Clinical trial NCT01998256: Clinical Benefit of Rigourous AV Delay Optimization in Patients With a Dual Chamber Pacemaker
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Quality of Life
Pacemaker Ddd Permanent
Atrial Dysfunction
Keywords: AV optimization
Interatrial conduction delay
Lead sponsor: Jessa Hospital
Sponsor class: OTHER
First posted: 2013-11-28
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in exercise capacity, expressed by oxygen uptake efficiency slope
timeFrame: baseline, 4 weeks, 8 weeks
Secondary outcomes:
measure: Change in exercise capacity, expressed by VO2max (maximal oxygen consumption)
timeFrame: baseline, 4 weeks, 8 weeks
measure: Change in NYHA class: New York Heart Association Class
timeFrame: baseline, 4 weeks, 8 weeks
measure: Change in quality of life
timeFrame: baseline, 4 weeks, 8 weeks
measure: Change in 6-Minute Walk test Distance (6MWD)
timeFrame: baseline, 4 weeks, 8 weeks
measure: Change in serum brain natriuretic peptide (BNP)
timeFrame: 4 weeks, 8 weeks
measure: Change in left atrial function, measured by left mitral annular late diastolic peak velocity (A'm(c))
timeFrame: baseline, 4 weeks, 8 weeks
measure: Change in left atrial function, measured by left atrial late diastolic peak strain (εm)
timeFrame: baseline, 4 weeks, 8 weeks
measure: Change in left atrial function, measured by left atrial late diastolic peak strain rate (SRm)
timeFrame: baseline, 4 weeks, 8 weeks
measure: Change in systolic pulmonary artery pressure (PAPs)
timeFrame: baseline, 4 weeks, 8 weeks
Other outcomes:
measure: Prevalence of interatrial conduction delay (IACD) in the study population
timeFrame: baseline
measure: Correlation of IACD with age
timeFrame: baseline
measure: Correlation of IACD with P Wave Duration (PWD)
timeFrame: baseline
measure: Correlation of IACD with left atrial function
timeFrame: 4 weeks
measure: Correlation of change in VTI(A) (velocity-time integral) after AV optimization with clinical response (measured by OUES) after AV optimization
timeFrame: baseline, 4 weeks, 8 weeks
measure: Correlation of change in mitral annular late diastolic peak velocity (A'm(c)) after AV optimization with clinical response (OUES) after optimization.
timeFrame: baseline, 4 weeks, 8 weeks
measure: Prevalence of right and left intraatrial asynchrony.
timeFrame: baseline
measure: Role of P sense offset in IACD (interatrial conduction delay)
timeFrame: baseline
measure: Change of the incidence of atrial fibrillation on a short term after rigourous AV optimization
timeFrame: baseline, 4 weeks, 8 weeks
measure: Correlation between atrial pacing frequency and duration of the IACD
timeFrame: baseline
measure: Correlation between atrial pacing frequency and left atrial function (measured by left mitral annular late diastolic peak velocity (A'm(c)).
timeFrame: 4 weeks
measure: Correlation between IACD and pacing indication
timeFrame: baseline
measure: Correlation between IACD and the length of the optimal AV delay.
timeFrame: baseline, 4 weeks
measure: Correlation between 3 distinct measurements of interatrial conduction delay (IACD)
timeFrame: baseline
Locations:
city: Hasselt
country: Belgium
facility: Jessa Hospital
state: Limburg
Study officials:
affiliation: Jessa hospital, Hasselt
name: Thijs Cools, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Jessa hospital, Hasselt
name: Paul Dendale, MD, PhD
role: STUDY_DIRECTOR
affiliation: Jessa hospital, Hasselt
name: Lieven Herbots, MD, PhD
role: STUDY_CHAIR
affiliation: Jessa hospital, Hasselt
name: Rob Geukens, MD
role: STUDY_CHAIR
affiliation: Jessa hospital, Hasselt
name: Jan Verwerft, MD
role: STUDY_CHAIR
affiliation: University Hasselt
name: Tara Daerden
role: STUDY_CHAIR
affiliation: University Hasselt
name: Dominique Hansen, PhD
role: STUDY_CHAIR
References:
citation: Ariyarajah V, Spodick DH. Progression of partial to advanced interatrial block. J Electrocardiol. 2006 Apr;39(2):177-9. doi: 10.1016/j.jelectrocard.2005.08.016. Epub 2005 Nov 10.
