Clinical implications of idiopathic pulmonary arterial hypertension phenotypes defined by cluster analysis

https://doi.org/10.1016/j.healun.2019.12.012Get rights and content

BACKGROUND

>Despite advances in drug development, life expectancy in idiopathic pulmonary arterial hypertension (IPAH) remains unacceptable. Contemporary IPAH characterization is based on criteria that may not adequately capture disease heterogeneity and may be proposed as a possible explanation for why patient outcome is still unfavorable. The aim of this study was to apply cluster analysis to improve phenotyping of patients with IPAH and analyze long-term clinical outcome of derived clusters.

METHODS

Patients with IPAH from 2 referral centers (n = 252) were evaluated with clinical, hemodynamic, and echocardiographic assessment and cardiopulmonary exercise test. Patients were classified according to cluster analysis and followed for clinical worsening occurrence.

RESULTS

The cluster analysis identified 4 IPAH phenotypes. Cluster 1 was characterized by young patients, mild pulmonary hypertension (PH), mild right ventricular (RV) dilation and high oxygen (O2) pulse; Cluster 2 by severe PH and RV dilation and high O2 pulse; and Cluster 3 by male patients, severe PH and RV dilation, and low O2 pulse. Cluster 4 patients were older and overweight, with mild PH and RV dilation and low O2 pulse. After a mean follow-up of 995 ± 623 days, 123 (48.8%) patients had clinical worsening. Cluster 1 patients presented the best prognosis, whereas Cluster 3 had the highest rates of clinical worsening. Compared with Cluster 1, risk of clinical worsening ranged from 4.12 (confidence interval [CI] 1.43–11.92; p = 0.009) for Cluster 4 to 7.38 (CI 2.80–19.40) for Cluster 2 and 13.8 (CI 5.60–34.0; p = 0.0001) for Cluster 3.

CONCLUSIONS

Cluster analysis of clinical variables identified 4 distinct phenotypes of IPAH. Our findings underscore the high degree of disease heterogeneity that exists within patients with IPAH and the need for advanced clinical testing to define phenotypes to improve treatment strategy decision-making.

CONDENSED ABSTRACT

Idiopathic pulmonary arterial hypertension (IPAH) characterization is based on criteria that may not adequately capture disease heterogeneity. The aim of this study was to apply cluster analysis to improve phenotyping of IPAH. Patients with IPAH (n = 252) were evaluated with clinical, hemodynamic, and echocardiographic assessment and cardiopulmonary exercise test.

Within the umbrella category of IPAH, it was the combination of mean pulmonary arterial pressure, right ventricular size, and oxygen pulse that further stratified patients into novel IPAH phenotypes that significantly associate with clinical worsening. These findings underscore the need for novel multidimensional IPAH phenotyping for improved patient care and trial quality.

Section snippets

Study population

Patients with prevalent IPAH (n = 252) from 2 referral centers, Policlinico Umberto I/Sapienza University of Rome and the University of Arizona, Tucson, Arizona, were enrolled in the study. The diagnosis of IPAH was confirmed according to the international guidelines1 (mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg, pulmonary wedge pressure < 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 240 dynes•s/cm5).

Baseline clinical data included a medical history, physical examination, a

Results

The 30 clinical variables were available for all the subjects included in the cluster analysis (n = 252 patients), as routinely used in clinical practice by both centers. The overall cohort included a mixture of consecutive patients with IPAH with a range of hemodynamic severity, RV function, and exercise capacity. Patients from the 2 sites had similar demographic characteristics and WHO functional class, but U.S. patients had greater RV sizes and lower 6MWD and VO2 peak compared with the

Discussion

We applied a novel approach to a relatively large population of patients with IPAH, well representative of daily practice activity close to a European and a US referral center.

Within the umbrella category of IPAH, it was the combination of mPAP, RVEDA, and O2 pulse that further stratified patients into novel IPAH phenotypes that significantly associate with CW. These findings underscore the significant heterogeneity that exists within patients with IPAH and the need for novel multidimensional

Study limitations

First, this study was not meant to propose a phenotype classification for IPAH, as the clusters are likely to vary according to patient characteristics and available data. However, we decided to consider the simplest and commonly used parameters in clinical practice. These results serve to underscore the need for a novel multidimensional IPAH phenotyping approach and should be validated in multicenter studies with larger and different PAH populations. Second, the study population represented

Conclusions

This study shows that by using a clustering algorithm on clinically available data of patients with IPAH, we can identify 4 phenotypically distinct and clinically meaningful groups. We have also shown that patients in each cluster presented different outcomes on long-term follow-up. These findings highlight the significant heterogeneity that exists within patients with IPAH and the need for improved advanced phenotyping with exercise and imaging to enhance current risk assessment tools.

Disclosure statement

R. Badagliacca has received fees as speaker and scientific consultant for GSK, UT, Dompè, Ferrer, Bayer, MSD, and AOPOrphan Pharmaceuticals. CD Vizza has received fees as speaker and scientific consultant for GSK, UT, Dompè, Bayer, and MSD. The other authors have no conflicts of interest to disclose.

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