Phenotyping of idiopathic pulmonary arterial hypertension: a registry analysis

Abstract

Background: Among patients meeting diagnostic criteria for idiopathic pulmonary arterial hypertension (IPAH), there is an emerging lung phenotype characterised by a low diffusion capacity for carbon monoxide (DLCO) and a smoking history. The present study aimed at a detailed characterisation of these patients.

Methods: We analysed data from two European pulmonary hypertension registries, COMPERA (launched in 2007) and ASPIRE (from 2001 onwards), to identify patients diagnosed with IPAH and a lung phenotype defined by a DLCO of less than 45% predicted and a smoking history. We compared patient characteristics, response to therapy, and survival of these patients to patients with classical IPAH (defined by the absence of cardiopulmonary comorbidities and a DLCO of 45% or more predicted) and patients with pulmonary hypertension due to lung disease (group 3 pulmonary hypertension).

Findings: The analysis included 128 (COMPERA) and 185 (ASPIRE) patients with classical IPAH, 268 (COMPERA) and 139 (ASPIRE) patients with IPAH and a lung phenotype, and 910 (COMPERA) and 375 (ASPIRE) patients with pulmonary hypertension due to lung disease. Most patients with IPAH and a lung phenotype had normal or near normal spirometry, a severe reduction in DLCO, with the majority having no or a mild degree of parenchymal lung involvement on chest computed tomography. Patients with IPAH and a lung phenotype (median age, 72 years [IQR 65-78] in COMPERA and 71 years [65-76] in ASPIRE) and patients with group 3 pulmonary hypertension (median age 71 years [65-77] in COMPERA and 69 years [63-74] in ASPIRE) were older than those with classical IPAH (median age, 45 years [32-60] in COMPERA and 52 years [38-64] in ASPIRE; p<0·0001 for IPAH with a lung phenotype vs classical IPAH in both registries). While 99 (77%) patients in COMPERA and 133 (72%) patients in ASPIRE with classical IPAH were female, there was a lower proportion of female patients in the IPAH and a lung phenotype cohort (95 [35%] COMPERA; 75 [54%] ASPIRE), which was similar to group 3 pulmonary hypertension (336 [37%] COMPERA; 148 [39%] ASPIRE]). Response to pulmonary arterial hypertension therapies at first follow-up was available from COMPERA. Improvements in WHO functional class were observed in 54% of patients with classical IPAH, 26% of patients with IPAH with a lung phenotype, and 22% of patients with group 3 pulmonary hypertension (p<0·0001 for classical IPAH vs IPAH and a lung phenotype, and p=0·194 for IPAH and a lung phenotype vs group 3 pulmonary hypertension); median improvements in 6 min walking distance were 63 m, 25 m, and 23 m for these cohorts respectively (p=0·0015 for classical IPAH vs IPAH and a lung phenotype, and p=0·64 for IPAH and a lung phenotype vs group 3 pulmonary hypertension), and median reductions in N-terminal-pro-brain-natriuretic-peptide were 58%, 27%, and 16% respectively (p=0·0043 for classical IPAH vs IPAH and a lung phenotype, and p=0·14 for IPAH and a lung phenotype vs group 3 pulmonary hypertension). In both registries, survival of patients with IPAH and a lung phenotype (1 year, 89% in COMPERA and 79% in ASPIRE; 5 years, 31% in COMPERA and 21% in ASPIRE) and group 3 pulmonary hypertension (1 year, 78% in COMPERA and 64% in ASPIRE; 5 years, 26% in COMPERA and 18% in ASPIRE) was worse than survival of patients with classical IPAH (1 year, 95% in COMPERA and 98% in ASPIRE; 5 years, 84% in COMPERA and 80% in ASPIRE; p<0·0001 for IPAH with a lung phenotype vs classical IPAH in both registries).

Interpretation: A cohort of patients meeting diagnostic criteria for IPAH with a distinct, presumably smoking-related form of pulmonary hypertension accompanied by a low DLCO, resemble patients with pulmonary hypertension due to lung disease rather than classical IPAH. These observations have pathogenetic, diagnostic, and therapeutic implications, which require further exploration.

Funding: COMPERA is funded by unrestricted grants from Acceleron, Bayer, GlaxoSmithKline, Janssen, and OMT. The ASPIRE Registry is supported by Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.

