Author's Accepted Manuscript

Association between Ventricular Pacing and Persis-

tent Atrial Fibrillation In Patients Indicated to
Elective Pacemaker Replacement: Results of the
Prefer for Elective Replacement Mvp (Prefer Mvp)
Randomized Study
Renato P Ricci M.D., Giovanni Luca Botto M.D.,
Juan M Bénézet M.D., Jens Cosedis Nielsen M.D.,
Luc De Roy M.D., Olivier Piot M.D., Aurelio
Quesada M.D., Raffaele Quaglione M.D., Diego www.elsevier.com/locate/buildenv

Vaccari M.D., Lorenza Mangoni M.S., Andrea

Grammatico Ph.D., Milan Kozák M.D., on behalf
of the PreFER MVP Investigators

PII: S1547-5271(15)00815-2
DOI: http://dx.doi.org/10.1016/j.hrthm.2015.06.041
Reference: HRTHM6340

To appear in: Heart Rhythm

Cite this article as: Renato P Ricci M.D., Giovanni Luca Botto M.D., Juan M Bénézet M.
D., Jens Cosedis Nielsen M.D., Luc De Roy M.D., Olivier Piot M.D., Aurelio Quesada
M.D., Raffaele Quaglione M.D., Diego Vaccari M.D., Lorenza Mangoni M.S., Andrea
Grammatico Ph.D., Milan Kozák M.D., on behalf of the PreFER MVP Investigators,
Association between Ventricular Pacing and Persistent Atrial Fibrillation In Patients
Indicated to Elective Pacemaker Replacement: Results of the Prefer for Elective
Replacement Mvp (Prefer Mvp) Randomized Study, Heart Rhythm, http://dx.doi.org/
10.1016/j.hrthm.2015.06.041

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Association between ventricular pacing and persistent atrial fibrillation in patients

indicated to elective pacemaker replacement: results of the Prefer For Elective

Replacement MVP (PreFER MVP) randomized study

1 2 3
Renato P Ricci M.D., Giovanni Luca Botto M.D., Juan M Bénézet M.D., Jens Cosedis
4 5 6 7
Nielsen M.D., Luc De Roy M.D., Olivier Piot M.D., Aurelio Quesada M.D., Raffaele
8 9 10 10
Quaglione M.D., Diego Vaccari M.D., Lorenza Mangoni M.S., Andrea Grammatico

Ph.D., Milan Kozák 11 M.D. on behalf of the PreFER MVP Investigators

1 San Filippo Neri Hospital, Rome, Italy; 2 S. Anna Hospital, Como, Italy; 3 Hospital General

de Ciudad Real, Ciudad Real, Spain; 4 Aarhus University Hospital, Skejby, Aarhus N, Denmark;

5 Cliniques Universitaires UCL de Mont-Godinne, Yvoir, Belgium; 6 Centre Cardiologique du

Nord, Saint-Denis, France; 7 Consorcio Hospital General Universitario de Valencia, Valencia,

Spain; 8 Policlinico Umberto I, Rome, Italy; 9 Presidio Ospedaliero di Montebelluna,

Montebelluna, Italy; 10 Medtronic EMEA Regional Clinical Centre, Rome, Italy; 11 Fakultni

nemocnice Brno Bohunice, Brno, Czech Republic

Short title: Ricci - Atrial fibrillation and ventricular pacing after cardiac device replacement

Conflict of interest: Renato Ricci received modest consultant honoraria from Biotronik and

Medtronic. For other authors, see Disclosure section.

Address for correspondence

Dr Renato Pietro Ricci, Department of Cardiology San Filippo Neri Hospital, Via Martinotti, 20

00135 Rome, Italy; Phone +390633063934 - email: renatopietroricci@tin.it

Abstract

Background. Pacing in the right ventricle can cause a variety of detrimental effects, including

1
atrial tachyarrhythmias (AT/AF).

Objective. To evaluate incidence and predictors of persistent AT/AF in patients with long term

exposure to ventricular pacing.

