Ventricular Tachycardia Ablation and Myocardial Scar Characterization With Magnetic Resonance
Ventricular Tachycardia Ablation and Myocardial Scar Characterization With Magnetic Resonance
Previous monocentric experiences have already highlighted the role of preoperative cardiac
 imaging, in particular of cardiac magnetic resonance (CMR) and tomography (CT), in improving
 the ablation results of scar-related ventricular tachycardia (VT). A better characterization
 of scar obtained with high quality CMR images and post processing data with creation of maps
 exploring the heart in concentric layers from the endocardium to the epicardium could allow a
 personalized and more precise approach to this pathology.

 Aim of the study - Evaluating the feasibility and possible benefit of CMR-guided ablative
 approach (group 1: ablation of the "anatomical" channels of heterogeneous tissue within the
 scar) compared to CMR-aided approach (group 2: ablation of the "electrical" conduction
 channels within the scar) and standard approach (group 3: ablation guided by an
 electro-anatomical system without the aid of CMR) in a multi-center Tuscan study.

 What would add the project to what we know - The achievement of the objectives by the project
 would allow to propose a personalized ablation on the basis of the scar characterization and
 would allow a better efficacy, efficiency of the procedure and probably also a safer
 treatment
State of the art and preliminary data

 Patients with structural heart disease (SHD) are at increased risk of VAs that can promote
 life-threatening events, for whom a proper treatment has a pivotal role. The use of
 antiarrhythmic drugs is limited due to their ineffectiveness in reducing related mortality or
 their common side effects. Implantable cardioverter defibrillator (ICD) can improve survival
 in a certain group of patients with SHD, but recurrent ventricular tachycardia (VT) needing
 ICD shocks reduce quality of life and probably patients survival. Moreover, ICD implant is
 affected by a noticeable risk of acute and chronic complications, that can reduce the
 survival of ICD recipient. Catheter ablation is an effective technique especially for the
 management of post-myocardial infarction ventricular tachycardia (post-myocardial infarction
 VT) and the recent VANISH trial showed that ablation reduced the composite primary outcome of
 death, VT storm or appropriate ICD shocks compared to patients with an escalation of
 amiodarone.

 The introduction of a catheter in the ventricular chambers through a vascular access, allows
 to map the VT circuit that is usually inside the scar, and perform an ablation of the tissue
 responsible of the VAs substrate. The signals recorded by the catheter and the fluoroscopy
 images have been used to localize the target since 90s, but in the last decade the emergence
 of technological innovations, such as three-dimensional electroanatomic mapping (3D-EAM), has
 enhanced our ability to identify ablation targets. Three-dimensional electroanatomic mapping
 enables to generate a 3D reconstruction of any part of the heart without needing fluoroscopic
 navigation. Integration between anatomic and electrocardiographic (ECG) data it is very
 useful in choosing an optimal location for VA ablation, and the use of mapping systems
 contributed to reduce procedural, fluoroscopy and radiofrequency time. However, the efficacy
 of 3D-EAM can be suboptimal when we decide to follow a strategy of substrate ablation.
 Substrate ablation is characterized by an ablation of abnormal electrograms (EGMs) identified
 during sinus rhythm or ventricular pacing. In a recent meta-analysis, the combined risk of
 ventricular arrhythmia recurrence and all-cause mortality during long-term follow-up was
 lower when using a substrate-based approach compared to standard ablation of stable VT.
 However, efficacy was greatly reduced if the homogenization of the arrhythmic substrate was
 incomplete.