citation: Bayes de Luna A, Platonov P, Cosio FG, Cygankiewicz I, Pastore C, Baranowski R, Bayes-Genis A, Guindo J, Vinolas X, Garcia-Niebla J, Barbosa R, Stern S, Spodick D. Interatrial blocks. A separate entity from left atrial enlargement: a consensus report. J Electrocardiol. 2012 Sep;45(5):445-51. doi: 10.1016/j.jelectrocard.2012.06.029.
citation: Bayés de Luna A. Electrocardiographic alterations due to atrial pathology. Clinical Electrocardiography: A Text Book. New York: Futura Company; 1998: p69.
citation: Daubert JC, Pavin D, Jauvert G, Mabo P. Intra- and interatrial conduction delay: implications for cardiac pacing. Pacing Clin Electrophysiol. 2004 Apr;27(4):507-25. doi: 10.1111/j.1540-8159.2004.00473.x.
citation: Burri H, Bennani I, Domenichini G, Ganiere V, Sunthorn H, Stettler C, Gentil P, Shah D. Biatrial pacing improves atrial haemodynamics and atrioventricular timing compared with pacing from the right atrial appendage. Europace. 2011 Sep;13(9):1262-7. doi: 10.1093/europace/eur099. Epub 2011 Apr 6.
citation: Doi A, Takagi M, Toda I, Yoshiyama M, Takeuchi K, Yoshikawa J. Acute hemodynamic benefits of bi-atrial atrioventricular sequential pacing with the optimal atrioventricular delay. J Am Coll Cardiol. 2005 Jul 19;46(2):320-6. doi: 10.1016/j.jacc.2005.04.032.
citation: Verlato R, Botto GL, Massa R, Amellone C, Perucca A, Bongiorni MG, Bertaglia E, Ziacchi V, Piacenti M, Del Rosso A, Russo G, Baccillieri MS, Turrini P, Corbucci G. Efficacy of low interatrial septum and right atrial appendage pacing for prevention of permanent atrial fibrillation in patients with sinus node disease: results from the electrophysiology-guided pacing site selection (EPASS) study. Circ Arrhythm Electrophysiol. 2011 Dec;4(6):844-50. doi: 10.1161/CIRCEP.110.957126. Epub 2011 Sep 23.
citation: Kindermann M, Frohlig G, Doerr T, Schieffer H. Optimizing the AV delay in DDD pacemaker patients with high degree AV block: mitral valve Doppler versus impedance cardiography. Pacing Clin Electrophysiol. 1997 Oct;20(10 Pt 1):2453-62. doi: 10.1111/j.1540-8159.1997.tb06085.x.
citation: Antonini L, Auriti A, Pasceri V, Meo A, Pristipino C, Varveri A, Greco S, Santini M. Optimization of the atrioventricular delay in sequential and biventricular pacing: physiological bases, critical review, and new purposes. Europace. 2012 Jul;14(7):929-38. doi: 10.1093/europace/eur425. Epub 2012 Feb 6.
citation: Barold SS, Ilercil A, Herweg B. Echocardiographic optimization of the atrioventricular and interventricular intervals during cardiac resynchronization. Europace. 2008 Nov;10 Suppl 3:iii88-95. doi: 10.1093/europace/eun220.
