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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

(CC)
Jesus Almendral, Fernando Arribas, Christian Wolpert, Renato Ricci, Pedro Adragao, Erik Cobo, Xavier Navarro, Aurelio Quesada
DOI: http://dx.doi.org/10.1093/europace/eun072 528-535 First published online: 7 April 2008

Abstract

Aims This randomized trial evaluated clinically significant adverse events (CSAEs), in patients implanted with dual-chamber (DC) vs. single-chamber (SC) implantable cardioverter defibrillator (ICD). DC-ICD had atrial tachyarrhythmia (AT) therapy capabilities. Strict programming recommendations were reinforced.

Methods and results Patients with conventional SC-ICD indication were randomized to DC-ICD, SC-ICD, or a DC-ICD programmed as an SC-ICD (SC-simulated) and followed for 16 months. Patients in the DC and SC-simulated groups crossed over after 8 months. The primary endpoint was a composite of CSAE: all-cause mortality; invasive intervention; hospitalization (>24 h) for cardiovascular causes; inappropriate shocks (two or more episodes); and sustained symptomatic AT lasting >48 h. The outcome variable was a pre-specified score that corrected for clinical severity and follow-up duration. Three hundred and thirty-four patients were analysed (DC-ICD, n = 112; SC-ICD, n = 111; SC-simulated, n = 111). The mean left ventricular ejection fraction was 0.36 ± 0.13, 69% were in functional class ≥II. CSAE occurred in 65 DC-ICD, 82 SC-ICD, and 84 SC-simulated patients. The outcome variable was 33% lower in the DC-ICD group (OR 0.31; 95% CI 0.14–0.67; P = 0.0028). Mortality was 4% in DC, 9% in SC, and 10% in SC-simulated.

Conclusion In patients with a standard SC-ICD indication, DC-ICD was associated with less CSAE when compared with SC-ICD.

Keywords
  • Defibrillation
  • Tachyarrhythmias
  • Pacing

Introduction

The therapeutic benefits of implantable cardioverter defibrillators (ICDs) have been primarily studied in patients implanted with single-chamber (SC) devices. However, dual-chamber (DC)-ICDs provide atrial pacing, atrioventricular (AV) synchrony, information about the atrial rhythm during tachycardia, and (some DC-ICD) electrical therapy for atrial tachyarrhythmias (ATs). On the other hand, DC-ICDs involve a more complex implant procedure and some of these features could even be harmful.

When the DATAS Trial started its inclusion phase, in year 2000,1 the information regarding DC-ICD was emerging.2 Two additional concerns were: (a) some laboratory findings, available at that time, suggested negative effects of right ventricular (RV) pacing;3 (b) clinical studies had suggested that the ICD electrode could itself be proarrhythmic, at least transiently after implantation,4 raising the concern for some proarrhythmic effect of the atrial electrode.

The DATAS Trial was designed to compare DC-ICD (capable of electrical therapies for AT) and SC-ICD, the outcome being clinically significant adverse events (CSAEs). We hypothesized that both the potential for device-related complications and the potential to reduce or increase spontaneous deleterious effects of the primary disease process would translate into relatively simple and clinically measurable consequences, i.e. CSAE. In order to reduce the potentially negative effects of RV pacing and homogenize the population, strict programming recommendations were made to reduce RV pacing, with the tools available in the ICD at that time. Finally, in order to assess the potential for proarrhythmia (and for a better look at AT in SC devices), a ‘third arm’ of patients with a DC hardware but a SC programming was added to the usual parallel design. The main outcome of the trial is presented here.

Methods

Study design, randomization, and data collection

The design of the trial has been published.1 Briefly, DATAS was a prospective, multicentre, randomized study, with three arms: SC-ICD, DC-ICD, and a DC-ICD system but programmed as SC-ICD (‘SC-simulated arm’) (Figure 1). The DC-ICD and SC-simulated arms crossed over after 8 months (‘programmed crossover’). All other crossovers were considered ‘premature crossovers’ and had to be authorized by an independent Adverse Events Advisory Committee (AEAC). In addition, the AEAC analysed all events (masked as to the patient's group assignments), classified all adverse events, and validated primary endpoints. The study complies with the Declaration of Helsinki. The study protocol was approved by the IRB at each centre, and informed consent of the subjects was obtained. The randomization procedure was centralized through a specifically designed web site. DATAS investigators are listed in the Appendix.

