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9.1 Diagnosis

In patients with lung disease, symptoms of PH, especially exertional dyspnoea, overlap with those of the underlying condition. Physical findings may also be non-specific, for example: ankle swelling is common during episodes of ventilatory failure in COPD, where activation of the renin–angiotensin–aldosterone system may cause fluid retention, usually in the setting of preserved RV function. Non-invasive tests—such as ECG showing right axis deviation or RV strain, elevated levels of BNP/NT-proBNP, CPET, or features on cross-sectional imaging—may suggest the diagnosis of PH in patients with lung disease.725,726 Echocardiography remains the most widely used non-invasive diagnostic tool for assessing PH; however, the accuracy of echocardiography in patients with advanced respiratory diseases is low, with a TRV unmeasurable in .50% of patients in some studies, and there is a tendency to overestimate PAP and misclassify patients with PH.86,87,727 More recent data suggest that a stepwise, composite, echocardiographic score can identify patients with severe PH, with and without an estimate of TRV, using other echocardiographic features including RA area, RV:LV ratio, and LV eccentricity index.728 Where PH is suspected, combining echocardiography with a contrast-enhanced CT may aid diagnostic assessment and disease classification.108,729–731 Pulmonary artery enlargement, RV outflow hypertrophy, and increased RV:LV ratio may suggest a diagnosis of PH.108 Ideally, assessments should be made or repeated when the patient is clinically stable, as exacerbations can significantly raise PAP. Key parts of evaluating suspected PH in lung disease include integrating: (1) the presence or absence of risk factors for PAH, CTEPH, or LHD; (2) clinical features, including disease trajectory (e.g. rapid recent deterioration vs. gradual change over years, and oxygen requirements); (3) PFTs, including DLCO and blood gas analysis; (4) NT-proBNP measurements, ECG, and echocardiography; and (5) cross-sectional imaging with contrast-enhanced CT, SPECT, or V/Q lung scan and, in selected cases, cMRI732 to assess the need for RHC. Cardiopulmonary exercise testing may be helpful in assessing ventilatory or cardiac limitation in patients with lung disease,121,733 although data are limited regarding its clinical use in identifying patients with PH in lung disease. Indications for RHC in lung disease include assessment for surgical treatments (selected patients considered for LTx and lung volume reduction surgery), suspected PAH or CTEPH, and where further information will aid phenotyping of disease and consideration of therapeutic interventions (Figure S3).712,718,734 Such testing should ideally be conducted in PH centres when patients are clinically stable and treatment of underlying lung disease has been optimized. Consideration should be given to how pressure measurements are made, due to the impact of changing intrathoracic pressures on pulmonary haemodynamics during the respiratory cycle (see Section 5.1.12).735

9.2 Therapy

The therapeutic approach to group 3 PH starts with optimizing the treatment of the underlying lung disease, including supplementary oxygen and non-invasive ventilation, where indicated, as well as enrolment into pulmonary rehabilitation programmes.736 There is limited and conflicting evidence for the use of medication approved for PAH in patients with group 3 PH, and these drugs may have variable and sometimes detrimental effects on haemodynamics, exercise capacity, gas exchange, and outcomes in this patient population.181,737–740 9.2.1 Pulmonary hypertension associated with

chronic obstructive pulmonary disease or emphysema Studies using drugs approved for PAH in patients with PH associated with COPD or emphysema have yielded conflicting results and are mostly limited by small sample size, short duration, and insufficient haemodynamic characterization of PH.739,741,742 In a 16 week RCT of 28 patients with COPD and severe PH confirmed by RHC, sildenafil therapy resulted in statistically significant improvements in PVR and quality of life.743 Registry data identified that ≏30% of patients with COPD and severe PH, predominantly treated with PDE5is, had improved WHO-FC, 6MWD, and PVR vs. baseline, and those with a treatment response had improved transplant-free survival.51,718 However, in the absence of large randomized trials, the evidence is insufficient to support the general use of medication approved for PAH in patients with COPD and PH. Patients with COPD and suspected or confirmed severe PH should be referred to PH centres for individual decision-making.

9.2.2 Pulmonary hypertension associated with

interstitial lung disease Numerous phase 2 and phase 3 studies have investigated the use of ERAs to treat ILD, all with negative results.740,744,745 In addition, the PDE5i sildenafil has been investigated in phase 3 trials of patients with ILD, also with negative results.746,747 Few data from RCTs are available for patients with PH associated with ILD, and many of the studies performed for this indication748,749 suffered from the same limitations as the aforementioned studies in PH associated with COPD. In addition, there were several adverse safety signals: ambrisentan was associated with an increased risk of clinical worsening in patients with ILD with and without PH,740,750 while riociguat was associated with an increased risk of clinical worsening events, including potential excess mortality, in patients with PH associated with idiopathic interstitial pneumonia.181 In contrast, promising results have been obtained with the use of inhaled treprostinil. A phase 3 RCT (INCREASE) examined inhaled treprostinil at a target dose of 72 μg given four times daily in 326 patients with PH associated with ILD.734,751 The PH diagnosis was confirmed by RHC within 1 year prior to enrolment. At week 16, the placebo-corrected 6MWD improved by 31 m with inhaled treprostinil. There were also improvements in NT-proBNP and clinical worsening events, the latter driven by a lower proportion of patients whose 6MWD declined by .15% from baseline. Given the significant impact of even non-severe PH in patients with lung disease, eligible patients should be referred for LTx evaluation. In patients with ILD and PH, inhaled treprostinil may be considered based on the findings from the INCREASE study, but further data are needed, especially on long-term outcomes. The routine use of other medication approved for PAH is not recommended in patients with ILD and non-severe PH. For patients with severe PH and/or severe RV dysfunction, or where there is uncertainty regarding the treatment of PH, referral to a PH centre is recommended for careful evaluation, to facilitate entry into RCTs, and consider PAH therapies on an individual basis (Figure S3). Registry data show that some patients with group 3 PH are being treated with PAH medication, predominantly PDE5is,718,752,753 but it is unclear if and to what extent these patients benefit from this treatment. Downloaded from academic.oup.com/eurheartj/article/43/38/3618/6673929 by guest on 07 October 2026