Evaluation of cardiac magnetic resonance Imaging in follow up assessmenT of patients with
pulmonary Arterial hypertension (EVITA) is a prospective cohort study of cMRI in PAH.
EVITA is a multicenter biomedical research study. All the investigation centers belong to the
French network of severe pulmonary hypertension.
Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary
vascular resistance leading to right ventricular (RV) failure and eventually to death. The
therapeutic strategy has become complex and needs to perform recurring follow up evaluations
including right heart catheterizations (RHC). Although, RHC performed in experience centers
has low mortality and low morbidity, repeated invasive pulmonary hemodynamic measurements are
burdensome and still presents some risk of complications. Once the diagnosis of PAH is
established, follow up evaluation devoted to modifying specific therapy relies mainly on RV
function parameters. Thus, echocardiography and cardiac magnetic resonance imaging (cMRI)
meet many of the criteria of ideal monitoring tools.
Echocardiography is safe, inexpensive and widely available. However, this test has several
limitations. Firstly, due to the complexity of the right ventricle chamber, the measurement
of RV volumes is difficult. Secondly, criteria are numerous and for quantitative measurements
different thresholds are applied without accepted definition. Thirdly, operator dependency
could make it difficult to obtain reproducible images.
Cardiac MRI has the advantage to accurately assess RV volumes and important prognostic
predictors such as cardiac index, stroke volume (SV) and right ventricular ejection fraction
(RVEF).
It has been demonstrated that inter-observer and intra-observer variability for cMRI right
ventricle measures in PAH patients were low. In addition, MRI-derived cardiac index, SV and
RVEF significantly improved after few months of PAH specific therapy and had prognostic
values regardless of changes of pulmonary vascular resistance in few trials of small size.
In a preliminary study performed in the CHRU-Nancy the investigators found in 21 subjects
with PAH a significant correlation between cardiac output measured with cMRI and RHC (0.85,
p<0.001). Furthermore, the agreement between the 2 methods was correct according to
Bland-Altman plot.
The purpose of the present study is to investigate a strategy for assessing PAH severity. The
investigators propose to replace a currently recommended method, i.e. RHC, by cMRI.
The researchers plan to use validated cardiac MRI measurements of RV volumes and cardiac
output to demonstrate that cMRI can accurately assess the severity of the disease in a
follow-up strategy.
The objectives of this project are to show that an assessment of the severity of the disease
by a non-invasive pulmonary hemodynamic measurement using the cMRI is as effective as the
RHC, and that it is reliable and safe.
The primary objective is to assess the performance of the cMRI (sensitivity and specificity)
at baseline and during follow-up visits to detect an unfavorable hemodynamic state compared
to the results of the RHC (current guidelines).
The secondary objectives are:
1. To assess the predictive value of the first morbi-mortality event in 2 different
analyses derived, firstly from RHC criteria (cardiac index (CI)< 2.5 l/min/m² or a right
atrial pressure > or = 8 mm Hg) and secondly from cMRI criteria (CI < 2.5 l/min/m² or
RVEF < 35% or an absolute decrease of 10% of RVEF at a follow-up evaluation).
2. To assess the link between the first morbi-mortality event and New York Heart
Association (NYHA) functional class, 6-minute walk distance, plasma level of B-type
natriuretic peptide (BNP)/N-terminal(NT)-proBNP, and continuous hemodynamic variables
from cMRI, RHC and echocardiography, data collected at baseline and after 3-6 months of
follow-up in univariate analyses.
3. To assess the link between the first morbi-mortality event and the above factors,
identifying clinical and hemodynamic variables independently contributing to prognosis
in multivariate analyses. Using the results of this analysis the investigators plan to
build a multiparameter prognostic score.
4. To quantify complications due to cMRI and to RHC.
5. To compare acceptability and tolerability of cMRI over RHC for the patient.
6. To create a biobank for diagnosis and prognosis purposes This study is a prospective
cohort study. PAH patients will be recruited in 20 centers of the French network of
severe pulmonary hypertension.
A routine search for conditions known to cause pulmonary hypertension will be performed
according to current guidelines. Therefore, all patients will undergo at baseline an
echocardiography, an RHC and other routine tests.
A determination of NYHA functional class, BNP or NT-proBNP, 6-minute walk test and ECG 12
derivation should be performed at the earliest 2 days before the RHC during the screening
period. As a reminder, RHC and cardiac MRI should be performed within 5 working days. Other
examinations should be performed 12 months prior to the initial visit if the patient is
prevalent, or 3 months prior to the initial visit if the patient is an incident patient.
If any specific PAH treatment is already in place (less than one year prior to the date of
inclusion), it should be in stable dose for at least 1 month prior to the initial baseline
visit.
This will be the screening period. Then all patients selected will sign the written informed
consent of the main study, then the consent for the biobank if they accept them. The consent
for the genetic study may be obtained at these visits or at a follow-up visit (no later than
24 months).