Figure 1

Study design. Flow chart of the three arms of the study.

Follow-up started immediately after randomization. A 1-month wash out period was implemented after programmed crossover.

Primary endpoint and main outcome

The primary endpoint was a composite of five pre-determined CSAE: (i) all-cause mortality, (ii) invasive intervention due to cardiovascular cause, (iii) hospitalization (longer than 24 h) or prolongation of hospitalization due to cardiovascular cause, (iv) inappropriate shocks: two or more episodes with inappropriate shocks, and (v) sustained symptomatic ATs that (a) require urgent termination or (b) lasted more than 48 h leading to therapeutic intervention.

Since this composite endpoint was specifically designed to assess the global impact of clinically relevant events, a CSAE-score was created in order to rank clinical severity. Death was obviously the worst outcome; we assigned a high score to a premature crossover because it represented a basic failure of the assigned therapy. Point assignment was as follows: each CSAE: 1 point; death: maximum number of CSAE points in any individual patient in the entire study plus one; premature crossover: maximum number of CSAE points in any individual patient in that study period. Main outcome was defined as the CSAE-score over length of follow-up, i.e. CSAE-score rate.

Patient eligibility criteria

Patients were eligible for the study if they met a standard Class I indication for an SC-ICD according to the 1998 ACC/AHA guidelines for implantation of cardiac pacemakers and antiarrhythmia devices. After November 2001, patients as those enrolled in the MUSTT study5 were also accepted for inclusion. Every patient eligible for ICD therapy was screened at each centre.

Exclusion criteria were the following: (i) permanent AT; (ii) absence of structural heart disease; (iii) implantation criteria for DC pacing: symptomatic sinus node disease, second degree AV block (except asymptomatic Mobitz I), and complete AV block; (iv) a previously implanted pacemaker or ICD; (v) mechanical right heart valve; (vi) any medical condition that would preclude the testing required by the protocol; (vii) any medical condition that would limit study participation; (viii) the patient is unwilling or unable to cooperate or give written informed consent; (ix) legal guardians (of a minor) refuse to give informed consent; (x) inaccessibility for follow-up at the study centre; (xi) indication for cardiac resynchronization therapy; (xii) enrolment or planning to be enrolled in another clinical trial.

Implantable cardioverter defibrillator devices and programming

All devices were commercially available from Medtronic Inc. (Minneapolis, MN, USA). The DC devices had automatic atrial tiered antitachycardia therapies.

There were strong programming recommendations as previously reported1 and summarized as follows: (i) for all devices, a zone with antitachycardia pacing for cycle length <360 ms; (ii) for SC (or SC-simulated) devices: (a) stability criteria of 50 ms for arrhythmia discrimination; (b) lower pacing rate of ≤50 bpm or less; (iii) for DC devices: (a) arrhythmia discrimination via the ‘PR logic’ function; (b) lower pacing rate of 70 bpm, in the DDD mode; (c) paced AV of ≥230 ms, sensed AV of ≥200 ms, or even longer values to reduce RV pacing; (d) atrial tachycardia detection zone: atrial cycle length ≤320 ms; (e) atrial fibrillation detection: atrial cycle length <150 ms; (f) tiered therapies for AT (antitachycardia pacing, 50 Hz, cardioversion).

Statistical analysis

It should be noted that: (a) the DC group included twice the number of patients since it pooled together patients from the two crossover arms (first period of DC/SC-simulated group and second period of SC-simulated/DC true group) and (b) every patient in the SC group would be followed for a longer period of time (17 months) than patients in DC (8 month); (c) in order to make groups as comparable as possible, a 1-month ‘window’ (absence of adverse events counting) was opened at the 9th month in the SC arm. We accounted for this disparity in follow-up duration by calculating a CSAE-score rate; defined as the CSAE-score value divided by months of follow-up. The intention-to-treat principle was used.

