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Characteristics of a large sample of candidates for permanent ventricular pacing included in the Biventricular Pacing for Atrio-ventricular Block to Prevent Cardiac Desynchronization Study (BioPace)

Reinhard C. Funck , Hans-Helge Mueller , Maurizio Lunati , Christopher Piorkowski , Luc De Roy , Vince Paul , Michael Wittenberg , David Wuensch , Jean-Jacques Blanc
DOI: http://dx.doi.org/10.1093/europace/eut343 354-362 First published online: 7 November 2013

Abstract

Aims The general clinical profile of European pacemaker recipients who require predominant ventricular pacing (VP) is scarcely known. We examined the demographic and clinical characteristics of the 1808 participants (out of 1833 randomized patients) of the ongoing Biventricular Pacing for Atrio-ventricular Block to Prevent Cardiac Desynchronization (BioPace) study.

Methods and results BioPace recruited patients between May 2003 and September 2007 predominantly in European medical centres. We analysed demographic data and described clinical characteristics and electrophysiological parameters prior to device implantation in 1808 enrolled patients. The mean age ± standard deviation (SD) of the 1808 patients was 73.5 ± 9.2 years, 1235 (68%) were men, 654 (36%) presented without structural heart disease, 547 (30%) had ischemic, 355 (20%) hypertensive, 146 (8%) valvular, and 102 (6%) non-ischemic dilated cardiomyopathy. Mean left ventricular ejection fraction was 55.4 ± 12.3%. The main pacing indications were (a) permanent and intermittent atrioventricular (AV) block in 973 (54%), (b) atrial fibrillation with slow ventricular rate in 313 (17%), and (c) miscellaneous bradyarrhythmias in 522 (29%) patients. Mean QRS duration was 118.5 ± 30.5 ms, left bundle branch block was present in 316 (17%), and atrial tachyarrhythmias in 426 (24%) patients.

Conclusion To the best of our knowledge, this sample is a representative source of description of the general profile of European pacemaker recipients who require predominant VP. Patients' characteristics included advanced age, predominantly male gender, preserved left ventricular systolic function, high-grade AV block, narrow QRS complex, and atrial tachyarrhythmias, the latter being present in nearly one-fourth of the cohort.

  • Bradycardia
  • Atrioventricular block
  • QRS width
  • Left ventricular function
  • Atrial tachyarrhythmias
  • Structural heart disease
  • Permanent ventricular pacing

What's new?

This study is the first to provide comprehensive information on

  • Demographics

  • Structural heart diseases

  • Cardiovascular risk factors and comorbidities

  • Left ventricular ejection fraction

  • QRS width and morphology

  • Prevalence of atrial tachyarrhythmias and history of atrial tachyarrhythmias and

  • Interdependencies of QRS width, ejection fraction and atrial tachyarrhythmias in European pacemaker recipients with need for ventricular pacing.

This kind of information on European pacemaker recipients whose main pacemaker indication is derived from their need for ventricular pacing is lacking until so far. We considered this body of evidence valuable enough to dedicate an own paper to it.

Introduction

During the last decades there have been many technical innovations in the field of cardiac pacing and various pacing modalities have been evaluated in comparative and controlled studies.14 However, precise knowledge of the demographic and clinical characteristics of patients who require ventricular pacing (VP) is lacking. Yet this information has become particularly important in view of the potentially adverse effects of right ventricular pacing (RVP).5,6 We describe baseline characteristics in 1808 almost exclusively European participants in the Biventricular pacing for Atrioventricular Block to Prevent Cardiac Desynchronization (BioPace) trial7 which enrolled patients anticipated to require VP during more than two-third of the time.

Methods

Study design

This analysis is based on patients who have been enrolled in the BioPace study7 between May 2003 and September 2007 according to the practice guidelines.8 The study was approved by the responsible ethics committees, it was conducted according to the Declaration of Helsinki and the patients have given their written informed consent. Rationale, design, and endpoints of the BioPace trial have been described before.7 In brief, BioPace is a controlled, randomized, single blind, parallel group trial which enrolled patients expected to need VP at least two-third of the time. Prior to implantation patients were randomized to RVP or biventricular pacing (BVP) devices. The primary objective of the study is to determine whether synchronous BVP to prevent iatrogenic ventricular desynchronisation confers a clinical benefit in patients with conventional indications for permanent VP, regardless of spontaneous QRS duration and morphology or left ventricular (LV) size and function. The primary endpoint of the study is survival.

