Aligned Clinical Protocol And Assessment Report

129 Pages·2011·12.08 MB·English

D3.1 Aligned Clinical Protocol and Assessment Sim-e-Child (SeC)
Report FP7-ICT-2009-4

FP7-ICT-2009-4 (248421)
SeC
Sim-e-Child

Collaboration Project

Thematic Priority: ICT

Deliverable D3.1
Aligned Clinical Protocol and Assessment Report

Due date of delivery: 31 May 2010

Actual submission date: 31 August 2011

Start date of project: 1 January 2010
Ending date: 30 June 2012

Partner responsible for this deliverable: OPBG

Revision 2

Project co-funded by the European Commission within the FP7
Dissemination level
RE Restricted to a group specified by the consortium
1
D3.1 Aligned Clinical Protocol and Assessment Sim-e-Child (SeC)
Report FP7-ICT-2009-4

Document Classification

Title Aligned Clinical Protocol and Assessment
Report
Deliverable D3.1
Reporting Period January 2010 - October 2010
Authors
Workpackage WP3 - Clinical Protocol and Data Alignment
Security Restricted
Nature Report
Keywords

Document History

Name Remark Version Date
Martin Huber Template 0.1 15.04.2010
Martin Huber 1.0 28.05.2010
Benedetta Leonardi Added OPBG protocols 1.1 20.07.2011
Michael Suehling Reviewed document and 1.2 22.07.2011
revised clinical validation
section
Edwin Morley-Fletcher 1.3 03.08.2011
Allen Everett Reviewed and edited 1.4 23.08.2011
document (added clinical goals
and validation studies)
Benedetta Leonardi Revised clinical goals and 1.5 25.08.2011
validation section
Michael Suehling Review and minor edits 2.0 30.08.2011

Sim-e-Child Consortium
The partners in this project are:

01. Siemens AG (Siemens)
02. Lynkeus Srl (Lynkeus)
04. maat France (MAAT)
05. Technische Universität München (TUM)
06. I.R.C.C.S. Ospedale Pediatrico Bambino Gesù (OPBG)
07. Siemens Corporate Research, Inc. (SCR)
08. Johns Hopkins University (JHU)
10. American College of Cardiology Foundation (ACCF)
11. Siemens Program and System Engineering srl (PSE)

List of contributors

Name Affiliation Co-author of
Allen Everett JHU
Giacomo Pongiglione OPBG
Benedetta Leonardi OPBG
2
D3.1 Aligned Clinical Protocol and Assessment Sim-e-Child (SeC)
Report FP7-ICT-2009-4

Gerard Martin ACC
Razvan Ionasec SCR
Martin Huber Siemens
Michael Suehling Siemens
Edwin Morley-Fletcher Lynkeus

