Long-term Outcomes and Vascular Evaluation After Coarctation of the Aorta Treatment (LOVE-COARCT)

August 24, 2017 updated by: Centro Hospitalar de Lisboa Central

LOVE-COARCT Study: Long-term Outcomes and Vascular Evaluation After Coarctation of the Aorta Treatment

Background: Coarctation of the aorta (CoA) can be treated using surgery, balloon angioplasty or stent implantation. Although short-term results are excellent with all three treatment modalities, long term cardiovascular (CV) morbidity and mortality remain high, likely due to persistently abnormal vascular function. The effects of treatment modality on long term vascular function remain uncharacterized. The goal of this study is to assess vascular function in this patient population for comparison among the treatment modalities. Methods: Vascular function in large and small arteries will be prospectively assessed fusing multiple non-invasive modalities, and the results will be compared among the three groups of CoA patients previously treated using surgery, balloon angioplasty or stent implantation after frequency matching for confounding variables. A comprehensive vascular function assessment protocol was created to be used in 7 centers. The primary outcome is arterial stiffness measured by arterial tonometry. Inclusion and exclusion criteria were carefully established after consideration of several potential confounders. Sample size was calculated for the primary outcome variable. Conclusions: Treatment modalities for CoA may have distinct impact on large and small arterial vascular function. The results of this study will help identify the treatment modality that is associated with the most optimal level of vascular function, which, in the long term may reduce CV risk.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Study overview. This cross-sectional prospective observational study of patients with CoA previously treated using one of three treatment modalities assesses if treatment type is associated with differences in vascular function. The three treatment groups will be frequency-matched for key confounding variables.

Study feasibility. The investigators assembled a multi-disciplinary team with proven expertise in epidemiology, clinical trial design, congenital heart disease, non-invasive imaging, interventional cardiology, vascular function assessment, preventive cardiology and statistical analysis. A multicenter design is used to ensure sufficient statistical power in evaluating the hypothesis.

Participating centers and study core laboratories. Patients are recruited at six large pediatric cardiac centers from Portugal and USA.

Screening procedures. The medical records of potentially eligible patients are screened by a local study investigator using a pre-specified screening form to ensure that they satisfy our selection criteria.

Overview of the study workflow. Study procedures will occur in a one- or two-day visit. Upon arrival for testing, formal consent for participation will be obtained. Assessment of arterial stiffness, endothelial function, and blood sampling for biomarkers will be done while fasting. Cardiopulmonary stress test will be performed on the same day. CMR and ambulatory blood pressure monitoring (ABMP) will be arranged for the same or for the following day. When the study tests cannot be completed at the first visit, they will be completed within 3 months of the first visit. The study protocol was approved by the Institutional Review Board or Institutional Ethics Committee at each participating center, and informed consent and assent will be obtained, depending on age, from patients and their parents/legal guardians before trial enrollment.

Recruitment. A review of the patient database at each participating institution will be performed to assemble a cohort of patients with CoA who have previously undergone treatment with balloon dilation, surgery or stenting. Study data will be collected and managed using REDCap electronic data capture tools hosted at Boston Children's Hospital.

Data collection. A retrospective chart review will be performed to collect demographic and clinical data including severity of coarctation, type and details of CoA treatment and presence of associated conditions.

Diagnostic procedures.

Arterial Stiffness Plan & Rationale:

Measurements: Carotid-femoral PWV (cfPWV) will be measured using applanation tonometry. Segmental PWV is measured using CMR. Segmental measures of arterial distensibility will be measured using CMR. Other parameters that describe arterial stiffness reflect the relationship of arterial change in diameter to change in pressure and include aortic strain (relative change in diameter), compliance (absolute change in diameter in response to a change in pressure), distensibility (relative change in diameter in response to a change in pressure), and the aortic stiffness β index (distensibility using the logarithmic conversion of the relative pressure). Applanation tonometry, which uses a probe or tonometer to record the pulse wave with a transducer, is the most widely accepted method for estimating PWV and both the NIHem (Cardiovascular Engineering, Inc., Norwood, MA USA) and the SphygmoCor (AtCor Medical, West Ryde, NSW, Australia) devices have been validated in large cohort trials. Both devices will be used, based on local availability.