Two statistical analyses were pre-planned before and during the inclusion phase in the absence of any information about allocated group. The protocol, as well as the sample size calculation, was based on the distribution free Mann–Whitney–Wilcoxon statistic. In order to obtain a more standard effect size measure, an additional primary analysis was changed to the odds ratio (OR) of CSAE-score between DC and SC obtained from SAS GENMOD procedure with the length of follow-up as an ‘offset’ variable and making the assumption of a negative binomial distribution in order to allow the over-dispersion introduced by the highest values imputed to deaths. Both statistics would be able to observe a combination of effects both in the reduction of the proportion of patients with tendency to develop a CSAE, as well as in the mean of CSAE over all patients.

Sample size and power for the main analysis

The assumed effect of the DC treatment was a reduction from 30 to 15% in the proportion of patients who develop a CSAE, as well as a 15% reduction in the mean of CSAE (from 6 to 5.1). The estimated sample size1 was 200 (DC true) vs. 100 (SC true) patients followed for 8 months, with a two-sided α = 0.05 and a power of 88.8%. The sample size was set up to 360 patients (120 patients per arm), considering loses in follow-up.

Results

Study population

Patients were enrolled between November 2000 and December 2003. Figure 2 depicts a flow diagram of patients entering the trial with a final number of 334 patients for analysis. Their relevant clinical data are provided in Table 1.

Figure 2

Summary of patient recruitment and follow-up.

View this table:
Table 1

Patient baseline characteristics

CharacteristicDCa (n = 112)SC (n = 111)SC-simulateda (n = 111)
Age in years, mean ± SD66 ± 963 ± 1062 ± 11
Male, n (%)92 (82)100 (90)90 (81)
NYHA functional class ≥2, N/total (%)77/110 (70)77/108 (71)70/109 (64)
Clinical History, n (%)(n = 112)(n = 111)(n = 110)
 Hypertension, n/total (%)54 (48)55/109 (50)64 (58)
 Diabetes, n (%)20 (18)32 (29)28 (25)
 Coronary artery disease, n (%)98 (87)99 (90)88 (80)
 Cardiomyopathy, n/total (%)46 (41)56/110 (51)51 (46)
 Valvular heart disease, n/total (%)11 (10)11/110 (10)19 (17)
Indications for ICD therapy, n (%)
 VF or cardiac arrest31 (28)41 (37)47 (42)
 Sustained VT46 (41)42 (38)37 (33)
 Syncopal VT/syncope with inducible VT/VF19 (17)16 (14)16 (14)
 Primary prevention16 (14)12 (11)11 (10)
Laboratory findings
 LVEF34 ± 1235 ± 1339 ± 14
 Bundle branch block, n (%)24 (21)26 (23)33 (30)
  • DC, dual chamber; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; SC, single chamber; VF, ventricular fibrillation; VT, ventricular tachycardia.

  • aRefers to original randomization assignment arm to which these patients belonged during the first 8-month follow-up study period.

Device implantation and follow-up

Lead- and procedure-related complications are depicted in Table 2. There were no statistically significant differences among groups, with a non-significant trend towards a higher procedure-related complication rate in DC-ICD, even if considering DC and SC-simulated (identical hardware, see fourth column in Table 2) as a single group [14/223 (6.3%) vs. 3/111 (2.7%), P = NS].

