Clinical trial NCT02346097: Electrophysiological Optimization of Left Ventricular Lead Placement in CRT
Official title: ElectroCRT - Left Ventricular Lead Implant and Optimization Guided by Electrocardiography in Cardiac Resynchronization Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Congestive Heart Failure
Keywords: Cardiac Resynchronization Therapy
Heart Failure
Ejection Fraction
Narrow
Pacemaker
Electrophysiology
Electrical activation mapping
Coronary Sinus
Mapping
QRS
QRS width
Pacing Interval
Left Ventricular Lead
Cardiac CT
Echocardiography
Myocardial Scintigraphy
6 Minutes Walk Test
Imaging
Left ventricular ejection fraction
Epicardial veins
Resynchronization
ImagingCRT
Optimal electrical resynchronization
Cardiac computed tomography
Lead sponsor: University of Aarhus
Sponsor class: OTHER
Collaborators: name: Aarhus University Hospital
First posted: 2015-01-26
Enrollment: 122
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to investigate if "optimal electrical resynchronization" achieved by targeting left ventricular lead placement to the myocardial region with the latest electrical activation combined with post-implant pacemakersettings for narrowing the paced QRS width causes an excess improvement in the pumping function of the heart (the left ventricular ejection fraction) in Cardiac Resynchronization Therapy (CRT)

Detailed description: Background:

Cardiac resynchronization therapy (CRT) is an established therapy in patients with a left ventricular (LV) ejection fraction (EF) \< 35 %, and an electrocardiogram (ECG) with prolonged QRS duration (1). The treatment is implemented by implanting a pacemaker with three pacing leads: One in the right atrium, one in the right ventricle (RV) and one in an epicardial vein through the coronary sinus, thereby establishing atrial-synchronized biventricular pacing to coordinate RV and LV contraction.

Despite the convincing effect of CRT on survival, symptoms, and LV function (2,3,4) as much as 30-40 % of the patients do not benefit clinically from the treatment, so-called non-responders (5,6). Annually around 600 CRT-systems are implanted in Denmark and about 3000 patients live with a CRT. The risk of complications associated with CRT-treatment is considerable (7), and a conservative estimate of the expenses for implanting a CRT-device is DKK 80.000. Consequently, the costs of CRT in non-responders are high, both for the patients and for the health economy.

Potential correctable reasons for non-response to CRT are non-optimal LV lead positioning and non-optimal pacemaker programming (5). At the Department of Cardiology, Aarhus University Hospital, Skejby, the clinical practice is to place the LV lead in the non-apical postero-lateral region aiming towards a myocardial segment with electrical activation occurring in the second half of the QRS complex in the surface ECG.

Retrospective studies have documented an improved response rate to CRT when the LV lead is placed in a myocardial region with late electrical activation and without scar tissue (8,9). Furthermore, lack of electrical resynchronization after CRT illustrated by unchanged or prolonged QRS duration is associated with poor clinical outcome (10) and programming the interventricular (VV) delay to obtain the narrowest QRS-complex has been suggested to increase CRT response rate (11,12).

A recent randomized controlled trial (ImagingCRT) conducted at our institution demonstrated that an imaging guided LV lead placement strategy targeting the latest mechanically activated myocardial segment (assessed by pre-implant echocardiography) and separate from scar tissue (determined by pre-implant myocardial scintigraphy) improves clinical response rate to CRT (data not yet published). This method has the potential to become routine clinical practice for LV lead placement at our institution.

Aim and hypothesis:

We aim to investigate if optimal electrical resynchronization achieved by targeting LV lead placement to the myocardial region with the latest electrical activation determined by systematic electrical mapping of all available epicardial veins combined with post-implant VV electrical optimization for narrowing the paced QRS width causes an excess improvement in LVEF after CRT.

We hypothesize that this will cause an excess increase in LVEF of 4 %, to an absolute increase in LVEF of 12 % as compared to an absolute increase in LVEF to 8 % using an imaging guided CRT-implantation strategy.

Methods:

All patients referred to CRT at Aarhus University Hospital, Skejby will be assessed for eligibility. Eligibility criteria and outcomes measures elsewhere at clinicaltrial.gov.

Study Course:

After written informed consent the patient will follow the study course as specified below.

The day before implantation of the CRT the following investigations are scheduled: Echocardiography (to asses LV function and dimensions), cardiac CT-scan (to localize all available epicardial veins), myocardial scintigraphy (82Rubidium positron emission tomography (Rb-PET)), to determine the extent and distribution of scar tissue and LVEF (13,14)), blood samples and clinical evaluation.

The patients are randomized to EITHER imgaging guided placement of the LV lead targeting the myocardial region with the latest mechanical activation and VV-interval settings programmed with simultaneous biventricular pacing (routine CRT-strategy arm) OR LV lead placement guided by procedural electrical mapping of all available cardiac veins targeting the myocardial region with the latest electrical activation combined with VV electrical optimization the day after implantation to achieve the narrowest paced QRS width (intervention arm).

The day after the implantation all patients undergo a high-pitch cardiac CT to verify LV lead position (15), pacemaker test, programming of VV-intervals and echocardiographic atrioventricular (AV) optimization.

One month after the implantation all patients have their pacemaker tested by a research nurse according to standard clinical practice.

Six months after CRT implantation the following investigations are repeated: Echocardiography, clinical evaluation, pacemaker test and blood samples. Rb-PET is also repeated to determine potential changes in myocardial perfusion and LVEF. Thereafter the patient will attend standard controls of the pacemaker every six month according to standard procedures.

