Pulmonary Hypertension: Intensification and Personalisation of Combination Rx

The goal of this clinical trial is to evaluate the capacity of implantable/remote technology for early evaluation of drug therapies in patients with pulmonary arterial hypertension (PAH). The main question it aims to answer is whether structured changes in clinical therapy will be detectable using implanted regulatory approved devices. Participants will will be implanted with approved medical devices and will enter into a study of approved drugs to assess physiology, activity and patient reported quality-of-life (QoL) outcomes. Researchers will compare two therapeutic strategies in each individual patient to see if the study design provides enough evidence to personalise drug treatment plans

In this study, patients established on guideline recommended therapy will be implanted with devices and remote monitoring established. Patients will then enter into a 2x2 crossover study of approved drugs during which standard clinical investigations will be undertaken at baseline and maximal therapy on each drug. The cross-over design will provide multiple increases and decreases of drugs known to alter haemodynamics and 6MWT. The study is powered to detect improvement in right ventricular stroke volume measured by MRI from baseline to maximal therapy for each drug. It will then be established if changes in remote monitored measures provide an early indication of clinical efficacy when compared to the MRI, haemodynamics, NTproBNP and 6MWT made at 12-weeks. Remote measurement of haemodynamics during the two periods of de-escalation will inform understanding of physiology and inform clinical practice. The comparison of the two therapeutic strategies in individual patients in one study will facilitate novel clinical study designs and provide evidence for data-driven personalised medicine in the area.

Eligibility Criteria:
Inclusion Criteria:

* Able to provide informed consent
* Age 18-80 years
* PAH which is idiopathic, heritable or associated with drugs, toxins or connective tissue disease
* Stable PAH therapeutic regime comprising any combination of ERA and PDE5i for at least 1 month prior to screening (unless unable to tolerate therapy)
* WHO functional class III
* Resting mPAP ≥20 mmHg, pulmonary capillary wedge pressure ≤15 mmHg, pulmonary vascular resistance ≥2 Wood Units measured by right heart catheterisation at time of diagnosis
* 6MWT \>50m at entry
* Estimated glomerular filtration rate (eGFR)\>30 ml/min/1.73 m² at entry (Appendix C)
* Inadequate treatment response (clinically determined)

Exclusion Criteria:

* Unable to provide informed consent
* Pregnancy
* Unprovoked pulmonary embolism (at any time)
* Acute infection at time of screening (rescreening is permitted)
* PAH due to human immunodeficiency virus, portal hypertension, schistosomiasis, congenital heart disease
* Pulmonary hypertension due to left heart, lung, thromboembolic or unclear/multifactorial disease (Group II-V)
* Unable to tolerate aspirin or P2Y12 inhibitor
* Hypersensitivity to selexipag or riociguat
* Clinically-significant renal disease (eGFR≤30 ml/min/1.73m2)
* Anaemia (haemoglobin \<10 g/dl)
* Left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following: aortic or mitral valve disease greater than mild aortic insufficiency; mild aortic stenosis; mild mitral stenosis; or moderate mitral regurgitation