View this table:
Table 2

Lead- and procedure-related complications

VariableDC (n = 112)SC (n = 111)SC-simulated (n = 111)DC + SC-simulated (n = 223)
Lead-related complications
 Atrial lead dislodgement (%)1 (0.9)03 (2.7)4 (1.8)
 Atrial lead reposition (%)001 (0.9)1 (0.4)
 Ventricular lead dislodgement and reposition (%)1 (0.9)4 (3.6)3 (2.7)4 (1.8)
 Total (%)2 (1.8)4 (3.6)7 (6.3)9 (4.0)
Procedure-related complications
 Venous access problem (%)1 (0.9)02 (1.8)3 (1.3)
 Pocket infections (%)1 (0.9)1 (0.9)2 (1.8)3 (1.3)
 Pocket haematoma (%)2 (1.8)1 (0.9)1 (0.9)3 (1.3)
 Pneumotorax (%)2 (1.8)02 (1.8)4 (1.8)
 RV perforation (%)01 (0.9)1 (0.9)1 (0.4)
 Total (%)6 (5.4)3 (2.7)8 (7.2)14 (6.3)
  • DC, dual chamber; SC, single chamber; RV, right ventricular.

Of the 334 patients, 12 (3.6%) were lost to follow-up (Figure 2). The mean follow-up duration was 16 months in DC, 15.6 in SC, and 15.5 in SC-simulated.

There were no significant differences among groups in the percentage of patients on each cardioactive medication at hospital discharge, and at 8- or 17-month follow-up, except for digoxin at the 8-month follow-up (12% in DC, 3% in SC-simulated, P = 0.03).

There were 20 premature crossovers during follow-up with only one of those being in the SC-ICD arm (Table 3, Figure 2).

View this table:
Table 3

Follow-up: premature crossover, proportion of ventricular pacing

VariableDC (n = 112)SC (n = 111)SC-simulated (n = 111)
Premature crossoverDC→SCsimSC→DCSCsim→DC
 Due to symptoms119
 Due to venous access300
 Due to atrial lead problems400
 Unclear reason102
 Total9111
Ventricular pacing
 Mean % of paced beats40 ± 353 ± 96 ± 13
 Median no. of % paced beats3001
 P with >40% paced beats (%)42 (43)2 (2)1 (1)
  • DC, dual chamber; SC, single chamber; RV, right ventricular; P, patients.

The percentage of ventricular pacing, obtained from the device counters at each follow-up visit, is shown in Table 3.

Primary endpoint

The absolute number of CSAEs was 65 in the DC group when compared with 82 in the SC and 84 in the SC-simulated groups (Figure 3A). The correspondent CSAE-score is depicted in Figure 3B. The rate of CSAE-score (Figure 3C) was 33% lower in the DC group, a difference that was statistically significant (P = 0.0028; OR 0.31; 95% CI 0.14–0.67). The proportion of patients performing better with DC was also statistically significant (P = 0.030; OR 0.56; 95% CI 0.51–0.62). A secondary sensitivity analysis was performed, including also the 20 patients randomized but not included in the analysis, showing similar results.

Figure 3

Number, score, and rate of score of clinically significant adverse events. CSAE, clinically significant adverse effects. See text for details.

Although the study was not powered to make statistical comparisons for each of the components of the primary endpoint, these are shown in Table 4 and Figure 4. Of note, total mortality was similar in SC (9%) and SC-simulated (10%) groups, but tended to be lower in the DC group (4%).

Figure 4

Odds ratio for each individual clinically significant adverse effect.

View this table:
Table 4

Clinically significant adverse effects: death, invasive interventions, hospitalizations, inappropriate shocks, long-duration AT, each further divided into first and second follow-up periods, and into individual components

VariableDC (n = 112)SC(n = 111)SC-simulated (n = 111)
Death (%)4 (4)10 (9)11 (10)
 1st period/2nd period3/17/38/3
 Arrhythmic031
 Heart failure254
 Other226
Invasive interventions (%)10 (9)11 (10)12 (11)
 1st period/2nd period9/16/59/3
Hospitalizations (%)47 (42)42 (38)51 (46)
 1st period/2nd period31/1631/1142/9
 Arrhythmia related (%)18 (16)18 (16)17 (15)
 1st period/2nd period13/516/212/5
CHF related (%)14 (13)6 (5)19 (16)
 1st period/2nd period8/65/116/3
 Device/procedure related (%)4 (4)3 (3)5 (5)
 Other (%)11 (10)15 (14)10 (9)
Inappropriate shocks (%)3 (3)13 (12)7 (6)
 1st period/2nd period3/013/07/0
Long-duration AT (%)1 (1)6 (5)3 (3)
 1st period/2nd period1/04/23/0
  • AT, atrial tachyarrhythmias; CHF, congestive heart failure; DC, dual chamber; P, patients; SC, single chamber.

