**4. Discussion**

360 Perioperative Considerations in Cardiac Surgery

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

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

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

± 3 days in group B and 1.1 ± 3 days in group C) (Table 2).

combined ivabradine or metoprolol therapy (2.8%) groups (Table 2).

Note. AV, atrioventricular.

The present study is, to the best of our knowledge, the first study which evaluated the use of ivabradine for prevention of postoperative atrial fibrillation or other tachyarrhythmias in patients undergoing coronary artery bypass surgery and assessed the efficacy and safety of ivabradine therapy in this setting. Atrial fibrillation is the most common complication which occurs after cardiac surgery, with frequencies ranging from 30% after coronary artery bypass grafting, 40% after valve surgery, and 50% after combined coronary artery bypass grafting/valve surgery (Camm et al., 2010). Development of atrial fibrillation immediately after coronary artery bypass grafting results in longer intensive care unit and hospital stays (Villareal et al., 2004; Tamis & Steinberg, 2000), and a significantly higher (two- to three-fold)


Table 3. Relative risks for the composite efficacy and safety endpoint of 30-days mortality, in-hospital atrial fibrillation/arrhythmias, in-hospital atrioventricular block/need for pacing, or in-hospital heart failure worsening in metoprolol versus ivabradine-treated patients

risk of postoperative stroke (Villareal et al., 2004; Reed et al., 1988). Post-operative atrial fibrillation has also been shown to independently predict post-operative delirium and neurocognitive decline (Burgess et al., 2006). Patients at risk for postoperative atrial fibrillation have been identified and include those with chronic obstructive pulmonary disease, proximal right coronary artery disease, prolonged cross-clamp time, atrial ischemia, advanced age, and withdrawal of beta-blockers (Eagle et al., 2004). Withdrawal of betablockers before surgery is a significant risk factor for the development of postoperative atrial fibrillation and should be avoided (Camm et al., 2010).

Because of the increased morbidity and mortality risk and of longer hospitalisations (up to five days [Eagle et al., 2004]) associated with the development of atrial fibrillation during the immediate postoperative period and because of the economic burden of these outcomes, prevention of postoperative atrial fibrillation becomes increasingly important. Various metaanalyses and systematic reviews assessed and identified pharmacologic and nonpharmacologic intervention to best prevent and treat postoperative atrial fibrillation.

At present, beta-blockers are the mainstay of therapy for prevention of postoperative atrial fibrillation in cardiac surgery. Both the ACC/AHA 2004 Guideline update for coronary artery bypass graft surgery for and the most recent ESC Guidelines for the management of atrial fibrillation recommend beta-blocker therapy as a class I indication in the prophylactic management of postoperative atrial fibrillation in patients without contraindications to betablocker therapy (Camm et al., 2010; Eagle et al., 2004). Studies showed that withdrawal of

Previous episodes of atrial fibrillation 7.9 5.3 Preoperative conduction abnormalities 8.2 6.3

Table 3. Relative risks for the composite efficacy and safety endpoint of 30-days mortality, in-hospital atrial fibrillation/arrhythmias, in-hospital atrioventricular block/need for pacing, or in-hospital heart failure worsening in metoprolol versus ivabradine-treated

risk of postoperative stroke (Villareal et al., 2004; Reed et al., 1988). Post-operative atrial fibrillation has also been shown to independently predict post-operative delirium and neurocognitive decline (Burgess et al., 2006). Patients at risk for postoperative atrial fibrillation have been identified and include those with chronic obstructive pulmonary disease, proximal right coronary artery disease, prolonged cross-clamp time, atrial ischemia, advanced age, and withdrawal of beta-blockers (Eagle et al., 2004). Withdrawal of betablockers before surgery is a significant risk factor for the development of postoperative atrial

Because of the increased morbidity and mortality risk and of longer hospitalisations (up to five days [Eagle et al., 2004]) associated with the development of atrial fibrillation during the immediate postoperative period and because of the economic burden of these outcomes, prevention of postoperative atrial fibrillation becomes increasingly important. Various metaanalyses and systematic reviews assessed and identified pharmacologic and nonpharmacologic intervention to best prevent and treat postoperative atrial fibrillation.