 Real-time integration of anatomical VT substrate from data coming from cardiac image such as
 cardiac magnetic resonance (CMR) and multidetector computed tomography (CT) with EAM seems to
 improve efficacy of VA radiofrequency ablations and use of scar integration from imaging was
 an independent predictors of VT-free survival after catheter ablation in post-MI VT in recent
 papers. However, integration of CMR and CT images in the EAM system hasn't allowed to avoid,
 until now, an EAM that is time consuming, often imprecise and allowing only an incomplete
 substrate modification. Based on this consideration, we thought that an image integration
 taking into account not only the location of scar, but also its quantification and
 characterization could increase the efficiency of the ablation procedure, with an improvement
 of acute and chronic outcome. For this purpose, CMR has a pivotal role, allowing at
 characterizing the scar tissue via color-coded pixel signal intensity (PSI) maps that have a
 high correlation with the electroanatomic maps obtained during the ablation procedures.
 Particularly, the VT isthmuses found with the EAM correlated with the presence of
 heterogeneous tissue channels (HTCs) depicted in the PSI maps. Previous experiences
 demonstrated that these PSI maps can be imported in the navigation system to help substrate
 ablation, but only if they are obtained from high spatial resolution late gadolinium
 enhancement (LGE)-CMR images. One recent publication showed that CMR-aided scar dechanneling
 was associated with a lower need for ablation delivery, higher non-inducibility rates after
 substrate ablation, and reduced VT recurrences in the follow-up. In brief, in this experience
 the target ablation sites were the conducting channels (CC) entrances (i.e. entrances of VT
 isthmuses) identified in the substrate EAM, but PSI maps integrated into the navigation
 system were used to focus on specific regions of the scar. The authors found 23% of false
 negative (CCs evidence outside the HTCs entrances) and 16% of false positives (HTCs only
 identified in PSI maps). The HTCs identified only in the PSI maps, without matching with a CC
 on the EAM, were not targeted for ablation. Very recently, the same group presented results
 about a possible improvement of the outcome (particularly the efficiency, but probably with
 extension to efficacy and safety) using a CMR guided ablation, targeting only the HCTs (all
 of them). However, both experiences with CMR aided and guided ablation had been performed
 with a retrospective design and in a single-centre high volume laboratory, and for this
 reason we don't know the potential application of this technique in the real world of
 clinical electrophysiology.

 We sought to evaluate the feasibility, efficacy, safety and efficiency of a VT ablation
 guided or aided by CMR in comparison with VT ablation guided only by EAM (standard approach
 nowadays).

 General goal of the Project

 The project aims at developing a network between Tuscany centres for scar-related VT
 ablation, based on an accurate patients' selection, an anatomic substrate definition with
 radiomics, a qualitative analysis of the radiomic data via an artificial intelligence with a
 cardiac shell reconstruction that will be used in the electrophysiological laboratory to
 tailor a specific and personalized ablation procedure. To test whether this tailored approach
 could improve our clinical approach we built the following experimental design. Briefly,
 patients with VT arriving at each hospital of the consortium from either emergency room,
 outpatient clinic, or other hospitals, will be evaluated for SHD. Patients with confirmed
 diagnosis of SHD can be enrolled in the study and will be further evaluated to determine
 whether there are no contraindications to CMR. If they have contraindications to CMR or CMR
 images are suboptimal the patients will undergo EAM-guided VT ablation, vice versa they will
 be randomized to a CMR-guided or -aided ablation. Data obtained from LGE-CMR will be
 processed with the ADAS-VT software (Galgo Medical, Barcelona, Spain), an artificial
 intelligence suite used to create a 3D multi-layer map of the ventricular wall.

 At the end, we will have 3 groups for study:

 -  Group 1: patients undergoing CMR guided VT ablation (ablation focused only on HTCs)

 -  Group 2: patients undergoing CMR aided VT ablation (ablation focused only on CCs on EAM,
 but with integration of CMR derived shell in the map and with scar projection (with HTCs
 on the EAM)

 -  Group 3 (control): patients with contraindication to CMR (or poor-quality images deemed
 unsuitable for further analysis) undergoing EAM-guided VT ablation without any CMR data
 about scar (core and border zone)

 Aim of the study

 Evaluating the feasibility and possible benefit of CMR-guided ablative approach (group 1:
 ablation of the "anatomical" channels of heterogeneous tissue within the scar) compared to
 CMR-aided approach (group 2: ablation of the "electrical" conduction channels within the
 scar) and standard approach (group 3: ablation guided by an electro-anatomical system without
 the aid of CMR) in a multi-centre Tuscan study.

 Primary objective (see after)

 Secondary objective (see after)

 Study design (see after)

 Population of the study

 103 patients with VT in patients with SHD will be recruited in 7 Tuscan hospitals
 participating in the project.