Discussion

Main findings

The main finding of this study is that in a setting where the excess hardware-related complications of DC devices are limited and the RV pacing effects are reduced by strict programming, the impact of CSAEs was lower in patients with a DC-ICD than in patients with an SC-ICD device.

Primary outcome

Since efficacy for termination of ventricular tachyarrhythmias is expected to be identical in SC and DC devices, but common sense suggests that DC-ICD may have more complications but also some advantages and risks, we addressed the question of whether adverse events differ in these two types of ICD. Some DC-ICDs are also able to sense and treat AT,6,7 with the ability to potentially improve the clinical status of patients by reducing AT burden, an additional element of the study. Not all adverse events have the same clinical implications, and what finally matters is the likelihood of those that (whether produced or reduced by ICD) are clinically relevant, i.e. resulting in death, an invasive intervention, hospitalization, undesired shocks, or prolonged ATs (what we have considered as CSAE). For these reasons, our study focused on CSAE and a score was developed for further ‘tuning’ by assigning a ‘weight’ to each CSAE.

Several studies have now been published comparing DC and SC-ICD,814 but to the best of our knowledge, this is the first study with a pooled CSAE as the primary endpoint. The results of the primary outcome of the DATAS study are, in this sense, unique, as they show that this outcome variable is better with a DC-ICD than with an SC-ICD device.

Procedure/lead-related complications

The overall incidence of lead- and device-related complications of 9% compares favourably with that of most recent ICD trials of SC- and DC-ICD that provided a detailed report of complications.8,10 Most of the complications resulted in a CSAE, indicating that the parameters selected for our composite CSAE were sensitive enough to pick up procedure- and lead-related complications.

Ventricular pacing

The issue of the negative effects of RV pacing on ventricular function facilitating heart failure has been of increasing interest,15 and this deleterious effect shown to be clinically relevant in DAVID.9 More recently, subanalyses from randomized clinical trials (RCTs) have described the effect of the proportion of paced beats on clinical outcome.1618 In our study, this effect was not so obvious. The number of heart failure-related hospitalizations was higher in DAVID than in DATAS (13.3 and 22.6% in SC and DC, respectively, at 1 year in DAVID, 5 and 8% at 8 months in DATAS). DAVID selected patients with lower left ventricular ejection fraction (LVEF) (mean LVEF 27% in DAVID and 36% in DATAS) and had more ventricular pacing (∼60% in DAVID and 40% in DATAS).

The recent INTRINSIC RV trial showed if ventricular pacing is minimized with an algorithm, DC-ICD is not inferior to SC-ICD.13 Our results, with an intermediate decrease in %RV pacing producing less deleterious effects, could be consistent with these findings.

Inappropriate shocks

The extent to which DC-ICD devices decrease inappropriate therapies has been controversial. Some studies found no benefit of DC devices.8,14 More recently, both in a population with slow VT10 and in a more general population,11 a modest reduction was found. Since frequent ICD shocks are detrimental for patient's well-being, in our clinically focused approach, it was considered that two or more inappropriate shocks (first inappropriate shock could just mean a need for reprogramming, then preventing further inappropriate shocks) represented a significant problem. Our results point in a similar direction as these recent studies: it is infrequent to have two or more inappropriate shocks, but seems to be even more so in patients with DC-ICD.

