# Assessment of cardiac resynchronisation therapy in patients with wide QRS and non-specific intraventricular conduction delay: rationale and design of the multicentre randomised NICD-CRT study

Romain Eschalier Eschalier, Sylvain Ploux, Bruno Pereira, Nicolas Clementy, Antoine da Costa, Pascal Defaye, Stéphane Garrigue, Jean-Baptiste Gourraud, Daniel Gras, Benoît Guy-Moyat, et al.

► To cite this version:

Romain Eschalier Eschalier, Sylvain Ploux, Bruno Pereira, Nicolas Clementy, Antoine da Costa, et al. Assessment of cardiac resynchronisation therapy in patients with wide QRS and non-specific intraventricular conduction delay: rationale and design of the multicentre randomised NICD-CRT study. BMJ Open, 2016, 6 (11), pp.e012383. 10.1136/bmjopen-2016-012383. hal-01464278

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# BMJ Open Assessment of cardiac resynchronisation therapy in patients with wide QRS and non-specific intraventricular conduction delay: rationale and design of the multicentre randomised NICD-CRT study

Romain Eschalier,¹ Sylvain Ploux,² Bruno Pereira,³ Nicolas Clémenty,⁴

Antoine Da Costa,⁵ Pascal Defaye,⁶ Stéphane Garrigue,⁷ Jean-Baptiste Gourraud,⁸

Daniel Gras,⁹ Benoît Guy-Moyat,¹⁰ Christophe Leclercq,¹¹ Pierre Mondoly,¹²

Pierre Bordachar²

**To cite:** Eschalier R, Ploux S, Pereira B, et al. Assessment of cardiac resynchronisation therapy in patients with wide QRS and non-specific intraventricular conduction delay: rationale and design of the multicentre randomised NICD-CRT study. *BMJ Open* 2016;6:e012383.
doi:10.1136/bmjopen-2016-012383

► Prepublication history for this paper is available online. To view these files please visit the journal online (http://dx.doi.org/10.1136/bmjopen-2016-012383).

Received 22 April 2016
Revised 13 September 2016
Accepted 14 September 2016

<figure><img src="image_2.png" /></figure>

CrossMark

For numbered affiliations see end of article.

**Correspondence to**

Pr Romain Eschalier;
reschalier@chuclermontferrand.fr

## ABSTRACT

**Introduction:** Cardiac resynchronisation therapy (CRT) was initially developed to treat patients with left bundle branch block (LBBB). However, many patients with heart failure have a widened QRS but neither left-BBB nor right-BBB; this is called non-specific intraventricular conduction delay (NICD). It is unclear whether CRT is effective in this subgroup of patients.

**Methods and analysis:** The NICD-CRT study is a prospective, double-blind, randomised (1:1), parallel-arm, multicentre trial comparing the effects of CRT in patients with heart failure, a reduced left ventricular ejection fraction (LVEF <35%) and NICD, who have been implanted with a device (CRT-pacemaker or CRT-defibrillator) that has or has not been activated. Enrolment began on 15 July 2015 and should finish within 3 years; 40 patients have already been randomised and 11 centres have agreed to participate. The primary end point is the comparison of the proportion of patients improved, unchanged or worsened over the subsequent 12 months. 100 patients per group are required to demonstrate a difference between groups with a statistical power of 90%, a type I error of 0.05% (two-sided) and a loss to follow-up of 10%. This trial will add substantially to the modest amount of existing data on CRT in patients with NICD and should reduce uncertainty for guidelines and clinical practice when added to the pool of current information.

**Ethics and dissemination:** Local ethics committee authorisations have been obtained since May 2015. We will publish findings from this study in a peer-reviewed scientific journal and present results at national and international conferences.

**Trial registration number:** NCT02454439; pre-results.

## Strengths and limitations of this study

- This is the first prospective study designed to evaluate the effectiveness of cardiac resynchronisation therapy (CRT) in patients with non-specific intraventricular conduction delay (NICD).

- The strong design of NICD-CRT study may help to give a clear answer to this crucial question.

- The NICD-CRT study is a multicentre study involving teams with high experience in CRT trials and cardiac rhythm management.

- An experimented ECG CoreLab may avoid bias of ECG pattern recruitment.

- Including patients with NICD may be a limitation since it is difficult sometimes to differentiate between left bundle branch block and NICD patterns.