 Study setting

 Regional network of hospitals including tertiary centres with an electrophysiology team of
 qualified investigators/physicians with proven experience in performing ventricular
 tachycardia ablation.

 Inclusion Criteria (see after)

 Exclusion Criteria (see after)

 Withdrawal from the study

 -  Informed consent withdrawal

 -  Patients enrolled without satisfied inclusion criteria or in presence of exclusion
 criteria

 Acute Procedure endpoints Acute success will be defined as non-inducibility of any sustained
 monomorphic VT at the end of the procedure. Partial success will be considered with the
 clinical VT successfully ablated with other monomorphic VTs remaining inducible. Pre-ablation
 inducibility is not be required.

 Device programming

 All patients involved in the study, regardless of Group allocation, will have their ICD
 programmed following 2019 HRS/EHRA/APHRS/LAHRS expert consensus statement on optimal ICD
 programming, following the manufacturer specific recommendations about therapy and detection
 in patients where VT cycle is known, alongside any anti-bradycardia setting necessary for
 therapeutic needs. Particularly, the VT zone with lower rate detection should be set at 10-20
 ipm slower than the clinical VT to guarantee a good sensitivity in recurrences diagnosis and
 therapy should be programmed in order to reduce unnecessary shocks. 26

 Medical therapy

 Patients involved in the study will be treated with antiarrhythmic drugs and any other
 medical therapy considered standard of care for the SHD and VT. Particularly, use of
 amiodarone is allowed at enrollment but is strongly suggested to stop it at 1 month
 follow-up, if not contraindicated, to avoid drug-related toxicity and not to confound trial
 results about primary objective.

 Potential risks

 No extra risks appear to be related to study participation. Risks are related to the
 procedure itself, which is explained on the informed consent sheet.

 Potential benefits

 Thanks to preprocedural CMR imaging, patients assigned to both interventional groups (1 and
 2) could benefit from potentially shorter procedures and lower radiological exposure with
 shorter fluoroscopy time. Patients assigned to Group 2 will benefit from an overall shorter
 EAM acquisition phase, given the fact that the area of interest will be determined by CMR-LGE
 data. Due to the complete absence of EAM, patients assigned to Group 1 could benefit from
 even smaller procedural time and radiological exposure.

 Moreover, patients assigned to CMR-guided ablation (group 1) and CMR-aided ablation (group 2)
 could benefit from improved VT substrate identification. CMR-derived PSI maps could improve
 CC entrance localization compared to the standard technique based on the voltage map obtained
 from EAM. We anticipate that improved scar definition and CC entrance localization could lead
 to a significant improvement in substrate elimination, and, ultimately, to better acute and
 long-term outcomes. The ablation at HTCs entrance in group 1 could improve acute efficacy
 compared to the other groups, as showed by recent unpublished data (Soto Iglesias et al. JACC
 EP 2020).

 Study conclusion

 The study will conclude with the 12-months follow-up of the last enrolled patients (see
 sample size), and each patient with 12-months follow-up will exit from the study. Patients
 will have the possibility to exit from the study at any time they decide without any
 explanation about it. Principal investigator will have the ultimate authority to stop the
 trial at any time of enrollment if any harms emerge during trial conduction. Once the study
 is completed, principal investigator or delegate will notify the site of closeout and a study
 closeout visit will be performed.

 Study endpoint (see after)

 Procedural evaluation

 Any variables evaluated as study endpoint (see above) will be collected.

 Quality of life assessment

 To evaluate potential differences between different interventional approaches in
 health-related quality of life changes, the 36-Item Short Form Survey (SF-36) will be
 administered at baseline (before ablation) and at the 12-months follow up visit.

 Follow-up

 Clinical follow-up (FU) will include outpatient clinic visits at 1, 6 and 12 months after the
 ablation procedure. If no contraindications, amiodarone (if used) should be stopped at the
 1-month FU visit.

 At all follow up visits, the following parameters and information will be taken:

 -  Physical examination

 -  12 lead surface ECG

 -  Transthoracic echocardiography (at 6 and 12 months)

 -  ICD interrogation, analyzing any event marked as VT or VF by the device.