Methods. In a multi-center international trial, 605 patients (75±11 years, 240 females), referred

for replacement of an implanted pacemaker or cardioverter defibrillator (ICD), with history of

high percentage (>40%) ventricular pacing, were randomly allocated to standard dual-chamber

pacing or Managed Ventricular Pacing (MVP), a pacing modality which minimizes ventricular

pacing. Main end point of this secondary analysis of the PreFER MVP randomized study was

persistent AT/AF, defined as ≥7 consecutive days with AT/AF or AT/AF interrupted by atrial

cardioversion or AT/AF present during 2 consecutive follow-up visits.

Results. Persistent AT/AF was observed in 71 patients (11.7%) after 2 years of follow-up. At

multivariable Cox regression analysis, prior AT/AF (hazard ratio (HR)=2.85, 95% confidence

intervals (CI)=1.20-6.22, p=0.017) and ventricular pacing percentage, estimated in the first 3

months, ≥10% (HR=3.24, CI=1.13-9.31, p=0.029) resulted as independent predictors for

persistent AT/AF. MVP was associated with persistent AT/AF risk (HR=3.41, CI=1.10-10.6,

p=0.024) in the subgroup of patients with a baseline long PR interval (PR>230 ms), but not in

the whole population.

Conclusion. In pacemaker and ICD replacement patients, high percentage of ventricular pacing

is associated with higher risk of persistent AT/AF. The use of algorithms which minimize right

ventricular pacing may benefit patients with normal spontaneous AV conduction but should be

evaluated with caution in patients with long PR interval.

Keywords: Cardiac pacing; Managed Ventricular Pacing; Randomized controlled trial; Atrial fibrillation; PR interval.

Clinical Trial Registration: URL http://www.clinicaltrials.gov. Identifier: NCT00293241

Abbreviations

AF=atrial fibrillation

2
AAI=single-chamber atrial pacing mode

AT/AF=atrial tachyarrhythmia

CI= 95% confidence intervals

DDD=dual-chamber pacing mode

HF=heart failure

HR= hazard ratios

ICD=implantable cardioverter defibrillator

IQR=interquartile range

LVEF=left ventricle ejection fraction

MVP=managed ventricular pacing

NYHA=New York Heart Association

SD=standard deviation

Introduction

Atrial fibrillation (AF) is a frequent condition in patients with implantable cardiac devices, being

present in about one fourth of patients at first device implant and in up to half of patients during

follow-up (1-2). AF has been associated with increased mortality and morbidity and with

impairment of quality of life (3).

The best pacing modality to reduce AF incidence is still being debated (4-10). A number of

clinical studies (4-9) have shown that, in patients with intact AV conduction, unnecessary

chronic right-ventricular pacing can cause a variety of detrimental effects, including AF and

congestive heart failure (HF). These effects are believed to result from the mechanical

3
dyssynchrony and ventricular chamber dysfunction that occurs with chronic, single-site, apical

ventricular stimulation.

Managed Ventricular Pacing (MVP), has been designed to give preference to intrinsic ventricular

activation by minimizing ventricular pacing (11-12). This is accomplished by an atrial-based

dual-chamber pacing mode that provides functional single-chamber atrial (AAI) pacing with

ventricular monitoring and automatic switch from AAI to dual-chamber (DDD) pacing during

episodes of AV block.

The PreFER MVP study (13) was designed to compare standard DDD pacing with MVP in

patients with pacemaker or implantable cardioverter defibrillator (ICD) who needed device

replacement. This population is of particular interest because of its long pacing history and

because it represents an important portion of the total implants, ranging from 13% to 21%. (14)

The results of PreFER MVP study in terms of primary end point, showed no significant

difference in cardiovascular hospitalizations between the two study groups (15). Aim of this

predefined secondary analysis of PreFER MVP study was to evaluate the incidence of persistent

atrial tachyarrhythmias (AT/AF) in relation to patient characteristics and pacing modality in

patients indicated for device replacement.

Methods

Study design and patient population

The design of the PreFER MVP study has been previously described (13, 15). In brief, the study

was a global, prospective, randomized, single-blinded multi-center trial.

