Balloon pulmonary angioplasty versus pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension: a non-inferiority randomized trial

CTEPH is a rare and potentially life-threatening disease. CTEPH evolves from
unresolved pulmonary embolism that over time becomes fibrotic and obstructs the
pulmonary arteries. The crude incidence of CTEPH is 2-5 cases per 100,000
population but the disease is underdiagnosed and undertreated. CTEPH is a
progressive disease. The increase in pulmonary artery pressure induced by
mechanical obstruction induces microvascular remodeling which further increases
pulmonary vascular resistance and worsens pulmonary hypertension. The
progressive increase in pulmonary vascular resistance increases strain on the
right ventricle and eventually leads to right ventricular failure and death.
If left untreated, mean life expectancy of patients with CTEPH is less than
three years.

Gold standard treatment for CTEPH is PEA, although no controlled studies
exist. Surgical management of CTEPH is complex and requires institutional
skills and experience. The results after PEA are excellent and patients treated
in experienced centers have a reported three years survival of 89%. Few
centers are available across the world and we know that only ~60% of patients
referred to CTEPH centers undergo PEA which leaves a large proportion of CTEPH
patients untreated. Main reasons for not undergoing PEA are distribution of
the vascular lesions making the patient technically inoperable, co-morbidities
or patient choice. For patients not eligible for PEA, medical treatments and
interventional balloon BPA have emerged as effective treatment strategies. BPA
can be performed in most inoperable patients. As a classical percutaneous
procedure, BPA may offer faster recovery and the procedure can be done in
patients in whom risks of complex surgery outweigh benefits. Because of small
vessel access, BPA can be done in patients with predominantly distal vascular
lesions who are deemed technically inoperable. Registry data suggest that
one-year mortality may be higher in PEA than in BPA but, that decrease of
pulmonary vascular resistance may be more substantial with PEA.9-12 However,
all current knowledge in that regard is based on retrospective observations.
Because BPA is commonly performed in patients not eligible for PEA, differences
may be due to selection bias.

The diagnosis of CTEPH, disease characterization, distribution of lesions and
recommended treatment is done at a multidisciplinary team conference at the
local CTEPH centre. This evaluation is based on patient history, right heart
catheterization, imaging (pulmonary angiograms and computed tomography
pulmonary angiograms and echocardiography) and blood sampling (cardiac
biomarkers, kidney function etc.).
Common practice is that PEA is performed in patients with predominantly
proximal disease, and BPA is performed in patients with more distal disease,
but in a subset of patients, the lesions are accessible by both PEA and BPA as
shown in Figure 2. The guideline recommended approach in patients, with lesions
accesible for both PEA and BPA is to perform PEA,6 but several centers with
limited surgical acces have reported good results of BPA in this patient
population11, 12 and we do not know if BPA or PEA are equally good for treating
this subgroup of patients with CTEPH. Common practice is that PEA is performed
in patients with more proximal disease, and BPA is performed in patients with
more distal disease, but local expertise determines individual treatment
selections in CTEPH centers, sometimes leading to PEA in more distal CTEPH, and
BPA in more proximal CTEPH in selected cases.7 In a subgroup of patients, both
BPA and PEA may be safely performed. Therefore, there is an unmet need for a
comparative study of PEA versus BPA in patients with CTEPH who are eligible for
both procedures.

To evaluate if balloon pulmonary angioplasty (BPA) is non-inferior to pulmonary
endarterectomy (PEA) in patients with chronic thromboembolic pulmonary
hypertension (CTEPH) who are eligible for both treatments.

This is an investigator-initiated multicenter prospective, randomized,
controlled, open label non-inferiority trial. The study will randomize 139
patients with CTEPH who are eligible for both PEA and BPA. Patients will be
screened for eligibility for study inclusion at the local CTEPH
multidisciplinary team (MDT) conference and eligibility for both PEA and BPA
will be confirmed by a central adjudication committee. If eligible for study
inclusion patients will be included after informed consent and randomized 1:1
to PEA or BPA at the first patient visit following the MDT conference. If PAH
targeted therapy is instituted or changed after MDT this should be done during
a run-in period of up to 3 months before randomization. The run-in period
allows for up-titration of medical treatment and a minimum of one-month
stabilization on medical treatment after target dose is reached. Baseline right
heart catheterization will be done before MDT, but an additional baseline RHC
should be performed if changes in PAH targeted medical therapy have been
instituted after the screening RHC or if >3 months from screening RHC till
PEA/BPA. PEA or BPA will be completed within 6 months from randomization.
Follow up visit with right heart catheterization will be completed at 4 months
after PEA or last BPA session, to assess the primary end point, and at 12
months after PEA or last BPA session. (Figure 1)

No changes in PAH medical therapies shall be instituted until after the
follow-up evaluation unless the treating physician finds it un-safe not to
institute, increase dose of, or terminate PAH medical therapies in this period
of time.