In total, 1833 patients who were anticipated to require predominant VP were randomized in 94 medical centres, from 15 predominantly European countries (see Acknowledgement). Twenty-five patients were excluded from this analysis. In 23 patients, signed informed consent was lacking, in one, pre-implant data were not available and in another patient the indication for VP was unknown.

Sample population

All patients had class I indications for implantation of a permanent pacing device,8 they were likely to be predominantly ventricular paced with no previous history of permanent pacing. During the initial phase of the recruitment period, only patients with dilated and dysfunctional left ventricles [LV end diastolic diameter (mm)/body height (m) >30 mm/m and left ventricular ejection fraction (LVEF) (%) < 45%] had been eligible for the study. These criteria were suspended by a protocol amendment in January 2004 after n = 14 patients (7.6‰ of total study population) had been enrolled in Europe. Thereafter, patients could be enrolled without restrictions on LV size, LVEF, QRS width, QRS morphology, structural heart disease, or clinical presentation of bradycardia as long as the inclusion criteria of the study were fulfilled. Once the indication for primary preventive implantable cardioverter defibrillator (ICD) implantation in patients with low LVEF was approved, an additional amendment in July 2005 allowed for implantation of an ICD for pacing, thus providing the access of these patients to the study. At that point, 301 (16.4% of total study population) had been enrolled.

Main objective

We report on demographic, clinical, echocardiographic, and electrophysiological characteristics of a largely unselected and well-defined cohort of almost exclusively European patients with a requirement for predominant VP.

Data collection, monitoring, and management

Data were collected on paper case record forms (CRFs). After having been monitored they were sent to the Centre for Clinical Trials of Marburg (KKS), Germany for data entry and data management including query handling.

The data were stored in a Microsoft SQL Server 2008 database, using the program MACRO, version 3 (InferMed), managed by the KKS.

Demographic, clinical, and electrophysiological data were taken from CRFs. However, QRS complex and LVEF data were lacking in the CRFs of 87 (4.8%) and 168 (9.3%) patients, respectively. In these cases the data were taken from the randomization facsimiles sent to the KKS. Left ventricular ejection fraction data, documented in the CRFs in three apical planes, the four-chamber view (4CV), the apical long axis (apLAX) and the dual-chamber view (2CV), were taken for the present analysis in the priority sequence 4CV > apLAX > 2CV.

Medical history data are derived from patient file analyses and direct patient interviews. Arterial hypertension was considered to be present either if mentioned as such in the patients' medical history or if the blood pressure at baseline was >140/90 mmHg. Not every patient with a history of arterial hypertension was considered to have hypertensive heart disease (HHD) as main underlying cardiac disease. The study centres used to consider HHD to be present if documented as such in the patients' history, usually based on the presence of left ventricular hypertrophy in patients with hypertension.

Statistical analysis

The data were analysed descriptively, using the SAS statistical software package 9.2 (SAS Institute). All analyses were performed using standard procedures in SAS for calculation of frequencies and means as well as descriptive P values like those from Fisher's exact test. Results are expressed as absolute number and proportion (%) and mean ± standard deviation unless specified otherwise.

As not the entire study population was recruited from European countries and patient enrolment was initially restricted to patients with dilated and dysfunctional left ventricles study data were analysed for (A) the entire cohort (n = 1808), (B) for the patients enrolled in European countries (n = 1771) less the 14 patients who were randomized before amendment one of the BioPace study (n = 1757), and (C) for patients who had been enrolled in non-European countries (n = 37) (Table 1).