A total of 630 patients, planned to have their dual-chamber pacemaker or ICD replaced, were

enrolled in 76 centers in Europe, Canada, Australia, Israel, Kuwait, Hong Kong and South

Korea. Enrollment took place between February 21, 2006, and August 19, 2009.

4
The trial was conducted in accordance with the Helsinki Declaration. The Institution Review

Board or Medical Ethic Committee approved the study protocol and all patients provided their

informed consent.

Inclusion criteria required that patients had been implanted with a dual-chamber device for a

minimum duration of 2 years, received more than 40% ventricular pacing as detected by the

device over a period of >4 weeks before replacement and that there was no clinical need to

change the pacing mode or the AV intervals.

Exclusion criteria are detailed elsewhere (see ref 13) and included cardiac resynchronization

therapy indication, permanent AF, permanent 3rd degree AV Block, age less than 18 years, and

neurocardiogenic syncope as primary pacemaker indication.

Randomization was provided by an electronic database and was stratified by left ventricular

ejection fraction (LVEF) - ≤40% or >40% - and by pacemaker versus ICD.

Follow-up and study end points

Clinical information was retrieved at baseline and at scheduled follow-up visits at 1 month, 12

months and 24 months. After the 2 years follow-up visit, patients remained in the study and

clinical and device data were collected until the last enrolled subject reached 24 months of

follow-up.

Daily total AT/AF duration as detected by the device was retrieved from device memory.

The main objective of this secondary analysis was to identify predictors of persistent AT/AF

among baseline patient characteristics and pacing modalities. The primary end point was

persistent AT/AF, defined as either longer than 7 consecutive days with device diagnostics

5
showing 20 or more hours in AT/AF or AT/AF interrupted by atrial cardioversion or AT/AF

present at 2 consecutive follow-up visits. This analysis was pre-specified in the study protocol

and in the statistical analysis plan.

We also measured other AT/AF-related end points such as the first occurrence of at least 5

minutes, 1 hour and 6 hours of AT/AF, and permanent AT/AF defined as one of the following: 7

consecutive days with device diagnostics showing AT/AF for ≥20 hours and either failed

cardioversion or the investigator decided not to cardiovert the patient.

Device Programming

Once a patient was randomized, the following programming requirements were defined: patients

in the DDD arm should be programmed as in the exchanged device, without a change in sensed

and paced AV intervals, and no features switched on which had not been available or switched

on in the previous device, while patients in the MVP arm should be programmed in

AAI(R)<=>DDD(R) pacing mode, with Sensed AV interval, Paced AV interval and Rate

adaptive AV left to physician discretion. Mode switch and AT/AF detection were required to be

enabled in both study arms.

Medical Treatment

Medical treatment was left to physician discretion and investigators were requested to treat HF

patients with the optimal medical therapy available as described in the ESC Guidelines for the

diagnosis and treatment of chronic HF (16).

Statistical analysis

Descriptive statistics were reported as mean and standard deviation for normally distributed

continuous variables, or median with 25th-75th percentile interquartile range (IQR) in the case of

skewed distribution. The incidence of end points at 2 years follow-up was estimated by the

6
Kaplan–Meier method and compared with the log-rank test. Cox regression was used to calculate

hazard ratio (HR) with 95% confidence interval (CI). Univariable and multivariable Cox

regression analysis was used to identify risk factors for persistent AT/AF occurrence. Two Cox

regression models were estimated, one using the median PR interval and one using the upper

quartile PR interval value. Beside baseline patient’s characteristics, also ventricular pacing

percentage, as retrieved from device memory, was tested as a predictor of persistent AT/AF. We

chose to use ventricular pacing percentage as estimated in the first 3 months of each patient

observation period, in order to characterize the patient with a variable measured in a follow-up

period as near as possible to baseline evaluation. Patients were deemed to have high ventricular

pacing percentage if their ventricular pacing percentage was equal or higher than 10% and were

compared with patients with ventricular pacing percentage lower than 10%.

The main analysis considered all occurrences of persistent AT/AF. A sensitivity analysis was

also performed excluding persistent AT/AF events which occurred in the first 3 months, to

account for the fact that baseline ventricular pacing was estimated in the first 3 follow-up months

after implant.