Conflict of interest statement

Declaration of interests MMH received fees for lectures or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, and Pfizer. KD has received research funding from Janssen Pharmaceuticals, National Institute of Health Research (NIHR), UK and The Wellcome Trust, UK. RAL has received honoraria and research grants from Janssen Pharmaceuticals. KMO has received fees for lectures or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer, and United Therapeutics. DH has received travel compensation from Shire. DP has received fees for consultations from Actelion, Amgen, Aspen, Bayer, Biogen, Boehringer Ingelheim, Daiichi Sankyo, MSD, Novartis, Sanofi-Genzyme, Takeda and Viatris. EG has received fees for lectures or consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer, and United Therapeutics. GS has received honoraria for lectures or consultancy for Actelion, Bayer, GlaxoSmithKline, Novartis, and Pfizer. CDV has received fees for lectures or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer, and United Therapeutics. HG reports personal fees from Actelion, AstraZeneca, Bayer, Bristol Myers Squib, GlaxoSmithKline, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. OD has or has had a consultancy relationship or has received research funding from 4 D Science, Actelion, Active Biotec, Bayer, Biogen Idec, Boehringer Ingelheim Pharma, Bristol Myers Squib, ChemoAb, EpiPharm, Ergonex, espeRare foundation, GlaxoSmithKline, Genentech/Roche, Inventiva, Janssen, Lilly, medac, MedImmune, Mitsubishi Tanabe, Pharmacyclics, Pfizer, Sanofi, Serodapharm, and Sinoxa in the area of potential treatments of scleroderma and its complications including PAH; and reports a patent mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143). JSRG has received fees for lectures or consultations from Acceleron, Actelion, Aerovate, Bayer, Complexia, Janssen, MSD, Pfizer, and United Therapeutics. MD reports research grants from Actelion/J&J; speaker and consultant fees from Bayer, MSD, Acceleron, AOP, Daiichi Sankyo, outside of the submitted work; and being a holder of the Janssen Chair for Pulmonary Hypertension at the Katholieke Universiteit Leuven, Leuven, Belgium. D-HP has received lecture fees from Janssen Pharmaceuticals. HAG has received honorariums for consultations or speaking at conferences from Bayer HealthCare, Actelion, Pfizer, Janssen, Merck/MSD, and Gossamer; is member of advisory boards for Acceleron, Bayer HealthCare AG, Pfizer, GlaxoSmithKline, Actelion, Merck/MSD, Janssen, and Gossamer; and has received public grants from the German Research Foundation, Excellence Cluster Cardiopulmonary Institute, State Government of Hessen, and the German Ministry for Education and Research. RE has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, and United Therapeutics. HKa has received honoraria for lectures or consultancy from Actelion, Bristol Myers Squibb, and Janssen. H-JK has received fees from Actelion, Anamed, AstraZeneca, Berlin Chemie/Menarini, Boehringer Ingelheim, Chiesi, Daiichi-Sankyo, Dräger, Fisher & Paykel Healthcare, GlaxoSmithKline, Heinen + Löwenstein, Lilly, MSD, Novartis, Pfizer, Weinmann, Philips Healthcare, Pulmonx, ResMed, Roche, Sanofi-Genzyme, Sapio Life, Weinmann. DS received fees for lectures, consulting, or research support to institution from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. JB received grants from Actelion, Boehringer Ingelheim and Roche; and honoraria from Bayer, Biogen, Boehringer-Ingelheim, Galapagos, Novartis, Roche, and Sanofi/Genzyme. KM has received fees from Actelion, AstraZeneca, GlaxoSmithKline, Janssen, MSD, Novartis and Sanofi-Aventis. TJL has received speaker fees and honoraria for consultation from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen-Cilag, MSD, Pfizer, and United Therapeutics. HW received fees for lectures or consultations from Actelion, Bayer, Biotest, Boehringer, GlaxoSmithKline, Janssen, Pfizer and Roche. H-JS has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, and MSD. MHe has received speaker fees and honoraria for consultations from Actelion, Bayer, Boehringer Ingelheim Pharma, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, Nycomed, Roche and Servier. DD declares honoraria for lectures or consultancy from Actelion, AstraZeneca, Bayer, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, Servier and Vifor. IT has received fees from Actelion, Bayer, ELPEN, GlaxoSmithKline, Janssen, MSD, Pfizer, and United Therapeutics. AV-N reports receiving fees for lectures or consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. SU reports personal fees from Actelion, Janssen, MSD, and Orpha-Swiss outside of the submitted work. HKl has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, and United Therapeutics. MC reports honoraria for lectures from Boehringer Ingelheim Pharma and Roche Pharma, and for serving on advisory boards from Boehringer Ingelheim. SE has received honoraria for lectures or consultations from Actelion, MSD, Bayer, Acceleron, Gilead, AstraZeneca, Pulmox, Boston Scientific, and Boehringer Ingelheim. K-HS has received fees for lectures and educational events from Abbott, Janssen, and MSD. AJS has received research grants from GlaxoSmithKline, Janssen Pharmaceuticals, Wellcome Trust, and NIHR; has undertaken consultancy work and received honoraria for lectures from Janssen Pharmaceuticals; and has undertaken consultancy work for General Electric. AART is supported by a British Heart Foundation Intermediate Clinical Fellowship (FS/18/13/33281) and has received research grants to their institution from Janssen Pharmaceuticals and GlaxoSmithKline. CAE has received honoraria for lectures or consultations from Actelion, GlaxoSmithKline, Janssen and MSD. SR has received fees for lectures or consultations from Abbott, Acceleron, Actelion, Bayer, Bristol Myers Squib, Gilead, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, United Therapeutics, and Vifor; and research grants to institution from AstraZeneca, Actelion, Bayer Janssen and Novartis. RC has received honoraria for lectures or consultations from Actelion, GlaxoSmithKline, Janssen, and MSD. DGK has received honoraria for lectures or consultations from Acceleron, Actelion, Ferrer, GlaxoSmithKline, Janssen Pharmaceuticals, and MSD; and research grants to institution from Actelion, GlaxoSmithKline and Janssen Pharmaceuticals. MHa has received speaker fees and honoraria for consultations from Acceleron, Actelion, AstraZeneca, Bayer, BerlinChemie, GlaxoSmithKline, Janssen, and Novartis. All other authors declare no competing interests.