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Table 1

Baseline characteristics of 1808 patients with ventricular pacing indication

 Mean ± SD or number (%) of observations
AaBaCa
n = 1808n = 1757n = 37
Age (years)73.5 ± 9.273.5 ± 9.273.0 ± 9.9
Men1235 (68.3)1203 (68.5)23 (62.2)
Height (m)1.69 ± 0.091.70 ± 0.091.63 ± 0.08
Weight (kg)78.9 ± 15.179.1 ± 15.170.5 ± 15.6
Body mass index (kg/m2)27.4 ± 4.527.4 ± 4.526.4 ± 5.2
Left ventricular ejection fraction (%)55.4 ± 12.355.5 ± 12.159.6 ± 13.2
Blood pressure (mmHg)
 Systolic140 ± 21140 ± 21138 ± 24
 Diastolic76 ± 1276 ± 1172 ± 16
Underlying non-cardiac diseases
 None1102 (61.0)1066 (60.7)29 (78.4)
 Renal disease270 (14.9)261 (14.9)5 (13.5)
 Chronic obstructive pulmonary disease224 (12.4)222 (12.6)1 (2.7)
 Stroke126 (7.0)122 (6.9)3 (8.1)
 Peripheral artery disease101 (5.6)98 (5.6)0 (0.0)
 Neoplastic diseases92 (5.1)90 (5.1)2 (5.4)
 History of ulcers89 (4.9)87 (5.0)0 (0.0)
 Chronic anaemia48 (2.7)46 (2.6)0 (0.0)
 Hepatic disease28 (1.6)28 (1.6)0 (0.0)
 Other diseases37 (2.1)36 (2.1)1 (2.7)
Underlying non-cardiac diseases per patient
 1494 (27.3)485 (27.6)5 (13.5)
 2165 (9.1)160 (9.1)3 (8.1)
 >247 (2.6)46 (2.6)0 (0.0)
Cardiovascular risk factors
 Hypertension1361 (75.3)1328 (75.6)23 (62.2)
 Smoking (current and past)638 (35.3)618 (35.2)15 (40.5)
 Current smoking133 (7.4)130 (7.4)3 (8.1)
 Past smoking505 (27.9)488 (27.8)12 (32.4)
 Hyperlipidaemia598 (33.1)584 (33.2)7 (18.9)
 Diabetes mellitus505 (27.9)494 (28.1)8 (21.6)
Cardiovascular risk factors per patient
 0197 (10.9)186 (10.6)10 (27.0)
 1618 (34.2)601 (34.2)12 (32.4)
 2583 (32.2)571 (32.5)8 (21.6)
 3322 (17.8)315 (17.9)3 (8.1)
 488 (4.9)84 (4.8)4 (10.8)
  • aA is the entire cohort of n = 1808 patients, B (n = 1757) represents the patients recruited in Europe (n = 1771) less the patients enrolled before amendment 1 of the BioPace study (n = 14) and C is the subgroup recruited outside Europe. Subgroups B and C have been recruited without restrictions with respect to cardiac structure and function in European and non-European centres, respectively.

Results

Patient characteristics

Of 1808 patients enrolled by the 94 participating medical centres, 1771 (98%) were enrolled in 12 European countries, 1757 of them (97.2%) after the first amendment. One Tunisian centre enrolled 23 (1.3%) patients, 7 (0.4%) patients were enrolled in 1 Australian centre, and 7 patients (0.4%) in 2 Canadian medical centres (Appendix). The mean age was 73.5 ± 9.2 years and 1235 (68.3%) were men (Table 1). Nearly half (48%) of patients were between 70 and 79 years of age, 25% were ≥80 years of age, nearly 20% between 60 and 69, and the remainder (7%) were <60 years of age (Tables 1, 5 and 6).

Indications for device implantation

Devices were implanted according to published practice guidelines.8 The minority of patients, n = 157 (8.7%) of the entire cohort, n = 145 (8.3%) of the patients recruited in European centres after the first amendment and n = 7 (18.9%) of the patients recruited in non-European centres had more than one pacemaker indication. According to the expected percentage of VP after device implantation all indications were hierarchically ordered in the sequence presented in Table 2. Patients, scheduled for atrioventricular (AV) node ablation were assessed based on their status before ablation. Of the various pacemaker indications in each patient with more than one indication the one which was expected to contribute most to the patients' ventricular pacing percentage was identified as the ‘leading’ indication.

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Table 2

Indications for device implantationa

 AbBbCb
n = 1808n = 1757n = 37
Indication
1. Fixed 3rd degree AV block with or without atrial fibrillation400 (22.1)379 (21.6)16 (43.2)
Chronic atrial fibrillation/flutter with resting ventricular rate
2. ≤60 b.p.m.218 (12.1)215 (12.2)2 (5.4)
3. ≤75 b.p.m. and need for negative chronotropic therapy95 (5.3)92 (5.2)1 (2.7)
4. Intermittent 3rd degree AV block + 1st degree AV block with PR interval ≥220 ms260 (14.4)252 (14.3)6 (16.2)
5. Type II 2nd degree AV block combined with prolonged PR interval313 (17.3)306 (17.4)6 (16.2)
6. Symptomatic type I 2nd degree AV block combined with prolonged PR interval ≥220 ms108 (6.0)107 (6.1)1 (2.7)
7. PR interval ≥220 ms + prolonged HV interval139 (7.7)136 (7.7)2 (5.4)
8. Sinus node dysfunction + PR interval ≥220 ms223 (12.3)218 (12.4)3 (8.1)
9. Preparation for AV node ablation52 (2.9)52 (3.0)0 (0.0)
  • aNumbers of observations are numbers of ‘leading’ indication since a single patient can have more than one indication for device implantation. Leading indications were prioritized from 1 to 9 according to the expected need for ventricular pacing

