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. 2025 Feb 25;11(1):00466-2024.
doi: 10.1183/23120541.00466-2024. eCollection 2025 Jan.

Association of pulmonary hypertension-targeted therapy and survival in precapillary pulmonary hypertension with mean pulmonary arterial pressure between 21 and 24 mmHg

Athiththan Yogeswaran  1 , Meike Fünderich  1 , Horst Olschewski  2 , Gabor Kovacs  2 , David G Kiely  3 , Allan Lawrie  3 , Paul M Hassoun  4 , Aparna Balasubramanian  4 , Ziad Konswa  4 , Joanna Pepke-Zaba  5 , John Cannon  5 , Martin R Wilkins  6 , Luke Howard  6 , Hossein Ardeschir Ghofrani  1   7 , Friedrich Grimminger  1 , Werner Seeger  1 , Khodr Tello  1
Affiliations

Association of pulmonary hypertension-targeted therapy and survival in precapillary pulmonary hypertension with mean pulmonary arterial pressure between 21 and 24 mmHg

Athiththan Yogeswaran et al. ERJ Open Res. .

Abstract

Introduction: The definition of pulmonary hypertension (PH) was recently changed and led to a new subset of PH patients with mildly impaired pulmonary haemodynamics, characterised by a mean pulmonary artery pressure (mPAP) of 21-24 mmHg and with a pulmonary vascular resistance (PVR) >2 WU. We evaluated the association of PH-targeted therapy and outcome in mild precapillary PH using the PVRI GoDeep meta-registry.

Methods: All patients with mild precapillary PH (mPAP 21-24 mmHg, pulmonary arterial wedge pressure ≤15 mmHg and PVR >2 WU) diagnosed with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) were enrolled. Patients were considered as "treated" if PH-targeted therapy was initiated within 6 months of diagnostic right heart catheterisation. Various statistical models, including in-depth sensitivity analyses, were used to examine the association between PH-targeted therapy and transplant-free survival.

Results: 132 patients with group 1 or group 4 mild PH were identified, of whom 34 patients received PH-targeted therapy. There were no differences in baseline haemodynamics between untreated and treated groups, whereas treated patients suffered more frequently from renal comorbidities and required long-term oxygen treatment more often. Most prescribed were phosphodiesterase-5-inhibitors. PH-targeted therapy was associated with significantly higher survival rates. Cox-regression analyses revealed significantly reduced hazard ratios among treated patients adjusted for various confounders. Subgroup analyses in PAH (n=78) similarly indicated higher survival rates and reduced hazard ratios in treated patients.

Conclusion: PH-targeted therapy may be associated with improved survival in PAH and CTEPH patients with mild PH. To mitigate potential bias of the results due to the retrospective study design, randomised controlled trials are warranted.

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Conflict of interest statement

Conflict of interest: A. Yogeswaran reports nonfinancial support from the University of Giessen during the conduct of the study, and personal fees from MSD outside the submitted work. P.M. Hassoun reports personal fees from Merck Co., outside the submitted work. M.R. Wilkins reports personal fees from MorphogenIX, Janssen, Chiesi and Aerami, grants from the British Heart Foundation and the NIHR, personal fees from MSD, Benevolent AI and Tiakis Biotech, outside the submitted work; in addition, M.R. Wilkins has a patent Zip12 as a drug target issued. Dr Howard reports personal fees and nonfinancial support from Janssen, personal fees from MSD, personal fees from Gossamer, personal fees from Altavant, outside the submitted work. H.A. Ghofrani reports grants from the German Research Foundation and nonfinancial support from the University of Giessen during the conduct of the study, and personal fees from Bayer, Actelion, Pfizer, Merck, GSK and Takeda, grants and personal fees from Novartis, Bayer HealthCare and Encysive/Pfizer, and grants from Aires, the German Research Foundation, Excellence Cluster Cardiopulmonary Research and the German Ministry for Education and Research, outside the submitted work. W. Seeger reports grants from the German Research Foundation and nonfinancial support from the University of Giessen during the conduct of the study, and personal fees from Pfizer and Bayer Pharma AG outside the submitted work. K. Tello reports nonfinancial support from the University of Giessen during the conduct of the current study and speaker honoraria from Actelion and Bayer outside the submitted work. All other authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Patient selection in PVRI GoDeep. PVRI: Pulmonary Vascular Research Institute; PH: pulmonary hypertension; mPAP: mean pulmonary arterial pressure; PVR: pulmonary vascular resistance.
FIGURE 2
FIGURE 2
Sanity check of the imputation. The diagrams show the empirical cumulative distributions of the variables for which values were imputed. The black line shows the distribution of the original data, the red lines show the distributions of the variables, including the imputed values. WHO FC: World Health Organization functional class; BNP: B-type natriuretic peptide; 6MWD: 6-min walk distance; ECDF: empirical cumulative distribution function.
FIGURE 3
FIGURE 3
Adjusted Kaplan–Meier survival analysis comparing mild pulmonary hypertension (PH) patients receiving PH-targeted therapy versus untreated patients. Kaplan–Meier estimators were adjusted for patient's age as a natural spline with two degrees of freedom, as well as sex as strata and centre as cluster. a) Adjusted Kaplan–Meier for overall study group. b) Adjusted Kaplan–Meier for PH group 1. HR: hazard ratio.
FIGURE 4
FIGURE 4
Cox-regression models exploring the association between pulmonary hypertension (PH)-targeted therapy and mortality risk. a) Base model: PH-targeted therapy adjusted for PH centre, diagnosis decade and sex as strata, along with patient's age as a natural spline with 2 degrees of freedom and centre as a cluster. Full model: base model with additional adjustment for World Health Organization (WHO) functional class (FC), 6-min walk distance (6MWD), pulmonary vascular resistance (PVR), pulmonary arterial wedge pressure (PAWP), cardiac index (CI), B-type natriuretic peptide, creatinine, PH group, renal comorbidities, oxygen treatment, cardiovascular disease (CVD) and metabolic syndrome. First estimates from the base model are shown with the respective terms added and afterwards the estimates from the full model from which the respective terms were removed. b) Subgroup examinations are depicted. The estimates for the analysis for the base and the full model for patients included in the propensity score matching and patients with cardiovascular disease are then presented, as well as the base model for the complete dataset (without imputation) and landmark analysis. c) Base and full model for PH group 1 patients only. First estimates from the base model are shown with the respective terms added and afterwards the estimates from the full model from which the respective terms were removed. d) Subgroup examinations for patients included in the propensity score matching, as well as patients with landmark analysis are depicted. The diagrams show the estimates with 95% confidence intervals. The p-values are from Wald z-tests. BMI: body mass index; RHC: right heart catheterisation; HR: hazard ratio; lower, upper: lower and upper limits of the 95% confidence interval of the HR; PSM: propensity score matching.
FIGURE 5
FIGURE 5
Change in European Society of Cardiology/European Respiratory Society 4-strata risk from baseline to follow-up (FU) within 6–60 months for (a) untreated and (b) treated patients. Int.: intermediate.
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