Effect of Ivabradine and Beta-blockers Combination Versus Beta-blockers Up-titration on Right Ventricular Pacing
Effect of Ivabradine and Beta-blockers Combination Versus Beta-blockers Up-titration on Right Ventricular Pacing
The aim of this prospective, randomized and controlled trial is to evaluate the use of the
 ivabradine in combination to a low-dose of beta-blocker (bisoprolol) versus up-titration of
 beta-blocker (bisoprolol) to obtain heart rate (HR) control with reduction in RV pacing in
 single-chamber or dual chambers ICD recipients HF patients with moderate to severe left
 ventricular dysfunction (FE ≤ 40%) and an heart rate ≥ 70 bpm in sinus rhythm over a
 12-months follow up.

 Besides the investigators want to assess if the combination of ivabradine to a low-dose of
 beta-blocker (bisoprolol) versus up-titration of beta-blocker (bisoprolol) may determine a
 lower degree of left ventricular dysfunction progression, the reduction of ventricular
 arrhythmias burden and ICD appropriate therapy occurrence and the improvement of quality of
 life in ICD heart failure patients.
Background

 High heart rate (HR) represent per se a risk factor for cardiovascular mortality and heart
 failure (HF) progression, despite optimal HF therapy. Beta-blockers remain the therapy of
 choice in all patients with systolic HF, but they may worsen atrioventricular (AV) conduction
 and increase right ventricular (RV) pacing percentage. Several studies have demonstrated
 detrimental effects of RV pacing on cardiac function. Percent RV pacing > 40-50% is an
 independent predictor of death and hospitalization for HF in implantable
 cardioverter-defibrillator(ICD) patients, particularly in those with preexistent left
 ventricular dysfunction.1,2 Cumulative RV pacing > 2% and ejection fraction (EF) < 40% are
 independent predictors for Ventricular Tachycardia(VT)/Ventricular Fibrillation (VF)
 occurrence in ICD patients.3 Therefore reduction of cumulative RV pacing as far as possible
 should be achieved in ICD patients. Ivabradine is a specific inhibitor of the If current of
 the sinus node, that induces a selective and dose dependent HR reduction; it is a pure HR
 lowering agent without effects on AV conduction or contractility.4 In HF patients implanted
 with an ICD ivabradine could act as an heart rate control drug in combination with a
 beta-blocker without increase right ventricular (RV) pacing percentage and may be an option
 to reduce left-ventricular dysfunction progression and ventricular arrhythmias burden and
 appropriate ICD therapy.

 Aim

 The aim of this prospective, randomized and controlled trial is to evaluate the use of the
 ivabradine in combination to a low-dose of beta-blocker (bisoprolol) versus up-titration of
 beta-blocker (bisoprolol) to obtain heart rate (HR) control with reduction in RV pacing in
 single-chamber or dual chambers ICD recipients HF patients with moderate to severe left
 ventricular dysfunction (FE ≤ 40%) and an heart rate ≥70 bpm in sinus rhythm over a 12-months
 follow up.

 Besides we want to assess if the combination of ivabradine to a low-dose of beta-blocker
 (bisoprolol) versus titration of beta-blocker (bisoprolol) may determine a lower degree of
 left ventricular dysfunction progression, the reduction of ventricular arrhythmias burden and
 ICD appropriate therapy occurrence and the improvement of quality of life in ICD heart
 failure patients.

 Endpoints of the study

 Primary endpoints:

 Right ventricular pacing percentage increase > 50% or Cardiovascular death or Heart failure
 decompensation or Crossover due to worsening heart failure.

 Secondary endpoints:

 Ejection fraction decrease < 5% and Left Ventricular End-Systolic Volume decrease <15%.

 Ventricular arrhythmias and ICD appropriate therapy reduction. Heart rate variability
 improvement NYHA Classification improvement Minnesota Living With Heart Failure Questionnaire
 (MLHFQ) total score reduction.

 Right ventricular pacing percentage. Composite endpoint: cardiovascular death and
 hospitalization due to worsening heart failure.

 Crossover rate due to worsening heart failure

 Study protocol:

 Baseline assessment:

 Clinical visit: demographic data, risk factors for cardiovascular disease, primary cause of
 heart failure, NYHA class, comorbidities, echocardiographic parameters, drug therapy,
 cardiovascular hospitalizations in the last year.

