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Original research
Efficacy and safety of novel left ventricular pacing leads: 1-year analysis of the NAVIGATOR trial
  1. Juan Gabriel Martinez1,
  2. Joao De Sousa2,
  3. Antoine Dompnier3,
  4. Mario Martins -Oliveira4,
  5. Carsten W Israel5,
  6. Elvis Teijeira6,
  7. José Manuel Rubin7,
  8. Frederic Sebag8,
  9. Maria Martino9,
  10. Yann Michel9 and
  11. Pedro Marques2
  1. 1Hospital General Universitario Dr.Balmis. Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain
  2. 2Hospital de Santa Maria, Lisboa, Portugal
  3. 3Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France
  4. 4Hospital Santa Marta, Lisboa, Portugal
  5. 5Bethel-Clinic, Bielefeld, Germany
  6. 6Hospital Alvaro Cunqueiro, Vigo, Spain
  7. 7Hospital Universitario Central de Asturias, Oviedo, Spain
  8. 8Institut Mutualiste Montsouris, Paris, France
  9. 9Microport CRM, Clamart, Île-de-France, France
  1. Correspondence to Dr Juan Gabriel Martinez; martinez_juagab{at}


Objectives Assess safety and performance of novel quadripolar preshaped left ventricular (LV) leads: NAVIGO 4LV 2D (‘S shaped’) and NAVIGO 4LV ARC (‘U shaped’).

Methods Patients indicated for cardiac resynchronisation therapy were enrolled in a multicentre, prospective, controlled study (NAVIGATOR, NCT03279484). Patients were implanted with either a NAVIGO 4LV 2D or ARC lead, and assessed at 10 weeks, 6, 12 and 24 months post-implant. Co-primary safety and performance endpoints were assessed at 10 weeks. Safety endpoint was the patients’ rate free from lead-related complications. Performance endpoint was the rate of patients with successful lead performance, defined as LV pacing threshold ≤2.5 V at 0.5 ms on at least one pacing vector, and the absence of phrenic nerve stimulation at the final programmed configuration. Lead-related complications and electrical parameters were monitored throughout study.

Results A NAVIGO 4LV lead was successfully implanted in 211 out of 217 patients (97.2%). The safety endpoint was met, with 100% and 96.1% of patients free from complications for NAVIGO 4LV 2D and ARC, respectively. The performance endpoint was met with 98.1% and 98.9% of patients with a successful lead performance for NAVIGO 4LV 2D and ARC, respectively. Over 12 months, the global complication-free rate for both leads was 97.1% (95% CI: 93.71% to 98.70%), with a mean pacing capture threshold of 1.23 V±0.73 V and a mean impedance of 951 Ω±300.1 Ω.

Conclusion A high implantation success rate and low complication rate was reported for the novel NAVIGO 4LV 2D and ARC leads, along with successful performance up to 12 months.

  • cardiac resynchronization therapy
  • LV lead
  • complication
  • safety

Data availability statement

No data are available.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

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  • Existing knowledge suggests that quadripolar left ventricular leads have improved the effectiveness of cardiac resynchronisation therapy (CRT) by providing more pacing options and potentially reducing complications compared with traditional bipolar leads.

  • Previous research indicates that lead-related complications and lead performance, such as pacing thresholds and phrenic nerve stimulation, are critical factors in the success of CRT, with various lead designs and technologies being explored to enhance patient outcomes


  • The study introduces novel quadripolar preshaped left ventricular leads, NAVIGO 4LV 2D and NAVIGO 4LV ARC and demonstrates a high implantation success rate along with low complication rates.

  • These leads exhibit successful performance up to 12 months, with a mean pacing capture threshold of 1.23 V±0.73 V and a mean impedance of 951 Ω±300.1 Ω.