At present, beta-blockers are the mainstay of therapy for prevention of postoperative atrial fibrillation in cardiac surgery. Both the ACC/AHA 2004 Guideline update for coronary artery bypass graft surgery for and the most recent ESC Guidelines for the management of atrial fibrillation recommend beta-blocker therapy as a class I indication in the prophylactic management of postoperative atrial fibrillation in patients without contraindications to betablocker therapy (Camm et al., 2010; Eagle et al., 2004). Studies showed that withdrawal of

**Relative risk metoprolol group N = 104** 

> 1.5 7.8

> 1.5 8.7

> 3.9 1.3 1.2

> 6.2 6.7 6.3

**Relative risk ivabradine groups (with or without metoprolol) N = 211** 

> 1.5 4.9

> 1.2 5.7

> 2.5 1.2 1.1

> 3.8 3.8 3.3

**Composite endpoint of 30-days mortality, in-hospital atrial fibrillation/arrhythmias, in-hospital atrioventricular block/need for pacing, or in-hospital heart failure worsening** 

Age ≤70 years >70 years

NYHA class NYHA I-II NYHA III-IV

≥3 grafts 2 grafts 1 graft

Graft type

patients

Number of grafts

Exclusively arterial Exclusively venous

Combined venous and arterial

fibrillation and should be avoided (Camm et al., 2010).

Fig. 4. Relative risks for the composite efficacy and safety endpoint of 30-days mortality, inhospital atrial fibrillation/arrhythmias, in-hospital atrioventricular block/need for pacing, or in-hospital heart failure worsening in metoprolol versus ivabradine-treated patients in a subgroup analysis according to age, preoperative conduction abnormalities, NYHA class, previous episodes of atrial fibrillation and grafts number and type.

beta-blockers in the perioperative period doubles the incidence of postoperative atrial fibrillation after coronary artery bypass grafting (Eagle et al., 2004). Virtually every study of beta-blockers administered for the purpose of reducing postoperative atrial fibrillation has shown benefit in this regard, even if data regarding improvement of hospital stay or reduction of stroke incidence are still controversial (Iliuta et al., 2009). Most beta-blockers trials have examined the initiation of prophylaxis in the postoperative period. But it seems to be an even greater benefit if beta-blocker therapy is initiated before surgery. That is why the ESC guidelines for the management of atrial fibrillation recommend that treatment should be started at least 1 week before surgery with a beta1-blocker without intrinsic sympathomimetic activity (Camm et al., 2010). The beta-blockers used in studies assessing atrial fibrillation prevention in cardiac surgery were propranolol (Matangyi et al., 1985), atenolol (Lamb et al., 1988), metoprolol (Lucio et al., 2004; Crystal et al., 2004; Kamei et al., 2006; Celik et al., 2009), acebutolol (Daudon et al., 1986), timolol (White et al., 1984), carvedilol (Kamei et al., 2006; Celik et al., 2009), betaxolol (Iliuta et al., 2009), either compared to control or to another beta-blocker.

Another antiarrhythmic agent used for the prevention of atrial fibrillation in cardiac surgery patients is sotalol which was shown to reduce the incidence of postoperative atrial fibrillation (Burgess et al., 2006; Crystal et al., 2004) compared to placebo or to other betablocker such as atenolol (Sanjuan et al., 2004), metoprolol (Parikka et al., 1998) or propranolol (Suttorp et al., 1990) but it had no impact on length of hospital stay, risk of strokes, or mortality (Crystal et al., 2004). However, the use of sotalol in postoperative atrial fibrillation is limited because of its significant side effects such as bradycardia and torsade de pointes, especially in patients with electrolyte disturbances. For these reasons, sotalol therapy for atrial fibrillation prevention in cardiac surgery patients is a class IIb indication in the ESC Guidelines for the management of atrial fibrillation (Camm et al., 2010).

Amiodarone and its beneficial effect in postoperative atrial fibrillation prevention was the subject of various studies and meta-analyses. Amiodarone decreased the incidence of postoperative atrial fibrillation (Burgess et al., 2006; Bagshaw et al., 2006) and significantly shortened the duration of hospital stay, and reduced the incidence of stroke and postoperative ventricular tachyarrhythmia (Burgess et al., 2006; Bagshaw et al., 2006), but not postoperative mortality (Bagshaw et al., 2006). The beneficial effects of amiodarone were observed irrespective of patients age, type of cardiac surgery (coronary artery bypass grafting only or valve surgery with or without coronary artery bypass grafting), and preoperative beta-blocker therapy. At present, amiodarone has a class IIa indication for atrial fibrillation prevention in patients undergoing cardiac surgery as recommended in the in the ESC Guidelines for the management of atrial fibrillation (Camm et al., 2010).