  • bFor A, B, and C see text and legend of Table 1, values are numbers (%) of observations.

In more than half of the patients (n = 1081/59.8%) the indication for device implantation was permanent or intermittent AV block (Table 2).

Underlying cardiac and non-cardiac disorders and cardiovascular risk factors

The prevalence of the respective underlying heart diseases and the corresponding mean LVEFs are shown in Table 3. Of note, more than one-third of these mostly elderly patients presented without structural heart disease (Table 3). Ischemic heart disease (IHD, n = 547; 30.3%) with prior myocardial infarction (n = 307; 17%), and HHD (n = 355; 19.6%) were the most prevalent disorders in patients with structural heart disease. Mean LVEF was preserved in most patients, except in patients who presented with non-ischemic dilated cardiomyopathy and in patients with prior myocardial infarction and valvular disease. The majority of patients (n = 1102; 61%) were free from non-cardiac diseases (Table 1).

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Table 3

Prevalence of heart diseasesa and associated left ventricular ejection fraction

 AbBbCb
n = 1808n = 1757n = 37
n (%)Mean LVEF ± SDn (%)Mean LVEF ± SDn (%)Mean LVEF ± SD
None654 (36.2)59.6 ± 9.7635 (36.1)59.5 ± 9.518 (48.7)62.4 ± 14.1
Hypertensive304 (16.8)57.7 ± 9.7298 (17.0)57.7 ± 9.75 (13.5)56.4 ± 6.3
Valvular146 (8.1)58.6 ± 11.2144 (8.2)58.8 ± 10.91 (2.7)66.0
Hypertensive + valvular51 (2.8)56.4 ± 11.049 (2.8)56.3 ± 10.61 (2.7)78.0
Ischaemic240 (13.3)54.9 ± 12.2236 (13.4)54.8 ± 12.34 (10.8)62.3 ± 5.0
 Only124 (6.9)55.2 ± 12.3123 (7.0)55.2 ± 12.31 (2.7)55.0
 +Hypertensive57 (3.2)54.1 ± 12.155 (3.1)53.7 ± 12.12 (5.4)65.5 ± 0.7
 +Valvular42 (2.3)53.8 ± 13.642 (2.4)53.8 ± 13.60 (0.0)
 +Hypertensive + valvular17 (0.9)57.9 ± 8.516 (0.9)57.6 ± 8.31 (2.7)63.0
Ischaemic with prior myocardial infarction307 (17.0)47.9 ± 12.6298 (17.0)48.1 ± 12.63 (8.1)51.7 ± 8.9
 Only183 (10.1)48.2 ± 12.3177 (10.1)48.4 ± 12.33 (8.1)51.7 ± 8.9
 +Hypertensive72 (4.0)49.8 ± 13.070 (4.0)50.1 ± 13.10 (0.0)
 +Valvular36 (2.0)44.1 ± 13.136 (2.1)44.1 ± 13.10 (0.0)
 +Hypertensive + valvular16 (0.9)43.5 ± 10.415 (0.9)44.3 ± 10.20 (0.0)
Dilated cardiomyopathy94 (5.2)39.0 ± 12.387 (5.0)39.0 ± 12.53 (8.1)38.7 ± 11.0
 Only52 (2.9)39.2 ± 12.348 (2.7)38.8 ± 12.52 (5.4)43.0 ± 11.3
 +Hypertensive16 (0.9)39.4 ± 9.314 (0.8)39.7 ± 9.51 (2.7)30.0
 +Valvular16 (0.9)39.3 ± 11.716 (0.9)39.3 ± 11.70 (0.0)
 +Hypertensive + valvular10 (0.6)37.0 ± 18.49 (0.5)38.2 ± 19.10 (0.0)
Hypertrophic cardiomyopathy8 (0.4)63.6 ± 9.16 (0.3)62.0 ± 10.12 (5.4)68.5 ± 0.7
Miscellaneous others4 (0.2)53.8 ± 8.44 (0.2)53.8 ± 8.40 (0.0)
  • aSingle patient may have combination of heart diseases, clinically leading entity in bold.