List of reviewers

Name Affiliation
Allen Everett JHU
Giacomo Pongiglione OPBG

3
D3.1 Aligned Clinical Protocol and Assessment Sim-e-Child (SeC)
Report FP7-ICT-2009-4

Table of Contents
1. INTRODUCTION...........................................................................................................................6
1.1. COARCTATION OF THE AORTA (COA).............................................................................6
1.2. THORACIC AORTIC ANEURYSMS.....................................................................................6
1.3. ABBREVIATIONS............................................................................................................7
1.4. REFERENCES................................................................................................................8
2. CLINICAL PROTOCOL OVERVIEW............................................................................................9
3. OPBG PROTOCOLS FOR AORTIC COARCTATION AND ANEURYSMS...............................10
3.1. IMAGE EVALUATION.....................................................................................................12
3.1.1. Transthoracic Echocardiography in COA and Thoracic Aortic Aneurysm Patients12
3.1.2. Cardiac Magnetic Resonance in Coarctation and Aortic Aneurysm Patients.....14
3.1.3. Data Quality Assurance......................................................................................17
4. THE COAST PROTOCOLS FOR AORTIC COARCTATION.....................................................19
4.1. COAST CLINICAL PROTOCOLS....................................................................................20
4.1.1. Demographics.....................................................................................................20
4.1.2. Study Termination...............................................................................................21
4.1.3. Baseline Characteristics.....................................................................................22
4.1.4. Screening and Enrollment...................................................................................25
4.1.5. Pre-Implant Catherization, Implant Catherization, Post-Implant Catherization...27
4.1.6. Post-Implant Echo...............................................................................................35
4.1.7. Follow-Up............................................................................................................36
4.1.8. Adverse Events...................................................................................................39
4.1.9. Unanticipated Adverese Device Effects..............................................................43
4.1.10. Surgical Intervention...........................................................................................44
4.1.11. Reinterventions...................................................................................................45
4.1.12. MRI or CT Scan..................................................................................................50
4.1.13. Fluroscopy..........................................................................................................52
4.1.14. Angiography........................................................................................................53
4.1.15. Study Deviation...................................................................................................55
4.1.16. Death Report.......................................................................................................57
5. THE HEALTH-E-CHILD PROTOCOLS FOR REPAIRED TETRALOGY OF FALLOT..............58
5.1. PROTOCOL CHANGES IN SIM-E-CHILD..........................................................................58
5.2. HEALTH-E-CHILD PROTOCOLS FOR REPAIRED TETRALOGY OF FALLOT..........................59
5.2.1. Demographics, family and clinical history...........................................................59
5.2.2. Physical examination..........................................................................................68
5.2.3. Exercise Testing.................................................................................................75
5.2.4. Imaging and ECG...............................................................................................79
6. DATA PROTOCOL COMMONALITIES AND ALIGNMENT ......................................................83
6.1. DATA PROTOCOL COMMONALITIES BETWEEN AORTIC COARCTATION AND THORACIC AORTIC
ANEURYSM PROTOCOLS...........................................................................................................83
6.2. COMMONALITIES AND ALIGNMENT BETWEEN OPBG AND COAST PROTOCOLS..............83
7. CLINICAL ASSESSMENT OF PATIENT-SPECIFIC HEART MODELS AND SIMULATIONS..85
7.1. ASSESSMENT OF MODEL ACCURACY AND ROBUSTNESS...............................................85
7.1.1. Left-Heart Chambers – Left Ventricle.................................................................85
4
D3.1 Aligned Clinical Protocol and Assessment Sim-e-Child (SeC)
Report FP7-ICT-2009-4

7.1.2. Left-Heart Valves – Aortic Valve and Mitral Valve..............................................86
7.1.3. Aorta...................................................................................................................87
7.2. CLINICAL VALIDATION AND IMPACT ON DIAGNOSIS AND THERAPY DECISIONS.................88
8. ANNEX1: THE GENTAC PROTOCOLS FOR THORACIC AORTIC ANEURYSMS.................91
8.1. GENTAC CLINICAL PROTOCOLS..................................................................................92
8.1.1. Clinical Evaluation...............................................................................................92
8.1.2. Patient Enrollment...............................................................................................96
8.1.3. Family History...................................................................................................106
8.1.4. Imaging.............................................................................................................114
8.1.5. Genetics............................................................................................................119
8.1.6. Interventions.....................................................................................................120

5
D3.1 Aligned Clinical Protocol and Assessment Sim-e-Child (SeC)
Report FP7-ICT-2009-4

1. Introduction

This document mainly describes clinical data acquisition and its usage within Sim-e-Child. In
particular, the document explains
• The clinical protocols used for acquiring the data utilized,
• The clinical assessment procedures for validating the patient-specific models and simulations
developed.

