Symptom-related Screening for Early Detection of CTEPH.

Sponsor

Luis Jara-Palomares, MD (Other)

Overall Status

Completed

CT.gov ID

NCT03953560

Collaborator

Merck Sharp & Dohme LLC (Industry), Sociedad Española de Neumología y Cirugía Torácica (Other)

646

Enrollment

Locations

Arm

Actual Duration (Months)

40.4

Patients Per Site

1.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Routine screening for Chronic thromboembolic pulmonary hypertension (CTEPH) i after PE is not supported by current evidence and guidelines.

This study aims to evaluate if a screening program for patients with acute PE based on telephone monitoring of symptoms and further examination if only symptomatic patients could help an early detection of CTEPH.

Condition or Disease	Intervention/Treatment	Phase
CTEPH Pulmonary Embolism Symptoms and Signs Dyspnea	Diagnostic Test: dyspnea grade ≥ II according NYHA-WHO	N/A

Detailed Description

Chronic thromboembolic pulmonary hypertension (CTEPH) is a long-term complication following an acute or silent pulmonary embolism (PE). A history of acute PE was reported in 75% of CTEPH patients. Nevertheless, incidence of CTEPH after a confirmed acute PE vary widely depending of the studies, with estimated incidence from 0.5 to 4%. Performing a follow-up examination of patients diagnosed with acute PE regardless of persisting symptoms and using all available technical procedures is not cost-effective. As a consequence, routine screening for CTEPH after PE is not supported by current evidence and guidelines.

CTEPH is a very disabling and mortal disease, although it is a potential curable disease. However, delayed diagnosis and misdiagnosis is common. Patients are frequently diagnosed with CTEPH at advanced stages of the disease leading to worse clinical outcomes. Early diagnosis of CTEPH is essential, as delay in diagnosis may be associated with a worse prognosis, higher perioperative mortality and inoperable diseases stages. Overall, evidence from various sources suggests that early detection and treatment of CTEPH is advantageous in achieving favorable clinical outcomes. Therefore, there is an important unmet need for early diagnosing this disease.

Focusing diagnostic procedures only on symptomatic patients may be a practical approach for detecting relevant CTEPH.

Objectives

Primary outcome: To estimate the impact of an easy and simple strategy to identify CTEPH.
Secondary outcomes:
To identify patients with CTED after PE
To obtain external validation from scores to identify patients at risk to develop CTEPH
To develop new score to identify high risk population to develop CTEPH

Hypothesis Conceptual hypothesis: The use of a strategy to detect CTEPH will increase number of patients diagnosed of pulmonary hypertension.

Operational hypothesis: The use of a strategy to detect CTEPH will increase in a 200% the number of patients diagnosed with CTEPH.

Design Cohorts study in consecutive patients with objectively confirmed PE.

Specialists implied Internal medicine, Pulmonologist, Hematologist from 20 hospitals.

Inclusion criteria: 1) Age > 18 year 2) Objectively confirmed diagnosis of acute PE by multidetector CT, V/Q lung scan, or selective pulmonary angiography, according to established diagnostic criteria, with or without symptomatic DVT, 3) Ability of subject to understand the character and consequences of the study, 4) informed consent of the subject. Exclusion criteria: refused informed consent, inability to cooperation.

Intervention Investigator from each center will recover consecutive PE patients and collect baseline, demographic and co-morbidities.

In all patients enrolled in the study a short questionnaire regarding dyspnea symptoms will be performed. All patients that refer dyspnea grade ≥ II according NYHA-WHO modified scale will be cited as outpatient to be evaluated

A written informed consent will be required all patients evaluated in consultant.

Imaging studies and right heart catheterization is the procedure agreeing with the standard care according to current ESC/ERS Guidelines.