## INTRODUCTION

Several randomised control trials have found¹⁻⁴ cardiac resynchronisation therapy (CRT) to be beneficial in heart failure (HF) patients with reduced left ventricular ejection fraction (LVEF) and prolonged QRS duration. The concept of resynchronisation therapy is challenged by the observation that for patients with similar QRS duration, those with left bundle branch block (LBBB) respond significantly better than patients with non-specific intraventricular conduction delay (NICD).⁵ ⁶ An important issue is to identify such patients with NICD pattern since current guidelines use a definition by default and that this population represents a
large proportion of HF patients with reduced ejection
fraction and wide QRS (6.1–30.3% in dilated cardiomy-
opathy).⁷⁻⁹ The American Heart Association/American
College of Cardiology Foundation/Heart Rhythm
Society (AHA/ACCF/HRS) recommendations,¹⁰ pub-
lished in 2009, specified that non-specific or unspecified
intraventricular conduction disturbance is defined by “a
QRS duration greater than 110 ms in adults (...) without
meeting the criteria for RBBB or LBBB. The definition
may also be applied to a pattern with RBBB criteria in
the precordial leads and LBBB criteria in the limb leads,
and vice versa”. Furthermore, patients with NICD have a
poorer prognosis since the presence of NICD in patients
with or without heart disease is associated with an
increased risk of death.¹¹⁻¹⁵ NICD delay is observed in a
variety of cardiac diseases (eg, ischaemic, hypertensive)
and results obtained following CRT have only been
assessed on limited sample sizes, without dedicated ran-
domised studies.¹⁶ Moreover, the observed results have
at times been conflicting.⁶ ¹⁷ ¹⁸ The latest international
guidelines tend to restrict the indications in this setting
and the question arises as to whether to continue to
implant HF patients with NICD. However, these guide-
lines are based on retrospective subgroup analyses¹⁹ and
do not distinguish between RBBB and NICD. A dedi-
cated prospective study is therefore warranted in order
to assess the clinical effectiveness of CRT in HF patients
with NICD pattern.

METHODS AND ANALYSIS

As highlighted above, there is currently uncertainty as to
whether a CRT device implantation is beneficial in
patients with NICD given the absence of dedicated pro-
spective, randomised, blinded trials in this setting. The
present NICD-CRT clinical trial was designed as a study
to investigate whether a CRT device implantation may
be beneficial in patients with wide QRS and NICD
pattern.

The study is a prospective, controlled, two-parallel
arm, randomised, therapeutic, double-blind design and
multicentric clinical trial comparing a CRT-D (defibrilla-
tor) or CRT-P (pacemaker) ON group versus CRT-D or

CRT-P OFF group in HF patients with NICD and
reduced ejection fraction (figure 1).

Objectives

Primary objective

To assess the clinical effectiveness of CRT in HF patients
with NICD and reduced ejection fraction on a 12-month
HF status.

Secondary objectives

To assess the impact of CRT in HF patients with NICD and reduced ejection fraction on all-cause, cardiac and HF deaths and hospitalisations, quality of life, functional capacity and reduction in left ventricular (LV) volumes at 6 and 12 months.

Study end points

Primary end point

The comparison in terms of z-score defined as a com-
posite of two clinical end points (12 months all-cause
deaths and percentage of hospitalisations for HF at
12 months) combined using an average z-score. This
framework allows the combination of multiple clinical
end points (especially time-to-event end points) into a
single statistical assessment, without assigning a rank of
relative importance to each domain as is required with
other related methods (ref). Time-to-event variables will
be first transformed into log-rank scores and then con-
verted to z-scores by subtracting the mean and dividing
by the SD of the pooled data. The z-scores are then
aligned to the same direction so that worse outcomes
have smaller scores. The z-scores will be then averaged
across end points for each patient. Treatment groups will
be compared with respect to this average z-score.