 VT recurrence will be defined as any documented sustained VT (more than 30 s) or appropriate
 ICD therapy at ICD check.

 To assess changes in health-related quality of life, the 36-Item Short Form Survey (SF-36)
 will be administered at the 12-months follow up visit.

 Sample size To test the primary hypothesis, 103 patients will be necessary with 80% power and
 5% type 1 error, considering 50% of group 1-2 (low risk), 50% of group 3 (high risk), 16% of
 likelihood of VT recurrences at 12 months in low risk patients and 44% of likelihood in high
 risk patients with HR (high risk/low risk of recurrences ) of 2,75 (Cox PH, 2 sided
 equality).

 Screening phase

 All patients referred to or directly evaluated at one of the participating centres for VT
 will be screened for ablation and for study participation. The presence of structural heart
 disease will be evaluated on the basis of past medical history and available imaging carried
 out during patient evaluation, such as echocardiography, cardiac CT, or previous CMR.

 Enrollment procedure - Recruitment and agenda

 All participant centres are referral centres for VT ablation within their health care
 network. All patients who give informed consent for participation and fulfill the inclusion
 eligibility criteria will be consecutively enrolled. We expect to include all the patients
 within a 2-years period. The 12-month follow-up information of the last included patient
 should be available approximately 3 years after the first inclusion. A monthly assessment of
 screening database will be performed in order to increase the enrollment procedure.

 Group allocation

 Patients deemed suitable for CMR according to comorbidities, device MRI-compatibility and
 willingness to undergo the examination, will be randomly allocated to groups 1 and 2.
 Patients eligible to join the study but unsuitable for CMR or with poor CMR images will be
 assigned to Group 3.

 Randomization

 Randomization will be performed in patients undergoing CMR (Groups 1 and 2) in 1:1 fashion
 using the app "Randomizer for Clinical Trial Lite" or equivalent web-based platform. The
 scientific coordinator of the study or a delegate should be the unique responsible of
 randomization and will be contacted upon all new recruitments.

 Blindness

 Blindness of patients is not required.

 Study procedures

 Routine baseline analysis, clinical visit, 12 lead ECG, transthoracic echocardiography,
 transoesophageal echocardiography, cardiac CT, CMR (if possible), VT ablation. Patients will
 be hospitalized for the ablation procedure and may undergo any clinical, imaging or lab
 examination considered necessary for clinical management during their stay.

 Data collection

 The principal investigator or delegate is responsible of the data collection on the
 electronic Case Report Forms (eCRFs). The principal investigator or delegate will review all
 the data on the eCRFs and will sign to verify he has reviewed the data collected. Original
 anonymized paper support forms will be stored in a secure place and manner at each
 participating centre. Anonymization codes will be stored in a safely manner by the local
 principal investigator. Access to the online study data (eCRFs) will be restricted through
 passwords. In addition, centre coordinators will only have access to their own centre's data.
 Paper files will be physically stored until 5 years after the completion of the study

 Data management

 Source documents shall be created and maintained by the investigation site team throughout
 the clinical investigation. The data reported on the eCRFs shall be derived from, and be
 consistent with, these source documents, and any discrepancies shall be explained in writing.
 The eCRFs shall be signed and dated by the principal investigator or a delegated
 investigator. Any change or correction to data reported on a paper CRF shall be dated,
 initialed and explained if necessary, and shall not obscure the original entry.

 Traceability of documents and data

 The investigator shall ensure accuracy, completeness, legibility and timeliness of the data
 reported to the principal investigator on the eCRFs and in all required reports. When copies
 of the original source document as well as print outs of original electronic source documents
 are retained, these shall be signed and dated by a member of the investigational site team
 with a statement that it is a true reproduction of the original source document.