  • The findings suggest that NAVIGO 4LV 2D and ARC leads could be a safe and effective option for patients indicated for cardiac resynchronisation therapy, potentially improving patient outcomes in the management of heart conditions


Implantable electronic cardiac devices have become a vital part of heart failure physicians’ therapeutic toolkit. Cardiac resynchronisation therapy (CRT) is a life-saving therapy with the highest recommendations in European Society of Cardiology (ESC) and American College of Cardiology (ACC)/Amerian Heart Association (AHA)/Heart Rhythm Society (HRS) guidelines.1 2 CRT improves symptoms and reduces mortality and hospitalisations in a specific subgroup of patients with heart failure and left ventricular (LV) systolic dysfunction, and intraventricular conduction delays, such as left bundle-branch block.3–6

Heart failure patients have highly varying cardiac venous system anatomies and resynchronising needs.7 The benefits of CRT vary between individual patients, with around 30% of patients not reporting any improvement in symptoms or cardiac function after implant.3 8 It is recognised that CRT may still provide benefits despite clinical deterioration.9–11 Some device settings driven by sensors may contribute to haemodynamic improvement,12 although it has never been confirmed in big controlled studies. In addition, it is generally thought that an adapted LV lead positioning could contribute to improved outcomes even if absence of strong evidences have been published.13 In recent years, quadripolar leads have become a preferred option in order to face three challenges encountered with CRT: allowing an easier compromise between lead stability and acceptable threshold, offering more possibilities to avoid phrenic nerve stimulation (PNS) and potential improved haemodynamic response by careful electrode selection.14 15 Indeed, quadripolar leads may increase the chance of successful capture and allow for reprogramming to an alternate pacing vector in case of microdislodgement resulting in fewer surgical re-interventions.14–17

Availability of different lead models provides higher flexibility to choose a lead model adapted to the patient’s anatomy. In this paper, we report on the safety and performance of new quadripolar coronary venous leads, NAVIGO 4LV, designed for multipoint stimulation in CRT devices, equipped with four electrodes and allowing choice of 14 programmable pacing vectors.


The NAVIGATOR pivotal clinical study (NCT03279484) is an open-label, interventional prospective, multicentre, parallel-arm trial designed to evaluate the safety and electrical performance of NAVIGO 4LV leads up to 24 months. This analysis reports data for NAVIGO 4LV 2D and NAVIGO 4LV ARC models over a time period of 12 months.

Study population

Patients were included if they presented with an indication for Cardiac Resynchronization Therapy Defibrillator (CRT-D), either de novo or upgraded from an existing implantable cardioverter-defibrillator, as detailed in ESC guidelines.18 19 Patients received a PLATINIUM 4LV CRT-D device (MicroPort CRM S.r.l Saluggia, Italy) connected to a NAVIGO 4LV 2D or NAVIGO 4LV ARC lead, as deemed appropriate by the investigator.

Patients were excluded if they presented with contraindications for the lead-eluting steroid dexamethasone sodium phosphate (DSP) or with venous anomalies precluding a transvenous lead implant, in case of active myocarditis, pocket and/or lead infection or stroke/myocardial infarction 1-month prior to implant. All patients provided written, informed consent.

The trial was conducted in compliance with the International Conference on Harmonisation and the Declaration of Helsinki, and approved by the local institutional review board or medical ethics committee at each centre. Applicable regulatory and ethical approval were obtained.

Study design

Patients were enrolled in the study if a NAVIGO 4LV lead implantation was attempted.

Patients successfully implanted were followed-up at predischarge, 10 weeks, 6 months and 12 months after implant. During week 10 visit, the electrical performance and PNS were assessed for all 14 pacing vectors.

All serious adverse events, complications and device deficiencies were assessed at all study visits. A complication was defined as any investigational device deficiency or any serious adverse device event (SADE) that resulted in patient death or required a reintervention (excluding reprogramming).

Study leads

The NAVIGO 4LV leads (figure 1) are steroid eluting leads, equipped with an IS4 connector, as per international standards (ISO 27186:2010). The leads provide stimulation capability from four electrodes: a distal tip electrode (LVtip1) and three ring electrodes (LV2, LV3, LV4). The interelectrode distances are, respectively, 19 mm, 13 mm and 20 mm for LVtip1-LV2, LV2-LV3 and LV3-LV4, and pacing surfaces are 2.2 mm² for LVtip1 and 7.5 mm² for LV2, LV3 and LV4. They can be programmed in 14 pacing vectors (figure 1) using the Orchestra/Orchestra Plus programmer (MicroPort CRM S.r.l Saluggia, Italy).