Other pharmacologic agents used in clinical study for the prevention of postoperative atrial fibrillation were digoxin, which was not found to be effective for atrial fibrillation prevention (Kowey et al., 1992) or calcium channel blockers, of which non-dihydropyridines significantly reduced supraventricular tachyarrhythmias in a subgroup analysis of a metaanalysis (Wijeysundera et al., 2003). Hypomagnesaemia is an independent risk factor for postoperative atrial fibrillation. A meta-analysis of randomized trials showed that prophylactic i.v. magnesium reduced the probability of postoperative atrial fibrillation (Miller et al., 2005).

From the non-pharmacologic interventions investigated for atrial fibrillation prevention in the postoperative setting, prophylactic atrial pacing reduced the incidence of post-operative atrial fibrillation regardless of the atrial pacing site or pacing algorithm used, (Burgess et al., 2006; Crystal et al., 2004) but results are controversial.

Despite this relative large range of prophylactic interventions for postoperative atrial fibrillation, there are subgroups of patients with conditions that limit the use of betablockers or other antiarrhythmic drugs. Among such conditions are cardiac conduction abnormalities or severe left ventricular dysfunction, active bronchospasm. In these patients ivabradine, a selective sinus node inhibitor, could be a viable alternative. Ivabradine is a specic inhibitor of the If current in the sinoatrial node. Consequently, it is a pure heart-ratelowering agent in patients with sinus rhythm, without affecting blood pressure, myocardial contractility, intracardiac conduction, or ventricular repolarisation.

In BEAUTIFUL study, performed in patients with coronary artery disease and left ventricular systolic dysfunction (left ventricular ejection fraction of less than 40%), even if ivabradine failed to change the primary composite endpoint of cardiovascular death, admission to hospital for acute myocardial infarction, or admission to hospital for newonset or worsening heart failure in any of the subgroups analysed, in a subgroup of patients with baseline heart rate of 70 bpm or higher it reduced the incidence of endpoints related to coronary artery disease (admission to hospital for fatal and non-fatal acute myocardial infarction) (Fox et al., 2008). Therefore, ivabradine can be used safely to patients with coronary artery disease and impaired left-ventricular systolic function, in conjunction with beta-blockers. Furthermore, a combination of ivabradine with β blockade also improved coronary artery disease outcomes in patients with heart rates of 70 bpm or more (Fox et al., 2008). These results suggest that further lowering of heart rate has beneficial effects on coronary disease outcomes.

In SHIFT study, performed in patients with stable symptomatic chronic heart failure and a left ventricular ejection fraction of 35% or lower, with a resting heart rate of 70 bpm or higher, ivabradine substantially and significantly reduced major risks associated with heart failure when added to optimal standard treatment: cardiovascular death or hospital admission for worsening heart failure (Swedberg et al., 2010).

The results of these two studies supporting the importance of heart rate reduction with ivabradine for improvement of clinical outcomes in heart failure or coronary artery disease with systolic left ventricular dysfunction were the rationale for using ivabradine alone or in combination with metoprolol for prevention of postoperative atrial fibrillation and reduction of subsequent morbidity, mortality and associated economic costs in patients undergoing coronary artery bypass grafting.

In our study, heart rate reduction and prevention of postoperative atrial fibrillation or tachyarrhythmias in the combined therapy group (ivabradine and metoprolol) was proven to be more effective than with metoprolol or ivabradine alone during the immediate postoperative management of patients undergoing coronary artery bypass grafting. Ivabradine-treated patients' quality of life was improved due to shortened hospital stay, reduced immobilization duration in the immediate postoperative period, less atrial or ventricular arrhythmias, less worsening heart failure.

Because postoperative atrial fibrillation is associated with increased morbidity and mortality and longer, more expensive hospital stays, we defined a composite efficacy and safety endpoint of 30-days mortality, in-hospital atrial fibrillation/arrhythmias, in-hospital atrioventricular block/need for pacing, or in-hospital heart failure worsening. Ivabradine and combined therapy (ivabradine and metoprolol) were superior to metoprolol in respect to the composite efficacy and safety endpoints for prevention of atrial fibrillation after coronary artery bypass grafting.
