Ignite Creation Date:
2024-05-06 @ 8:52 AM
Last Modification Date:
2024-10-26 @ 12:06 PM
Study NCT ID:
NCT02845518
Status:
RECRUITING
Last Update Posted:
2024-05-20
First Post:
2016-06-21
Brief Title:
Study of Cardiac MRI in the Follow up Assessment of Patients With PAH EVITA
Sponsor:
Central Hospital Nancy France
Organization:
Central Hospital Nancy France
Study Overview
Official Title:
EValuation of Cardiac Magnetic Resonance Imaging in Follow up assessmenT of Patients With Pulmonary Arterial Hypertension EVITA
Status:
RECRUITING
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
EVITA
Brief Summary:
Pulmonary arterial hypertension PAH is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and eventually to death The therapeutic strategy has become complex and needs to perform recurring follow up evaluations including right heart catheterizations RHC
Cardiac magnetic resonance imaging cMRI has the advantage to accurately assess right ventricular volumes and important prognostic predictors such as cardiac index stroke volume and right ventricular ejection fraction
The main objective of EVITA is to assess the hemodynamic diagnosis performances at baseline and at follow up visits of cMRI in comparison with the results of the RHC current guidelines to detect an unfavorable hemodynamic status
The primary endpoint is sensitivity and specificity of cMRI for the diagnosis of an unfavorable status defined by the current RHC criteria with 95 confidence interval
The secondary objectives are 1 to identify clinical and hemodynamic variables independently contributing to prognosis 2 to describe complications due to cMRI and to RHC 3 to compare acceptability and tolerability of cMRI over RHC for the patient 4 to constitute biological collection of blood samples to determine diagnostic and prognostic PAH biomarkers 5 To compare the measurements of indexed stroke volume performed by RHC and by cMRI 6 To evaluate the prognostic value to predict an unfavourable hemodynamic status of cMRI variables including indexed stroke volume after taking into account NYHA functional class 6-minute walk test distance and BNP or NT-proBNP after 4 months of PAH treatment and 7 To evaluate the prognostic value to predict the first occurrence of morbimortality events of cMRI variables including indexed stroke volume after taking into account NYHA functional class 6-minute walk test distance and BNP or NT-proBNP after 4 months of PAH treatment
PAH patients will be recruited in centers of the French network of severe pulmonary hypertension in a prospective cohort study
180 subjects will be enrolled in the study that size will give the study 90 power to find significant at the 5-level
If the primary endpoint were achieved since first strategies and procedures planed in this project are consistent with those currently used in routine and second inclusion criteria are not limited to a sub-population of PAH patients 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 Moreover all clinical procedures would be performed in outpatient clinics and thereby would reduce the cost to assess the severity of the disease Current recommendations for evaluation of severity and follow-up being mainly derived from consensus of opinion of the experts positive results will also improve the level evidence of severity assessment of PAH patients
According to secondary objectives we expect to better predict morbimortality events with cMRI compared to RHC
Cardiac magnetic resonance imaging cMRI has the advantage to accurately assess right ventricular volumes and important prognostic predictors such as cardiac index stroke volume and right ventricular ejection fraction
The main objective of EVITA is to assess the hemodynamic diagnosis performances at baseline and at follow up visits of cMRI in comparison with the results of the RHC current guidelines to detect an unfavorable hemodynamic status
The primary endpoint is sensitivity and specificity of cMRI for the diagnosis of an unfavorable status defined by the current RHC criteria with 95 confidence interval
The secondary objectives are 1 to identify clinical and hemodynamic variables independently contributing to prognosis 2 to describe complications due to cMRI and to RHC 3 to compare acceptability and tolerability of cMRI over RHC for the patient 4 to constitute biological collection of blood samples to determine diagnostic and prognostic PAH biomarkers 5 To compare the measurements of indexed stroke volume performed by RHC and by cMRI 6 To evaluate the prognostic value to predict an unfavourable hemodynamic status of cMRI variables including indexed stroke volume after taking into account NYHA functional class 6-minute walk test distance and BNP or NT-proBNP after 4 months of PAH treatment and 7 To evaluate the prognostic value to predict the first occurrence of morbimortality events of cMRI variables including indexed stroke volume after taking into account NYHA functional class 6-minute walk test distance and BNP or NT-proBNP after 4 months of PAH treatment
PAH patients will be recruited in centers of the French network of severe pulmonary hypertension in a prospective cohort study
180 subjects will be enrolled in the study that size will give the study 90 power to find significant at the 5-level
If the primary endpoint were achieved since first strategies and procedures planed in this project are consistent with those currently used in routine and second inclusion criteria are not limited to a sub-population of PAH patients 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 Moreover all clinical procedures would be performed in outpatient clinics and thereby would reduce the cost to assess the severity of the disease Current recommendations for evaluation of severity and follow-up being mainly derived from consensus of opinion of the experts positive results will also improve the level evidence of severity assessment of PAH patients
According to secondary objectives we expect to better predict morbimortality events with cMRI compared to RHC
Detailed Description:
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 085 p0001 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 ie 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 25 lminm² or a right atrial pressure or 8 mm Hg and secondly from cMRI criteria CI 25 lminm² 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 BNPN-terminalNT-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
7 To compare the measurements of indexed stroke volume performed by RHC and by cMRI
8 To evaluate the prognostic value to predict an unfavourable hemodynamic status of cMRI variables including indexed stroke volume after taking into account NYHA functional class 6-minute walk test distance and BNP or NT-proBNP after 4 months of PAH treatment
9 To evaluate the prognostic value to predict the first occurrence of morbimortality events of cMRI variables including indexed stroke volume after taking into account NYHA functional class 6-minute walk test distance and BNP or NT-proBNP after 4 months of PAH treatment
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 BNPNT-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 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 p005
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 BNPNT-proBNP and other potential baseline characteristics using univariable analysis Factors found significant at the p020 level will then be entered in a multivariable analysis with stepwise forward-backward selection Only factors significant at the p005 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 Fishers 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
Measurements of indexed stroke volume Continuous variables indexed stroke volume will be compared by a paired t test
Prognostic value A multivariable model will be performed including all mentioned variables The association of MRI variables with outcome will be assessed within the models In addition models with and without MRI variables will be compared with C-index and Net Reclassification Index NRI statistics to identify the added value of MRI variables
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
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 085 p0001 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 ie 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 25 lminm² or a right atrial pressure or 8 mm Hg and secondly from cMRI criteria CI 25 lminm² 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 BNPN-terminalNT-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
7 To compare the measurements of indexed stroke volume performed by RHC and by cMRI
8 To evaluate the prognostic value to predict an unfavourable hemodynamic status of cMRI variables including indexed stroke volume after taking into account NYHA functional class 6-minute walk test distance and BNP or NT-proBNP after 4 months of PAH treatment
9 To evaluate the prognostic value to predict the first occurrence of morbimortality events of cMRI variables including indexed stroke volume after taking into account NYHA functional class 6-minute walk test distance and BNP or NT-proBNP after 4 months of PAH treatment
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 BNPNT-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 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 p005
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 BNPNT-proBNP and other potential baseline characteristics using univariable analysis Factors found significant at the p020 level will then be entered in a multivariable analysis with stepwise forward-backward selection Only factors significant at the p005 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 Fishers 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
Measurements of indexed stroke volume Continuous variables indexed stroke volume will be compared by a paired t test
Prognostic value A multivariable model will be performed including all mentioned variables The association of MRI variables with outcome will be assessed within the models In addition models with and without MRI variables will be compared with C-index and Net Reclassification Index NRI statistics to identify the added value of MRI variables
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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None