Figure 1

NAVIGO 4LV 2D and ARC lead design, and choice of choice of 14 LV pacing vectors. The leads are available as ‘S shaped’ (NAVIGO 4LV 2D) and ‘U shaped’ (NAVIGO 4LV ARC) models for optimised suitability to various venous anatomies and their sizes (figure 1). All models are available in 78 cm and 88 cm versions. LV: left ventricular, CRT-D: Cardiac Resynchronization Therapy Defibrillator.

Study endpoints

The NAVIGATOR trial included two co-primary endpoints, assessed after implant, independently for each NAVIGO 4LV lead. The safety co-primary endpoint was the rate of patients free from LV lead-related complications, defined as any device deficiency or any SADE resulting in patient death or reintervention within 70 days (10 weeks) after successful implant of the CRT-D system. The efficacy co-primary endpoint was the rate of patients with successful LV lead performance defined as LV pacing threshold ≤2.5 V at 0.5 ms observed at 10 weeks on at least one pacing vector and the absence of PNS at the final programmed configuration.

Secondary endpoints included implant success rate and operator experience of lead handling during implant (lead manoeuvrability, advancement through the guiding catheter and ability to make progress into the targeted coronary sinus veins), incidence of patients with at least 2 pacing vectors with pacing threshold ≤2.5 V and no PNS at 10 weeks follow-up (all 14 pacing vectors were tested for each patient at week 10 visit), lead electrical performance (including LV pacing threshold and LV pacing impedance) up to 12 months and LV lead-related complications up to 12 months. All safety events leading to deaths and with a potential relationship with NAVIGO 4LV leads were reviewed and assessed by an independent adjudicator.

Statistical methods

Sample sizes were calculated on the basis of 90% power to reject the respective primary endpoints. For the safety co-primary endpoint, an expected event rate of 96% of patients free from lead-related complications at 10 weeks was assumed14; for the efficacy co-primary endpoint, 95.3% of patients were assumed to have LV pacing threshold ≤2.5 V at 0.5 ms without PNS at 10 weeks.15 Assuming a drop-out rate of 7%, 108 patients were targeted for enrolment in each lead group.

The safety goal performance was defined as ≥85% of patients free from lead-related complications at 10 weeks post-implant (safety co-primary endpoint). The device performance goal performance was defined as ≥80% of patients with pacing threshold lower than 2.5 V at 0.5 ms and no PNS at the final programmed configuration, in at least one pacing vector at 10 weeks (efficacy co-primary endpoint). The co-primary safety endpoint outcomes were evaluated in the intention-to-treat (ITT) population (all enrolled patients successfully implanted with a NAVIGO 4LV lead), who did not discontinue from the study before 10 weeks post-implant (Full Analysis Set(FAS)-safety population), using the one-sided exact binomial test. The co-primary efficacy endpoint was evaluated in the ITT population of patients with an LV pacing threshold measurement available for at least one vector at 10 weeks (FAS-performance population), using the one-sided exact binomial test. Both safety and performance co-primary endpoints were tested at a 0.025 one-sided level of significance.

Demographics and secondary outcomes were analysed using descriptive statistics at all-time points: for continuous parameters, means and SD; for categorical variables, number and percentages; for time-to-event variables, Kaplan-Meier estimates including 95% CI. Subjects who were free from events at the time of statistical analysis were censored at the last date at which they were known to be free of events.

The results were analysed and are presented for each lead model separately.


Patient population

The study enrolled 218 patients at 38 European Investigational sites between November 2017 and February 2019, among whom 211 were successfully implanted (ITT population). The study flow chart is shown in figure 2. Among the 218 enrolled patients, the coronary sinus could not be cannulated in 1 patient, in whom CRT implantation was suspended. The implant was successful in 211 out of the remaining 217 patients (97.2%). Six patients could not be implanted with a NAVIGO 4LV lead (four patients were implanted with another endovenous IS-1 LV lead and two patients required an epicardial implantation). The average duration of follow-up (with a 12-month follow-up cut-off date for each patient) was 11.4±2.3 months.

