PDE5i therapy may improve survival in ILD-PH

Treatment with phosphodiesterase 5 inhibitors (PDE5i) may provide survival benefits to patients with interstitial lung disease (ILD)-related pulmonary hypertension (PH), particularly in those with severe disease and normal baseline right ventricular (RV) dysfunction, suggest the results of a retrospective observational cohort study.

“Randomized controlled trial confirmation is crucial before recommending widespread implementation,” said the researchers who followed consecutive incident patients with ILD-PH and right heart catheterization, echocardiography, and spirometry data from diagnosis to death, transplantation, or censoring, with all follow-up and survival data modelled by Bayesian methods.

Overall, 128 patients were identified, of which 74 (58 percent) had been diagnosed with idiopathic pulmonary fibrosis (IPF), 17 (13 percent) with hypersensitivity pneumonitis, 12 (9 percent) with nonspecific interstitial pneumonia, eight (6 percent) with undifferentiated ILD, and 17 (13 percent) with other lung diseases. [Respirology 2023;28:262-272]

Death was the final outcome in 106 patients (83 percent), transplantation in nine (7 percent), and censoring in 13 (10 percent).

Fifty (39 percent) patients who were treated with PDE5i displayed higher mean pulmonary artery pressure (median 38 vs 35 mm Hg; p=0.07) and percentage predicted forced vital capacity (FVC; median 57 percent vs 52 percent; p=0.08), but the differences were not statistically significant.

In addition, patients who received PDE5i had longer survival than those who did not (median 2.18 vs 0.94 years; p=0.003), regardless of all other prognostic markers by Bayesian joint-modelling (hazard ratio [HR], 0.39, 95 percent confidence interval [CI], 0.23‒0.59; p<0.001) and propensity-matched analyses (HR, 0.38, 95 percent CI, 0.22‒0.58; p<0.001).

Notably, survival difference with PDE5i treatment was significantly longer if RV function was normal at presentation (normal vs abnormal RV function: 2.55 years, 95 percent CI, ‒0.03 to 3.97 vs 0.98 years, 95 percent CI, 0.47‒2.00; p=0.04).

“Concerns about worsening ventilation/perfusion mismatch have focused investigations on inhaled therapies,” the researchers said. [N Engl J Med 2021;384:325-334; Eur Respir J 2015;46:903-975; Am J Respir Crit Care Med 1999;160:600-607]

“Despite this, our data and that of others, support the view that oral pulmonary vasodilators including PDE5i may enhance normoxic vasodilatation without affecting ventilation/perfusion matching,” they added. [Lancet 2002;360:895-900; N Engl J Med 2010;363:620-628; N Engl J Med 2018;379:1722-1731]

Bayesian approach

The current study also demonstrated how Bayesian joint-modelling approaches could address missing and asynchronous data, which dispute the use of real-world data for research.

“Rare-disease analysis is well-suited to Bayesian approaches, since cohorts are small and clinical approach is influenced by experience from similar clinical experience,” the researchers said.

In this analysis of a large, prospective, clinical database with in-house protocolization of treatment, the researchers attempted to control for all relevant prognostic factors. However, ILD severity, haemodynamic, and quality of life markers were lacking, and the potential for selection bias persisted.

“Emphysema may spuriously preserve FVC, pulmonary hypertension may reduce carbon monoxide adjusted for alveolar volume, and [the] Composite Physiologic Index has not been validated outside IPF,” the researchers said. [Am J Respir Crit Care Med 2003;167:962-969]

“The emPHasis-10 questionnaire is designed for patients with pulmonary arterial hypertension not ILD-PH, and follow-up invasive catheterization is used judiciously to minimize risk,” they added. [Eur Respir J 2014;43:1106-1113]