 Protocol deviation

 A protocol deviation is defined as a situation in which there is a non-compliance with the
 protocol. The following situations are considered protocol deviations and must be
 appropriately documented:

 1. Patient assigned to Group 1 or 2 and with a good quality CMR is not treated in his
 predefined group.

 2. Patient assigned to control group undergo good quality CMR, which is used to plan
 ablation strategy.

 3. Patient assigned to control group undergo good quality CMR and eventually a CMR-guided
 or aided ablation.

 4. Amiodarone is not discontinued at 1 month Follow-up.

 5. ICD is not programmed following guidelines, as previously stated.

 6. Patient without SHD, or in presence of other exclusion criteria, is enrolled in the
 study.

 Investigators will be required to adhere to the investigational plan, signed investigator's
 agreement, applicable national or local, laws and regulations, and any conditions required by
 the appropriate Ethics Committees or applicable regulatory authorities. The reporting of all
 the deviations will be performed through the electronic case report form (e-CRF) application.
 In the event of repeated protocol deviation as determined by the principal investigator, a
 clinical research associate or clinical representative will attempt to secure compliance by
 one or more of the following actions: 1) contacting the investigator by telephone, or 2)
 contacting the investigator in writing.

 Statistics

 All applicable statistical tests will be 2-sided and will be performed using a 5%
 significance level. Continuous variables will be reported as mean ± standard deviation, or
 median (range or interquartile range if data are skewed) if not normally distributed; these
 variables will be compared using Student's t-test if normally distributed, Aspin-Welch test
 if normally distributed with unequal variance demonstrated using Variance-ratio F-test, or
 Mann-Whitney U test if not normally distributed. Categorical variables will be expressed as
 total number (percentage) and will be compared by chi-squared test. As far as the primary
 endpoint, data will be analyzed according to the intention-to-treat principle. Survival free
 from ventricular arrhythmia, will be evaluated using a time-to-first-event analysis with the
 Logrank test and the Kaplan-Meier cumulative event rate. A multivariable Cox proportional
 hazards model will be performed to investigate the effects of baseline characteristics in
 predicting ablation results.

 Event definitions

 Adverse event: any untoward medical occurrence in a clinical trial participant that does not
 necessarily have a causal relationship with the treatment.

 Adverse reaction: any untoward or unintended response to an investigational therapy.

 Serious adverse event: any untoward medical occurrence that

 -  Results in death

 -  Is life-threatening

 -  Requires inpatient hospitalization or causes prolongation of existing hospitalization

 -  Results in persistent or significant disability/incapacity,

 -  May have caused a congenital anomaly/birth defect, or

 -  Requires intervention to prevent permanent impairment or damage.

 Event registration and causal relationship

 All adverse events judged by an investigator as having a reasonal possibility of a causal
 relationship to an investigational therapy would qualify as an adverse reaction. The
 expression "reasonable causal relationship" means to convey, in general, that there is
 evidence or argument to suggest a causal relationship.

 Event reporting

 Any adverse event will be stored in the eCRF and reported to the principal investigator, the
 local Institution Review Board and the Ethics Committee according to the ICH Guideline for
 Clinical Safety Data Management and the 2016 EMA/CHMP/ICH/135/1995 Guideline for good
 clinical practice E6(R2).

 Funding

 The project will receive government funding from the only sponsor Regione Toscana according
 to the "Bando Ricerca Salute 2018 - D.D n.975, 16/1/2020".

 Role of the sponsor (Tuscan region)

 According to Regional Law 20/2009 the research project has already undergone initial
 evaluation and approval by the sponsor and will undergo further scrutiny during the
 preliminary phase, during enrollment and after study completion. Technical financial reports
 will be filed to the sponsor mid-enrollment and upon study completion.

 The sponsor will not play any role in patient selection and trial management.

 Insurance

 A Trials insurance will provide protection for the sponsors/organisers of clinical trials,
 covering their legal liability to pay compensation in the event of an injury to a trial
 participant. The coverage of insurance cost is included in the budget of the funding received
 from the sponsor.

 Review of data

 The clinical investigation will be monitored by reviewing the e-CRF submitted by the
 investigators. The following activities will occur:

 -  All e-CRFs will be reviewed for completeness and accuracy upon receipt by the principal
 investigator or delegate.

 -  The investigator (co-investigator) and/or delegate will be contacted by the principal
 investigator regarding any missing or unclear data.

 An interim analysis will be conducted after 12 month since the first patient enrollment to
 evaluate the enrollment rate, the initial results and other factors which reflect the overall
 progress and integrity of the study.

