Clinical trial NCT02555137: Early Non-invasive Detection of CTEPH After Pulmonary Embolism
Official title: Early Non-invasive Detection of CTEPH After Pulmonary Embolism - The InShape-2 Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Chronic Thromboembolic Pulmonary Hypertension
Keywords: chronic thromboembolic pulmonary hypertension
pulmonary embolism
pulmonary hypertension
screening
echocardiography
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
First posted: 2015-09-21
Enrollment: 424
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Consecutive patients treated for objectivated symptomatic acute PE

Brief summary: This is a prospective, international, multicenter outcome cohort study. This study starts at the moment patients visit the outpatient clinic 3 to 6 months after a diagnosis of acute PE as part of routine medical care. If patients consent to study participation, the CTEPH clinical prediction score will be calculated. CTEPH is considered to be not present in patients with a low probability (≤6 points) and no symptoms suggestive of CTEPH, i.e. dyspnea on exertion, edema, newly developed palpitations, syncope or chest pains.The remaining patients with either high probability (\>6 points) or who report symptoms that may be associated with CTEPH will be subjected to the 'rule-out criteria'. CTEPH will be assumed not present in patients with an age- and gender dependent normal NT-proBNP level (as defined by the assay's manufacturer), in the absence of any of the 3 ECG criteria. Patients who have an abnormal result from the 'rule-out criteria' will be referred for transthoracic echocardiography. All echocardiograms will be performed according to a predefined standardized protocol.

In case of echocardiographic intermediate or high probability of PH, patients will be referred for further diagnostic work-up of suspected CTEPH starting with perfusion lung scan or VQ-scan and right heart catheterization, of which the results will be discussed by an independent interdisciplinary working group of PH specialists, to ensure optimal diagnostic management. This latter diagnostic work-up of an abnormal echocardiograph lies within the setting of standard medical care.

All patients who were not diagnosed with pulmonary hypertension of any origin, or with NYHA class III or IV heart failure due to left ventricular systolic dysfunction, left ventricular diastolic dysfunction or significant valvular lesions, will be followed for a total of 2 years from the index PE diagnosis. During that period, the study protocol will not interfere with standard patient care, allowing diagnostic tests as deemed indicated by the treating physician including echocardiography in case of new respiratory symptoms. At the end of the follow-up period, all patients will be subjected to a second echocardiography that will be handled according to the above stated procedures to evaluate the presence of CTEPH.

Detailed description: This is a prospective, international, multicenter outcome cohort study. This study starts at the moment patients visit the outpatient clinic 3 to 6 months after a diagnosis of acute PE as part of routine medical care. If patients consent to study participation, the CTEPH clinical prediction score will be calculated. This score consists of 6 variables that should be assessed at the time of PE diagnosis: unprovoked PE (+6 points), known hypothyroidism (+3 points), diagnostic delay \>2 weeks (+3 points), right ventricular dysfunction on computed tomography pulmonary angiography (CTPA) or echocardiography (+2 points), known diabetes mellitus (-3 points) and thrombolytic therapy or embolectomy for the acute PE event (-3 points) CTEPH is considered to be not present in patients with a low probability (≤6 points) and no symptoms suggestive of CTEPH, i.e. dyspnea on exertion, edema, newly developed palpitations, syncope or chest pains. The remaining patients with either high probability (\>6 points) or who report symptoms that may be associated with CTEPH will be subjected to the 'rule-out criteria'. CTEPH will be assumed not present in patients with an age- and gender dependent normal NT-proBNP level (as defined by the assay's manufacturer), in the absence of these 3 ECG criteria: 1) rSR' or rSr' pattern in lead V1, 2) R:S \>1 in lead V1 with R \>0.5mV and 3) QRS axis \>90o. Patients who have an abnormal result from the 'rule-out criteria' will be referred for transthoracic echocardiography. All echocardiograms will be judged by the echocardiographic criteria for suspected PH according to the 2015 ESC guidelines.

In case of echocardiographic intermediate or high probability of PH, patients will be referred for further diagnostic work-up of suspected CTEPH starting with perfusion lung scan or VQ-scan and right heart catheterization, of which the results will be discussed by an independent interdisciplinary working group of PH specialists, to ensure optimal diagnostic management. This latter diagnostic work-up of an abnormal echocardiograph lies within the setting of standard medical care.