 Rest ECG (for assessment of rest heart rate, presence of sinus rhythm or device-induced
 rhythm, QRS duration); Blood pressure measurement; Electronic device control (for assessment
 of right ventricular stimulation percentage; electrical parameters and arrhythmias diagnostic
 data); Echocardiogram (for assessment of left ventricular end-diastolic and end-systolic
 volumes, left ventricular ejection fraction); MLHFQ

 Assignment of consecutive patients to treatment with ivabradine plus beta-blocker(bisoprolol)
 or beta-blocker (bisoprolol) titration. Mean Heart Rate Target is 55-70 bpm for both groups.

 Ivabradine will be administered at a dose of 5 mg twice daily in addition to a low dose of
 beta-blocker (bisoprolol 1,25 or 2,5 mg). After four weeks of treatment ivabradine will be
 eventually lowered up to 2,5 mg twice daily in the presence of side effects (phosphenes,
 diplopia, headache or dizziness).

 Beta blocker Bisoprolol will be up-titrated biweekly starting from the initial dose of
 1,25-2,5 mg daily up to the max dose of 10 mg daily or to the maximum tolerated dose.

 Patients are controlled in office follow-up visits after 3, 6 and 12 months, in addition to a
 Remote Monitoring program for clinical data and trend reviewing at least every 15 days or as
 soon as possible whenever a Remote Monitoring alert notification is received. Besides every
 15 days patients will receive a telephone contact in order to evaluate their clinical state
 and to uptitrate the beta blocker therapy based on mean heart rate detected trough remote
 control of the ICD.

 Three months in-office follow-up:

 Clinical visit: symptoms, NYHA class, drug therapy, cardiovascular hospitalizations in the
 last three months.

 Rest ECG (for assessment of rest heart rate, presence of sinus rhythm or device-induced
 rhythm, QRS duration); Blood pressure measurement; Echocardiogram (for assessment of left
 ventricular end-diastolic and end-systolic volumes, left ventricular ejection fraction);
 Electronic device control (for assessment of right ventricular stimulation percentage;
 electrical parameters and arrhythmias diagnostic data) .

 Six months in office follow-up:

 Clinical visit: NYHA class, comorbidities, echocardiographic parameters, drug therapy,
 cardiovascular hospitalizations in the last three months.

 Rest ECG (for assessment of rest heart rate, presence of sinus rhythm or device-induced
 rhythm, QRS duration); Echocardiogram (for assessment of left ventricular end-diastolic and
 end-systolic volumes, left ventricular ejection fraction); Electronic device control (for
 assessment of right ventricular stimulation percentage; electrical parameters and arrhythmias
 diagnostic data).

 MLHFQ

 One year in office follow-up:

 Clinical visit: NYHA class, comorbidities, echocardiographic parameters, drug therapy,
 cardiovascular hospitalizations in the last three months.

 Rest ECG (for assessment of rest heart rate, presence of sinus rhythm or device-induced
 rhythm, QRS duration); Electronic device control (for assessment of right ventricular
 stimulation percentage; electrical parameters and arrhythmias diagnostic data).

 Echocardiogram (for assessment of left ventricular end-diastolic and end-systolic volumes,
 left ventricular ejection fraction); MLHFQ
Inclusion Criteria:

 Age ≥ 18 years.

 Patients with stable chronic heart failure implanted with mono-cameral or bicameral ICD
 with a home monitoring remote control.

 Moderate to severe left ventricular dysfunction (FE ≤ 40%).

 Any cause of heart failure was allowed apart congenital heart disease.

 Bicameral ICD programmed in DDD or AAI/DDD with AV interval < 300 msec.

 Rest ECG heart rate ≥70 bpm;

 Sinus rhythm.

 In therapy with low-dose of beta-blocker (bisoprolol 1,25-2,5 mg) and with the maximum dose
 tolerated of angiotensin-converting enzyme inhibitor or blockade of angiotensin II
 receptor, mineralocorticoid antagonist, antiplatelet and lipid-lowering therapy, unless
 contraindicated.

 Exclusion Criteria:

 Inability of providing informed consent;

 Age < 18 years.

 State of pregnancy or lactation.

 Recent (<2 months) myocardial infarction;

 Contraindications to beta-blockers and ivabradine;

 Rest ECG heart rate < 70 bpm;

 No sinus rhythm.

 Administration of non-dihydropyridinic calcium channels antagonists, digitalis, class I
 antiarrhythmic drugs, strong inhibitors of cytochrome P450 3A4 at the time of enrollment.