Phenotypic characterization of pulmonary hypertension associated with left heart disease in contemporary practice: insights from the Re-PHIRE Trial

Background

Pulmonary hypertension associated with left heart disease (PH-LHD; Group 2) is the most prevalent form of PH and linked to increased morbidity and mortality. The Re-PHIRE (NCT05737940) Phase IIb trial enrolled a contemporary, globally representative cohort of patients with heart failure (HF) and PH-LHD, offering an opportunity to characterise their clinical, haemodynamic, and biomarker profile.

Purpose

To provide phenotypic characterization of a contemporary cohort of patients with PH-LHD enrolled in Re-PHIRE trial.

Methods

RePHIRE was a randomised, double-blind, placebo-controlled, multicentre study evaluating AZD3427 in participants with HF and PH-LHD, agnostic to ejection fraction (EF) and pulmonary vascular resistance (PVR). Participants underwent screening echocardiography, and those with intermediate or high probability of PH per ESC/ERS guideline criteria underwent right heart catheterisation (RHC) for confirmation of haemodynamic diagnostic criteria (Figure).

Results

Of 450 screened participants, 260 were randomised and 259 treated across 14 countries and 52 sites.

The mean age of the study population was 69±13 years with 41.7% being 75 years or older; 50.6% were female. The mean BMI was 30.1±6.8 kg/m2. Majority of study participants (62.5%) had HF with preserved EF, while a minority had HF with reduced EF (17.0%). 51% of participants were in NYHA Class III. Geometric mean NT-proBNP was 710 pg/mL (geometric coefficient of variation (gCV%) 192). Common comorbidities were hypertension (73.0%) and atrial fibrillation (59.8%) (Table).

Geometric mean PVR was 180.2 dyn.s/cm5 (gCV% 92.2), with 106 (40.9%) participants having PVR of ≤160 dyn.s/cm5, and 93 (35.9%) - PVR of >240 dyn.s/cm 5. Mean mPAP was 33.2±10.3 mmHg, with 45 (17.3%) participants having mPAP 20–24.9 mmHg (Table).

The majority of participants had reduced left ventricular (LV) longitudinal strain; abnormal left atrial (LA) volume, E/E’ and LA reservoir strain; and reduced right ventricle to pulmonary artery (RV-PA) coupling (Table).

6-minute walk distance (6MWD) and Kansas City Cardiomyopathy Questionnaire (KCCQ-TSS) score were impaired (Table).

Conclusions

Re-PHIRE provides one of the largest contemporary multi-country cohorts of patients with RHC-confirmed diagnosis of PH-LHD across the EF continuum and a wide PVR range, thereby capturing a spectrum of haemodynamic and clinical phenotypes. It is characterised by advanced age, HFpEF predominance, high comorbidity burden and functional limitations despite guideline-directed medical HF therapy. There is a marked heterogeneity in the PVR and a notable subset with lower-range mPAP. These findings delineate the phenotypic spectrum of PH-LHD across EF and PVR and may inform future trial design, stratification strategies, and development of targeted therapies.Figure:Re-PHIRE patient populationFor image description, please refer to the figure legend and surrounding text.Table:Baseline characteristicsFor image description, please refer to the figure legend and surrounding text.