The 2 year incidence of persistent AT/AF was estimated also in patients sub-groups selected as a

function of PR interval, ventricular pacing percentage and randomization arm.

Statistical tests were two-tailed, and p<0.05 was considered significant. The analysis adhered to

the intent-to-treat principle. All the statistical analyses were performed using SAS 9.3.

Results

All 605 patients randomized in the PreFER MVP study were included in the analysis. Baseline

patient characteristics are described in table I. In total, 186 (30.7%) patients had a known history

of AF and 43 (7.1%) patients had a history of atrial tachycardia or atrial flutter.

7
Mean follow-up was 2.2 ± 1.0 years.

Clinically defined persistent AT/AF

Clinically defined persistent AT/AF was observed in 71 patients (actuarial incidence: 13.2%,

CI=10.6%-16.5%) at 2 years. In univariable Cox regression analysis, persistent AT/AF was

significantly associated with prior AF, coronary artery disease, cardiomyopathy, use of

antiarrhythmic drugs, LVEF, ventricular pacing percentage and PR interval, but not with the

randomization group, as shown in table II. In particular, the risk of developing persistent AT/AF

for the whole study population increased by a factor 4.09 (HR=4.09, CI=2.11-7.94, p<0.001) in

patients with ventricular pacing percentage higher than 10%. These patients represent two third

of the whole patient population as shown in the ventricular pacing percentage distribution (figure

1). Median ventricular pacing percentage was 53.4% (lower-upper quartile 2.7%-96.0%) in the

whole population, 88.0% (lower-upper quartile 44.5%-98.4%) in the DDD arm and 5.1% (lower-

upper quartile 0.5%-64.2%) in the MVP arm. The association between persistent AT/AF and

baseline PR interval was found for PR intervals longer or equal to 230 ms, corresponding to the

upper quartile PR value in the studied population (HR =1.84, CI=1.00-3.37, p=0.049) while it

was not significant (HR =1.35, CI=0.71-2.56, p=0.355) for PR≥210 ms, corresponding to the

median PR interval in the studied population.

Figure 2 shows time to first persistent AT/AF for the entire population in patients with

ventricular pacing percentage ≤10% (continuous line) and >10% (dotted line).

Figure 3 shows time to first persistent AT/AF in patients with PR interval < 230 ms (continuous

line) and ≥ 230 ms (dotted line).

Multivariable Cox regression analysis (table II) demonstrated that only a history of prior AT/AF

(HR =2.85, CI=1.20-6.22, p=0.017) and high ventricular pacing percentage (HR =3.24, CI=1.13-

8
9.31, p=0.029) were independent predictors for persistent AT/AF. No qualitative differences

were identified by repeating Cox Regression model on the sensitivity analyses.

Secondary end points

In the first 2 years post randomization 44.3% of the patients experienced 1 or more days with at

least 5 minutes of device-detected AT/AF, 35.7% with at least 1 hour of AT/AF, 18.8% with at

least 6 hours of AT/AF, while 7.9% of the patients had AT/AF longer than 7 days and 3.5% of

patients were considered having permanent AT/AF.

The randomization arm was not associated with statistically significant differences for any of the

described AT/AF conditions when evaluating the whole study population. In the subgroup of

patients with long PR interval (PR≥230 ms) MVP was related to a higher incidence of persistent

AT/AF when compared with DDD pacing (HR 3.41, CI=1.10-10.6, p=0.024). In the subgroup of

patients with shorter PR interval (PR<230 ms), patients randomized to MVP mode and having a

ventricular pacing percentage lower than the median pacing percentage were associated with

lower incidence of persistent AT/AF either when compared with patients randomized to DDD

pacing and having a ventricular pacing percentage lower than the median pacing percentage (HR

0.25, CI=0.067-0.900, p=0.034) or when compared with patients randomized to MVP pacing

and having a ventricular pacing percentage higher than the median pacing percentage.