Figure 2

Study flow chart. LV: left ventricular; FAS: Full Analysis Set.

The population baseline characteristics criteria are shown in table 1. There were no significant differences among patients receiving NAVIGO 4LV 2D and NAVIGO LV ARC models. The mean age of patients enrolled in the study was 68.2±9.0 years and 80.6% were men. The mean LV ejection fraction was 28.1%±7.2%, 51.5%/44.6%/3.9% of patients presented with New York Heart Association class I–II/III/IV. 37.2% had ischaemic cardiomyopathy. At the time of device implantation, 133 patients (63.0%) had hypertension, 72 patients (10.8%) had diabetes and 43 patients (20.4%) had renal insufficiency. Table 1 describes all the cardiovascular medication taken by patients.

Table 1

Baseline criteria (ITT population)

Lead handling and placement

The overall handling was rated as ‘good’ in 86.9% and 85.4% of cases; and ‘acceptable’ in 12.1% and 14.6% of cases for NAVIGO 4LV 2D and NAVIGO 4LV ARC, respectively. There was no particular difference in the handling experience of the two lead models. Lead’s manoeuvrability, advancement through the guiding catheter and ability to make progress into the targeted veins were rated, respectively, as ‘good’ in 84.1%, 88.9% and 83.3%, and ‘acceptable’ in 15%, 11.1% and 16.7% for NAVIGO 4LV 2D leads. For NAVIGO 4LV ARC, these three criteria were rated as ‘good’ in 80.2%, 91.3% and 84.4%, and ‘acceptable’ in 17.8%, 7.8% and 11.7%, respectively.

The leads were placed predominantly in the lateral position (53.1%). The other lead positions were posterolateral (31.3%), anterolateral (11.8%), posterior (2.8%) and anterior (0.5%). The right ventricle leads were placed predominantly in the apex (50% of NAVIGO 4LV 2D group, and 60.2% of NAVIGO 4LV ARC group) with a septal position being the second most common (39% of NAVIGO 4LV 2D group, and 34% of NAVIGO 4LV ARC group).

Lead’s placement time (from introduction to final location) was 14.4±17.3 min for NAVIGO 4LV 2D and 13.8±17.6 min for NAVIGO 4LV ARC (p=0.8020). The mean total procedure time (from guide catheter insertion to peel-away) was 35.9±28.7 min.

Lead performance at 10 weeks (co-primary performance endpoint)

The primary lead performance objective was met in 102/104 patients (98.1%) in the NAVIGO 4LV 2D group (p<0.0001) and in 94/95 patients (98.9%) in the NAVIGO 4LV ARC group (p<0.0001).

Overall, patients’ percentage with at least one successful LV pacing vector (defined as LV pacing threshold amplitude ≤2.5 V and no PNS at the final programmed configuration) was 98.5%. The percentages of patients with at least two, four and eight successful LV pacing vectors for NAVIGO 4LV 2D leads were 95.2%, 85.6% and 54.8%, respectively. The percentages of patients with at least two, four and eight successful LV pacing vectors for NAVIGO 4LV ARC leads were 94.7%, 89.5% and 58.9%, respectively.

The mean pacing thresholds ranged from 0.85 V to 3.08 V (NAVIGO 4LV ARC) and from 0.99 V to 3.30 V (NAVIGO 4LV 2D), for the 14 configurations, with an amplitude >3 V recorded in only 2 and 3 configurations, for NAVIGO 4LV ARC and NAVIGO 4LV 2D, respectively (mainly LV3 and LV4). The highest thresholds were observed for LV3 and LV4 vectors (figure 3).

Figure 3

Phrenic nerve stimulation test and mean pacing threshold per vector at 10 weeks visit. LV, left ventricular; PNS, phrenic nerve stimulation.

The presence of PNS was systematically tested and reported for each pacing vector of the 14 configurations (figure 3). PNS was predominantly observed with LVtip1 and LV2 as cathodes, and with pacing vectors programmed between the cathode and the can.