The collection of blood samples on one vein of the forearms for the biobank (and possibly for
genetic analysis) will take place during this visit.
Subsequently, in the context of the study, a cMRI will be performed at the baseline visit
(V1).
According to the current guidelines shortly after the baseline visit (V1) PAH-specific drug
therapy will be initiated or associated to the treatment already in progress in incident
cases or prevalent cases, respectively.
The follow-up period will be 24 months. A comprehensive severity evaluation will be performed
after 3-6 months (V2 or V3) of the inclusion visit, after 24 months after the inclusion visit
(V9) and in case of clinical worsening. According to current guidelines, these follow-up
assessments will include NYHA functional class, 6-minute walk distance, plasma level of
BNP/NT-proBNP and RHC. As part of one of the secondary objectives, 22 ml of venous blood will
be collected during all RHC. During the visit 3-6 months (V2 or V3), 5 ml of blood from the
pulmonary artery will be taken. Throughout the 24-month follow-up, patients will be seen on
an outpatient basis every 3 or 6 months, depending on the practices of each center.
During the follow-up an echocardiography could be carried out at the discretion of the
investigator at any visit in accordance with the current recommendations. According to the
purpose of the present study, at all these visits a cMRI will also be performed.
All clinical procedures except cMRI and blood sample for the biobank, are those of standard
care.
Morbidity and mortality will be collected prospectively up to 48 months (maximum delay) or
until the last patient has completed his 24-month follow-up visit.
RHC will be performed according to currently recommended.
MRI data interpretation:
MRI protocol and post-processing guidelines will be sent prior to site initiation in order to
apply the same method of cMRI in all centers. This will avoid important measurement error.
RV contouring and indexed aortic flow measurement will be performed locally with the
dedicated software used in clinical practice by the physicians of each center. Cardiac index
and RVEF will be derived from these measures. All cMRI images will be sent and stored at the
CHRU Nancy. MRI interpretation will be performed blindly with respect of clinical and RHC
data.
All adverse events will be collected during the follow up. The questionnaire assessing
physical and psychological distress will be presented a few minutes after all RHC and all
cMRI.
180 subjects will be enrolled in the study: that size will give the study 90% power to find
significant at the 5%-level a sensitivity or specificity of:
- - 90% with a lower 95% confidence limit of 75%,
- 60% with a lower 95% confidence limit of 40%.
General considerations:
Analysis of primary and secondary endpoints will be performed in the intention-to-treat and
confirmatory analyses in the per-protocol populations. The 2-tailed significance level will
set to p<0.05.
Analyses to respond to the main objective:
The aim of the trial is to assess the sensitivity and specificity cMRI regarding the
diagnosis of unfavorable hemodynamic status determined from RCH measurements. Exact 95%
confidence intervals of sensitivity and specificity will be computed.
Analyses to respond to secondary objectives:
Kaplan Meier life tables and curves will be produced as well as estimates of survival
(morbi-mortality event) according to cMRI and RHC criteria given in the primary end point
section.
Association between baseline factors and time to the first event of morbi-mortality will be
assessed using Cox proportional hazard regression. Candidate factors will be identified among
cMRI, RHC and echocardiography measurements along with NYHA functional class, 6-minute walk
distance, plasma level of BNP/NT-proBNP and other potential baseline characteristics using
univariable analysis. Factors found significant at the p<0.20 level will then be entered in a
multivariable analysis with stepwise forward-backward selection. Only factors significant at
the p<0.05 level will be kept in final multivariable model.
The same analyses will be repeated on data collected after 3-6 months of PAH specific
treatment.
Complications of cMRI and RHC will be collected. The frequency of adverse events reported
during the follow-up will be compared between groups using the Chi-Square test (or Fisher's
exact test where requested).
Relative tolerability of cMRI and RHC will also be collected. The investigators will use the
Kruskal-Wallis test to determine if the overall physical and psychological distress scores
are different across the two groups.
If the primary endpoint were reached, positive results could allow to broadly extend our
findings. Therefore, it will be possible to decrease the number of RHC, an invasive and
cumbersome procedure without altering the prognosis. Positive results will also improve the
level evidence of severity assessment of PAH patients.
According to the secondary objectives the investigators expect to better predict
morbi-mortality events with cMRI compared to RHC. Thus, a composite score will be constructed
including cMRI parameter and will be internally validated. Such a score can then be easily
externally validated and widely used.
An ancillary study will be carried out in a few centers. This ancillary study is entitled
"BI4P: BIomecanical Property of Pulmonary artery and Prognosis assessment in Pulmonary
hypertension".
The main objective of BI4P is to assess the hemodynamic diagnosis performance of
biomechanical parameters of the pulmonary artery at baseline and at follow up visits of 4D
MRI to detect an unfavorable status in comparison with the results of the RHC.