In patients randomized to the MVP arm, the median (IQR) ventricular pacing percentage

was 50.5 % (10.9%-97.2%) in patients who developed persistent AT/AF and 2.7% (0.4%-

47.8%) in patients who did not develop persistent AT/AF.Discussion

Main results

The main result of this secondary analysis of PreFER MVP study was that in patients referred for

replacement of an implanted pacemaker or ICD, prior AT/AF and high ventricular pacing

9
percentage were independent predictors of persistent AT/AF during the follow-up. In patients

with long PR intervals (PR≥230 ms) MVP mode was associated with higher risk of persistent

AT/AF compared with DDD mode. In patients with shorter PR intervals (PR<230 ms) MVP

mode was associated with lower risk of persistent AT/AF compared with DDD mode, in patients

with a low percentage of ventricular pacing.

Atrial fibrillation prevalence in patients wearing implantable cardiac devices

Our data confirm previous findings about the high prevalence of AT/AF in pacemaker and

defibrillator patients [1-3]. A history of AT/AF was present in 37.8% of patients at baseline and

these arrhythmias were documented in the device memories in 44.3% of patients during the 2-

year observation period; in real clinical practice AT/AF prevalence has to be estimated even

higher when including permanent AT/AF which was an exclusion criterion in our study.

Predictors of persistent atrial fibrillation

In our patient population the development of persistent AT/AF was significantly associated with

high ventricular pacing percentage (table II and figure 2). This finding confirms results of

previous studies (4-7, 9). Some small clinical studies (4-6) and the post-hoc analyses of the

MOST trial (7) suggested the association between the risk to develop AT/AF and high

ventricular pacing percentage. The SAVEPACe trial (9), in 1065 patients with sinus-node

disease, intact atrioventricular conduction, and normal QRS interval, compared conventional

dual-chamber pacing with dual-chamber minimal ventricular pacing using pacemaker features

designed to promote spontaneous atrioventricular conduction and to minimize ventricular pacing.

The results showed that the incidence of persistent AT/AF was significantly reduced by 40%

(p=0.009) in the group of patients assigned to minimal ventricular pacing compared with the

DDD arm, in which the mean right ventricular pacing was 99%.

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In our study, persistent AT/AF was not reduced in the MVP arm of the PreFER MVP trial,

despite the fact that the MVP mode significantly reduced ventricular pacing percentage

compared with DDD mode. This represents an intriguing issue, for which we propose the

following possible explanations. First, PreFER MVP (15), by study design, selected a population

of patients who were paced more than 40% of time by previous pacemaker or ICD and who

survived their first implant without developing permanent AF and were therefore more

predisposed to tolerate long term ventricular pacing. Secondly, risk for persistent AT/AF

strongly increased for ventricular pacing percentage higher than 10%, and in the MVP arm of the

study, in spite of a median value of 5.1%, a proportion of patients continued to be highly paced

in the ventricle (upper quartile was 64.2%). Interestingly, in patients randomized to the MVP

arm, the median ventricular pacing percentage was 50.5 % in patients who developed persistent

AT/AF and 2.7% in patients who did not develop persistent AT/AF. Finally, persistent AT/AF

was significantly associated with long PR (PR≥230 ms) and this finding may have overwhelmed

the benefits of ventricular pacing reduction in MVP patients. As a matter of fact, in the

DANPACE trial (10, 17), which randomly assigned 1415 sick sinus syndrome patients referred

for first pacemaker implantation to AAIR (707) or DDDR (708) pacing, followed for a mean of 5

years, an excess of AF was observed in patients paced with single lead atrial pacing as compared

with those paced in DDD mode, in particular in patients with prolonged intrinsic PR interval.

Clinical implications

As reported by Botto et al. (15), the PreFER MVP study aimed to compare MVP and DDD

pacing modes in patients indicated to elective pacemaker or ICD replacement with high prior

ventricular pacing percentage. The main analysis showed that in these patients, with clinically

well tolerated long term exposure to more than 40% pacing in the ventricle, a strategy to

11
minimize ventricular pacing is not superior in reducing incidence of cardiovascular

hospitalization compared to standard DDD pacing.