Atrial tachyarrhythmias

Several reports have substantiated the efficacy of some DC-ICD to detect and terminate AT.6,7 However, since most of these ATs lasted only minutes to hours19 and the symptomatic status was largely ignored (device retrieved arrhythmias), their clinical significance is unclear. In contrast, our study considered AT as part of the primary endpoint only if the episodes were symptomatic and/or long-lasting requiring therapeutic intervention, thus with undisputable clinical significance. As such, they were observed in a minority of patients, but mostly in patients with SC devices.

Total mortality

Two RCTs reported a non-significant trend towards a higher mortality in DC-ICD.9,12 A recent RCT,13 including only patients in whom a DC algorithm minimized ventricular pacing to <20%, reported non-inferiority of DC-ICD with a favourable mortality trend. In DATAS, with a strict but relatively simple programming and no patient exclusion as to the amount of ventricular pacing, mortality trended similarly. Moreover, the mortality of the SC-simulated group (10%) was similar to that of the SC group, showing inherent consistency of our findings. It can be argued that the short follow-up in DATAS (before crossover) minimizes the deleterious effects of RV pacing. However, an increase in mortality was an early effect in DAVID.9

In contrast to the other reported RCT, our study included electrical therapy for AT. ATs in patients with decreased LVEF are associated with an increase in total mortality, and the composite of death or hospitalization.20 AT left untreated could promote ventricular tachyarrhythmias.21 Inappropriate recognition and therapy of AT could even lead to a vicious life-threatening cycle.22

Limitations

The follow-up might have been too short to reveal differences in heart failure-related hospitalizations and related mortality, since by the crossover design of DATAS, each DC patient was not followed for >8 months. However, hospitalizations in the second 8-month period tended to decrease in all arms.

It is possible that recently introduced sophisticated algorithms designed to minimize RV pacing could have further decreased RV pacing.13,23 However, they were introduced after the enrolment of patients in DATAS.

Premature crossovers are a limitation of RCT. Despite the need for AEAC authorization, ∼10% of the patients implanted with a DC-ICD hardware crossed over as opposed to 1% in the SC-ICD. This was likely to have reflected the ease for ‘software crossover’ once the DC hardware is in place (in the DC and SC-simulated arms) when compared with a ‘hardware upgrade’ (in the SC-ICD arm). However, our scoring system severely penalized the premature crossover, thus correcting for this difference.

Clinical implications

The characteristics of our patient population seem to be similar to those of other recently published ICD series in which patients were not selected based on LV function1012 and thus represents an unselected ICD population, with mean LVEF over 0.30. To this extent, DATAS can be considered representative of the daily clinical ICD practice in typical European countries.

In this context, the DATAS study demonstrates a reduction in pooled CSAE with the use of DC-ICD. The study's conclusions could lead to the development of trials to explore if CSAE can be reduced even further with algorithms intended to minimize RV pacing.

Funding

This study was funded in full by Medtronic.

Acknowledgements

This study would not have been possible without Mercedes Ortiz, from Hospital Gregorio Marañon (Madrid, Spain), our study data coordinator.

Author contributions: original idea and launching of the study: Aurelio Quesada. Members of the Steering Committee: Aurelio Quesada, Jesus Almendral, Fernando Arribas, Christian Wolpert, Renato Ricci, Pedro Adragao, Xavier Navarro. Statistical design and analysis: Erik Cobo. Funding to pay the Open Access publication charges for this article was provided by Medtronic.

www.clinicaltrials.gov Identifier: NCT00157820.

Conflict of interest: J.A. has received honoraria from Medtronic, Guidant (now Boston Scientific), Johnson & Johnson and St Jude Medical for lectures, and has served as a consultant for Johnson & Johnson. C.W. has received honoraria from Medtronic and St Jude Medical for lectures. E.C. is a consultant for Ferrer International and Medtronic, and receives teaching grants from Instituto de Formación Novartis. X.N. is an employee of Medtronic. A.Q. is currently conducting research sponsored by Medtronic and has served as a paid consultant for Medtronic and Boston Scientific.