Secondary end points

► Twelve-month deaths (HF, cardiovascular and all-cause deaths),

► Quality-of-life questionnaires at 6 and 12 months:

- Minnesota Living With Heart Failure Questionnaire (MLWHFQ): improvement of at least 20 points

► Functional capacity at 6 and 12 months:

<figure><img src="image_3.png" /><figcaption>**Figure 1** Flow chart describing NICD-CRT. After verification of eligibility and signing of the informed consent form, CRT device implantation will be performed according to current clinical practice. Initially, quadripolar LV lead will be used in the present study. In case of failure of quadripolar LV lead implantation, a bipolar LV lead may be used. Randomisation will be performed following the inclusion consultation. Follow-up will be the same in both groups: inclusion/baseline visit, and M6–12 visits in the investigation centre. LV, left ventricular; NICD-CRT, non-specific intraventricular conduction delay/cardiac resynchronisation therapy.</figcaption></figure>
- New York Heart Association (NYHA) classification reduction ≥ 1 class,²⁰

- Six-minute walk test improvement of at least 10% in distance,²⁰

- Peak oxygen consumption increased by 1.0 mL/kg/min²¹

► Percentage of hospitalisations for HF, for cardiovascular reasons and for all causes at 6 and 12 months,

► Decrease >15% in end-diastolic and/or end-systolic volumes of the left ventricle at 6 and 12 months.²² ²³

## Trial inclusion/exclusion criteria

The patients must fulfil the following criteria before their enrolment in the trial:

► Patients over 18 years old

► NYHA class II to IV ambulatory

► QRS duration >130 ms

► Patients in sinus rhythm

► LVEF <35%

► QRS morphology: NICD according to the AHA/ACCF/HRS recommendations¹⁰ (non-LBBB and non-RBBB):

- Absence of broad notched or slurred R wave in leads I, aVL, V5 and V6;

- Presence of a Q wave in leads I, V5, V6;

- No rsr', rsR' or rSR' pattern in leads V1 or V2.

► Life expectancy expected to exceed 1 year with good functional status

► Optimal pharmacological therapy of HF according to the attending clinician.

Patients will be excluded from the trial for the following reasons:

► Inability to understand or decline the study,

► Impaired mobility,

► Inability to fill out the questionnaire independently,

► Patients with permanent atrial fibrillation,

► Pregnant women,

► Dependent adults,

► Life expectancy <1 year due to causes other than HF.

## Study protocol

Patients meeting the inclusion criteria, admitted to each cardiology department (University Hospital, Clermont-Ferrand, France; University Hospital, Bordeaux, France; University Hospital, Saint-Etienne, France; University Hospital, Grenoble, France; University Hospital, Limoges, France; University Hospital, Nantes, France; Saint-Augustin Clinic, Bordeaux, France; Nouvelles Cliniques Nantaises, Nantes, France; University Hospital, Tours, France; University Hospital, Toulouse, France; University Hospital, Rennes, France) for CRT device implantation with NICD pattern (de novo or upgrading without previous chronic right ventricular pacing indications) will be screened. Eligible patients will receive a clear verbal explanation and a written information sheet by the physicians. Finally, written consent of each patient (records stored by the promoter in a dedicated archives room) will be obtained.

An ECG CoreLab will review each ECG and validate the NICD pattern, before inclusion and CRT device implantation, according to AHA/ACCF/HRS recommendations¹⁰ (figure 2).

After verification of patient's eligibility and the signing of the informed consent form, randomisation will be performed following the inclusion consultation. An automatic randomisation (stratified for QRS duration: 130-150 ms vs >150 ms, gender and investigator centre) will ensure balance between the two groups by minimisation with hierarchical stratification,²⁴ using Stata software by a statistician independent of the protocol. An immediate answer, sent by secured email, will specify the patient's randomisation group (CRT ON vs CRT OFF) and inclusion code.

A CRT system will be implanted in all patients and will be activated (CRT ON) or inactivated (CRT OFF) after randomisation (data will be transmitted by an assistant of the clinical researcher who is not in direct contact with the patient). CRT device implantation will be performed according to the standard practice of each clinician. The decision to implant a pacemaker or a defibrillator associated with the CRT system will be made by the interventional cardiologist according to guidelines, age of the patient, aetiology of the heart disease and habits. Initially, a quadripolar LV lead will be used in the present study. In case of failure of quadripolar LV lead implantation, a bipolar LV lead may be used. The position of the LV lead will depend on coronary venous anatomy, lead stability and pacing threshold (sites with phrenic nerve capture will be avoided). Remote monitoring will be activated systematically in all included patients prior to hospital discharge.

Antitachycardia treatments (in case of implanted defibrillator) will be programmed at the discretion of the clinicians.

However, the two groups will be programmed as follows with regard to pacing modes:

► In the CRT ON group: DDD biventricular mode; clinicians will define the best atrioventricular (80-150 ms) and interventricular (0-40 ms) delays and the minimal heart rate for each patient;

► In the CRT OFF group: back-up stimulation mode: VVI 40 bpm (right ventricular pacing only).