In all patients, the following tests will be performed:

Pulsioximetry.
Electrocardiogram.
Blood sample with determination of NT-ProBNP.
Echocardiography. Only an echocardiography indicative of PH warrants further evaluation
V/Q scintigraphy. Possible CTEPH can be assumed when mismatched perfusion defects are detected by VQ scan.
Right heart catheterization & Pulmonary CT Scan are required for confirming the diagnosis

The relationship of Doppler echocardiography-estimated PASP with right heart catheterization (RHC)-measured PASP was examined using Spearman's correlation coefficients. The Bland-Altman method was then used to assess the agreement between Doppler echocardiography-estimated and RHC measured PASP. Doppler echocardiography-estimated PASP within +/- 10mmHg of the value measured on RHC was considered accurate, consistent with the cutoffs used in other publications.

Secondary outcome include number of patients with chronic thromboembolic disease (CTED), described as chronic thromboembolic pulmonary vascular obstruction with normal resting pulmonary artery pressures.

Treatment: No treatment required

Statistical Plans Sample size calculation We estimate CTEPH prevalence in reference group of 1%, and a prevalence of CTEPH in interventional group of 2.8%. With unilateral test, con confidence level of 95%, statistic power of 80% and losses expected of 25%, we calculated a final sample size of 947.

The investigators calculate that 16-20 centers in Spain are needed to recruit patients

Investigators will compare baseline characteristics of patients with and without CTEPH using chi-square tests for categorical variables and non-parametric rank tests for continuous variables. Cumulative incidence of CTEPH will be estimated using the Kaplan-Meier technique.

To do external validation of previous score to predict CTEPH discriminative power by calculating the area under the receiver-operating characteristic (ROC) curve will be done, performing a non-parametric test of the equality of the areas under the ROC curves. Goodness-of-fit of the score points for each score in a logistic regression model using Pearson's chi-square test.

Student's t test and X2 test (or Fisher's exact test where appropriate) will be used to compare continuous or categorical variables, and multivariable analysis through a logistic regression model using the Wald method (step back) to identify independent predictors for the occurrence of CTEPH. Covariates entering in the model will be selected by a significance level of p <0.20 on univariable analysis, or by a well-known association reported in the literature. Then, the investigators will build a prognostic score assigning points to each independent variable according to regression coefficients β, rounding to the nearest integer. The investigators will assign a risk score to each patient by adding up points for each independent variable. Performance will be quantified in terms of calibration using the Hosmer-Lemeshow test. Model discrimination will be assessed using the C-statistic. Internal validity of the score will be confirmed using bootstrap analysis. For the statistical analysis the investigators will use the IBM SPSS Statistics program (version 19; SPSS Inc., Chicago, IL), and a two-sided p<0.05 was considered to be statistically significant.

Study Design

Study Type:

Interventional

Actual Enrollment :

646 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Design Cohorts study in consecutive patients with objectively confirmed PE.Design Cohorts study in consecutive patients with objectively confirmed PE.

Masking:

None (Open Label)

Primary Purpose:

Diagnostic

Official Title:

Symptom-related Screening Program Following Pulmonary Embolism for Early Detection of Chronic ThromboEmbolic Pulmonary Hypertension (CTEPH)

Actual Study Start Date :

Jan 16, 2019

Actual Primary Completion Date :

Dec 31, 2021

Actual Study Completion Date :

Feb 15, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Screening Intervention Investigator from each center will recover consecutives PE patients and collect baseline, demographic and comorbidities. In all patients enrolled in the study a short questionnaire regarding dyspnea symptoms will be performed. All patients that refer dyspnea grade ≥ II according NYHA-WHO (6) modified scale will be cited as outpatient to be evaluated Imaging studies and right heart catheterization is the procedure agreeing with the standard care according to current ESC/ERS Guidelines. In all patients, the following tests will be performed: Pulsioximetry. Electrocardiogram. Blood sample with determination of NT-ProBNP. Echocardiography. Only an echocardiography indicative of PH warrants further evaluation V/Q scintigraphy. Possible CTEPH can be assumed when mismatched perfusion defects are detected by VQ scan. Right heart catheterization & Pulmonary CT Scan are required for confirming the diagnosis	Diagnostic Test: dyspnea grade ≥ II according NYHA-WHO Intervention Investigator from each center will recover consecutives PE patients and collect baseline, demographic and comorbidities. In all patients enrolled in the study a short questionnaire regarding dyspnea symptoms will be performed. All patients that refer dyspnea grade ≥ II according NYHA-WHO (6) modified scale will be cited as outpatient to be evaluated Imaging studies and right heart catheterization is the procedure agreeing with the standard care according to current ESC/ERS Guidelines. In all patients, the following tests will be performed: Pulsioximetry. Electrocardiogram. Blood sample with determination of NT-ProBNP. Echocardiography. Only an echocardiography indicative of PH warrants further evaluation V/Q scintigraphy. Possible CTEPH can be assumed when mismatched perfusion defects are detected by VQ scan. Right heart catheterization & Pulmonary CT Scan are required for confirming the diagnosis