The average capture thresholds (at 0.5 ms) at the final programmed vector were 1.15±0.64 V and 1.11±0.56 V with the NAVIGO 4LV 2D and the NAVIGO 4LV ARC lead, respectively. The mean impedance of NAVIGO 4LV 2D and NAVIGO 4LV ARC were 917±379 Ω and 927±296 Ω, respectively.

Lead performance up to 12 months

At the 6-month visit, 165 of 166 evaluable patients (98.4%) in the overall cohort had a pacing capture threshold ≤2.5 V at 0.5 ms and no PNS at the final LV configuration programmed. At 12 months, 138 of 146 evaluable patients (94.5%) met these criteria. At the final LV configuration programmed, the mean pacing threshold was 1.120±0.52 V and 1.235±0.73 V at 0.5 ms, and the mean impedance was 957±338 Ω and 952±300 Ω, at 6 and 12 months, respectively. At M12, the final programmed pacing vector configurations were the following: 25.9% with LVtip1-LV2, 16.7% with LV3-RVcoil, 13.0% with LV3-LV4, 8.3% with LV2-RVcoil and 8.3% with LV4-RVcoil for NAVIGO 4LV 2D leads. For NAVIGO 4LV ARC leads, the main final configurations programmed were: LVtip1-LV2 (49.5%), LV2-RVcoil (13.6%), LV3-LV2 (5.8%) and LV4-RVcoil (5.8%).

The electrical performances over time, per lead model and combined, are detailed in table 2.

Table 2

Electrical performance over time of NAVIGO 4LV 2D and NAVIGO 4LV ARC leads

Lead safety at 10 weeks (co-primary safety endpoint)

In both groups, the co-primary safety endpoint was met at 10 weeks post implant. All 108/108 patients (100%) implanted with NAVIGO 4LV 2D (p<0.0001) and 97/101 patients (96.1%) implanted with NAVIGO 4LV ARC (p=0.0004) were free from any complication related to the NAVIGO 4LV leads. The four complications reported in the NAVIGO 4LV ARC group included two cases of lead dislodgement that required reintervention, one case of PNS that delayed discharge from hospital and was solved by reprogramming of the pacing vector. There was one case of acute pulmonary oedema resulting in death 22 days after implant, classified by the adjudicator in a conservative approach as probably related to the NAVIGO lead since there was no data demonstrating successful delivery of CRT therapy at the time of the event.

Lead safety up to 12 months

Up to 12 months, there were six complications and the overall complication-free rate for NAVIGO 4LV 2D and NAVIGO 4LV ARC leads was 97.1% (95% CI: 93.71% to 98.70%). No unanticipated adverse event was reported. Between 10 weeks and 12 months there were two additional lead dislodgements in the NAVIGO 4LV ARC group, one requiring repositioning and one leading to explantation and replacement by a lead from a different manufacturer.

The overall occurrence of PNS was 6.6% (15 events occurred in 14 patients); 14 events (93.8%) were resolved by reprogramming, without reintervention or patient hospitalisation, 10 by reprogramming of the pacing vector and 4 by reprogramming of the LV pacing output. One event of PNS (6.2%) resulted in hospitalisation and was solved by device reprogramming.


Findings of this study show that the novel NAVIGO 4LV 2D and NAVIGO 4LV ARC leads perform favourably in terms of implant success and in the range (94.9%–100%) published in literature so far.20 21 The co-primary safety and performance endpoints were both met.