Endothelial Function Measurements: Endothelium-dependent reactive hyperaemia index and augmentation index will be measured using the EndoPAT 2000 system (Itamar Medical, Caesarea, Israel). The protocol includes measures to minimize the influence of the autonomic nervous system.

Pulse Waveform Analysis: Central aortic pressure and pulse pressure will be measured using applanation tonometry). Augmentation index will be measured using applanation tonometry and Endo-PAT. CAP, PP and AIx can be measured non-invasively using radial or carotid applanation tonometry (and Endo-PAT for AIx), calibrated by the peripheral diastolic and mean arterial pressure. Both the NIHem system and the SphygmoCor device were used.

Blood Pressure Phenotype will be measured using conventional standard techniques including auscultatory right arm BP measurement, measurement of BP gradient between arm and leg, BP response during treadmill exercise stress testing (ET) and ABPM. Based on the auscultatory BP and ABPM results, the appropriate children and adult guidelines will be used to classify patients. Patients currently on antihypertensive medication will be classified as hypertensive.

Biomarkers: The researchers will measure biomarkers of endothelial function (total oxides of nitrogen- NOx and ADMA), inflammation (hs-CRP), vascular wall function (VCAM-1 and IL-1β) and vascular remodeling (MMP-2; MMP-9 and TGF-beta1). NOx will be determined by chemiluminescence (Sievers NOAnalyzer 280i) and all remaining measurements will be performed with appropriate enzyme-linked immunosorbent assay (ELISA) kits: ADMA (Sunred Biological Technology, Shanghai, China); hs-CRP (BoosterBio, Pleasanton, USA); VCAM-1; IL-1β; MMP-9; MMP-2 and TGFβ-1 (RayBiotech, Inc. Norcross, USA).

Left Ventricular Mass Assessment by CMR. The altered blood pressure phenotype that persists after CoA treatment represents an increase in afterload that leads to LV hypertrophy. Our CMR protocol will include sequences that allow this quantification.

Cardiovascular Health Assessment: The researchers will assess health factors (blood pressure, total cholesterol, plasma glucose), behaviors (smoking, body mass index BMI, physical activity and diet) and family history of cardiovascular disease and risk factors. A questionnaire was implemented to assess family history of CV disease and ICVH according to the procedures and recommendations of the American Heart Association.

Statistical Considerations. The treatment groups will be frequency-matched for documented confounders. The confounding variables will include: (a) Age at treatment; (b) Current age; (c) Bicuspid aortic valve as it is associated with impaired aortic elasticity. Because of the relatively large number of matching variables and three treatment groups, matching individual subjects was not feasible. During analysis, the treatment groups will be compared for each of these confounding variables and appropriate adjustments made, if needed. Differences in the confounding variables across the three treatment groups will be evaluated using Fisher's exact test for severity of coarctation and the Kruskal-Wallis test for age at treatment, current age and bicuspid aortic valve. The primary outcome variable will be carotid-femoral PWV assessed by tonometry. Differences in cfPVW across groups will be explored using one-way analysis of variance. If differences in matching variables are detected among the groups, adjustment will be made using analysis of covariance. Post-hoc analyses will be performed as necessary.

Sample size estimates were obtained based on prior data that show that ascending- descending PWV measured by CMR is 3.3±0.6 m/s in normal subjects and 4.7±1.1 m/sec after CoA surgery.22, 70 Sample size estimates for comparison of PVW between three equal sized treatment groups (assuming overall significance level=0.05 and power=0.8) are shown in table 2. The investigators plan on recruiting 24 to 30 patients in each group for a total sample size of 72 to 90.

Study Type

Observational

Enrollment (Anticipated)

90

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Portugal
      • Lisboa, Portugal, 1169-024
        • Recruiting
        • Department of Pediatric Cardiology, Hospital de Santa Marta, Centro Hospitalar de Lisboa Central
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

8 years to 35 years (ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients with isthmic coarctation of the aorta, treated after 1994, submitted to only one of either of the three procedures described above.

Description

Inclusion Criteria:

  • Diagnosis of isthmic coarctation of the aorta;
  • Current age between 8 (to allow cooperation with study procedures) and 35 years (to avoid confounding by aging-related vascular dysfunction); and
  • Treatment for CoA after 1994, after which all three modalities were in clinical use.