No optimisation of A-V and V-V delay are planned in this NICD-CRT study since the European guidelines do not recommend such optimisation.²⁵

## Patient follow-up

Follow-up will be the same in groups: inclusion/baseline visit, and M6-12 visits in the investigation centre. The planned data collection is summarised in table 1. At baseline, clinical examination (NYHA class, quality of life, 6 min walk test, blood pressure, aetiology of heart disease, peak and threshold oxygen consumption), ECG, biological sample (haemoglobin, kalemia, serum sodium, modification of diet in renal disease and brain natriuretic peptide), transthoracic echocardiography
<figure><img src="image_4.png" /><figcaption>**Figure 2** Example of ECG of a NICD pattern. ECG of a 65-year-old woman with an induced chemotherapy cardiomyopathy and a LV ejection fraction of 27%. On the ECG, the rS pattern in lead I and aVL are criteria against the diagnosis of LBBB. LBBB, left bundle branch block; LV, left ventricular; NICD, non-specific intraventricular conduction delay.</figcaption></figure>

(LVEF, LV dimensions and volumes, Strain) and myocardial MRI will be performed. The same evaluation (clinical examination and different examinations) will be performed at 6 and 12 months associated with device interrogation. All these tests will be performed by a clinical research assistant and the physicians will be blinded to the randomisation group.

## Sample size calculation

Owing to lack of data and reported discrepancies in the literature regarding the impact of CRT in patients with NICD,⁶ ¹⁷ ¹⁸ proposing an accurate sample size estimation appeared a priori difficult. In a previous review, we had shown that the number of patients with NICD pattern included in the major CRT trials showed considerable variation, ranging from 1% in the MIRACLE trial to 21% in the REVERSE study, that is, from 961/5245 patients.¹⁶ The number of participants to be included in the present pilot study has been extrapolated from data obtained in previous works, according to which 100 patients per group will be included. For a two-sided type I error at 5% and a statistical power equals 90%, n=86 randomised patients will allow highlighting a clinical and realistic effect-size of 0.5 which could be considered significant according to Cohen's recommendations (Statistical power analysis for the behavioural sciences (2nd edn). New Jersey: Lawrence Erlbaum, 1988) which has defined effect-size bounds as: small (ES: 0.2), medium (ES: 0.5) and large (ES: 0.8, 'grossly perceptible and therefore large'). To take into account loss to follow-up (around 10%) and to maximise the statistical power, the inclusion of 100 patients per group was proposed. For 100 evaluable patients (50 per group), a difference in Z-score between the two arms will be considered

<table><caption>**Table 1** Schedule of visits and contents</caption><thead><tr><th>Testing or evaluation</th><th>Baseline</th><th>Six months</th><th>Twelve months</th></tr></thead><tbody><tr><td>Physical examination</td><td>✓</td><td>✓</td><td>✓</td></tr><tr><td>NYHA Class</td><td>✓</td><td>✓</td><td>✓</td></tr><tr><td>6 min walking test</td><td>✓</td><td>✓</td><td>✓</td></tr><tr><td>12-lead ECG</td><td>✓</td><td>✓</td><td>✓</td></tr><tr><td>Hb, Na, K, creatininaemia, NTproBNP</td><td>✓</td><td>✓</td><td>✓</td></tr><tr><td>QOL</td><td>✓</td><td>✓</td><td>✓</td></tr><tr><td>Transthoracic echocardiography</td><td>✓</td><td>✓</td><td>✓</td></tr><tr><td>Peak and threshold oxygen consumption</td><td>✓</td><td>✓</td><td>✓</td></tr><tr><td>Medication</td><td>✓</td><td>✓</td><td>✓</td></tr><tr><td>Cardiac MRI</td><td>✓</td><td></td><td></td></tr><tr><td>All-cause, HF and cardiac deaths</td><td></td><td>✓</td><td>✓</td></tr><tr><td>All-cause, HF and cardiac hospitalisations</td><td></td><td>✓</td><td>✓</td></tr><tr><td>CRT device interrogation</td><td></td><td>✓</td><td>✓</td></tr></tbody></table>

CRT, Cardiac resynchronisation therapy; Hb, haemoglobin; HF, heart failure; K, kalaemia; Na, serum sodium; NT-ProBNP, N-terminal portion of pro brain natriuretic peptide; NYHA, New York Heart Association; QoL, quality of life.

significant for an adjusted type I error as determined by the Land and DeMets method (East software).