The document is organized as follows. First, the remainder of this section gives a brief overview and
clinical background on aortic coarctation and thoracic aortic aneurysms, which are the main two
diseases targeted in Sim-e-Child. Section 2 gives a brief overview about the different data sources
utilized. Each of them is then described in detail in Sections 3, 4 and 5. For completeness, the GenTAC
protocol is described in the appendix, Section 8, although it turned out to be not suited for the special
needs of this project. Section 6 concludes the data protocol section by describing the commonalities and
the alignment between the different data sources. The clinical assessment and validation procedures
based on the described imaging protocols are then described in Section 7.
1.1. Coarctation of the Aorta (COA)
Coarctation of the aorta (COA) represents one of the most common congenital cardiac lesions and
accounts for ≈ 5-10% of all cases of congenital heart disease. It is a discrete narrowing most commonly
located just distal to the left subclavian artery at the site of insertion of the ductus arteriosus. Hypoplasia
and elongation of the distal transverse arch are frequently associated with COA. Treatment options for
COA include surgical approaches, transcatheter balloon angioplasty or stent placement. The mortality
associated with surgical repair is less than 1%, but it is higher for reoperation and in adult population.
However, the possible complications have to be taken into due consideration (paraplegia due to spinal
cord ischemia, recurrent laryngeal nerve palsy, phrenic nerve injury, aneurysm and pseudoaneurysm
formation). Consequently, percutaneous balloon angioplasty, with or without stent implantation, is the
preferred treatment for recurrent postsurgical COA in the absence of confounding features such as
aneurysm or pseudoaneurysm formation, or significant coarctation that affects the adjoining arch arterial
branches. However, percutaneous treatment for unoperated COA in the young children remains still
controversial. For localized discrete narrowing of the native aorta, transcatheter balloon angioplasty or
stent placement, can be now an acceptable alternative surgery in adults as a primary intervention;
however, it is still considered less suitable for long segment or tortuous form of coarctation. The problem
of greater concern for patients with native coarctation associated with percutaneous approach is the
formation of aneurysms following the procedure. Anyway, intermediate and long-term follow-up after
aortic stent implantation have been poorly documented and only very few of the series focusing on aortic
stent included a considerable number of patients. Many questions remain on the choice between the
surgical repair and the percutaneous approach. It could be the case that automatic patient-specific 3D
aortic arch geometrical model estimation from MRI images may provide a better understanding of the
geometry of the aortic arch anomaly and prove to be useful to preoperatively evaluate the best
treatment.
1.2. Thoracic Aortic Aneurysms
Ascending aortic disease can have devastating effects on affected individuals, resulting in severe
morbidities including aneurysms, tears, dissections, hemopericardium and associated aortic valve
diseases. Although rare, it is an important cause of mortality in children and young adults. There is no
6
D3.1 Aligned Clinical Protocol and Assessment Sim-e-Child (SeC)
Report FP7-ICT-2009-4