Power Calculations and statistics:

We hypothesize that a CRT-strategy targeting optimal electrical resynchronization will result in an excess increase of 4 % in LVEF compared with the routine CRT-strategy, where an 8 % increase is expected. To identify this absolute increase in LVEF and to achieve a statistical power of 80 %, the study will need a sample size of 98 patients, given a standard deviation (SD) of 7 % in both groups, and a two-sided alpha value of 0.05. Furthermore, to achieve a statistical power of \> 80 % with a margen of noninferiority of 20 % for the secondary endpoint of clinical non-response to CRT (assuming a 75 % clinical response rate in the control group) we will need a sample size of 116 patients (given a two-sided alpha value of 0.05 %). Taking into consideration an expected loss of follow-up in approximately 5 % of the patients, we will include 122 patients.

All analyses will be conducted according to the intention-to-treat principle. Differences between groups will be tested using Students t-test, when normality is demonstrated; otherwise a non-parametric test (Mann-Whitney) is used. Categorical variables will be analyzed by χ2 test. A two-sided P- value of \<0.05 is considered significant.

Research Plan:

The Department of Cardiology, Aarhus University Hospital, have the capacity and equipment to conduct this trial. The group of investigators contributes with a deep and long-lasting experience in CRT-treatment and 150 de-novo CRT-devices are annually implanted at our institution. We plan to enroll the patients during a two and a half-year period. This study is planned to start in February 2015 as a PhD program for Charlotte Stephansen, MD. Charlotte Stephansen will be the prime investigator in charge of including the patients and she will perform all clinical evaluations and image acquisitions during the admission for CRT implantation and at the six month follow-up. She will also be in charge of analyzing data after study completion.

The results will be published in peer-reviewed international journals, and are expected to result in at least three papers. None of the investigators have any conflicts of interest to declare.

The study will be conducted according to the principles of the Helsinki Declaration II. The study will be approved by The Central Denmark Region Committees on Health Research Ethics, reported to the Danish Data Protection Agency, and registered on ClinicalTrials.gov.

Perspective:

No prospective randomized trials have previously investigated the effect of a CRT treatment-strategy targeting optimal electrical resynchronization achieved by guiding LV lead placement to the myocardial region with the latest electrical activation combined with post-implant VV electrical optimization for narrowing the paced QRS width.

It is expected that this method improves the response to CRT. The human and economic costs of CRT in non-responders are therefore expected to be reduced. If an excess increase in LVEF is achieved in this study, it will be possible to prevent and relieve invalidating symptoms and reduce mortality in selected heart failue patients in the future. The utility and potential benefits of participating in this study are expected to equalize the risks of exposure to ionizing radiation, possible side effects and inconvenience to the patient.

References:

Please refer to the reference chapter

Eligibility criteria: Inclusion Criteria:

* Symptomatic heart failure (New York Heart Association (NYHA) functional class II - IV) despite optimal medical therapy
* ECG with left bundle branch block and QRS ≥ 120 ms
* LVEF ≤ 35 %
* Age \> 40 years
* Written informed consent Patients with an indwelling single- or dual chamber pacemaker and a paced QRS \> 180 ms are eligible for enrollment.

Exclusion Criteria:

* Expected lifetime \< 6 months
* Expected heart-surgery within the next 6 months
* Recent (\< 3 months) myocardial infarction or coronary artery bypass graft (CABG)
* Pregnant or lactating
* No written informed consent Cardiac CT will not be performed in patients where this is contraindicated, i.e. in the presence of depressed renal function (estimated Glomerular Filtration Rate (eGFR) \< 30 ml (milliters)/minute), thyrotoxicosis or in the case of former serious reactions to the contrast media.

Primary outcomes:
measure: Change in Left Ventricular Ejection Fraction (LVEF)
timeFrame: The day before implantation and 6 months after implantation
Secondary outcomes:
measure: All cause mortality
timeFrame: 6 months and until "3 years and 6 months" after implantation
measure: Hospitalization for heart failure
timeFrame: 6 months and until "3 years and 6 months" after implantation
measure: CRT-implant procedure time
timeFrame: The day of implantation
measure: Procedural radiation exposure
timeFrame: The day of implantation
measure: Perioperative and late complications
timeFrame: The day of implantation, 6 months and until "3 years and 6 months" after implantation
measure: Changes in Quality of Life
timeFrame: The day before implantation and 6 months
measure: Changes in New York Heart Association Functional Class
timeFrame: The day before implantation and 6 months
measure: Changes in Six Minutes Walk Test
timeFrame: The day before implantation and 6 months
measure: Changes in level of N-terminal prohormone of brain natriuretic peptide
timeFrame: The day before implantation and 6 months
measure: Changes in Left Ventricular End Systolic Volume
timeFrame: The day before implantation and 6 months
measure: Changes in Left Ventricular End Diastolic Volume
timeFrame: The day before implantation and 6 months
measure: Changes in Electrode Parameters (pacing threshold, sensing value, impedance)
timeFrame: The day after implantation and at 1 and 6 months follow-up
measure: Changes in Echocardiographic Dyssynchrony parameters
timeFrame: The day before implantation and at 6 months follow-up
measure: Clinical response to CRT at 6 months follow-up if the patient is: 1. Alive, and 2. Not hospitalized for heart failure, and 3. experience an improvement of NYHA Functional Class or > 10 % increase in 6MWT
timeFrame: At the 6 months follow-up.
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Aarhus University Hospital, Skejby, Department of Cardiology
Study officials:
affiliation: Aarhus University Hospital, Sekjby, Department of Cardiology
name: Jens Cosedis Nielsen, Professor
role: STUDY_DIRECTOR
affiliation: Aarhus University Hospital, Sekjby, Department of Cardiology
name: Mads Brix Kronborg, MD, PhD
role: STUDY_DIRECTOR
affiliation: Aarhus University Hospital, Sekjby, Department of Cardiology
name: Anders Sommer Knudsen, MD
role: STUDY_DIRECTOR
References:
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