The safety data over 12 months show that NAVIGO 4LV leads perform at similar safety levels as other quadripolar leads on the market.14 15 Rates of lead dislodgement (1.9%) and lead-related adverse events (2.8%) were both low, compared with the 3.2% of mechanical complications rate indicated in ESC guidelines on cardiac pacing and CRT.22 However, the safety numbers need to be considered in the perspective of the projected >10 years longevity of a modern CRT device.23

The leads achieved excellent electrical performance up to 12 months follow-up. Indeed, mean pacing threshold of NAVIGO 4LV 2D and NAVIGO 4LV ARC up to 12 months follow-up was 1.23±0.73 V, and are comparable to other quadripolar leads with a published range of 0.5 V–1.3 V.21 24 Impedance mean values up to 12 months were 951±300 Ω for NAVIGO 4LV 2D and NAVIGO 4LV ARC, and higher than values published in literature (between 353±80 Ω17 and 850±31 Ω).25 Pacing impedance remained stable following the implantation phase, comparably to the Attain Performa 4798 quadripolar LV lead (Medtronic, Dublin, Ireland).26 27 These higher and stable impedances, associated with comparable and stable thresholds, can lead to a reduced current drain, potentially enhancing device longevity.

Implanting physicians reported positive experiences with manoeuvrability, lead advancement and lead progress into the veins, with comparable implant times to similar LV leads.15 Pacing thresholds were low with all configurations though higher values could be observed for LV3 and LV4 pacing vectors configurations. Results indicate that NAVIGO 4LV leads will help physicians providing CRT delivery in individual patients at low pacing thresholds, which do not drain device batteries unnecessarily and with a low risk of PNS.

Quadripolar leads have become widely used to deliver LV pacing in CRT devices. By providing a wide range of configurations, these leads can adapt to varying anatomies of the coronary sinus veins, increase the chance of successful capture and reduce the risk of PNS.14–17

Improving the LV lead implant success rate has been a challenge for physicians since the introduction of the therapy two decades ago. Quadripolar leads provide versatility in terms of pacing configuration. Multipoint pacing can help avoid scarred myocardial regions and, therefore, allow effective LV stimulation.28 Some authors suggest that acute haemodynamic dP/dt (max) response between the best and worst pacing configurations with multipolar leads may vary up to 10%.29 This might contribute to a global better response, although recently the MORE-CRT MPP trial did not retrieve any significant difference or improvement of multipoint pacing versus BiV pacing, which may be due to a delay in the clinical response, thus not observed during the time of the study.30

Achieving low pacing thresholds reduces the likelihood of PNS and increases device longevity.15 The average thresholds for the 14 different configurations were <3 V for both models, which is similar to what has been reported for other recent quadripolar leads, generally showing lower thresholds than those of older generations.15 17 31 32 One reason for this may be the DSP eluted of the NAVIGO 4LV leads. Steroid elution has long been used to improve the stimulation threshold in traditional pacing leads33 and it may improve the performance of all poles in multipolar LV leads.15 33 Another benefit may come from the lead shape of the NAVIGO 4LV leads designed for an increased electrode-tissue contact force.

Availability of additional pacing vectors in quadripolar leads may also contribute to lower rates of PNS compared with standard bipolar leads, in both short-term and long-term. The low PNS rates observed with NAVIGO 4LV leads in this study compare favourably with bipolar leads, which have been reported to cause PNS in up to 20% of patients.34 In the present study, the rates of PNS obtained also compare well with what has been reported for other quadripolar leads in the literature,14 15 17 35–38 with no additional safety concerns emerging for any of the NAVIGO 4LV leads.

Over the past few decades, advancements of CRT-D technology have been successful in reducing implant complications, such as PNS, LV lead dislodgements, resulting in improved clinical outcomes for CRT-D patients. This is of particular interest in patients’ populations presenting severe comorbidities such as diabetes, for whom, according to Sardu et al, the use of a multipolar LV lead versus bipolar LV lead may reduce arrhythmic burden, hospitalisation rate, PNS, LV catheters dislodgements and reinterventions.24 It should be noted that, in the current study, 34.1% of patients had diabetes.


The choice of lead model for each patient may have introduced a selection bias. However, in a randomised study design would not have been possible to evaluate the performance and safety of the NAVIGO 4LV leads, as leads are chosen according to the veins morphology and not random by the implanter. Study population is small (218 patients) with patients receiving two lead shapes. It may therefore be underpowered to detect meaningful differences between the two lead shapes. Obviously, this 1-year efficiency and safety lead study does not address long-term safety and performance. These data are needed to confirm these initial findings. 34.1% of patients implanted with a NAVIGO 2D or a NAVIGO ARC LV lead have diabetes, and their medication, that could potentially positively affect clinical outcomes, has not been reported. Finally, effects of CRT therapy on clinical outcomes of patients have not been assessed.