Findings of the present analysis showing the association between ventricular pacing percentage

greater than 10% and persistent AT/AF confirms the favorable role of pacing modalities to

reduce unnecessary ventricular pacing in selected patients with normal spontaneous AV

conduction. Reducing ventricular pacing below 10% may require dedicated algorithms and may

be difficult to obtain by simply programming long AV interval. Indeed, subgroup analyses in our

study showed that patients with long baseline PR interval (PR≥230 ms) had a higher incidence of

persistent AT/AF if programmed in MVP compared with DDD pacing. We hypothesize that

enabling very long intrinsic atrioventricular conduction times, as in the MVP arm, may cause

AT/AF in patients with long PR intervals who were used to being chronically paced in the

ventricle for a long time. As reported earlier (17-18), a long PR interval could be responsible for

a higher incidence of AF, either in patients with or without history of AF. The actual reason of

this association remains still hypothetical. Conversely, patients with shorter PR interval (PR<230

ms) randomized to MVP mode and having a ventricular pacing percentage lower than 5.1%

(median pacing percentage in MVP mode) showed lower persistent AT/AF either compared with

patients in DDD mode and low ventricular pacing percentage or patients in MVP mode and high

ventricular pacing percentage. These data suggest that MVP is an effective pacing mode in

patients with normal or only slightly prolonged PR interval, while pacing at a relatively short AV

interval may be better in patients with a prolonged PR interval.

When comparing MVP and DDD pacing, clinical benefit may derive from the balance of two

conflicting factors, AV synchrony and ventricular pacing percentage. Although DDD pacing

guarantees AV synchrony, unnecessary pacing in the right ventricle may cause ventricular

remodeling due to the consequent change in electrical activation and contraction pattern of the

12
ventricles. Conversely, MVP preserves a normal ventricular contraction pattern, which is

expected to reduce ventricular remodeling in comparison with a higher percentage of ventricular

pacing, but at the cost of allowing a prolonged AV conduction in some patients.

In patients undergoing pacemaker or ICD replacement with high percentage ventricular pacing

history, the choice of the best pacing mode should be guided by careful evaluation of several

clinical factors, including ventricular pacing percentage in the previous device and spontaneous

PR interval. Our data suggest that programming the MVP mode is of major importance in

reducing the percentage of ventricular pacing and hence the incidence of AF. Only in patients

with a prolonged PR interval (≥ 230 ms) a DDD mode, with pacing at a relatively short AV

interval, should be recommended.

Study limitations

We report results of secondary analyses of the PreFER MVP study. The statistical methods of the

analyses on the main endpoint, persistent AT/AF, were pre-specified in the study protocol and in

the statistical analysis plan, with the only exemption of the ventricular pacing percentage cut-off

used to evaluate the association of this variable with persistent AT/AF. In particular, the cut-off

(10%) used to divide the patient population between patients with low vs. high ventricular pacing

percentage was chosen since it was the distribution tertile and possibly a good candidate to

differentiate pacing modes devoted to minimize ventricular pacing from standard DDD pacing

based on the observation of the skewed distribution of ventricular pacing percentage as measured

in our study (figure 1) and in previous trials. (11-12, 19-20)

The primary end point, persistent AT/AF, consists of three components, new-onset persistent

AT/AF in patients without previous history of AT/AF, persistent AT/AF in patients with history

of paroxysmal AT/AF, and recurrence of persistent AT/AF in patients with history of persistent

13
AT/AF. We cannot exclude that different mechanisms are responsible for the development of

persistent AT/AF in these different situations.

The use of antiarrhythmic drugs could have interfered with arrhythmia occurrence.

The results of our analyses should be regarded as characteristics of the studied population of

pacemaker and ICD replacement patients, with clinically well tolerated long term exposure to

more than 40% pacing in the ventricle. In particular the results refer to conventional right atrial

appendage pacing. We can not exclude that different results might have been observed in case of

alternative site atrial pacing.

Conclusions

In pacemaker and ICD replacement patients, high percentage of ventricular pacing is associated

with higher risk of persistent AT/AF. The use of algorithms which minimize unnecessary right

ventricular pacing may benefit patients with normal spontaneous AV conduction but should be

evaluated with caution in patients with long PR interval.

Funding

The PreFER MVP study was supported and sponsored by Medtronic Bakken Research Center.