Exclusion Criteria:

  • Residual CoA defined by a systolic upper-to-lower extremity BP gradient> 20mmHg;
  • Co-morbidities that may independently affect vascular function, including associated significant congenital heart disease, history of known vasculopathy, genetic syndromes or other cardiovascular risk factors;
  • History of two treatment types for CoA; and
  • CoA types likely representing a different entity or patients amenable to one single treatment type (surgery), including atypical CoA site (such as mid-thoracic or abdominal), severe hypoplasia of the aortic arch, and an age of treatment <1 year of age.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
surgery
Primary end-to-end surgical treatment of coarctation of the aorta
Procedure: Surgery
Primary end-to-end surgical treatment of coarctation of the aorta
balloon dilation
Primary balloon dilation treatment of coarctation of the aorta
Procedure: Balloon dilation
Primary balloon dilation treatment of coarctation of the aorta
stent
Primary stent dilation treatment of coarctation of the aorta
Procedure: Stent
Primary stent dilation treatment of coarctation of the aorta

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Vascular function
Time Frame: 6 months to 35 years after primary treatment
Arterial stiffness assessed with carotid-femoral PWV measurements by tonometry
6 months to 35 years after primary treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cardiac Magnetic Resonance functional indexes
Time Frame: 6 months to 35 years after primary treatment
Ascending-descending aorta PWV and aorta strain, distensibility, compliance and aortic stiffness β index measured by CMR
6 months to 35 years after primary treatment
Endothelial function
Time Frame: 6 months to 35 years after primary treatment
Endothelial function determined by endothelial pulse amplitude testing
6 months to 35 years after primary treatment
Pulse wave form
Time Frame: 6 months to 35 years after primary treatment
Pulse wave form analysis using arterial tonometry
6 months to 35 years after primary treatment
Blood pressure phenotype
Time Frame: 6 months to 35 years after primary treatment
Blood pressure phenotype at rest, during ambulatory measurement, and at peak exercise
6 months to 35 years after primary treatment
Left ventricular mass
Time Frame: 6 months to 35 years after primary treatment
Left ventricular mass assessed by Cardiac Magnetic Resonance
6 months to 35 years after primary treatment
Left ventricular systolic function
Time Frame: 6 months to 35 years after primary treatment
Left ventricular systolic function assessed by Cardiac Magnetic Resonance
6 months to 35 years after primary treatment
Biomarkers of endothelial function
Time Frame: 6 months to 35 years after primary treatment
biomarkers of endothelial function (total oxides of nitrogen- NOx and ADMA),
6 months to 35 years after primary treatment
Biomarkers of vascular inflammation
Time Frame: 6 months to 35 years after primary treatment
biomarkers of inflammation (hs-CRP).
6 months to 35 years after primary treatment
Biomarkers of vascular wall function
Time Frame: 6 months to 35 years after primary treatment
biomarkers of vascular wall function (VCAM-1 and IL-1β)
6 months to 35 years after primary treatment
Biomarkers of vascular remodeling
Time Frame: 6 months to 35 years after primary treatment
biomarkers of vascular remodeling (MMP-2; MMP-9 and TGF-beta1).
6 months to 35 years after primary treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Centro Hospitalar de Lisboa Central

Collaborators

Baylor College of Medicine
Children's Hospital Colorado
Boston Children's Hospital
University of Nebraska
Lucile Packard Children's Hospital
Centro de Estudos de Doenças Crónicas
Instituto Superior Técnico de Lisboa
Caselas, Ressonância Magnética, S.A.

Investigators

  • Principal Investigator: José D Martins, MD MSc, Centro Hospitalar de Lisboa Central
  • Study Chair: Miguel Mota Carmo, MD PhD, Centro de Estudos de Doenças Crónicas da Faculdade de Ciências Médicas da Universidade Nova de Lisboa

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

June 1, 2013

Primary Completion (ANTICIPATED)

September 30, 2017

Study Completion (ANTICIPATED)

December 30, 2017

Study Registration Dates

First Submitted

August 8, 2017

First Submitted That Met QC Criteria

August 24, 2017

First Posted (ACTUAL)

August 25, 2017

Study Record Updates

Last Update Posted (ACTUAL)

August 25, 2017

Last Update Submitted That Met QC Criteria

August 24, 2017

Last Verified

August 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CHLC.CI.69.2012

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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