## Statistical analyses

All analyses will be conducted with Stata statistical software, V.13 (StataCorp LP, College Station, Texas, USA).
A two-sided p value of <0.05 will be considered to indi-
cate statistical significance. Statistical analysis will be con-
ducted on an intention-to-treat (ITT) basis. The
continuous variables will be presented as their means
and SDs or as medians and IQRs according to statistical
distribution (Shapiro-Wilk test). The categorical para-
meters will be expressed as the number of patients and
associated percentages. The patients will be described
and compared at inclusion according to the following
variables: compliance with the eligibility criteria, epi-
demiological characteristics, clinical and biological
characteristics and treatment characteristics. Student's
t-test or Mann-Whitney U test if t-test's assumptions not
met ((1) normality studied using Shapiro-Wilk test and
(2) homoscedasticity verified by Fisher-Snedecor test)
was applied to compare primary end point (Z-score)
between randomised groups. Adjusted analysis will be
performed with the use of random-effects linear regres-
sion model in order to (1) take into account adjustment
on possible confounding covariates selected according
to clinical relevance (notably parameters considered for
stratification) and (2) consider within-centre and
between-centre variability. All effect sizes will be pre-
sented with 95% CIs. Other continuous variables
(eg, 6 min walk test, number of readmissions for all
causes and for HF, biomarkers for HF and QoL at
12 months on MLWHFQ and Short Form 12) will be
compared similarly with the use of the unpaired t-test or
the Mann-Whitney U test when appropriate. Adjusted
analyses will be performed using the same adjustment
variables described above. The $\chi^2$ test (or Fisher's exact
test as appropriate) will be used for secondary categor-
ical outcomes (eg, NYHA classification). The time-
to-event curves will be calculated with the use of the
Kaplan-Meier method. Comparisons of censored data
will be conducted in univariate analysis by log-rank test
and in multivariate analysis by the Cox proportional
regression model. The statistical analyses concerning
components of composite z-score were performed with
a corrected type I-error taking into account multiple
comparisons. Longitudinal analysis using mixed models
will be used to take into account between-patient and
within-patient variability. If the frequency of missing
data is >5%, an additional analysis will be performed
using the multiple imputation method (Stata command
mi).

Data monitoring safety committee

A Data Monitoring Safety Committee (independent
from the sponsor) will meet initially at the launch of the
study and thereafter throughout the study, on its own
initiative or at the request of the sponsor, and will
discuss the results of the intermediate analyses. It will
have a consultative role. It will provide a general opinion
on the progress of the study as well as provide input in
helping make difficult decisions during the course of
the study for which an independent judgement is desir-
able. The Data Monitoring Safety Committee will decide

on possible early termination in light of data transmitted
by the adjudication committee, the role of which will be
defined by the Data Monitoring Safety Committee. The
study will be terminated if the difference between the
two groups becomes excessive.

Data storage and management

Data storage and management will be performed
according to international guidelines relevant in French
institutions, as previously described.²⁶ ²⁷ All data will be
entered using electronic case report form (created by
Medsharing society) and data accuracy will be analysed
by the NICD-CRT data manager. Data quality control
measures will include queries to identify outliers and
missing data. Only the research assistant and NICD-CRT
study principal investigator (PI) will have access to pro-
tected personal health information. After inclusion, a
unique identifier (linked to the participant's medical
record number and a hard copy roster) will be stored in
a locked cabinet in the PI's locked private office). The
PI will ensure that the anonymity is preserved. The study
PI will have access to the final trial data set, as will a
biostatistician.

An adverse event (AE) is defined as any untoward
medical occurrence which has occurred in a patient
taking part in the study. A serious AE is defined as any
untoward occurrence that: requires hospitalisation or
prolongation of existing hospitalisation; results in persist-
ent or significant disability; is life threatening; results in
death or is otherwise considered medically significant by
the investigator. AE will be recorded on an AE form. An
assessment of the gravity, possible causality and expect-
edness event/reaction will be undertaken. At each visit,
participants will be asked whether they have had any
problems and if any AEs have occurred. The AE reaction
reporting period begins for NICD-CRT trial when the
participant is randomised and ends 12 months after the
randomisation. All recorded AE will be followed up until
they are resolved or the patient's participation in
NICD-CRT trial ends. Resolution of these events will be
entered on the AE form. Potential complications asso-
ciated with the CRT device implantation (only potential
serious AE in the present study, but however not
dependent of the present study) are: pain, haematoma,
infection, pericardial effusion and LV lead
dislodgement.