  • bFor A, B, and C see text and legend of Table 1.

Electrocardiographic observations

Sinus rhythm was present in three quarters of the population, the remainder presented with atrial fibrillation (AF) or flutter (Table 4). The mean spontaneous ventricular rate was 57.9 ± 18.9 beats per minute (b.p.m.) in the entire cohort and 44 ± 13.4 b.p.m. in the 383 patients (21.2%) with complete AV block. The mean spontaneous QRS duration in the entire sample was 118.5 ± 30.5 ms. Among patients with LVEF >50%, the QRS width was 115 ± 29.2 ms compared with 125.7 ± 31.6 ms and 126.7 ± 32.8 ms in patients with LVEF 36–50% and LVEF ≤ 35%, respectively. Right bundle branch block was present in 355 patients (19.6%), left bundle branch block in 260 (14.4%) patients, and the combination of both in 56 (3.1%) patients (Table 4).

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Table 4

Pre-implant 12-lead electrocardiographic and echocardiography observations

 AaBaCa
n = 1808n = 1757n = 37
n (%)Mean ± SDn (%)Mean ± SDn (%)Mean ± SD
Heart rate, b.p.m.1749 (96.7)57.9 ± 18.91699 (96.7)58.0 ± 19.036 (97.3)46.5 ± 10.7
Patients with complete AV-block400 (22.1)379 (21.6)16 (43.2)
 Heart rate during complete AV-block, b.p.m.383 (95.8)44.0 ± 13.4363 (95.8)44.0 ± 13.515 (93.8)40.4 ± 6.0
Rhythm
 Sinus rhythm1355 (74.9)1316 (74.9)32 (86.5)
 Atrial tachyarrhythmias426 (23.6)414 (23.6)5 (13.5)
 Rhythm undetermined27 (1.5)27 (1.5)0 (0.0)
Temporary paced rhythm40 (2.2)39 (2.2)0 (0.0)
QRS duration, ms
 In entire cohort

 In patients with LVEF
1808 (100)118.5 ± 30.51757 (100)118.3 ± 30.537 (100)115.4 ± 30.3
  ≤35%152 (8.4)126.7 ± 32.8144 (8.2)125.4 ± 32.13 (8.1)126.7 ± 30.1
  >35–≤50%418 (23.1)125.7 ± 31.6406 (23.1)125.6 ± 31.94 (10.8)115.0 ± 25.2
  >50%1238 (68.5)115 ± 29.21207 (68.7)115.0 ± 29.230 (81.1)114.3 ± 31.5
 In patients with LBBB316 (17.5)147.9 ± 24.1305 (17.4)147.8 ± 24.17 (18.9)140.0 ± 20.0
LVEF (%)
 In entire cohort1808 (100)55.4 ± 12.31757 (100)55.5 ± 12.137 (100)59.6 ± 13.2
 In patients with QRS
  ≤1201140 (63.1)56.5 ± 11.91110 (63.2)56.5 ± 11.826 (70.2)60.0 ± 14.1
  >120 and ≤150366 (20.2)55.0 ± 12.0355 (20.2)55.2 ± 12.06 (16.2)58.5 ± 7.4
  >150302 (16.7)51.6 ± 13.1292 (16.6)51.8 ± 12.95 (13.5)59.2 ± 15.8
 In patients with LBBB316 (17.5)51.5 ± 12.8305 (17.4)51.5 ± 12.67 (18.9)59.6 ± 13.9
Bundle branch block
 None1092 (60.4)1068 (60.8)19 (51.4)
 Rightb355 (19.6)344 (19.6)7 (18.9)
 Leftb260 (14.4)252 (14.3)4 (10.8)
 Right + leftb56 (3.1)53 (3.0)3 (8.1)
 Other45 (2.5)40 (2.3)4 (10.8)
  • LBBB, left bundle branch block.

  • aFor A, B, and C see text and legend of Table 1.

  • bSometimes additionally in combination with other.

