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 randomized clinical trials in PAH.
Methods We performed a meta-analysis using individual participant data from 18 randomized clinical trials of therapy for PAH submitted to the United States Food and Drug Administration to determine if predicted risk of one-year mortality at randomization modified the treatment effect on three outcomes: change in six-minute walk distance (6MWD), clinical worsening at 12 weeks, and time-to-clinical worsening.
Results Of 6561 patients with a baseline U.S. 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 three-point increase in REVEAL 2.0 score, there was a 12.49 meter (95%CI 5.86–19.12, 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 one-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.
Footnotes
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Conflict of interest: Hao-Min Pan has received funding support from the National Institute of Health (T32HL007891).
Conflict of interest: Robyn L. McClelland has received full-time-equivalent salary support via a subcontract from the University of Pennsylvania.
Conflict of interest: Jude Moutchia has declared no conflicts of interest.
Conflict of interest: Dina H. Appleby has declared no conflicts of interest.
Conflict of interest: Jason S. Fritz has had grants or contracts from United Therapeutics as monies paid to the institution for the conduct of multi-center pulmonary arterial hypertension drug trials.
Conflict of interest: John H. Holmes has received funding support from the Cardiovascular Medical Research and Education Fund. He has also received grants or contracts from the National Institutes of Health, University of Florida Juvenile Diabetes Research Foundation, and the University of Pavia. He has also served as a participant on the Clinical Data to Health External Advisory Board and COACH T2D (Columbia University. He has also served unpaid leadership or fiduciary role for the American College of Medical Informatics, American College of Epidemiology, and the Artificial Intelligence Society.
Conflict of interest: Jasleen Minhas has received funding support from the National Institutes of Health (T32HL007891) and the American Thoracic Society Early Career Investigator Award.
Conflict of interest: Harold I. Palevsky has participated in the Data Safety Monitoring Board for studies for pulmonary arterial hypertension sponsored by United Therapeutics.
Conflict of interest: Ryan J. Urbanowicz has declared no conflicts of interest.
Conflict of interest: Steven Kawut has received funding support from the National Institutes of Health (K24HL103844) and the Cardiovascular Medical Research and Education Fund. He has also received consulting fees from Janssen, Morphic, and Regeneron. He has also received payment or honoraria from Janssen, and continuing medical education courses through Accredo, Actelion, Aerovate, Bayer, Inari Medical, Merck, United Therapeutics, Janssen, Liquidia, and Pfizer. He has received support for attending meetings from Aerovate. He has participated in the data safety monitoring board or advisory board from United Therapeutics, Acceleron, Vivus, and Aerovate. He has also received leadership or fiduciary roles from the Editorial board of the European Respiratory Journal (ended 2022). He has received stock or stock options from Verve Therapeutics and receipt of remote monitory equipment from PhysIQ.
Conflict of interest: Nadine Al-Naamani has received funding support from the National Institutes of Health (K23HL141584) and from the Cardiovascular Medical Research and Education Fund.
- Received February 10, 2023.
- Accepted May 2, 2023.
- Copyright ©The authors 2023. For reproduction rights and permissions contact permissions{at}ersnet.org