Acknowledgements

The authors thank Bart Gerritse and Lidwien Vainer for contributing to and reviewing scientific

and statistical methods and manuscript draft.

Disclosures

Renato Ricci has received consultant honoraries from Biotronik and Medtronic, and speaker fees from

Biotronik. Giovanni Luca Botto has received research grants from Boston Scientific, St. Jude Medical,

Bayer Healthcare, Gilead, Sanofi, Medtronic, consultant honoraries from Biotronik, Boston Scientific,

St. Jude Medical, MSD, Bayer Healthcare, Sanofi, Medtronic, and speaker fees from Boston

14
Scientific, St. Jude Medical, Bayer Healthcare, Boheringer, Sanofi, Sorin, Pfizer, MSD and

Medtronic. Juan M Bénézet has received consultant honoraries and speaker fees from Medtronic. Jens

Cosedis Nielsen has received speaker fees from Biotronik and Biosense Webster, consultant

honoraries from Boston Scientific, and research grants for the MANTRA-PAF trial from Biosense

Webster. Luc De Roy received research and/or fellowship funds or consultant fees from Medtronic,

St Jude, Boston, Sorin and Biotronic. Olivier Piot has received consultant honoraries from St Jude

Medical, Sorin, Biotronik and Medtronic. Aurelio Quesada has received research grants from Sorin

and Medtronic. Diego Vaccari has received research grants from St. Jude Medical, and speaker fees

from Biotronik. Milan Kozak received consultant honoraries from Boston Scientific, Medtronic and

Biotronik. Lorenza Mangoni and Andrea Grammatico are employee of the Medtronic EMEA

Regional Clinical Centre.

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 Elective Replacement MVP (PreFER MVP) randomized study. Heart Rhythm 2014;

11:992-1000.

16. Swedberg K, Cleland J, Dargie H et al. Task Force for the Diagnosis and Treatment of

Chronic Heart Failure of the European Society of Cardiology. Guidelines for the

diagnosis and treatment of chronic heart failure: executive summary (updated 2005). Eur

Heart J 2005; 26:1115-40.

17. Cosedis Nielsen J, Thomsen PE, Højberg S et al. DANPACE investigators. Atrial

fibrillation in patients with sick sinus syndrome: the association with PQ-interval and

percentage of ventricular pacing. Europace 2012; 14:682-9.

18. Cheng S, Keyes MJ, Larson MG, McCabe EL, Newton-Cheh C, Levy D, Benjamin EJ,

Vasan RS, Wang TJ. Long-term outcomes in individuals with prolonged PR interval or

first-degree atrioventricular block. JAMA 2009; 301:2571-7.

19. Almendral J, Arribas F, Wolpert C, Ricci R, Adragao P, Cobo E, Navarro X, Quesada A;

DATAS Steering Committee; DATAS Writing Committee; DATAS Investigators. Dual-

chamber defibrillators reduce clinically significant adverse events compared with single-

chamber devices: results from the DATAS (Dual chamber and Atrial Tachyarrhythmias

Adverse events Study) trial. Europace. 2008;10(5):528-35

20. Barsheshet A, Moss AJ, McNitt S, Jons C, Glikson M, Klein HU, Huang DT, Steinberg

JS, Brown MW, Zareba W, Goldenberg I; MADIT-II Executive Committee. Long-term

implications of cumulative right ventricular pacing among patients with an implantable

cardioverter-defibrillator. Heart Rhythm. 2011;8(2):212-8.

Clinical perspectives

This secondary analysis of the PreFER MVP clinical trial provides new evidence about the

fact that in patients undergoing pacemaker or ICD replacement, high percentage of

18
ventricular pacing is associated with higher risk of developing persistent AT/AF. Our data

suggest that the use of algorithms minimizing unnecessary right ventricular pacing is

warranted in patients who have normal spontaneous AV conduction while it should be

evaluated with caution in patients with long PR interval. These finding have clinical

importance because patients undergoing pacemaker or ICD replacement who have a high

percentage ventricular pacing history, represent a relevant portion of total implants. So far no

data have been published about the choice of the best pacing mode in this specific

patientpopulation.

