Abstract
Background It is currently unknown if disease severity modifies response to therapy in pulmonary arterial hypertension (PAH). We aimed to explore if disease severity, as defined by established risk-prediction algorithms, modified response to therapy in randomised clinical trials in PAH.
Methods We performed a meta-analysis using individual participant data from 18 randomised clinical trials of therapy for PAH submitted to the United States Food and Drug Administration to determine if predicted risk of 1-year mortality at randomisation modified the treatment effect on three outcomes: change in 6-min walk distance (6MWD), clinical worsening at 12 weeks and time to clinical worsening.
Results Of 6561 patients with a baseline US Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL 2.0) score, we found that individuals with higher baseline risk had higher probabilities of clinical worsening but no difference in change in 6MWD. We detected a significant interaction of REVEAL 2.0 risk and treatment assignment on change in 6MWD. For every 3-point increase in REVEAL 2.0 score, there was a 12.49 m (95% CI 5.86–19.12 m; p=0.001) greater treatment effect in change in 6MWD. We did not detect a significant risk by treatment interaction on clinical worsening with most of the risk-prediction algorithms.
Conclusions We found that predicted risk of 1-year mortality in PAH modified treatment effect as measured by 6MWD, but not clinical worsening. Our findings highlight the importance of identifying sources of treatment heterogeneity by predicted risk to tailor studies to patients most likely to have the greatest treatment response.
Tweetable abstract
Disease severity in pulmonary arterial hypertension modifies treatment effect by change in 6-min walk distance but not clinical worsening in a meta-analysis of randomised clinical trials, highlighting the variable performance of surrogate end-points https://bit.ly/3NSJ9Pg
Footnotes
Author contributions: N. Al-Naamani and H-M. Pan had full access to all of the data and contributed to the study design, data collection, data analysis and interpretation, and the writing of the manuscript, and had the final decision to submit for publication. R.L. McClelland and J. Moutchia contributed to the design and interpretation of the data and the writing of the manuscript. J. Moutchia, D.H. Appleby, J.H. Holmes, J. Minhas and R.J. Urbanowicz contributed to the data collection and data organisation. J.S. Fritz and H.I. Palevsky provided critical revision of the manuscript for important intellectual contact. S.M. Kawut contributed substantially to the study design, data interpretation and the writing of the manuscript.
Conflict of interest: H-M. Pan has received funding support from the National Institutes of Health (T32HL007891). R.L. McClelland has received full-time-equivalent salary support via a subcontract from the University of Pennsylvania. J.S. Fritz has had grants or contracts from United Therapeutics as monies paid to the institution for the conduct of multicentre pulmonary arterial hypertension drug trials. J.H. Holmes has received funding support from the Cardiovascular Medical Research and Education Fund; has received grants or contracts from the National Institutes of Health, University of Florida Juvenile Diabetes Research Foundation and the University of Pavia; has served as a participant on the Clinical Data to Health External Advisory Board and COACH T2D (Columbia University); and has served unpaid leadership or fiduciary roles for the American College of Medical Informatics, American College of Epidemiology and the Artificial Intelligence Society. J. Minhas has received funding support from the National Institutes of Health (T32HL007891) and the American Thoracic Society Early Career Investigator Award. H.I. Palevsky has participated on a data safety monitoring board for studies for pulmonary arterial hypertension sponsored by United Therapeutics. S.M. Kawut has received funding support from the National Institutes of Health (K24HL103844) and the Cardiovascular Medical Research and Education Fund; received consulting fees from Janssen, Morphic and Regeneron; received payment or honoraria from Janssen; contributed to continuing medical education courses through Accredo, Actelion, Aerovate, Bayer, Inari Medical, Merck, United Therapeutics, Janssen, Liquidia and Pfizer; received support for attending meetings from Aerovate; participated in data safety monitoring boards or advisory boards for United Therapeutics, Acceleron, Vivus and Aerovate; participated in leadership or fiduciary roles for the editorial board of the European Respiratory Journal (ended 2022); received stock or stock options from Verve Therapeutics; and received remote monitory equipment from PhysIQ. N. Al-Naamani has received funding support from the National Institutes of Health (K23HL141584) and from the Cardiovascular Medical Research and Education Fund. The remaining authors disclose no potential conflicts of interest.
Support statement: Support was provided by the Cardiovascular Medical Research and Education Fund (S.M. Kawut), the National Institutes of Health (K24HL103844, S.M. Kawut; K23HL141584, N. Al-Naamani; and T32HL007891, H-M. Pan and J. Minhas). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received February 10, 2023.
- Accepted May 2, 2023.
- Copyright ©The authors 2023. For reproduction rights and permissions contact permissions{at}ersnet.org
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