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Archives of cardiovascular diseases
Volume 112, n° 3
pages 153-161 (mars 2019)
Doi : 10.1016/j.acvd.2018.09.005
Received : 18 May 2018 ;  accepted : 17 September 2018
Cliical research

Occurrence of significant long PR intervals in patients implanted for sinus node dysfunction and monitored with SafeR™: The PRECISE study
Allongement de l’intervalle PR chez des patients implantés pour dysfonction sinusale et programmés en mode SafeR™ : résultats de l’étude PRECISE
 

Jérôme Taieb a, , Pierre Le Franc b, Pierre Khattar c, Ghassan Moubarak d, Hervé Gorka e, Jean-Philippe Godenir f, Philippe Deutsch g, Bruno Degand h, Ayman Al Daoud i, Jean-Philippe Elkaim j, Nathalie Elbaz k, Sandrine Merlo l, Nicolas Lellouche k
a Service de cardiologie, centre hospitalier du Pays-d’Aix, avenue des Tamaris, 13616 Aix-en-Provence, France 
b Clinique Saint-Hilaire, 76000 Rouen, France 
c Centre hospitalier de Lorient, 56322 Lorient, France 
d Saint-Joseph's hospital, 75014 Paris, France 
e Centre hospitalier de Chartres, 28018 Chartres, France 
f Deceased, centre hospitalier de Forbach, 57600 Forbach, France 
g Centre hospitalier de Saint-Malo, 35400 Saint-Malo, France 
h CHU de Poitiers, 86021 Poitiers, France 
i CHR de Thionville, 57100 Thionville, France 
j Centre hospitalier de Douarnenez, 29100 Douarnenez, France 
k Henri Mondor hospital, 94101 Créteil, France 
l MicroPort CRM, 92140 Clamart, France 

Corresponding author.
Summary
Background

Long PR intervals may increase cardiovascular complications, including atrial fibrillation. In pacemakers, the SafeR™ mode monitors PR intervals, switching from AAI to DDD when criteria for atrioventricular block are met.

Aims

The PRECISE study evaluated the incidence and predictors of long PR intervals and their association with incident atrial fibrillation after 1 year in patients implanted for sinus node dysfunction and free from significant conduction disorders at baseline.

Methods

This French, prospective, multicentre, observational trial enrolled patients implanted with a REPLY™ dual-chamber pacemaker. Pacemaker memory recorded long PR intervals (defined as first-degree atrioventricular block mode switches occurring after six consecutive PR/AR intervals350/450ms) and atrial fibrillation incidence (fallback mode switch>1minute/day). Predictors were identified from baseline variables (age, sex, AR and PR intervals, atrial rhythm disorder and medication) using logistic regression.

Results

Of 291 patients with sinus node dysfunction enrolled, 214 were free from significant conduction disorders at baseline (mean age 79±8 years; 44% men; PR/AR intervals<350/450ms). After 1 year, long PR intervals had occurred in 116 patients (54%) and atrial fibrillation in 63 patients (30%). Amiodarone was the only independent predictor of long PR interval occurrence (odds ratio 2.50, 95% confidence interval 1.20–5.21; P =0.014). There was a strong trend towards an association between long PR interval and atrial fibrillation incidence (odds ratio 1.86, 95% confidence interval 0.97–3.61; P =0.051).

Conclusions

Half of the patients with pure sinus node dysfunction developed long PR intervals in the year following pacemaker implantation. Amiodarone was the only independent predictor of long PR intervals. There was a strong trend towards an association between long PR intervals and incident atrial fibrillation.

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Résumé
Contexte

L’allongement de l’intervalle PR peut entraîner des complications cardiovasculaires, y compris la fibrillation auriculaire. Dans certains modèles de stimulateur cardiaque, le mode SafeR permet de mesurer les intervalles PR au cours du temps.

Objectifs

L’étude PRECISE a pour objectif de déterminer l’incidence des PR longs chez des patients implantés pour dysfonction sinusale sans troubles de conduction.

Méthodes

Les patients, implantés d’un stimulateur cardiaque double chambre REPLY™, sont inclus et suivis pendant un an dans l’étude PRECISE, une étude française prospective, multicentrique et observationnelle. Un PR long est diagnostiqué dès que 6 intervalles consécutifs PR/AR350/450ms sont enregistrés. Un épisode de fibrillation auriculaire est défini par un repli>1minute par jour. La valeur prédictive de l’allongement du PR des caractéristiques à l’inclusion (âge, sexe, intervalles AR et PR, maladie de rythme auriculaire, médicaments) est analysée par la méthode de régression logistique.