The new NAVIGO 4L 2D and NAVIGO ARC leads have successfully demonstrated their electrical performances and can be used safely. Longer-term follow-up remains awaited to confirm these data.

Data availability statement

No data are available.

Ethics statements

Patient consent for publication

Ethics approval

The study complies with the Declaration of Helsinki. Participants gave informed consent to participate in the study before taking part. Moreover, this study involves human participants and was approved by ethical committees as follows: Ethik-Kommission bei der Medizinischen Fakultät der Universität Würzburg. Ethik-Kommission des Landes Berlin, Landesamt für Gesundheit und Soziales Berlin, Turmstr. 21, 10559 Berlin. Ethik-Kommission der Christian-Albrechts-Universität Kiel, Arnold-Heller-Str. 3, Haus U 27, 24105 Kiel. Ethikkommission der Medizinischen Fakultät der Ruhr-Universität Bochum, Georgstr. 11, 32545 Bad Oeynhausen. Ethik-Kommission der Ärztekammer Hamburg, Weidestr. 122b, 22083 Hamburg. Ethik-Kommission der Ärztekammer Westfalen-Lippe und der Westfälischen Wilhelms-Universität Münster, Gartenstraße 210 - 214, 48147. Ethikkommission der Fakultät für Medizin der Technischen Universität München Ismaninger Str. 22 81675 München. Ethik-Kommission der MHH, -OE9515-, Carl-Neuberg-Str. 1, 30625 Hannover. Ethik-Kommission - Universitätsklinikum Freiburg, Engelberger Straße 21, 79106 Freiburg. Ethikkommission der Landesärztekammer Hessen, Im Vogelsgesang 3, 60488 Frankfurt. Comité de Ética de la Investigación con Medicamentos (CEIm) CEIm del Hospital Universitario y Politécnico La Fe Avenida Fernando Abril Martorell, 106 Torre A 7ª planta. 46026. ValenciaComité de Ética de la Investigación con Medicamentos (CEIm) CEIm del Hospital Universitario de Alicante / Pintor Baeza, número 12, Planta 5ª Centro de Diagnósticos (Edf Gris) 03010 – Alicante.COMITE DE PROTECTION DES PERSONNES NORD-OUEST Hôpital Charles Nicolle – Cour d’Honneur – Porte 71, rue de Germont – 76031 ROUEN cedex. Comitato Etico Regioanle per la Spermentazione Clonica della Regione Toscana.Stabilimento di Santa Chiara - Via Roma 67 Pisa.Comitato Etico Regionale delle Marche C/O Azienda Ospedaliera Universitaria Ospedale Riuniti - Via Conca 71 Torsette di Ancona. Regione Autonoma Friuli Venezia Giulia EGAS. Comitato Etico Regionale Via Franco Gallini 2 Aviano (PN). Medisch Ethische Toetsingscommissie (METC) Isala Gebouw M (Mondriaan), kamer 0.25 Dokter van Deenweg 1-11 8025 BP Zwolle. CEIC Comissão de Ética para a Investigação Clínica . Parqué de Saude Lisboa - Av do Brasil, 53 Pav 17A - 1749-004 Lisboa.


The authors would like to thank: the member, Dr Giosuè Mascioli (CEC member, Hospital of Desenzano del Garda), and Pelle Stolt, PhD, and Anne Rousseau-Plasse, PhD, Serge Cazeau, MD, and Ghizlaine Siraoui, PharmD, MSc, for their editorial assistance.



  • Contributors All authors reviewed this work and agreed to publication. Juan Gabrial Martinez is acting as guarantor.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests ET: Honoraria from MicroPort CRM. CI: MicroPort CRM Honoraria for presentations, reimbursement for travel/congress costs, participation in this sponsored research activity. MO: MicroPort CRM Honoraria for presentations.

  • Provenance and peer review Not commissioned; externally peer reviewed.