Appendix

DATAS Investigators and study centres:

B. Lüderitz, J. Schwab, T. Lewalter, R. Schimpf, University Hospital, Bonn, Germany; M. Santini, R. Ricci, C. Pignalberi, M. Russo, San Filippo Neri, Rome, Italy; P. Hanrath, Ch. Stellbrink, K. Mischke, R. Koos, University Hospital RWTH, Aachen, Germany; J. Brugada, L. Mont, M. Matas, H. Clinic i Provincial, Barcelona, Spain; J. Gill, R. Simon, A. Rinaldi, N. Gall, St Thomas' Hospital, London, UK; M. Glikson, Sheba Medical Center, Tel-Hashomer, Israel; J. Roda, S. Villalba, V. Palanca, J. Belchi, H. General Universitario, Valencia, Spain; C. Muto, M. Canciello, G. Carreras, B. Tuccillo, Loreto Mare Hospital, Naples, Italy; A. Arenal, E. Gonzalez-Torrecillas, F. Atienza, H. Gregorio Marañon, Madrid, Spain; M. Borggrefe, S. Spehl, 1st Department of Medicine Cardiology, University Hospital Mannheim, Mannheim, Germany; J.L. Merino, R. Peinado, H. La Paz, Madrid, Spain; J.C. Rodriguez, O. Medina, J. García, H. Insular de Gran Canaria, Las Palmas, Spain; F. Morgado, Santa Cruz, Lisbon, Portugal; I. Lozano, J. Toquero, R. Arroyo, H. Puerta de Hierro, Madrid, Spain; J.M. Ormaetxe, M. Arkotxa, H. de Basurto, Bilbao, Spain; G. Steinbeck, E. Hoffman, S. Janko, U. Dorwarth, Ludwig-Maximilian-University Hospital, München, Germany; M. Geist, V. Turkisher, Wolfson Medical Center, Holon, Israel; P. Della Bella, G. Fassini, C. Carbucicchio, F. Giraldi, Centro Cardiologico Monzino, Milano, Italy; P. Golino, M. Viscusi, F. Mascia, Hospedale Civile, Caserta, Italy; L. Tercedor, M. Alvarez, H. Virgen de las Nieves, Granada, Spain; J.G. Martinez, A. Ibañez, H. General Universitario, Alicante, Spain; A. Moya, E. Rodriguez, C. Alonso, H. Valle Hebron, Barcelona, Spain; M. Lopez Gil, J. Sanz, H. 12 Octubre, Madrid, Spain; R. Garcia-Civera, R.Ruiz, S. Morell, R. SanJuan, H. Clinico Universitario, Valencia, Spain; A. García-Alberola, J. Martinez, J.J. Sanchez, H. Virgen de la Arrixaca, Murcia, Spain; M. Manz, D.Burkhardt, A. Markewitz, Krankenhaus Marienhof, Koblenz, Germany; E. Castellanos, L. Rodriguez-Padial, H. Virgen de la Salud, Toledo, Spain; M. Sassara, A. Achilli, E. Scabbia, Civile Hospital, Viterbo, Italy; J. Olagüe, J.E. Pareja, M.J. Sancho-Tello, H. La Fe, Valencia, Spain; S. Hohnloser, G. Grönefeld, Johann Wolfgang Goethe University, Frankfurt, Germany; T Fuchs, Assaf Harofe Medical Center, Tzerifin, Israel; W. Jung, N. Schwick, B. Roggenbuck-Schwilk, Klinikum Villingen-Schwenningen, Villingen, Germany; B. Lemke, T. Lawo, T. Deneke, S. Holt, BG Kliniken Bergmannsheil, Bochum, Germany; G.Baumann, H. Bondke, M. Claus, Campus Charite Mitte, Berlin, Germany; A. Maresta, S. Silvani, D. Cornacchia, E. Tampieri, Civile Hospital, Ravenna, Italy; J.J. Manzano, A. Medina, E. Caballero, F. Wangüemert, H. General Dr Negrín, Las Palmas, Spain.

References

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