Résultats

Parmi 291 patients inclus, 214 patients (âge 79±8 ans ; mâle 44 %) ne présentaient pas de troubles de conduction à l’inclusion (PR/AR<350/450ms). À 1 an, 116 patients (54 %) ont présenté des épisodes de long PR, et 63 patients (30 %) ont présenté au moins un épisode de fibrillation auriculaire. La prise d’amiodarone est le seul facteur prédictif indépendant de l’allongement du PR (OR 2,50, IC 95 % 1,20–5,21 ; p =0,014). Une tendance vers une association entre PR long et fibrillation auriculaire est observée (OR 1,86, IC 95 % 0,97–3,61 ; p =0,051).

Conclusions

Dans l’année qui suit l’implantation d’un stimulateur cardiaque pour dysfonction sinusale, la moitié des patients présente au moins un épisode de PR long. La prise d’amiodarone est le seul facteur prédictif indépendant de l’allongement du PR. Une potentielle association entre l’allongement du PR et la fibrillation auriculaire peut être observée.

The full text of this article is available in PDF format.

Keywords : First-degree atrioventricular block, Atrial fibrillation, Dual-chamber pacemaker, SafeR, Long PR interval

Mots clés : Bloc atrio-ventriculaire du premier degré, Fibrillation auriculaire, Stimulateur cardiaque double chambre, SafeR, Intervalle PR long

Abbreviations : AF, AV, AVB, AVB1, CI, OR, SND


Background

First-degree atrioventricular block (AVB1) is a disease of the cardiac electrical conduction system, in which the PR interval lasts for>200ms. Prolongation of the PR interval beyond 200ms is generally asymptomatic and benign [1, 2], although patients with prolonged PR intervals are more likely to become symptomatic with mild or moderate exercise [3]. Moreover, some studies have suggested that long PR intervals may increase the risk of cardiovascular complications, including atrial fibrillation (AF) [4, 5].

Patients with AF are at increased risk of death, particularly cardiovascular death [6]. AF is the cause of 20–30% of strokes, and represents a substantial burden in secondary healthcare, with an annual hospitalization rate of 10–40%. This condition also affects patients’ everyday lives because of its association with depressed mood and impaired quality of life [6]. The monitoring and management of long PR intervals and AF are therefore important clinical needs.

The SafeR™ algorithm (MicroPort CRM, Clamart, France) continuously monitors atrioventricular (AV) conduction and diagnoses AV blocks (AVBs) when they occur [7, 8]. The SafeR algorithm has been validated for all types of AVB, and its safety profile has been assessed in both sinus node dysfunction (SND) and AVB populations [8, 9]. More recently, a subanalysis revealed that 25% of patients with SND had a long PR interval at baseline, responsible for a high proportion of AVB1 switches, and that patients with long PR intervals were 1.68 times more likely to develop persistent AF (hazard ratio 1.68, 95% confidence interval [CI] 1.06–2.65; P =0.027) [10]. This result is in accordance with previously published data reporting an association between long PR intervals and AF [11, 12].

The PRECISE (Evolution of PR interval lengthening in patients implanted with a dual-chamber pacemaker with an algorithm for spontaneous AV conduction preservation) observational study, conducted in patients with SND, focused specifically on long PR intervals, as assessed by AVB1 switches, with the aim of further investigating:

the incidence and predictors of long PR intervals; and;
the association between long PR intervals and AF (ClinicalTrials.gov Identifier: NCT02586480).

Methods
Study design and follow-up

The PRECISE study was a multicentre, observational, prospective, cohort study. Enrolment took place between April 2012 and September 2013, and the clinical investigation ended in January 2015. Patients aged18 years were enrolled at 48 centres throughout France if they were eligible for pacemaker implantation (de novo, upgrade or replacement), according to contemporary guidelines [13, 14], and had received a SafeR-equipped dual-chamber pacemaker <3 months before enrolment. Patients were excluded if they had permanent AF or permanent high-degree AVB.

SafeR mode was activated at the time of implantation. Follow-up visits were scheduled 6 months (±3 months) and 12 months (±3 months) after implantation. The study was declared to all national competent authorities. Patients gave their informed consent, and the study conduct complied with ISO 14155 and the principles of the Declaration of Helsinki.

SafeR pacing mode

The SafeR algorithm (MicroPort CRM, Clamart, France) preserves AV conduction by pacing in AAI mode by default, and switching to DDD mode when AVB occurs. When in transitional DDD mode, the pacemaker switches back to AAI mode as soon as it identifies the return of intrinsic conduction [7].