No biobank or collection/retention of bodily materials is planned for this
clinical investigation.

Patients randomized to BPA will undergo and have finalized the procedures
within 6 months after randomization and optional run-in phase. Pre-planning of
target lesions will be done by pulmonary CT angiogram and conventional
pulmonary angiography. In local anesthesia, a guiding catheter will be advanced
to the pulmonary circulation through a femoral venous access and lesions will
be crossed with standard percutaneous coronary intervention (PCI) wires. A
balloon sized to the diameter of the target vessel (typically 2-6 mm) will be
advanced over the PCI wire and inflated with a pressure of 4-12 atm to restore
flow in the targeted vessel. Several vessels will be treated at each session,
but due to the vast number of lesions, radiation dose, amount of contrast, and
the risk of reperfusion edema, all lesions cannot be treated in one session and
several sessions (typically 4-8) are needed to treat the patient.9 After the
procedure, the patient will be managed and discharged according to local
guidelines. The specific pre-planning protocol, choice of wires and balloons,
the number of vessels treated per session, and the decision that no further BPA
sessions are needed is at the discretion of the treating physician. Standard
equipment for percutaneous interventions are used for BPA. BPA is performed as
standard and guideline based treatmsent for CTEPH at investigation sites and
choice of the specific utensils for the procedure is at the discretion of the
investigation site. All including centers are expert BPA centers with
experienced operators and BPA teams and BPA operators should have been properly
trained according to local guidelines. For details regarding BPA and medical
dilatation balloon devices used in this study with regards to technical
documentation, functional features traceability and materials, please see the
Investigator Brochure and respective instructions for use submitted for the
GO-CTEPH trial. The manufacturers are aware of the use of these devices in
routine practice for CTEPH indication. Procedural operations for BPA will
follow routine practice and will not deviate from routine clincal practice.
Tracability of the devices will be available through the CRF.

study related risk:
An additional Right heart catheterization guided with pressure wave forms if
changes in PAH targeted medical therapy have been substituted after RHC or if
>3 months from screening RHC till PEA/PEA.

Patients included in the trial and randomized to BPA will be exposed to
additional radiation exposure, but with a total load of less than 80 mSv. See
also section 8.7.1 in the protocol.

non health related risk: quality of life questionnaire, more frequent and
longer visit to the hospital, which can be inconvenient.

risk related to routine practice:
We know that PEA is an effective treatment with excellent long-term outcome for
patients with proximal CTEPH. However, in the subpopulation of CTEPH patients
with more distal CTEPH, where both procedures PEA and BPA could be considered.
PEA is a complex surgical procedure and it is not without risks. BPA is a
procedure where observational data suggest it to be as effective as PEA
regarding the reduction of pulmonary vascular resistance in short and
intermediate term, and with a lower periprocedural risk for the patient, but a
randomized trial is lacking. A patient included in the trial will be randomly
treated with either PEA as standard treatment or with BPA where preliminary
data suggest it to be as good, but with lower interventional risk than PEA.
Complications of BPA and PEA are mitigated through adherence to routine
practice and standard of care for these both treatments in CTEPH patients. The
principal complications for BPA are related to pulmonary vascular injury,
vessel injury/rupture, haemorrhage, pulmonary oedema and haemorrhagic plueral
effusion which are risks largely due to procedural error. The interventional
cardiologists and support staff at all participating sites are experienced in
performing both the BPA and PEA procedures in line with current guidelines and
are well trained to manage and reduce any procedural risks. Rigorous study
monitoring will ensure that all sites adhere to the study protocol and
reporting requirements in the case of protocol deviations, adverse events,
device deficiencies or use errors. Patient will be covered by the Hospitals
insurance sceems in the different countries.