Left ventricular systolic function

Mean LVEF was 55.4 ± 12.3% (Table 1) and 1238 patients (68.5%) had a LVEF>50% (Table 4). Moderate LV systolic dysfunction (LVEF >35–≤50%) was present in approximately one quarter of the sample and less than 10% of the patients had severe LV dysfunction (LVEF ≤ 35%). Left ventricular ejection fraction did not differ significantly in patients with QRS complexes ≤120 ms (56.5 ± 11.9%) compared to those with QRS durations >120 and ≤150 ms (55 ± 12%) while LVEF in patients with QRS widths >150 ms was slightly lower (51.6 ± 13%).

Atrial tachyarrhythmias

Atrial tachyarrhythmias increased with age (P = 0.0153 for trend) and LV dysfunction (P < 0.0001 for trend) but interestingly decreased with QRS duration (P < 0.0001 for trend) (Table 5).

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Table 5

Prevalence of atrial tachyarrhythmias on 12-lead electrocardiograms before device implantation, stratified according to age, left ventricular ejection fraction, and QRS duration

AaBaCa
n = 1808n = 1757n = 37
Atrial tachyarrhythmiasb426 (23.6)414 (23.6)5 (13.5)
Age, years
 <502/36 (5.6)2/36 (5.6)0/3 (0.0)
 50–5914/91 (15.4)14/88 (15.9)1/8 (12.5)
 60–6987/359 (24.2)86/349 (24.6)1/16 (6.3)
 70–79209/872 (24.0)204/848 (24.1)3/10 (30.0)
 ≥80114/450 (25.3)108/436 (24.8)
Left ventricular ejection fraction, %
 ≤3555/152 (36.2)54/144 (37.5)0/3 (0.0)
 36–50116/418 (27.8)111/406 (27.3)0/4 (0.0)
 >50255/1238 (20.6)249/1207 (20.6)5/30 (16.7)
QRS duration, ms
 ≤120324/1140 (28.4)320/1110 (28.8)3/26 (11.5)
 121–15058/366 (15.8)52/355 (14.6)2/6 (33.3)
 >15044/302 (14.6)42/292 (14.4)0/5 (0.0)
  • aFor A, B, and C see text and legend of Table 1, values are numbers of patients with atrial tachyarrhythmias/number of patients in that stratum (%).

  • bAtrial tachyarrhythmias include atrial fibrillation, flutter, and tachycardia.

A prior history of atrial tachyarrhythmias (ATA) before randomization was present in 723 patients (40%), in most cases (32.2%) it was AF. It was associated with advanced age (44% in patients with ≥80 years of age; <60 years vs. ≥60 years, P = 0.0018) and reduced LVEF (55% in patients with LVEF ≤ 35%; LVEF ≤ 35% vs. LVEF 36–50%, P = 0.0369; LVEF 36–50% vs. LVEF > 50%, P = 0.0053). On the basis of QRS duration, a prior history of ATA was present in 45.0, 34.2, and 28.1% of patients whose QRS duration was ≤120 ms, >120 and ≤150 ms, and >150 ms, respectively (QRS ≤ 120 ms vs. QRS 121–150 ms, P = 0.0003; QRS 121–150 ms vs. QRS >150 ms, P = 0.1116).

Discussion

At present we have evidence that BVP is on different levels superior to RVP. Yu et al.9 presented the PACE study which resulted in positive effects on preservation of LV function and prevention of cardiac dilatation. However, patients had received their biventricular devices prior to study randomization so that potential negative effects of the implantation procedure were not analysed. The study also included patients with intact AV conduction who did not have an indication for VP.9 Curtis et al.10 presented the BLOCK-HF study and reported on beneficial effects on a combined clinical and mechanistic endpoint. However, these data are derived from a fairly selected study population who had also received their biventricular devices before randomization. Patients who had unsuccessful implantations (n = 51), patients who died between study enrolment and randomization (n = 16), and patients who were enrolled but not randomized (n = 67) are missing in the final analysis. In total, 227 of 918 (24.7%) enrolled patients were excluded from the randomized part of the study.