Mode switch occurs in the presence of all types of AVB (AVB1 and second- and third-degree AVB). More specifically, in the presence of AVB1, the algorithm does not allow more than six consecutive PR or AR intervals longer than a programmable value (nominally 350 and 450ms, respectively). If a seventh long PR interval is detected, the algorithm switches to DDD pacing mode (Figure 1). SafeR allows the management of long PR intervals according to patients’ individual needs through the programming of the following parameters: minimum and maximum long PR interval, mode switch at rest and during exercise or only during exercise.



Figure 1


Figure 1. 

SafeR mode and the criterion for first-degree atrioventricular block (AVB1). AAI: atrium [paced] atrium [sensed] inhibited [response to sensing]; DDD, dual [paced] dual [sensed] dual [response to sensing].

Mode Safe R et critères de BAV du premier degré.

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Data

At each visit, the following data were collected: serious adverse events, symptoms, clinical condition and device data extracted from the pacemaker's memory. The data were reported to an electronic data system managed by the contract research organization Evamed (Hérouville-Saint-Clair, France).

Device data included fallback mode switch statistics, SafeR statistics and pacemaker-generated atrial and ventricular electrograms of AVB switches. These electrogram strips were verified and adjudicated by physicians for each patient, to ensure the appropriateness of the switch, based on the review of two independent A and V channels, which ensured robust adjudication thanks to good data quality. If an inappropriate switch was detected, all readings for this patient were excluded from subsequent analyses to safeguard the reliability of results.

Objectives and endpoints

The aim of the PRECISE study was to evaluate the incidence of long PR intervals at 1 year in patients implanted for SND without any conduction disorders at baseline, and the association between long PR intervals and AF incidence.

The primary endpoint of long PR intervals was defined as adjudicated AVB1 switches, ascertained from SafeR statistics. The secondary endpoint of AF incidence was defined as fallback mode switch lasting>1minute in 24hours, ascertained from fallback mode switch statistics.

Statistical methods

The incidence of long PR intervals was analysed overall and according to day/night (8am to 10pm/10pm to 8am) distribution. Logistic regression was performed to estimate the odds ratio (OR) of experiencing the event for patients with SND with 200ms<baseline PR interval<350ms compared with patients with SND with baseline PR interval<200ms. Predictors of long PR intervals were identified using univariate and multivariable logistic regression models using baseline variables, including age, sex, AR and PR intervals, atrial rhythm disorder and medications. In addition, a time-to-first event analysis was performed with the help of a Kaplan-Meier plot for the onset of long PR intervals. The incidence of AF was analysed overall. A logistic regression was performed to estimate the OR of experiencing an AF event for patients with long PR intervals compared with patients without long PR intervals. Predictors of AF were identified using logistic regression models with the baseline variables described above. Data are summarized as number (percentage), mean±standard deviation or median [interquartile range]. All statistical analyses were performed with the SAS® statistical software, version 9.4 (SAS Institute, Cary, NC, USA).

Results
Study population and follow-up

Two hundred and ninety-one patients with SND were enrolled in the study. In four patients, SafeR was disabled before the end of follow-up at 1 year; in 72 patients, baseline PR interval was not measured; and in one patient, the baseline PR interval was >350ms. Therefore subsequent analyses could only be performed in 214 patients with a confirmed baseline PR/AR interval<350/450ms. This group contained 143 patients with a baseline PR interval<200ms, and 71 patients with a baseline PR interval ranging from 200ms to 350ms (Figure 2, Figure 3).



Figure 2


Figure 2. 

Patient flowchart. AVB: atrioventricular block; AVB1: first-degree atrioventricular block; SND: sinus node dysfunction.

Organigramme patient.

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Figure 3


Figure 3. 

PR interval distribution in patients with sinus node dysfunction with PR interval<350ms at baseline.

Distribution des intervalles PR à l’état basal.

Zoom

Patients were elderly (mean age 78.9±8.4 years) and nearly half (48.5%) had a history of AF (Table 1). The most common medications were beta-blockers (32.2%) and amiodarone (21.3%). The mean PR interval was 192±49ms; the mean AR interval was 244±56ms. All patients were implanted with a REPLY™ dual-chamber pacemaker (MicroPort CRM, Clamart, France). For most (n =193, 90.2%), this was their first implant. The mean duration of follow-up was 370±78 days.

Study outcome
Incidence of long PR intervals

Over half (n =116, 54.2%) of the 214 patients experienced one or more long PR intervals during the study. A greater percentage of patients with SND with 200ms<baseline PR interval<350ms experienced a long PR interval during the study than patients with SND with baseline PR interval<200ms: 62.0% (44/71) vs. 50.4% (72/143).