Copyright © 2022 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Patient selection in COMPERA and ASPIRE ASPIRE=Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Centre. BMI=body-mass index. COMPERA=Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension. DLCO=low diffusion capacity for carbon monoxide. IPAH=idiopathic pulmonary arterial hypertension. mPAP=mean pulmonary arterial pressure. PAWP=pulmonary artery wedge pressure. PVR=pulmonary vascular resistance. WU=wood units. *More than one reason for exclusion could apply. †Classical IPAH defined by the absence of risk factors for left heart disease (BMI≥ 30 kg/m, hypertension, diabetes, and coronary heart disease), and a DLCO ≥45%. ‡Diagnosed with IPAH and a lung phenotype cohort defined by a smoking history (ie, current or former smoker) and a DLCO

Figure 2

Grouped bar plots showing age distribution of patients classified as classical IPAH, IPAH with a lung phenotype, and group 3 pulmonary hypertension in COMPERA (A) and ASPIRE (B) ASPIRE=Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Centre. COMPERA=Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension. IPAH=idiopathic pulmonary arterial hypertension.

Figure 3

Baseline and first follow-up measurement for functional class (A), 6MWD (B), NT-proBNP (C), and mortality risk (D) in COMPERA in patients with classical IPAH, IPAH with a lung phenotype, and patients with group 3 pulmonary hypertension (A) Bar graphs of WHO functional class at baseline and first follow-up after treatment initiation. (B) Box plots depicting the changes in 6MWD from baseline to first follow-up. (C) Box plots depicting the changes in NT-proBNP from baseline to first follow-up. (D) Bar graphs of mortality risk assessed by the European Society of Cardiology and European Respiratory Society 4-strata model at baseline and first follow-up after treatment initiation. COMPERA=Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension. IPAH=idiopathic pulmonary arterial hypertension. 6MWD=6-minute walking distance. NT-proBNP=N-terminal fragment of pro-brain natriuretic peptide.

Figure 4

Kaplan-Meier survival estimates for patients classified as classical IPAH, IPAH with a lung phenotype, and group 3 pulmonary hypertension in COMPERA (A) and ASPIRE (B) ASPIRE=Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Centre. COMPERA=Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension. IPAH=idiopathic pulmonary arterial hypertension.