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 Table I: Baseline patients characteristics

Subject Characteristics Total (N = 605)

Male gender N (%) 365 (60.3%)
Age (years) 75 ± 11
Implanted device - Pacemaker (N,%) 556 (91.9%)
Implanted device - ICD (N,%) 49 (8.1%)
Primary Device (pacemaker only) Indication
Sinus Node Dysfunction N (%) 372 (61.5%)
AV block N (%) 139 (23.0%)
Other brady indication N (%) 45 (7.4%)
Previous device implant duration (years) - mean ± SD 7.7 + 3.3
Ventricular pacing percentage in the period preceding study enrollment - median (IQR) 95% (IQR 75% – 99%)
History of Atrial fibrillation N (%) 186 (30.7%)
Paroxysmal N (%) 168 (27.8%)
Persistent N (%) 18 (3.1%)
History of Atrial flutter/tachycardia N (%) 43 (7.1%)
Cardiomyopathy N (%) 118 (19.5%)
Coronary Artery Disease N (%) 140 (23.1%)
Hypertension N (%) 307 (50.7%)
Diabetes mellitus N (%) 101 (16.7%)
Heart Failure N (%) 434 (71.7%)
NYHA Class I N (%) 186 (30.7%)
NYHA Class II N (%) 216 (35.7%)
NYHA Class III-IV N (%) 32 (5.3%)
LVEF (%) – mean ± SD 53 ± 13
Intrinsic P-R Interval (ms) median (IQR) 210 (170-230)
Cardiovascular Medications N (%)
Aspirin/Acetylsalicylic acid N (%) 296 (48.9%)
Anticoagulants N (%) 147 (24.3%)
Diuretics N (%) 196 (32.4%)
Angiotensin-converting enzyme inhibitors N (%) 214 (35.4%)
Angiotensin II receptor blockers N (%) 112 (18.5%)
Beta-blockers N (%) 245 (40.5%)
Calcium antagonists N (%) 117 (19.3%)
Digitalis/digoxin N (%) 56 (9.3%)
Amiodarone N (%) 100 (16.5%)
LVEF=left ventricle ejection fraction, NYHA=New York Heart Association, SD=standard deviation, IQR=25th-75th interquartile range

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Table II Cox regression model for predictors of persistent AT/AF

Univariate Multivariate

95% Hazard 95% Hazard

Hazard Ratio p Hazard Ratio p
Baseline Characteristic
Ratio Confidence value Ratio Confidence value
Limits Limits

Prior AT/AF 3.52 2.30-5.38 <0.001 2.85 1.20-6.22 0.017

Coronary artery disease 1.95 1.26-3.01 0.003 1.19 0.21-6.76 0.848

Cardiomyopathy 2.20 1.41-3.41 <0.001 1.43 0.46-4.40 0.533

Antiarrhythmic drugs 2.50 1.59-3.94 <0.001 1.66 0.68-4.09 0.267

LVEF (%) 0.97 0.97-0.99 0.001 0.99 0.95-1.03 0.557

PR interval (≥230 ms) 1.84 1.00-3.37 0.049 2.11 0.87-5.10 0.097

Randomization
1.35 0.88-2.05 0.167 2.43 0.95-6.22 0.063
[MVP ON / MVP OFF]

Ventricular pacing
percentage
4.09 2.11-7.94 <0.001 3.24 1.13-9.31 0.029
(estimated in the first 3
months – cut off ≥10%)

Figure legend

Figure 1 Distribution of ventricular pacing percentage as measured in the first 3 months of

the observation period in the whole population

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Figure 2 Time to first persistent AT/AF in patients with ventricular pacing percentage ≤ 10%

(continuous line) and > 10% (dotted line) in the whole population, for the subgroup

of 549 patients with complete data about ventricular pacing percentage.

Figure 3 Time to first persistent AT/AF in patients with PR interval < 230 ms (continuous

line) and ≥ 230 ms (dotted line) in the whole population, for the subgroup of 353

patients with complete data about PR interval.

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Figure 1
Figure 2
Figure 3