Nearly a quarter (23.4%) of the 214 patients experienced a first long PR interval within 30 days of implantation (Figure 4). As time progressed, 31.3%, 33.6% and 39.3% of these 214 patients experienced a first long PR interval within 60, 90 and 180 days, respectively. The majority (92/116, 79.3%) of patients experienced long PR intervals during both the day and the night, some (20/116, 17.2%) during the day only and a few (4/116, 3.5%) during the night only.



Figure 4


Figure 4. 

Kaplan-Meier curve showing time-to-first occurrence of long PR interval (n =214).

Courbe de kaplan-Meier montrant le délai de survenue du premier intervalle PR long.

Zoom

Predictors of long PR interval

Preliminary (univariate) analysis indicated that long PR intervals during the study were potentially associated with a history of atrial rhythm disorder, prolonged baseline PR and the use of flecainide or amiodarone (Table 2). Confirmation by multivariable analysis showed that only the use of amiodarone was an independent predictor of long PR intervals (OR 2.50, 95% CI 1.20–5.21; P =0.014).

Incidence and predictors of AF: association with long PR intervals

Almost a third of patients (n =63, 29.6%) had at least one episode of AF during the study. History of atrial rhythm disorders, medication, amiodarone, long PR interval (AVB1 switch) and age were shown by univariate analysis to be potentially associated with the incidence of AF (Table 3). Further analysis (multivariable) confirmed that only a history of atrial rhythm disorders at baseline was associated with AF incidence (OR 1.78, 95% CI 1.02–3.10; P =0.044). Almost twice as many patients with long PR interval occurrence experienced incident AF than patients without long PR interval occurrence (19.3% vs. 10.3%; OR 1.86, 95% CI 0.97–3.61; P =0.051).

Safety

There were no deaths in the SND population. Ten patients (4.7%) developed 12 adverse events, of which nine were serious adverse events: ventricular tachycardia (n =2), stroke (n =2), coronary artery procedure (n =1), pocket infection (n =1), acute coronary syndrome (n =1), weakness (n =1) and renal failure (n =1). There were no events that were related to the study device. There was one report of diaphragmatic stimulation related to unipolar stimulation, which was overcome by switching to bipolar stimulation.

Discussion

Over half of patients with SND with a baseline PR interval<350ms in the PRECISE study experienced one or more long PR intervals in the year after pacemaker implantation, with most episodes being potentially clinically relevant (i.e. not occurring solely at night). Most long PR intervals, the incidence of which was non-linear, occurred in the first 3 months. The use of amiodarone was an independent predictor of long PR intervals. Patients with long PR intervals were more likely to have incident AF than those without long PR intervals. Our findings add to the limited evidence about the development of long PR intervals in contemporary patients with SND, and their association with AF.

Because the SafeR algorithm enabled the continuous recording of PR conduction delays, the percentage of patients with SND with long PR intervals (54.2%) was higher than previously reported in studies using electrocardiogram monitoring [15], but in line with previously reported findings in SafeR-monitored patients with SND from the 3-year ANSWER (EvaluAtioN of the SafeR mode in patients With a dual-chambER pacemaker indication) study [10, 16]. Nevertheless, this result remains unexpectedly high. In MOde Selection Trial (MOST) [15], investigators reported the incidence of long PR intervals >200ms in 2010 pacemaker-implanted patients with SND and normal PR interval at baseline. Fewer patients with SND (24.6%) developed long PR intervals after 33 months – nearly three times the follow-up duration in the PRECISE study. The shorter duration of the PRECISE study and the relatively higher long PR interval threshold (>350ms for electrogram versus >200ms for electrocardiogram) should in theory have led to a lower incidence rate of long PR intervals in our study. However, as already mentioned, PR in the PRECISE study was measured continuously rather than intermittently, which explains the high incidence of long PR intervals observed.

