The importance of comorbidities in idiopathic and associated with connective tissue disease pulmonary arterial hypertension: from the Spanish Registry of Pulmonary Hypertension (REHAP Registry)
Authors: Bravo-Marques R , Rivas-Ruiz F , Tenes J A , Becerra-Munoz V M , Soto-Abanadez C I , Cruz-Utrilla A , Martin De Miguel I , Barbera J A , Lopez-Reyes R , Alcolea-Batres S , Jimenez-Arjona J , Nunez-Ares A , Cremer-Luengos D , Torroba G , Escribano-Subias P 
Published: October 2024

Abstract

Introduction
Comorbidities play a major role in the prognosis of patients with pulmonary arterial hypertension (PAH). These comorbidities are present in more than 80% of patients diagnosed in the last years with idiopathic PAH (iPAH) and their presence is associated with increased morbidity and mortality although its influence on PAH associated with connective tissue disease (PAH-SSc) is unknown. We studied the impact of comorbidities on iPAH and PAH-SSc in the Spanish population.

Methods
We collected patients diagnosed with iPAH, heritable, associated with drug or toxine exposure and PAH-SSc between 2014 and 2023 from the Spanish Registry of Pulmonary Hypertension. Patients are classified into: no comorbidities, 1-2 comorbidities and ≥3 comorbidities. We analyzed the impact of comorbidities in baseline characteristics, exercise capacity and hemodynamic profile, as well as in the risk profile and initial treatment. Survival analyses estimated by Kaplan-Meier analysis using the log-rank test and Cox proportional hazard analyses were performed to determine the effects of baseline characteristics on survival.

Results
757 patients were selected for this study.
The characteristics of the patients are shown in Table 1.
As the number of comorbidities increases (0/1-2/≥3) we found higher age (49/59/67 years; p&lt;0.001), higher percentage of male sex (12.9/29.9/43.4%; p&lt;0.001) and higher FC III at diagnosis (42.7/46.9/59.6%; p=0.013). We observed a shorter distance in 6MWD, higher NT-proBNP levels, lower DLCO and a less unfavorable hemodynamic profile (PAPm, PAWP, CI and PVR).
The most frequent comorbidities were a history of smoking (46.4%), followed by arterial hypertension (41.5%), obesity (24.6%) and chronic kidney disease (19.2%). Diabetes mellitus, although less frequent, reached more than 55% in patients with ≥3 comorbidities (p&lt;0.001).
The presence of ≥ 3 comorbidities was more frequent in iPAH than PAH-SSc (p&lt;0,001).
Intermediate risk profile was the most common (58.4%) and this reached 68.7% in those with ≥3 comorbidities due to a lower number of patients in a low-risk profile (p&lt;0.001).
A statistically significant lower survival (p&lt;0.001) was observed in patients with ≥ 3 comorbidities; however, we found no differences between 0 and 1-2 comorbidities at 7-year follow-up (Figure 1).
Variables associated with mortality were male sex (HR 1.88, 95% CI 1,26 – 2.8), age (HR 1.04, 95% CI 1.02 – 1.06) and the presence of ≥3 comorbidities (HR 1.49, 95% CI 0.98 – 2.27), not the presence of connective tissue diseases, which were not associated with increased mortality in our study.

Conclusions
The presence of comorbidities in iPAH and PAH-SSc is very frequent in the Spanish population. They are associated with a worse clinical profile, risk profile, lower use of oral double theraphy and prostacyclins. The presence of ≥3 comorbidities is associated with worse survival, not the presence of 1-2 comorbidities or connective tissue disease.