We are lacking evidence from a study which included patients with need for VP without any restriction to LVEF. Such a study should use hardware randomization in order not to expose the finally right ventricular paced patients to the extra risk of a biventricular implant procedure. To the best of our knowledge, these criteria are at present only fulfilled by the ongoing BioPace study7 which therefore represents a unique population in the field of pacing. Owing to hardware randomization and by having included predominantly patients with preserved LVEF (Table 4), the BioPace study cohort is quite different from the BLOCK-HF10 study population. There is no comparable historic study population which has been sufficiently characterized from the point of view of how these patients should be paced. The only study which probably included rather similar patients with second or third degree AV block is the UKPACE study.4 Systematic echocardiographic analyses of these patients are, however, lacking as well as detailed electrocardiographic and clinical results (Table 6). Other studies addressed predominantly patients with sick sinus syndrome3 or any kind of bradycardia1,2 and only a few characteristics of these populations are mentioned in the respective publications. We present in detail demographic, clinical, electrocardiographic, and echocardiographic characteristics of the patients included in the BioPace trial. Owing to hardware randomization prior to device implantation, the study design is very close to clinical decision making. Cardiac and extra-cardiac morbidity, especially the various combinations of cardiac diseases including the respective grades of LV dysfunction, the relatedness of QRS width to LVEF and the prevalence of AF with respect to LVEF and QRS width are interesting and important findings. Their presentation would have gone beyond the scope of a final result paper. These findings may have important implications for a more profound understanding of RVP induced cardiac remodelling and maybe the positive effects of BVP in this large and therefore epidemiologically important subgroup of pacemaker recipients who depend on VP.

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Table 6

Summary of main pacing studies

MOST3CTOPP1PASE2UKPACE4,14BioPace7
Year published2002200019982005Ongoing
Sample size2010147440720211808
Age, yearsMedian = 74.0Mean = 73.0Mean = 76.0Mean = 79.9Mean ± SD = 73.5 ± 9.2
Male gender, %52%58%60%57%68%
Indication for pacingSinus node dysfunction, concomitant AV block in 21% of patientsSymptomatic bradycardiaSymptomatic bradycardia2nd or 3rd degree AV blockAll types of bradycardia requiring ventricular pacing
Main study hypothesisDDD superior to VVI pacingPhysiologic superior to VVI pacingDDD superior to VVI(R) pacingDDD superior to VVI(R) pacingBiV superior to RV pacing
Primary study endpointAll-cause mortality or non-fatal strokeStroke or cardiovascular mortalityQuality of lifeAll cause mortalityAll cause mortality
Mean duration of follow-up2.8 years3.0 years2.5 years4.6 yearsOngoing (about 8 years)
Site of studyUSACanadaUSAUKMostly Europe (98% of pts.)
QRS duration, ms96Not specifiedNot specifiedNot specifiedMean ± SD = 118.5 ± 30.5
Left ventricular ejection fractionNot specifiedNormal: 70%

Depressed: 30%:
Normal in 56% of patients (known in 62%)Not specifiedMean ± SD = 55.4 ± 12.3% ≤35%: 8% of pts. >35% and ≤50%: 23% of pts. >50%: 69% of pts
History of myocardial infarction, %26%25%33%14%17%
NYHA functional classI and II: 83% of pts≥III: 39% of ptsI and II: 72% of ptsI: 28% of pts

II: 43% of pts

III: 24% of pts

IV: 2% of pts

Undetermined: 3%
Not specified
History of atrial tachyarrhythmiasAtrial fibrillation: 46%

others: 9%
Intermittent atrial fibrillation: 20%Miscellaneous atrial tachyarrhythmias: 29%Paroxysmal atrial fibrillation: 4%Atrial fibrillation and flutter whether paroxysmal or permanent 40%
Cumulative percentage ventricular pacing78%Not specifiedNot specifiedNot specifiedData pending
Main study findingDDD not superior to VVIPhysiologic not superior to VVI pacingDDD not superior to VVI pacingDDD not superior to VVI(R) pacingResults pending
  • AV, atrioventricular; BiV, biventricular; pts, patients; RV, right ventricular.

In contrast to studies on CRT, which enrolled patients whose mean age is approximately 65 years,11,12 our patient cohort was on average almost one decade older, closely resembling the patients described in the Danish pacemaker registry13 and other major pacing trials14,10,14 including the recently published BLOCK-HF study.10 Unlike large studies designed to study predominantly pacing for sinus node dysfunction1,3 or for miscellaneous bradycardia1,2 our cohort represents patients requiring VP. Furthermore, unlike CRT studies11,12 most of our cohort was either free from structural heart disease or suffered from IHD or HHD and only a minority had non-ischemic cardiomyopathy (Table 1).