Patients with long PR intervals were more likely to have new episodes of AF than those without long PR intervals. Similar results were obtained in MOST, where a trend towards an association between long PR intervals and AF incidence (30.5% for AVB1 vs. 23.4% for normal AV conduction; hazard ratio 1.22, 95% CI 0.97–1.53; P =0.089) was also observed [15]. Similarly, in the DANPACE (Danish multicentre randomized trial on single-lead atrial pacing versus dual-chamber pacing in sick sinus syndrome) study, a longer baseline PQ interval was associated with an increased risk of AF in 650 pacemaker-implanted patients with sick sinus syndrome [5]. The mean PQ interval at baseline was 179±30ms, the mean follow-up was 3.7 years and mode switch was used to detect the time spent in AF. The incidence of AF was higher among patients with a higher baseline PQ interval (>180 versus ≤180ms; P <0.001) [5]. Finally, a trend towards an association between long PR interval (>230ms) and persistent atrial tachycardia/AF (hazard ratio 2.11, 95% CI 0.87–5.10; P =0.097) was also seen after 2 years in Prefer for Elective Replacement Managed Ventricular Pacing (PreFER MVP) [12], which enrolled 630 previously-implanted patients (92% pacemakers, with SND [62%] or AVB [23%]) with an intrinsic PR interval of 210ms [interquartile range, 170–230ms] at baseline. All these results are in accordance with previous evidence indicating that a prolonged PR interval is an independent risk factor for AF [17, 18], associated with a general tripling of risk for advanced conduction system disease and a specific doubling of risk for AF [4, 19, 20].

The clinical association of SND and AF is probably the result of electrophysiological and anatomical remodelling [21]. Remodelling is a gradual process [22]. At a cellular level, cell numbers in the sinoatrial node diminish naturally over time. Disease accelerates the shrinking of the sinoatrial node and the substitution of nodal tissue with fibrolipid tissue [23]. In the sinoatrial node, remodelling leads to sinoatrial node arrest and re-entry, while in the atrium, remodelling leads to re-entry and production of its triggering mechanisms. There is still uncertainty about the relationship between sinoatrial dysfunction and atrial myocardium dysfunction, especially with regard to which causes which [22]. For example, even short-term exposure to AF is enough to cause dysfunction and remodelling in the sinoatrial node [21]. It has been suggested that SND and AF might be different phenotypes of a related pathophysiological mechanism (e.g. fibrosis) [24].

Today, the management of AF is improving thanks to a multifaceted approach focusing on intense risk factor management as well as anticoagulation and control of heart rate and rhythm [25]. Other steps that could advance the management of AF include using new imaging techniques to better demarcate atrial fibrosis [26, 27] and appropriate algorithms to minimize ventricular pacing [16, 28], as some algorithms may not suit all types of patient (e.g. managed ventricular pacing in patients with long PR intervals) [12].

Our data support the current practice of implanting SND patients with a dual-chamber pacemaker. Given the high incidence of long PR intervals in patients with pure SND reported in our study, and the potential negative impact of long PR intervals on the development of AF, we believe that the choice of a dual-chamber pacemaker with an algorithm for long PR interval management might be useful for these patients.

Study limitations

Care should be taken in generalizing these results, as the population size was relatively small and the follow-up duration was short. Furthermore, a lack of monitoring meant that a quarter of enrolled patients could not be included in the analysis because PR interval values were not measured at baseline. The incidence of long PR intervals may have been overestimated because of selection bias; doctors may have inadvertently selected patients at greater risk of AVB1, knowing that these patients were likely to benefit from having a SafeR-enabled dual-chamber pacemaker. Fallback mode switch has high sensitivity and specificity for detection of AF, but over- and undersensing of AF can occur. Although simultaneous readings of cardiac electrical activity obtained using electrograms and electrocardiograms should be similar, there were no data from surface electrocardiograms to confirm that this was the case. Information about the exact position of the lead in the right atrium may have had an effect on the results, but was not recorded. The choice of 350ms as the long PR interval cut-off was dictated by hardware rather than clinically, but it was judged lengthy enough to be clinically relevant. Typical limitations associated with observational studies, e.g. lack of placebo group and confounding, were present.

Conclusions

Among patients with SND, the implantation of a SafeR-enabled dual-chamber pacemaker allowed the safe and effective detection of long PR intervals and incident AF in 54.2% and 29.6% of patients during the year following implant. The significant predictors of long PR intervals and incident AF were amiodarone treatment and history of atrial rhythm disorder, respectively.

Funding

The PRECISE study was sponsored by MicroPort CRM (Clamart, France).

Disclosure of interest

All authors. Fees from the company MicroPort CRM.

N. L.: consulting fees from the companies Medtronic, Boston Scientific, Saint-Jude Medical and MicroPort CRM.

S. M.: employee of the company MicroPort CRM.

The other authors have not supplied their declaration of competing interest.


Acknowledgements

We would like to thank the trial participants and investigators who made the study possible; Bérangère Leroy for her support in study management; John Plant, BPharm, and Anne Rousseau-Plasse, PhD, for editorial assistance; and Françoise Tondu for statistical support.

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