.4±8.8 bpm at one month, and 64.4±7.6 bpm at four months (P<0.0001). Throughout the study, angina episodes were seen less frequently in these patients (P<0.0001). Consistent with these findings, in our study, the mean heart rate was 79.5±9.2 bpm at baseline, while it decreased to 60.3±7.11 bpm during OPCABG in Group I. This decline was significant compared to baseline values and that of Group M (P<0.001). As such, a decline in heart rate prolongs the diastolic phase and increases the coronary artery supply; it is associated with a lower risk of new-onset MI during OPCABG. In addition, this decline ensures comfort for the surgical team during surgery.

In their study, Nguyen et al.^[10] compared the efficacy of ivabradine versus placebo in patients who experienced low cardiac output and who were prescribed dobutamine following elective CABG. In the ivabradine arm, the medication was given as infusion therapy, and the median heart rate, which increased due to the effects of dobutamine, decreased from 112 bpm (range, 105 to 120) to 86 bpm (range, 78 to 96) (P<0.001). In the placebo arm, the median heart rate decreased from 112 bpm (range, 104 to 120) to 104 bpm (range, 89 to 118), indicating a statistically significant difference between groups (P<0.05). Furthermore, the median systolic blood pressure was 110 mmHg (range, 93 to 118), the median cardiac output was 4.7 L/min-¹ (range, 3.6 to 5.4), and the median cardiac index (CI) was 2.5 L/min-¹ (range, 2.0 to 2.8) at baseline in the intravenous ivabradine arm; after treatment, these values were 125 mmHg (range, 114 to 139), 5.3 L/min-¹ (range, 4.5 to 6.5), and 2.9 L/min-¹ (range, 2.4 to 3.4), respectively (P<0.05 for all). Likewise, in our study, preoperative oral ivabradine yielded a similar decrease in heart rate of patients with baseline LVEF. Although cardiac output and CI were not examined in our study, lower intraoperative inotropic support was achieved with ivabradine.

In a multicenter, double-blind, randomized, placebo-controlled study, Fox et al.^[33] examined the effect of additional ivabradine on standard therapy in patients with stable coronary artery disease without clinical heart failure. Nearly 20,000 patients from 1,139 centers in 51 countries were screened. Patients were divided into two groups: ivabradine group (n=9.539) and placebo group (n=9,544). Adverse events, including second- and third-degree AV block, AF, bradycardia, and supraventricular tachycardia during the study were evaluated. Asymptomatic bradycardia developed in 1,718 patients (18.0%) in the ivabradine arm and in 223 patients (2.3%) in the placebo arm (P<0.001). Second-degree AV block was seen in 44 patients (0.5%) and 31 patients (0.3%) in the ivabradine and placebo arms, respectively (P=0.13). Third-degree AV block was detected in 20 patients (0.2%) and 19 patients (0.2%) in the ivabradine and placebo arms, respectively (P=0.87). In addition, 508 patients (5.3%) in the ivabradine arm and 362 patients (3.8%) in the placebo arm developed AF (P<0.001). A total of 137 patients (1.4%) in the ivabradine arm and 65 patients (0.7%) in the placebo arm developed supraventricular tachyarrhythmia (P=0.13). The rates of bradycardia and AF were significantly higher in patients treated with ivabradine. In our study comparing ivabradine versus metoprolol, we also did not find a significantly higher rate of bradycardia or a need for pacing in the ivabradine group. Six patients (6.6%) in the ivabradine group and three patients (3.57%) in the metoprolol group required pacing (P=0.49). Additionally, the rate of postoperative AF was not significantly lower in Group I (n=7, 7.7%) than in Group M (n=10, 11.9%) (P=0.36). Two patients in each group developed VF and VT (P=1). The higher rate of bradycardia in the ivabradine group is consistent with the results of Fox et al.^[33]

These findings suggest that ivabradine may have a more prominent effect on heart rate, although it has no activity at the AV node and does not alter the ventricular rate in AF. In the present study, we monitored the patients for AF in the ICU setting and applied immediate interventions for possible causes of AF, such as electrolyte imbalance and reduced oxygenation, which may have yielded different results from the aforementioned study. In addition, Fox et al.^[33] administered ivabradine 10 mg/day b.i.d. in their study, which can explain the discrepancy between the results.

In their study, Abdel-Salam and Nammas^[9] compared the efficacy of preoperative ivabradine, bisoprolol, or combination therapy for the prevention of postoperative AF in patients undergoing CABG. Patients were divided into two groups as follows: ivabradine (48 h preoperatively, then 1 week postoperatively) 5 mg b.i.d. for 24 h, then 7.5 mg b.i.d. thereafter in patients who could tolerate it (Group 1, n=212); bisoprolol 5 mg b.i.d. (Group 2, n=288) or combination therapy (ivabradine as before + bisoprolol 5 mg once daily) (Group 3, n=240). The primary endpoint was the incidence of AF at the 30-day follow-up. There was no significant difference in baseline LVEF or clinical characteristics among the groups. However, the incidence of AF at the 30-day follow-up was 15.1% (n=32) in the ivabradine group, 12.2% (n=35) in the bisoprolol group, and 4.2% (n=10) in the combination therapy group (P<0.001). Subgroup analysis showed a significantly lower incidence of AF in the first two days in the combination therapy group (P<0.01). In our study, the rate of postoperative AF was not significantly lower in Group I (n=7, 7.7%) than in Group M (n=10, 11.9%) (P=0.36). The difference between the results can be attributed to the fact that the number of patients with valve diseases was higher in the ivabradine group in the study of Abdel-Salam and Nammas^[9], although without statistical significance. Additionally, prolonged aortic cross-clamp and cardiopulmonary bypass times during CABG may have increased the incidence of AF in patients treated with ivabradine.

CONCLUSION

As a result, in our study, ivabradine did not reduce the risk of AF in OPCABG patients compared to metoprolol. However, by effectively reducing the heart rate, surgical comfort during the operation was greatly improved. Ivabradine appears to be a useful choice to provide a more comfortable and effective anastomosis during OPCABG. It may be an effective strategy to reduce heart rate in selected OPCABG patients who cannot be given the targeted beta-blocker dose.