Brief Summary

Rationale:

Permanent cardiac pacing is the only available therapy in patients with atrioventricular (AV) conduction disorders and can be life-saving. Right ventricular pacing (RVP), the routine clinical practice for decades in these patients, is non-physiologic, leads to dyssynchronous electrical and mechanical activation of the ventricles, and may cause pacing-induced cardiomyopathy and heart failure.

Left ventricular septal pacing (LVSP) is an emerging form of physiologic pacing that can possibly overcome the adverse effects of RVP.

Study design and hypotheses:

The LEAP trial is a multi-center investigator-initiated, prospective, randomized controlled, open label, blinded endpoint evaluation (PROBE) study that compares LVSP with conventional RVP. A total of four hundred seventy patients with a class I or IIa indication for pacemaker implantation due to AV conduction disorders and an expected ventricular pacing percentage \>20% will be randomized 1:1 to LVSP or RVP. The primary endpoint is a composite endpoint of all-cause mortality, hospitalization for heart failure and a more than 10% decrease in left ventricular ejection fraction (LVEF) in absolute terms leading to a LVEF below 50% at one year follow-up. LVSP is anticipated to result in improved outcomes.

Secondary objectives are to evaluate whether LVSP is cost-effective and associated with an improved quality of life (QOL) as compared to RVP. Quality of life is expected to improve with LVSP and reduced healthcare resource utilizations are expected to ensure lower costs in the LVSP group during follow-up, despite initial higher costs of the implantation.

Study design: Multi-center investigator-initiated, prospective, randomized controlled, open label, blinded endpoint evaluation (PROBE) study.

Study population: Adult patients with a bradycardia-pacing indication because of AV conduction disorders with an expected ventricular pacing percentage of ≥ 20% and a left ventricular ejection fraction (LVEF) \>/= 40%. Four hundred seventy patients will be randomized 1:1 to LVSP or RVP.

Intervention: LVSP vs RVP.

Main study parameters/endpoints:

The primary endpoint is a composite of all-cause mortality, hospitalization for heart failure, and a more than 10% point decrease in left ventricular ejection fraction (LVEF) leading to an LVEF below 50%, which as a binary combined endpoint will be determined at one year follow-up.

Secondary endpoints are:

* Time to first occurrence of all cause mortality or hospitalization for heart failure.
* Time to first occurrence of all cause mortality.
* Time to first occurrence of hospitalization for heart failure.
* Time to first occurrence of atrial fibrillation (AF) de novo.
* The echocardiographic changes in LVEF at one year.
* The echocardiographic changes in diastolic (dys-)function at one year.
* The occurrence of pacemaker related complications.
* Quality of life (QOL), cost-effectiveness analyses (CEA) and budget impact analysis (BIA).

The secondary endpoints (other than echocardiographic LVEF change) will be determined at the end of the follow-up period, when the last included patient has reached one year follow-up. The individual follow-up time for patients at this time point will vary with a minimum of one year.

Conditions

• Cardiac Pacing
• Pacing-Induced Cardiomyopathy
• Conduction System Pacing
• Left Ventricular Septal Pacing
• Atrioventricular Block

Intervention / Treatment

• Procedure: Left ventricular septal pacing
• Procedure: Right ventricular pacing

Primary Outcome Measures

• Binary combined endpoint consisting of all-cause mortality, hospitalization for heart failure, and a more than 10% point decrease in left ventricular ejection fraction (LVEF) leading to a LVEF below 50%. (Determined at one year follow-up)
  Hospitalization for heart failure is defined as: 1. hospitalization or unplanned hospital visits for heart failure requiring intravenous diuretics and/or (adjustment of) other medical heart failure therapy; 2. hospitalization for upgrade to cardiac resynchronization therapy (CRT, ie biventricular pacing) for progression of heart failure with worsening NYHA class and/or (increased) need for diuretic therapy or other medical heart failure therapy; 3. or hospitalization for upgrade to CRT for developing a class I indication for CRT (includes symptomatic heart failure); 4. or hospitalization or unplanned hospital visit for heart failure triggered by an episode of atrial fibrillation with uncontrolled heart rate requiring intravenous diuretics or adjustment of rate control therapy. All-cause mortality is defined as death from any cause and subdivided into cardiovascular and non-cardiovascular death.

Countries

Belgium, Czechia, Italy, Netherlands, Poland, Spain, Switzerland

Locations and Investigators

• Ziekenhuis Oost Limburg, Genk, Belgium (Not yet recruiting)
  • Wilfried Mullens, MD, PhD
• University Hospital Gent, Gent, Belgium (Not yet recruiting)
  • Jan de Pooter, MD, PhD
• University Hospital Kralovske Vinohrady, Praha, Czechia (Recruiting)
  • Karol Curila, MD, PhD
• Policlinico Casilino, Rome, Italy (Not yet recruiting)
  • Domenico Grieco, MD, PhD
• Maastricht University, Maastricht, Netherlands (Recruiting)
  • Justin Luermans, PhD
• Noordwest Ziekenhuisgroep, Alkmaar, Netherlands (Recruiting)
  • Stefan Timmer, MD, PhD
• Reinier de Graaf Gasthuis, Delft, Netherlands (Recruiting)
  • Arnaud Hauer, MD, PhD
• Catharina Ziekenhuis, Eindhoven, Netherlands (Recruiting)
  • Nard Rademakers, MD, PhD
• Medisch Spectrum Twente, Enschede, Netherlands (Recruiting)
  • Jurren van Opstal, MD, PhD
• Sint Antonius Ziekenhuis, Nieuwegein, Netherlands (Recruiting)
  • Vincent van Dijk, MD, PhD
• University Hospital Jaegellonian, Kraków, Poland (Not yet recruiting)
  • Marek Jastrzebski, MD, PhD
• Hospital Universitario y Politecnico La Fe, Valencia, Spain (Not yet recruiting)
  • Óscar Cano Pérez, MD, PhD
• University Hospital of Geneva, Geneva, Switzerland (Not yet recruiting)
  • Haran Burri, MD, PhD

Study Officials

• Justin Luermans, MD PhD (Principal Investigator) — Department of Cardiology
• Kevin Vernooy, MD PhD (Principal Investigator) — Department of Cardiology