The promoters of the NICD-CRT study have initially
decided that the level of monitoring is low, which repre-
sent two visits/centre during the study after the begin-
ning of the inclusion (1 nearly after the beginning of
the active recruiting phase and 1 at the end of the
inclusion).

Ethics and dissemination

The NICD-CRT study is currently in an active recruiting
phase since the 15 July 2015 (first inclusion). The
present study complies with the Declaration of Helsinki.
Study completion date is estimated at July 2018. This
multicentre, randomised, parallel-group trial has been
registered at http://www.clinicaltrials.gov under the
registration number NCT02454439. All the 11 centres
have been activated since July 2015 (the last one in May
2016). Forty-one patients have been randomised and
included in the NICD-CRT study. We will publish find-
ings from this clinical study in a peer-reviewed scientific
journal and present results at national and international
conferences. All the centres have a good reputation in
CRT clinical trials. A total of 200 patients have to be
recruited in 24 months (0.7 patient/month/centre).

The statistical analysis plan and subsequent versions
will be maintained in the study file. The statistical ana-
lysis plan may be revised during the study to take into
account any changes to the protocol or other changes to
the study that may have an impact on the statistical ana-
lysis initially planned. Any changes to the statistical plan
or protocol analysis itself will be subject to the opinion
of the local ethics committee and the promoter and
communicated to the investigators (emails, newsletter
and/or postal letter).

DISCUSSION

The NICD-CRT trial will examine whether the implant-
ation of a CRT device in patients with NICD pattern and
heart failure with reduced LV ejection fraction will
improve the clinical status of this population.

The majority of patients previously included in the
main CRT clinical trials also included patients with
LBBB, since this therapy had been initially proposed to
specifically target the detrimental impact of the
LBBB-ventricular activation sequence. However, patients
with NICD pattern represent a large proportion of
patients with HF and reduced ejection fraction.
Important discrepancies have been described in several
studies regarding the potential benefit of CRT in
patients with NICD pattern. Current results are more-
over conflicting with, on the one hand, a reported
benefit in terms of quality of life, exercise time and peak
oxygen consumption in the MIRACLE²⁸ trial, while, on
the other, a reported lack of benefit in terms of clinical
composite score, LV remodelling and mortality observed
in other studies.⁶ ¹⁷ ¹⁸ A recent meta-analysis suggested
that CRT had a neutral effect in patients with NICD⁵
with observed outcomes being poorer than in patients
with LBBB. Furthermore, the findings regarding the
clinical benefit of CRT-D in LBBB, but not in non-LBBB
patients, were consistent throughout the Multicenter
Automatic Defibrillator Implantation Trial (MADIT)-
CRT population evaluated by age, sex, NYHA class,
ischaemic or non-ischaemic origin, QRS duration and
baseline haemodynamic status,³ and recently confirmed
by the long-term (7 years) analysis of the MADIT-CRT²⁹
study. Several mechanisms may explain the apparent
neutral effect of CRT in patients with non-LBBB: (1) the
high prevalence of ischaemic cardiomyopathy in the
NICD group, a factor known to adversely affect

prognosis;²⁸ ³⁰ (2) a lesser amount of electrical dyssy-
chrony compared to patients with LBBB ³¹ and (3) the
commonly performed aggregation of RBBB and patients
with NICD in these subgroup analyses which precludes
any firm conclusions regarding the effectiveness of
CRT in these groups. Our observations obtained from
epicardial electrical activation sequences³¹ ³² are in
strong opposition with the recent results of the IPD
meta-analysis, which consider QRS duration as the only
indicator of CRT response and that QRS morphology
does not provide additional information.³³

In addition, current data analysing the impact of CRT
in patients with NICD only stem from subanalysis
studies. The relevance of subgroup analyses should be
questioned however and the limited number of patients
included in these studies is insufficient to draw any firm
conclusions. Furthermore, no distinction was made
between RBBB and NICD in the guidelines, which is
somewhat surprising given the fact that electrical activa-
tion sequences and CRT effectiveness may differ
between these two patient groups. While there are a
number of limitations, the above results have nonethe-
less led to significant changes in the latest international
guidelines, such that the pattern of the QRS complex
and not solely QRS width has become a selection criter-
ion for candidates for CRT device implantation.²⁵ ³⁴

The discrepancies in the results obtained from differ-
ent subanalyses thus warrant performing a dedicated
randomised, controlled, double-blinded study to assess
whether CRT may be also beneficial for HF patients with
NICD and systolic dysfunction.