certain data on the incidence of the aneurysms in the paediatric population. In Puranik R et al study,
aortic dissections were found in 5.4% of autopsies performed for sudden cardiac deaths in young
individuals. Despite several recent case studies that have evaluated the histopathology of the ascending
aorta, the etiologies of most cases in young adults were unclassified. Aneurysm in young individuals
generally occurs in the setting of an inherited disorder. Among genetic disorder, a common final
aberration is an up-regulation of tumor grown factor (TGF) β activity in the ascending aorta. These
“TGFβ –myopathies include Marfan syndrome (MFS), Loeys – Dietz syndrome (LDS), Ehlers – Danlos
syndrome type IV, arterial tortuosity syndrome, autosomical dominant polycystic kidney disease and
autosomical recessive cutis laxa type I. In addition, ascending aortic illness can be associated with
bicuspid aortic valve (BAV) disease, secondary to abnormalities of the aortic media, independently of the
severity of valve dysfunction (Debl et al, Clin Res Cardiol 2009; 98; 114-120). Indeed the BAV, the most
common congenital cardiac defect, with a prevalence estimated between 0.5 and 2%, induce to have an
increased risk of progressive aortic dilatation and dissection, 5-9 times higher than in the general
population (Lewin MB, Circulation 2005; 111: 832-834). Several authors have shown that dilatation of the
ascending aorta is an independent risk factor for ascending aorta surgery in BAV population.
Furthermore, although dissection is more common in patients with dilated aortas, there are reports of
dissection in normal–sized aortic roots and after valve replacement. Consequently, special care is
needed in the evaluation of aortic dilatation in patients with BAV even without evidence of severe valve
dysfunction. Ascending and descending aortic aneurysm may develop also in adults with COA, despite
successful surgical repair in childhood. In addition, aneurysm formation at or near the site of repair
seems to be related not only to surgery but also to transcatheter relief of the coarctation. The
independent risk factors for aortic wall complications in COA patients appear to be the advanced age
and the BAV. In fact, the frequent association between COA and BAV would identify a more severe form
of aortic wall disease, representing part of the spectrum of a diffuse arteriopathy. Therefore evaluation of
aortic dilatation in these patients must be treated as a continuum and should utilize accurate and
sensitive modality for aortic arch anatomy as cardiac magnetic resonance (CMR) and/or CT. Adults with
COA, mostly when associated with a BAV, should be closely followed up to detect progressive aortic
dilation, especially because timing of surgical repair of aortic dilation is still being debated. Therefore,
accurate quantification of the morphology of aortic arch and its hemodynamic is absolutely necessary for
the medical treatment strategies and timing of intervention. Patient specific anatomy can be extracted
automatically from 3D CMR or CT images by segmentation approaches and geometrical representative
computational models of the vasculature can be created. However CMR has advantages over CT
because it allows physiologic assessment of the patient, using phase-contrast magnetic resonance
imaging. Indeed, with phase-contrast magnetic resonance imaging and blood pressure, it might be
possible to create 3D, time-varying representation of the hemodynamics of the singular case. Therefore,
3D automatic modelling of the aortic arch could provide greater understanding of this complex pathology
and assist the cardiologist to choose the best type of percutaneous or surgical approach and timing of
repair.
1.3. Abbreviations

HeC Health-e-Child
SeC Sim-e-Child
ToF Tetralogy of Fallot
ASD Atrial septal defect
CMP Cardiomyopathy
RVO Right ventricular overload
COA Coarctation of the aorta
MR Magnetic Resonance or Magnetic Resonance Imaging
7
D3.1 Aligned Clinical Protocol and Assessment Sim-e-Child (SeC)
Report FP7-ICT-2009-4

CT Computed Tomography
DICOM Digital Imaging and COmmunications in Medicine (ACR-NEMA 3.0) - the
DICOM standard facilitates interoperability of medical equipment by
addressing the exchange of digital information.
CRF Case report form
ECG Electrocardiography
CPEX Cardio-pulmonary exercise testing
LV, RV Left ventricle, right ventricle
LA, RA Left atrium, right atrium
WSS Wall shear stress
OSI Oscillatory shear index
CFD Computational fluid dynamics

1.4. References

[1] Health-e-Child “Project Proposal, Annex I: Description of Work, Project Phase IV”

[2] Sim-e-Child “Project Proposal, Annex I: Description of Work”

[3] COAST Worksheets, Version 2009_0710; COAST trial:
http://www.clinicaltrials.gov/ct2/show/NCT00552812?term=coast&rank=2

[4] GenTAC Case report forms, https://GenTAC.rti.org

[5] Health-e-Child clinical protocols, deliverable “D9.1 Report on Diagnostic Coding System”

8
D3.1 Aligned Clinical Protocol and Assessment Sim-e-Child (SeC)
Report FP7-ICT-2009-4

2. Clinical Protocol Overview

To a large extent, Sim-e-Child is a retrospective study relying on patient data already acquired by the
participating hospitals in clinical routine or the context of a clinical trial. In particular, Sim-e-Child mainly
utilizes the following sources of existing patient data:

Data from the US Food and Drug Administration “Coarctation Of the Aorta Stent Trial (COAST)” stent
safety trial for aortic coarctation. The protocol is described in detail in Section 4. In addition, on the basis
of the previous protocols, P8 JHU coordinates the enrolment of patients with aortic coarctation, either
after the first diagnosis or after any treatment, as well as patients with thoracic aortic aneurysm.

