Clinical Benefit of Rigourous AV Delay Optimization in Patients With a Dual Chamber Pacemaker

Study Overview
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Brief Summary
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Though AV optimization has become a cornerstone in optimization of patients with a cardiac resynchronization therapy (CRT) device, surprisingly the use of AV optimization in patients with a dual chamber (bicameral (BIC)) pacemaker is not fully implemented in daily clinical practice. Some patients with a BIC pacemaker have a too short AV delay (AVD), secondary to an important interatrial conduction delay (IACD), which can lead to an atrial dyssynchrony syndrome. Others have a too long AV delay, also leading to a suboptimal diastolic filling time. Some patients may not need an optimization. Our aim was to evaluate the effect of AV optimization in all comer ambulatory patients with a BIC pacemaker on clinical outcomes, with a correlation to atrial pathophysiology, since until now existing evidence only emphasizes a possible hemodynamic benefit of this non invasive intervention.

Detailed Description
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Given the high prevalence of interatrial block (WHO definition: PWD on surface ECG > 110 ms) in a general hospitalized population and especially in patient groups with tachyarrhythmias (18% and 52 % respectively), this phenomenon will be important to recognize in a BIC pacemaker patient population. Actually, the prevalence of advanced interatrial block (PWD > 120 ms with biphasic P wave morphology) is 10% in candidates for definitive pacing and 32 % in patients with a bradycardia-tachycardia syndrome. The main underlying mechanism is thought to lie in abnormalities of the Bachmann bundle resulting in partial or advanced interatrial conduction delay (IACD). A normal IACD varies between 60 and 85 ms. Two potential mechanisms are spatial dispersion of refractory periods or anisotropy resulting from scarce side-to-side electrical coupling and fibrosis disrupting the arrangement of atrial muscle fibers. Patients with an interatrial conduction delay may have a suboptimal left atrioventricular timing due to delayed contraction of the left atrium with foreshortening of ventricular filling. This may be an issue in pacemaker patients, with our without a substrate for heart failure. Beside the loss of reduction of left atrial contraction, it might even induce neurohormonal changes due to atrial stretch and pressure thus lowering blood pressure. Coronary sinus or multisite atrial pacing, both with the aim of synchronizing right and left atrial electrical activation, have shown to (i) improve hemodynamics in patients with an important IACD, both invasively and noninvasively, and to (ii) decrease recurrences of atrial fibrillation. In patients with a conventional BIC pacemaker, prevention of left atrioventricular asynchrony can be achieved by AV optimization (lengthening of the AV delay in case of too short nominal settings) as an alternative. Though all these interventions have proven to have positive hemodynamic results until now evidence about positive effects on clinical patient outcomes are lacking. On the other hand, some of the patients implanted with a bicameral pacemaker have a too long AV delay. As a consequence diastolic filling time is impaired. Without compromising left atrioventricular synchrony AV delay, optimal AVD (AVO) can be achieved by lengthening of the AVD with conventional methods. In contrast to the setting of CRT, AV optimization in patients with a bicameral (BIC) pacemaker is not fully implemented in daily clinical practice. Given the proven effect on mitral inflow on echocardiography, we wanted to evaluate the effect of this non invasive intervention on patient functionality and quality of life, based on a comprehensive assessment of atrial pathophysiology.

Official Title
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A Prospective, Patient Blinded, Cross-over Study of the Effect on Clinical Outcomes of AV Optimization in All Comer Ambulatory Patients With a Dual Chamber Pacemaker - The Role of Atrial Function and Interatrial Conduction Delay

Conditions
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Quality of Life, Pacemaker Ddd Permanent, Atrial Dysfunction

Intervention / Treatment
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* Device: AV optimization