In the present trial, it was decided to use a Z-score for
primary end point since Sun *et al*³⁵ have demonstrated
that the Z-score enables detection of therapeutic efficacy
(ie, CRT in the present study) using sample sizes of
100-150 patients per group, approximately double the
power achievable assessing the effects. A physician
blinded to CRT mode (CRT ON group or CRT OFF
group) will perform patient's clinical assessment so as to
limit any potential evaluation bias. In order to provide a
comprehensive answer to this crucial question, an echo-
cardiographic evaluation will be performed to assess the
impact of CRT on LV remodelling in this patient popula-
tion (secondary end point). Thus, a complete evaluation
will be performed using clinical and remodelling
assessments.

Finally, the use of a LV quadripolar lead in primary
intention has been decided since it is currently used in
French centres, thus enabling to achieve a crucial homo-
geneity of our population at baseline.

CONCLUSIONS

The NICD-CRT trial will add substantially to the modest
amount of existing data on CRT in patients with NICD
and should reduce uncertainty for guidelines and clin-
ical practice when added to the pool of current
information.
**Author affiliations**

¹Cardiology Department, Clermont Université, Université d'Auvergne, Cardio Vascular Interventional Therapy and Imaging (CaVITI), Image Science for Interventional Techniques (ISIT), UMR6284, and CHU Clermont-Ferrand, Clermont-Ferrand, France

²Hôpital Cardiologique du Haut-Lévêque, CHU Bordeaux, Université Bordeaux, IHU LIRYC, Bordeaux, France

³CHU Clermont-Ferrand, Biostatistics unit (Clinical Research and Innovation Direction), Clermont-Ferrand, France

⁴Cardiology Department, Trousseau Hospital, François-Rabelais University, Tours, France

⁵North Hospital, Saint-Etienne, France

⁶Arrhythmia Unit, Cardiology Department, University Hospital, Grenoble, France

⁷Cardiology Department, Saint-Augustin Clinic, Bordeaux, France

⁸Cardiology Department, PHU2, Nantes University Hospital, Saint Herblain, France

⁹Nouvelles Cliniques Nantaises, Nantes, France

¹⁰Cardiology Department, Limoges University Hospital, Limoges, France

¹¹Department of Cardiology and Vascular Disease, Pontchaillou Hospital, Rennes, France

¹²Federation of Cardiology, University Hospital Rangueil, Toulouse cedex 09, France

**Acknowledgements** The authors thank Mr Pierre Pothier for the editing of this manuscript and Miss Elodie Chazot for coordinating daily the NICD-CRT study.

**Contributors** RE, SP, BP, NC, ADC, PD, SG, J-BG, DG, BG-M, CL, PM and PB made substantial contributions to the conception, design of the work, acquisition, analysis or interpretation of data. RE, SP, BP, NC, ADC, PD, SG, J-BG, DG, BG-M, CL, PM and PB drafted the work and revised it critically for important intellectual content. RE, SP, BP, NC, ADC, PD, SG, J-BG, DG, BG-M, CL, PM and PB approved the final version of the manuscript to be published. RE, SP, BP, NC, ADC, PD, SG, J-BG, DG, BG-M, CL, PM and PB agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

**Funding** This clinical trial is funded by Boston Scientific (Cardiac Rhythm Management; 4100 Hamline Avenue North St. Paul, MN 55112; Kenneth Stein, MD, FACC, FHRS, Senior Vice President, Chief Medical Officer, CRM, kenneth.stein@bsci.com). However, the authors (under responsibility of the principal investigator of the NICD-CRT study: Romain Eschalier) are solely responsible for the design and conduct of this study as well as all study analyses and the drafting and editing of the article.

**Competing interests** None declared.

**Patient consent** Obtained.

**Ethics approval** Local ethics committee (CPP Sud Est VI, AU 1164) and ANSM (Agence Nationale de sécurité du medicament et des produits de santé, 2014-A01848-39) authorisations were obtained in March and May 2015, respectively.

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

**Open Access** 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 and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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