The Health-e-Child database for repaired Tetralogy of Fallot (mainly used for right ventricular model
validation). The corresponding protocols are described in Section 5.

Data acquired according to the GenTAC protocols for thoracic aortic aneurysms were also evaluated
and assessed for usage within Sim-e-Child; however, during the first project period, it turned out that
data from the GenTAC trial was not suitable for the specific needs of this project because it lacks a
standardized MRI/CT imaging protocol, many data elements in the study are incomplete and lacks data
auditing/validation for accuracy and completeness. Nevertheless, for completeness, the GenTAC
protocols are summarized in the annex (Section 8).

In addition to the existing clinical trial data, P6 OPBG is acquiring data from clinical routine coarctation
and aortic aneurysm patients during the course of the project. The acquisition protocol is described in
Section 3.

The clinical protocols were discussed on April 22nd 2010 in Sestri Levante, Italy, one day before the
final Health-e-Child conference that took place at the same location. Allen Everett (JHU), Giacomo
Pongiglione (OPBG) and Gerard Martin (ACC) discussed the clinical protocols in presence of IT
representatives from Siemens and MAAT. Since each of these data sources originates from a multi-
centre clinical study or research project, each of the corresponding clinical protocols has been carefully
designed and successfully been used over multiple sites and multiple years. Basically, no changes are
needed for Sim-e-Child. For each data source, significant amounts of very specific information are
necessary to guarantee the clinical goals of each study. To stay focused on the Sim-e-Child project
goals, information irrelevant for the validation of the developed modelling and simulation will not be
covered in the integrated Sim-e-Child data model (e.g. details regarding the catheterization and implants
in the COAST trial). This means that a subset of the existing protocols will be used in Sim-e-Child and
semantically mapped into the Web-based SciPort data base. Section 6 summarizes the communalities
between the COAST and OPBG data protocols that are mainly used for the cardiac and aortic modelling
and simulation within the project. The technical details of the data model mapping and integration are
described in the more technical deliverable “D3.2, Data Model Mapping Report”. Nonetheless, as a
reference, the complete data protocols are presented in this document.

9
D3.1 Aligned Clinical Protocol and Assessment Sim-e-Child (SeC)
Report FP7-ICT-2009-4

3. OPBG protocols for Aortic Coarctation and Aneurysms

This section describes the data protocol used by P6 OPBG for the data acquisition from aortic
coarctation and thoracic aortic aneurysm patients. The following tables reflect the general data elements
that are collected for each patient.

Basic Demographic
Height
Weight
Body surface area (bsa)
Age (years)
Gender (male o female)
Race
Heart rate
Blood pressure

Diagnosis
a. Marfan syndrome
b. Turner syndrome
c. Ehlers-Danlos syndrome, vascular type
d. Ehlers-Danlos syndrome, other types and with aortic enlargement
e. Loeys- Dietz syndrome
f. FBN1, TGFBR1, TGFBR2, ACTA2 or MYH11 genetic mutation
g. BAV with aortic enlargement, family history not required
h. BAV with family history
i. BAV with coarctation
j. Shprintzen – Goldberg syndrome
k. Familial thoracic aortic aneurysm and dissections with aortic
enlargement
l. Other aneurysms/dissections of the thoracic aorta in people< 50 years of
age
m. Other congenital disease with aortic enlargement (Tetralogy of Fallot)
n. 1 degree family member of proband already enrolled in the registry

Approximate age at earliest diagnosed above condition: ……Years
Ever diagnosed with a thoracic aortic aneurysm, dissection/rupture, or marked tortuosity?
Diagnostic criteria and organ system review

MUSCULOSKELETAL
1. pectus carinatum
2. pectus exacavatum
3. shield chest, broad with widely spaced nipples
10