Arm

Intervention/Treatment

Experimental: Screening

Intervention Investigator from each center will recover consecutives PE patients and collect baseline, demographic and comorbidities. In all patients enrolled in the study a short questionnaire regarding dyspnea symptoms will be performed. All patients that refer dyspnea grade ≥ II according NYHA-WHO (6) modified scale will be cited as outpatient to be evaluated Imaging studies and right heart catheterization is the procedure agreeing with the standard care according to current ESC/ERS Guidelines. In all patients, the following tests will be performed: Pulsioximetry. Electrocardiogram. Blood sample with determination of NT-ProBNP. Echocardiography. Only an echocardiography indicative of PH warrants further evaluation V/Q scintigraphy. Possible CTEPH can be assumed when mismatched perfusion defects are detected by VQ scan. Right heart catheterization & Pulmonary CT Scan are required for confirming the diagnosis

Diagnostic Test: dyspnea grade ≥ II according NYHA-WHO

Outcome Measures

Primary Outcome Measures

Number of new diagnosis of CTEPH [Up 3 years after PE]
New diagnosis of CTEPH

Secondary Outcome Measures

External validation from score to identify patients at risk to develop CTEPH [Up 3 years after PE]
external validation from score (Klok FA et al. Derivation of a clinical prediction score for chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. J Thromb Haemost. 2016)
Derivation of a score to identify high risk population to develop CTEPH [Up 3 years after PE]
With variables assocciated to CTEPH investigators will obtain derivation and validation of a score to identify high risk population to develop CTEPH
Number of patients with Chronic Thromboembolic Disease (CTED) after PE [Up 3 years after PE]
Describe the number and clinical characteristics of patients with CTED after PE

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age > 18 year
Objectively confirmed diagnosis of acute PE by multidetector CT, V/Q lung scan, or selective pulmonary angiography, according to established diagnostic criteria, with or without symptomatic DVT,
Ability of subject to understand the character and consequences of the study,
informed consent of the subject.

Exclusion Criteria:

refused informed consent, inability to cooperation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital Universitario Puerto Real	Puerto Real	Cadiz	Spain
2	Consorcio Hospitalario Provincial de Castellón	Castellón De La Plana	Castellon	Spain
3	Hospital de Galdakao	Galdakao	Vizcaya	Spain
4	Hospital General Universitario de Albacete	Albacete		Spain
5	Hospital Universitario de Bellvitge	Barcelona		Spain
6	Parc Sanitari Sant Joan de Deu	Barcelona		Spain
7	Hospital Virgen de la Luz	Cuenca		Spain
8	Hospital Universitario Reina Sofía	Córdoba		Spain
9	Hospital General Universitario de Elche	Elche		Spain
10	Hospital Universitari de Girona Dr. Josep Trueta	Gerona		Spain
11	Hospital Universitari Arnau de Vilanova	Lerida		Spain
12	Hospital Clínico San Carlos	Madrid		Spain
13	Hospital Universitario 12 de Octubre	Madrid		Spain
14	Hospital Virgen del Rocio	Sevilla		Spain	41014
15	Hospital Universitario Joan XXIII de Tarragona	Tarragona		Spain
16	Hospital Clínico Universitario Lozano Blesa	Zaragoza		Spain