All patients who were not diagnosed with pulmonary hypertension of any origin, or with NYHA class III or IV heart failure due to left ventricular systolic dysfunction, left ventricular diastolic dysfunction or significant valvular lesions, will be followed for a total of 2 years from the index PE diagnosis. During that period, the study protocol will not interfere with standard patient care, allowing diagnostic tests as deemed indicated by the treating physician including echocardiography in case of new respiratory symptoms. At the end of the follow-up period, all patients will be subjected to a second echocardiography that will be handled according to the above stated procedures to evaluate the presence of CTEPH.

Eligibility criteria: Inclusion Criteria:

* All patients with an objectivated first or recurrent diagnosis of symptomatic acute PE, who have been treated for at least three months with therapeutically dosed anticoagulant therapy according to current guidelines;
* Signed and dated informed consent of the subject available before the start of any specific study procedures;
* Age ≥18 years;

Exclusion criteria:

* Known CTEPH or PH;
* Known (i.e. echocardiographic confirmed) NYHA class III or IV chronic heart failure due to left ventricular systolic dysfunction, left ventricular diastolic dysfunction or significant valvular lesions;
* Severe renal failure (eGFR \<15 ml/min) or renal replacement therapy;
* Medical or psychological condition that would not permit completion of the study or signing of informed consent, including life expectancy less than six months, or unwillingness to sign informed consent;
* Non-compliance or inability to adhere to treatment or to the follow-up visits.

Primary outcomes:
measure: The accuracy of the screening algorithm to detect CTEPH, as reflected by the 2-year incidence of confirmed CTEPH in patients in whom CTEPH was initially considered not present based on the 'risk stratification score' and the 'rule out criteria'.
timeFrame: 2-year follow-up
Secondary outcomes:
measure: The cumulative incidence and incidence rate of CTEPH in the total study population with corresponding 95% confidence interval
timeFrame: 2-year follow-up
measure: Feasibility of the screening algorithm, the number of necessary echocardiograms at baseline and the number of relevant echocardiographic findings at baseline, i.e. those that require treatment
timeFrame: 2-year follow-up
measure: 3 Cost-effectiveness of the screening algorithm: a study-based cost-effectiveness analysis (CEA: diagnostic costs per early CTEPH diagnosis) and a model-based cost-utility analysis (CUA: societal costs per QALY).
timeFrame: 2-year follow-up
measure: incremental diagnostic accuracy of electrocardiographically derived ECG-vectoranalysis on top of the manual ECG assessment by comparing the c-statistics and reclassification numbers between the manually and automatically assessed ECG parameters
timeFrame: 2-year follow-up
measure: Inter-observer variability in the measurement of the RV/LV ratio on computed tomography pulmonary angiography (CTPA) expressed as the kappa-value of the ventricular dimension measurements by two independent researchers.
timeFrame: 2-year follow-up
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: UZ Leuven
city: Amsterdam
country: Netherlands
facility: VUmc
city: Den Haag
country: Netherlands
facility: Haga
city: Leiden
country: Netherlands
facility: LUMC
city: Warsaw
country: Poland
facility: medical university of Warsaw
Study officials:
affiliation: Department of Thrombosis and Hemostasis LUMC Leiden
name: F.A. Klok, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Klok FA, Tesche C, Rappold L, Dellas C, Hasenfuss G, Huisman MV, Konstantinides S, Lankeit M. External validation of a simple non-invasive algorithm to rule out chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. Thromb Res. 2015 May;135(5):796-801. doi: 10.1016/j.thromres.2014.12.009. Epub 2014 Dec 13.
citation: Klok FA, Surie S, Kempf T, Eikenboom J, van Straalen JP, van Kralingen KW, van Dijk AP, Vliegen HW, Bresser P, Wollert KC, Huisman MV. A simple non-invasive diagnostic algorithm for ruling out chronic thromboembolic pulmonary hypertension in patients after acute pulmonary embolism. Thromb Res. 2011 Jul;128(1):21-6. doi: 10.1016/j.thromres.2011.03.004. Epub 2011 Mar 30.
citation: Fabyan KD, Holley AB. Postpulmonary embolism syndrome. Curr Opin Pulm Med. 2021 Sep 1;27(5):335-341. doi: 10.1097/MCP.0000000000000789.