OT 4 – Development and prevention of pulmonary hypertension

PI: Yannick ALLANORE, Jérôme AVOUAC (UPD)

Investigative objective

 Pulmonary hypertension (PH) is a fatal disorder characterized by an increase in pulmonary vascular resistance, which leads to right ventricular failure. Despite being recently the object of greater attention and despite therapeutic advances, pulmonary hypertension due to SSc remains associated with a dismal 47 - 67% 3-year survival. Among SSc patients prospectively followed in the "European League Against Rheumatism Scleroderma Trials and Research" (EUSTAR) cohort, 26% of death was related to pulmonary hypertension. Although some previous data have suggested the protective effects of calcium channel blockers on the development of pulmonary hypertension, the potential preventive effects of vasodilators for the prevention of Pulmonary hypertension have not been determined yet. In addition to be considered routinely for the treatment of SSc-related pulmonary hypertension, prostanoids, endothelin receptor antagonists (ETRA) and Phosphodiesterase-5 inhibitors (PDE5i) can also be used for this indication.

Aim of this observational trial is:

• to compare the outcomes of adult and juvenile SSc patients who are at high risk of developing pulmonary hypertension and are receiving either different vasodilator treatments or no vasodilator treatment.

Primary endpoint(s)

 The number of patients with pulmonary hypertension at 2 years (Time Frame: 2 years)

Secondary endpoint(s)

The time to development of precapillary pulmonary hypertension (Time Frame: 2 years)

Exploratory endpoints

Identification other factors associated with the development of PH, in addition to treatments, such as autoantibodies (e.g. anti-centromere, anti-topoisomerase I, anti-RNA polymerase III, anti-angiotensin II type 1 receptor, anti-endothelin-1 type A receptor antibodies) and vascular phenotype (occurrence and recurrence of DU), in order to improve the prediction model

Safety endpoints

Incidence of drug-related adverse events, incidence of withdrawal from treatment due to drug-related adverse events

Participants

Study population justification

The study population are adult and juvenile SSc patients from the EUSTAR cohort (MEDSonline database) and the jSScWG cohort.

To increase the chance of detecting a preventive effect of vasodilators for the development of PH, the outcome of patients with or without vasodilator treatment will be primarily addressed in a population with a high risk of developing PH. EUSTAR investigators have recently validated a risk score for the prediction of PH based on simple and routinely made observations [29]. Indeed, the Cochin RPS requires only age, FVC and DLCO/AV for its calculation as follow: 0.0001107 x age + 0.0207818 x (100-FVC) + 0.04905 x (150- DLCO/AV).

Patients undergo a non-invasive screening for PH based on clinical evaluation, echocardiography and pulmonary function tests according to the standard of routine care. These assessments are performed at each visit (every 6 months) of the planned 24-month observational phase or in case of clinical worsening.

Patients with a suspicion of PH according to these non-invasive investigations (unexplained dyspnea on clinical examination, or estimated systolic PAP ≥40 mmHg on echocardiography, or DLCO <50% predicted in the absence of pulmonary fibrosis) will be offered to undergo RHC. Precapillary PH is defined at RHC as a mean resting PAP >25 mmHg in the presence of a PCWP ≤15 mmHg. Patients with precapillary PH at inclusion or with venous / post-capillary PH at any time will be excluded.

Inclusion criteria

• Juvenile and adult Systemic sclerosis patients, with diagnosis according to the ACR/EULAR adult SSc criteria and PRES/ACR/EULAR juvenile SSc criteria respectively
• Patients at high risk of pulmonary hypertension with a Cochin Risk prediction score >/= 3

Trial design

Observational trial with 3 treatment arms.

Treatment arms

Three different groups will be observed for analysis:

(1)   patients receiving no vasodilator

(2)   patients receiving a CCB for digital vasculopathy

(3)   patients treated with i.v. prostanoids or PDE5i or ETRAs regardless of whether a CCB is given in addition

Follow-up

Patients with a suspicion of PH according to these non-invasive investigations (unexplained dyspnea on clinical examination, or estimated systolic PAP ≥40 mmHg on echocardiography, or DLCO <50% predicted in the absence of pulmonary fibrosis) will be offered to undergo RHC. Precapillary PH is defined at RHC as a mean resting PAP >25 mmHg in the presence of a PCWP ≤15 mmHg. Patients with precapillary PH at inclusion or with venous / post-capillary PH at any time will be excluded.

Evaluations will be performed at baseline and every 6 months thereafter during a planned 24-month follow-up, or in case of clinical worsening.