Hemodynamics and Phosphodiesterase-5 Inhibitor Treatment Associated with Survival in Pulmonary Hypertension in Interstitial Lung Disease: A PVRI GoDeep Meta-Registry Analysis
Athiththan Yogeswaran, Paul M. Hassoun, Khaled Saleh, Meike Fünderich, Aparna Balasubramanian, Ziad Konswa, David G. Kiely, Allan Lawrie, Thenappan Thenappan, Christina A. Eichstaedt, Ekkehard Grünig, Martin R. Wilkins, Luke Howard, Horst Olschewski, Gábor Kovács, Héctor Cajigas, Robert P. Frantz, Hani Sabbour, Andrew J. Sweatt, Roham T. Zamanian, Alexandra Arvanitaki, George Giannakoulas, Jean Elwing, Arun Jose, Stephan Beckmann, Karen M. Olsson, Stefan Stadler, Matthias Held, Michael Halank, Ralf Ewert, Jürgen Behr, Katrin Milger, Christine Pausch, David Pittrow, Raphael W. Majeed, Jochen Wilhelm, Hossein Ardeschir Ghofrani, Friedrich Grimminger, Khodr Tello, Marius M. Hoeper, Werner Seeger
Abstract
Abstract Rationale Pulmonary hypertension (PH) in interstitial lung disease (ILD) lacks approved therapies. Objectives The Pulmonary Vascular Research Institute GoDeep metaregistry collects real-world data of patients with PH from international PH referral centers. Methods Patients with ILD-PH and relevant subgroups (idiopathic interstitial pneumonia [IIP], idiopathic pulmonary fibrosis [IPF]) were stratified by pulmonary vascular resistance (PVR). Kaplan-Meier survival analyses and adjusted Cox proportional hazards models were employed, additionally accounting for immortal time bias, sensitivity analyses, Heller explained relative risk statistics, and target trial emulation framework analysis. Measurements and Main Results Among 34,482 patients, 940 with hemodynamically fully characterized incident ILD-PH (median age, 67 [IQR, 59–74] yr) were identified. A total of 62% had severe ILD-PH with PVR >5 Wood units (WU) and poor survival rates (29% and 18% at 3 and 5 yr), significantly worse than patients with ILD-PH with PVR ≤5 WU and patients with pulmonary arterial hypertension. Survival was poorest in severe IPF-PH. A total of 59% of all patients ILD-PH received PH-targeted therapy, predominantly phosphodiesterase-5 inhibitors (PDE5is). PDE5i treatment was consistently associated with significantly improved survival in patients with severe PH (hazard ratios of 0.537 [0.370–0.781], 0.461 [0.233–0.913], and 0.435 [0.215–0.8] for IIP-PH, IPF-PH, and IIP-PH with nintedanib/pirfenidone background therapy), but not in patients with less severe hemodynamic impairment, supported by sensitivity analyses, Heller statistics, and target trial emulation framework analysis. The survival statistics of patients with PDE5i-treated IIP-PH or IPF-PH were validated in the independent COMPERA registry. Combination therapy with PDE5is and inhaled prostacyclin analogues was superior to monotherapy using PDE5is (hazard ratio, 0.341; 0.205–0.566). Conclusions Prognosis in ILD-PH was generally very poor and was related to PH severity. PDE5i treatment in severe IIP-PH and IPF-PH was associated with improved survival, which is to be further verified in controlled trials.