**2.2 Exclusion criteria**

Patients non-eligible for the study were patients exhibiting one or more of the following conditions:


Study drop out criteria included the occurrence of adverse events: severe bradycardia, skin reactions, gastrointestinal symptoms, cold extremities. The study protocol was approved by the institute Management and Ethics Committee. All patients included in the trial gave written informed consent for participation in this study.

#### **2.3 Study groups**

After inclusion in the study, two days before surgery, patients were randomized in three groups:


The treatment phase comprised 2 days preoperatively and at least 10 days postoperatively and the patients were followed-up for 30 days after surgery (Fig. 1).

Fig. 1. Study phases and distribution of study population

### **2.4 Clinical and laboratory assessments**

356 Perioperative Considerations in Cardiac Surgery

the benefits of ivabradine used postoperatively in patients with conduction abnormalities or

The main objectives of our study were to compare the efficacy and safety of heart rate lowering agent ivabradine versus beta-blocker metoprolol used perioperatively in patients undergoing coronary artery bypass grafting and having conduction abnormalities (first degree atrioventricular block or bundle branch block) or left ventricular dysfunction and also to determine whether prophylactic therapy with ivabradine can reduce hospital stay and economic

This trial was an open-label, randomized, clinical trial which enrolled 315 patients undergoing coronary artery bypass grafting with arteries (internal mammary, radial, gastroepiploic) or inverted saphenous veins in a single center (Cardiac Surgery Department of "Prof. Dr. C. C. Iliescu" Emergency Institute of Cardiovascular Diseases, Bucharest, Romania) between January 1st, 2006 and December 31st, 2007. Surgical management and

Patients included in the clinical trial were patients undergoing elective coronary artery bypass grafting who had conduction abnormalities, left ventricular systolic dysfunction or

Patients non-eligible for the study were patients exhibiting one or more of the following

2. bradycardia (heart rate less than 50 beats per minute) or conditions associated with

Study drop out criteria included the occurrence of adverse events: severe bradycardia, skin reactions, gastrointestinal symptoms, cold extremities. The study protocol was approved by the institute Management and Ethics Committee. All patients included in the trial gave

After inclusion in the study, two days before surgery, patients were randomized in three

2. Group B: 106 patients to receive metoprolol 50 mg once daily and ivabradine 5 mg

increased risk for bradycardia (vagal predominance, sick sinus syndrome)

5. severe chronic obstructive pulmonary disease or pulmonary impairment

8. failure to comply with the hospital protocol or absence to follow-up.

1. Group A: 104 patients to receive metoprolol 100 mg once daily;

3. Group C: 105 patients to receive ivabradine 5 mg twice daily.

costs after cardiac surgery by lowering the risk associated with an increased heart rate.

left ventricular dysfunction undergoing coronary surgery are scarce.

treatment of the patients were based on a common standard protocol.

1. second and third degree atrioventricular block

7. active participation in another clinical trial

6. known hypersensitivity to beta-blockers or ivabradine

written informed consent for participation in this study.

**2. Methods** 

**2.1 Eligibility criteria** 

**2.2 Exclusion criteria** 

4. cardiogenic shock

**2.3 Study groups** 

twice daily;

groups:

3. NYHA class IV heart failure

both.

conditions:

Patients were evaluated at baseline (ie. 2 days before surgery), daily from Day 1 until Day 10 postoperatively, on Day 15, and at the end of the treatment on Day 30 postoperatively. Patients with short in-hospital evolution were evaluated ambulatory.

Clinical parameters included NHYA class, ventricular rhythm, patient compliance, and quality of life.

Laboratory parameters assessed were: usual blood tests (white and red blood cell count, platelet count, hemoglobin, hematocrit, alanine aminotransferase and aspartate aminotransferase, lactate dehydrogenase, blood chemistry), electrocardiogram (ECG) (with the evaluation of rhythm and rate), 24-h ECG Holter monitoring and echocardiographic measurements of the left ventricular dimensions, left ventricular systolic and diastolic performance, left atrium dimensions and compliance (data not shown in the present report). Cardiac rhythm was continuously monitored in the intensive care unit. During further hospital stay, subsequent ECG tests and a 24-h ECG Holter monitoring was carried out prior to discharge.

Follow-up visits were in Day 15 and in Day 30 postoperatively and included a physical examination and a 15-minutes interview, a resting ECG, an echocardiogram and a 24-h ECG Holter monitoring. Early episodes of heart failure were diagnosed based on clinical signs and symptoms and by transthoracic and transesophageal echocardiography. The presence of bradycardia or second or third degree atrioventricular block was assessed using clinical examination, resting ECG and 24-h ECG Holter monitoring.

## **2.5 Study endpoints**

The efficacy endpoints were 30-days mortality, in-hospital occurrence of atrial fibrillation/arrhythmias, in-hospital occurrence of third degree atrioventricular block and need for pacing, in-hospital worsening heart failure and duration of hospitalization and immobilization. Safety endpoints were occurrence of bradycardia, gastrointestinal 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 defined.
