Early non-invasive detection of CTEPH after pulmonary embolism

The ultimate consequence of hemodynamic compromise and persistent pulmonary
perfusion defects after acute pulmonary embolism (PE) is chronic thromboembolic
pulmonary hypertension (CTEPH), which is a lethal condition unless a timely
diagnosis is followed by adequate treatment. The exact incidence of CTEPH after
PE is estimated to be 0.5% to 4.0% within the first 2 years after diagnosis.
Notably, there are no specific signs or symptoms of CTEPH and patients may
remain asymptomatic for months to years although clinically significant
pulmonary hypertension (PH) is already present. Also, subjecting all patients
who survived acute PE to transthoracic echocardiography, which is the
recommended screening tool for suspected PH, has been shown to have a low
diagnostic yield. Due to these uncertainties, international guidelines do not
provide a clear recommendation on the frequency and duration of medical
follow-up after acute PE or on specific screening programs for CTEPH. Early
diagnosis of CTEPH is nonetheless essential, since when detected in an early
stage, CTEPH may be cured by pulmonary endarterectomy while delay in diagnosis
may be associated with worse prognosis, higher perioperative mortality and
inoperable disease stages. It has been estimated that the majority of CTEPH
diagnoses nowadays still have a diagnostic delay well over 1 year.
We have developed a CTEPH screening program based on a combination of a very
recently derived risk stratification score11 and a validated non-invasive set
of rule-out criteria. This screening program is aimed at 1) early diagnosis of
CTEPH and 2) ruling out CTEPH with high certainty using standardized
non-invasive test in patients with persistent dyspnea after acute PE. The
former is likely associated with improved CTEPH prognosis, the latter with more
cost-efficient long-term care for PE patients.

The primary objective of the study is to evaluate the diagnostic accuracy of a
CTEPH screening program based on the stratification score and the *rule out
criteria*.

To prospectively assess the feasibility and cost-effectiveness of the CTEPH
screening algorithm as well as the incidence of CTEPH in the studied population.

To assess the prevalence of radiological signs of CTEPH in the studied
population.

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 ruled out 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 ruled out 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, and judged by the following echocardiographic
criteria for suspected PH according to the ESC guidelines. The presence of
CTEPH will be considered ruled out in the absence of all of these criteria.

In case PH is suspected by echocardiography, 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.

n.a.