 Clinical committee for Data Monitoring

 The monitoring of data accuracy will be performed by principal investigator or delegate as
 previously stated (see review of data). No external clinical committee are considered for
 this task.

 Protocol amendments

 Any modifications to the protocol which may impact on the conduct of the study, potential
 benefit of the patient or may affect patient safety, including changes of study objectives,
 study design, patient population, sample sizes, study procedures, or significant
 administrative aspects will require a formal amendment to the protocol. Any amendment to the
 protocol will be notified to the Ethical Committee, to the sponsor and to all participating
 centres.

 Ethics and Disseminations

 This protocol is in line with the standard ethic principles for clinic research and good
 clinical practice according to the ICH Guideline for Clinical Safety Data Management and the
 2016 EMA/CHMP/ICH/135/1995 Guideline for good clinical practice E6(R2), and must be reviewed
 and approved by the local institutional review board (IRB) of each centre.

 Informed consent form

 Any subject admitted as outpatient or inpatient at one the participating centres diagnosed
 with VT will be scrutinized for study participation. Patients deemed suitable to join the
 trial according to eligibility criteria will be asked informed consent for study enrolment.
 Patients willing to participate and diagnosed with SHD will be assigned to a Group according
 to protocol. Patients under 18 will not be screened according to eligibility criteria.
 Patients permanently or temporarily lacking legal capacity will not be screened. Patients
 eligible to join an interventional Group (1 and 2) will be randomized within 1 month since
 study enrolment.

 Confidentiality

 All study-related information will be stored securely at the study site up to 7 years after
 the end of the study. All participant information will be stored in locked file cabinets in
 areas with limited access. All laboratory specimens, reports, data collection, process, and
 administrative forms will be identified by a coded ID number only to maintain participant
 confidentiality. All records that contain names or other personal identifiers, such as
 locator forms and informed consent forms, will be stored separately from study records
 identified by code number. All local databases will be secured with password-protected access
 systems.

 Conflicts of interest

 Dr. Berruezo is a stockholder in Galgo Medical SL and has received financial support from
 Siemens Healthcare. The other authors have no other relevant affiliations or financial
 involvement with any organization or entity with a financial interest in or financial
 conflict with the subject matter or materials discussed in the study apart from those
 disclosed.

 After beginning of the project and financial coverage by the Tuscany region, other
 investigators will be defined (personnel with fixed-term employment relationships
 specifically hired for the project) for data management, study monitoring and Core Lab
 institution.

 Data property

 Project Principal Investigators will have direct access to their own site's data sets and may
 access to other sites' data only by request. To ensure confidentiality, data dispersed to
 project team members will be blinded of any identifying participant information.

 Dissemination policy

 The study results will be released to the participating physicians, referring physicians,
 patients and the general medical community during medical congresses or through publication,
 expected after the end of follow-up. The principal investigator of the coordinating centre of
 the study will take the decision to submit the report for publication and will have ultimate
 authority over all the activities.
Inclusion Criteria:

 -  Indication for VT ablation in patients with SHD (indications according to the 2015 ESC
 Guidelines for the management of patients with ventricular arrhythmias and the
 prevention of sudden cardiac death);

 -  Structural heart disease (clinical history, EKG, multimodality imaging)

 -  Signed informed consent;

 Exclusion Criteria:

 -  Age <18 y;

 -  ICD not already implanted nor expected within 1 month;

 -  High probability of non-adherence to the follow-up requirements (due to social,
 psychological or medical reasons);

 -  Inability to give written informed consent;

 -  Pregnancy (suspected or confirmed);

 -  Acute coronary syndrome in the previous 3 months;

 -  Creatinine clearance < 15 ml/min (stage 5 CKD) (according to clinical history or
 out/in-patient tests performed upon enrollment)

 -  Severe chronic liver disease (Child-Pugh score C) (according to clinical history or
 out/in-patient tests performed upon enrollment)

 -  Heart surgery for valve disease in the previous 6 months or expected within 6 months,

 -  NYHA functional class IV heart failure or CCS functional class IV angina

 -  Previous VT ablation (redo procedure).

 -  Systemic illness likely to limit survival to < 1 year