citation: Bowen TS, Cannon DT, Begg G, Baliga V, Witte KK, Rossiter HB. A novel cardiopulmonary exercise test protocol and criterion to determine maximal oxygen uptake in chronic heart failure. J Appl Physiol (1985). 2012 Aug;113(3):451-8. doi: 10.1152/japplphysiol.01416.2011. Epub 2012 May 31.
citation: Laurent G, Eicher JC, Mathe A, Bertaux G, Barthez O, Debin R, Billard C, Philip JL, Wolf JE. Permanent left atrial pacing therapy may improve symptoms in heart failure patients with preserved ejection fraction and atrial dyssynchrony: a pilot study prior to a national clinical research programme. Eur J Heart Fail. 2013 Jan;15(1):85-93. doi: 10.1093/eurjhf/hfs150. Epub 2012 Sep 27.
citation: Yasuoka Y, Abe H, Umekawa S, Katsuki K, Tanaka N, Araki R, Imanaka T, Matsutera R, Morisawa D, Kitada H, Hattori S, Noda Y, Adachi H, Sasaki T, Miyatake K. Interatrial septum pacing decreases atrial dyssynchrony on strain rate imaging compared with right atrial appendage pacing. Pacing Clin Electrophysiol. 2011 Mar;34(3):370-6. doi: 10.1111/j.1540-8159.2010.02976.x. Epub 2010 Nov 22.
citation: Sirbu C, Herbots L, D'hooge J, Claus P, Marciniak A, Langeland T, Bijnens B, Rademakers FE, Sutherland GR. Feasibility of strain and strain rate imaging for the assessment of regional left atrial deformation: a study in normal subjects. Eur J Echocardiogr. 2006 Jun;7(3):199-208. doi: 10.1016/j.euje.2005.06.001. Epub 2005 Jul 28.
citation: Van Beeumen K, Duytschaever M, Tavernier R, Van de Veire N, De Sutter J. Intra- and interatrial asynchrony in patients with heart failure. Am J Cardiol. 2007 Jan 1;99(1):79-83. doi: 10.1016/j.amjcard.2006.07.066. Epub 2006 Nov 9.
citation: Xie JM, Fang F, Zhang Q, Chan JY, Yip GW, Sanderson JE, Lam YY, Yan BP, Yu CM. Atrial dysfunction and interatrial dyssynchrony predict atrial high rate episodes: insight into the distinct effects of right atrial appendage pacing. J Cardiovasc Electrophysiol. 2012 Apr;23(4):384-90. doi: 10.1111/j.1540-8167.2011.02210.x. Epub 2011 Nov 7.
citation: Dabrowska-Kugacka A, Lewicka-Nowak E, Rucinski P, Zagozdzon P, Raczak G, Kutarski A. Relationship between P-wave duration and atrial electromechanical delay assessed by tissue Doppler echocardiography. Pacing Clin Electrophysiol. 2011 Jan;34(1):23-31. doi: 10.1111/j.1540-8159.2010.02939.x. Epub 2010 Oct 28.
citation: Chirife R, Pastori J, Mosto H, Arrascaite M, Sambelashvili A. Prediction of interatrial and interventricular electromechanical delays from P/QRS measurements: value for pacemaker timing optimization. Pacing Clin Electrophysiol. 2008 Feb;31(2):177-83. doi: 10.1111/j.1540-8159.2007.00966.x.
citation: Levin V, Nemeth M, Colombowala I, Massumi A, Rasekh A, Cheng J, Coles JA Jr, Ujhelyi MR, Razavi M. Interatrial conduction measured during biventricular pacemaker implantation accurately predicts optimal paced atrioventricular intervals. J Cardiovasc Electrophysiol. 2007 Mar;18(3):290-5. doi: 10.1111/j.1540-8167.2006.00744.x.
citation: Melzer C, Bondke H, Korber T, Nienaber CA, Baumann G, Ismer B. Should we use the rate-adaptive AV delay in cardiac resynchronization therapy-pacing? Europace. 2008 Jan;10(1):53-8. doi: 10.1093/europace/eum257. Epub 2007 Nov 23.