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ambulatory all comer patient population at least 3 months after implantation of a dual chamber pacemaker Programmed in a DDD(R) modus Right ventricular pacing percentage of > 50% Exclusion Criteria: permanent atrial fibrillation endstage chronic obstructive lung disease severe psychiatric, orthopedic or neurological comorbidity acute illness at the moment of inclusion changes in cardiovascular medication the month before inclusion until the end of the study protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Group I<br>All patients were programmed in the same nominal AV delay settings (sensed AV delay 120ms, paced AV delay 150 ms) before randomization. Patients in group I received a sham AV optimization; patients in group II received a real AV optimization. Baseline echocardiography measurements were repeated after (sham)optimization. At 4 weeks cross-over was done by AV optimization in group I and resetting pacemaker settings to nominal values in group II. At 8 weeks patients were evaluated with the same investigations as at week 4; every pacemaker was programmed in the most optimal AV setting. All optimizations were performed by 2 unblinded echocardiographists with experience in the field. | Device: AV optimization<br>* Iterative DFT (diastolic filling time) method for AV optimization. Optimal AV delay for both atrial sensed and atrial paced settings was defined by two experienced echocardiographists, after 3 separate measurements.<br>|
| Active Comparator: Group II<br>All patients were programmed in the same nominal AV delay settings before randomization. Patients in group I received a sham AV optimization; patients in group II received a real AV optimization. Baseline echocardiography measurements were repeated after (sham)optimization. At 4 weeks cross-over was done by AV optimization in group I and resetting pacemaker settings to nominal values in group II. At 8 weeks patients were evaluated with the same investigations as at week 4; every pacemaker was programmed in the most optimal AV setting. All optimizations were performed by 2 unblinded echocardiographists with experience in the field. | Device: AV optimization<br>* Iterative DFT (diastolic filling time) method for AV optimization. Optimal AV delay for both atrial sensed and atrial paced settings was defined by two experienced echocardiographists, after 3 separate measurements.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in exercise capacity, expressed by oxygen uptake efficiency slope | Ergospirometry protocol: Symptom-limited exercise testing was performed on an electronically braked cycle ergometer (eBike 1.8, GE (General Electric) Healthcare) in a non-fasting condition and under medication. All exercise tests took place at a standardized time for each patient. After 1minute (min) of rest followed by 1min of unloaded cycling, the initial load was set at 20W (Watt) for 1 min, and was increased by 10 or 20W every 2 min until exhaustion. Cycle load increments were based on previous exercise testing, aiming to yield a test duration of approximately 10min. All tests were continued to volitional fatigue and no patients were limited by angina. The recovery period lasted at least 2 minutes. A 12-lead electrocardiogram was monitored continuously (Cardiosoft 6.6); maximum heart rate was registered. The oxygen uptake efficiency slope (OUES) was calculated using [VO2= m(log10VE)+b, where m= OUES]. VO2=oxygen consumption | baseline, 4 weeks, 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in exercise capacity, expressed by VO2max (maximal oxygen consumption) | cf. Ergospirometry protocol | baseline, 4 weeks, 8 weeks | 
| Change in NYHA class: New York Heart Association Class |  | baseline, 4 weeks, 8 weeks | 
| Change in quality of life | Quality of life, measured by a standardized Heart Qol questionnaire | baseline, 4 weeks, 8 weeks | 
| Change in 6-Minute Walk test Distance (6MWD) |  | baseline, 4 weeks, 8 weeks | 
| Change in serum brain natriuretic peptide (BNP) |  | 4 weeks, 8 weeks | 
| Change in left atrial function, measured by left mitral annular late diastolic peak velocity (A'm(c)) |  | baseline, 4 weeks, 8 weeks | 
| Change in left atrial function, measured by left atrial late diastolic peak strain (εm) |  | baseline, 4 weeks, 8 weeks | 
| Change in left atrial function, measured by left atrial late diastolic peak strain rate (SRm) |  | baseline, 4 weeks, 8 weeks | 
| Change in systolic pulmonary artery pressure (PAPs) |  | baseline, 4 weeks, 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AV optimization, Interatrial conduction delay