Our analysis of the prevalence of concomitant diseases and cardiovascular risk factors yields valuable information pertaining to the disease burden and the cardiovascular risk profile of an important subgroup of today's European pacemaker recipients. It also gives an overview over the extra-cardiac morbidity of these elderly patients. The high prevalence of overt ATA (23.6%) and also the history of ATA in 40% of patients are noteworthy, but not surprising considering the mean age of the sample. Atrial tachyarrhythmias were more prevalent among patients with depressed LVEF, but interestingly not among patients with wide QRS complexes. The higher prevalence of ATA among patients with narrow QRS complexes compared with patients with wide QRS is a surprise and may reflect a high prevalence of diastolic LV dysfunction due to HHD.

The spontaneous QRS duration was normal or near normal (≤120 ms) in most of our patients. There was only a trend towards wider QRS complexes among the minority of patients presenting with moderate or severe LV dysfunction. Left bundle branch block was present in a minority of patients whose LVEF was interestingly quite well preserved.

Table 6 summarizes the main characteristics of the BioPace study cohort and compares it as far as possible with cohorts of other major pacing trials. Patients' mean age is for instance considerably lower in the BioPace than in the UKPACE study4 which included patients otherwise quite similar to the BioPace study. However cardiac function is not specified in the UKPACE study population. The patients included in the MOST,3 CTOPP1, or PASE2 studies are in terms of pacing indication not comparable to the BioPace study population.

Limitations

The cohort we report on is, to the best of our knowledge, at present the largest and best defined population of predominantly ventricular paced patients. We believe that this cohort of pacemaker patients is largely representative of European pacemaker recipients who require predominant VP, although the design of the BioPace study did not comprise a comprehensive epidemiological approach which would have ensured that every eligible patient was enrolled in the study. Owing to the study design and due to the fact that the included patients were to participate in a study minor selection bias with a certain preference for less severely diseased patients cannot be ruled out. The same holds true for those patients with reduced LVEF. During the enrolment period of the cohort, ICD implantation was approved for primary prevention of sudden cardiac death and it took some time to incorporate this in the BioPace study design. This delay may have prevented patients with severely reduced LVEF from being recruited in the study, thus leading to an underrepresentation of this subgroup in the study.

Despite these limitations, we do not expect them to interfere substantially with the general informative value of our description of the main characteristics of European patients who require predominant VP.

Conclusions

We report in detail on a large cohort of mostly European patients who are indicated for a pacemaker and require predominant VP. Most patients were of advanced age, male, and had preserved LV systolic function. Ischemic heart disease and HHD were their most frequent underlying cardiac diseases. Patients presented with a high prevalence of high-grade AV block, a narrow QRS complex, and ATA were frequent. This work is to our best knowledge the only one which provides detailed information on LVEF, QRS duration, prevalence of ATA, and many other parameters in patients who require VP. In terms of pure demographic data, the cohort resembles closely those of other pacing studies.

Supplementary material

A full list of BIOPACE investigators is available as supplementary material at Europace online.

Conflict of interest: R.F. is a member of the steering committee of the BioPace study, speakers and consultant fees: St. Jude Medical, Medtronic; speaker fees: Medtronic, MSD, Servier, St. Jude Medical; support for travel to meetings for study. H.-H.M. is charged by KKS Marburg for statistical support for the BioPace study, funded by St. Jude Medical. M.L. is a member of the steering committee of the BioPace study, research grants, speaker and consultant fees: St. Jude Medical, Medtronic, Sorin; speaker fees: Boehringer, Sanofi. Christopher Piorkowski is consulting fees: SJM, Biotronik, Siemens; lecture honoraria: SJM, Biotronik, Siemens, Biosense, Sanofi, Pfizer; research support: SJM, Biotronik, Siemens, Imricor. L.d.R. is a member of the steering committee of the BioPace study, no further disclosures. V.P. is a member of the steering committee of the BioPace study, proctor payments, speaker bureau: St. Jude Medical; training consultancy, speaker bureau, advisory board: Medtronic. M.W. is an employee of the KKS Marburg; K.K.S. is funded by St. Jude Medical for data and project management and statistical support for the BioPace study. D.W. is a study manager: no further disclosures. J.-J.B. is a member of the steering committee of the BioPace study, speaker and consultant fees: St. Jude Medical.

Funding

The BioPace study is supported by St Jude Medical International Inc.

ClinicalTrials.gov Identifier: NCT00187278.

References

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