To the Editor,
1.
We thank Drs. Zhang and Bao for their comment on our analysis regarding the role of angiotensin‐converting enzyme inhibition (ACEi) in patients with invasively diagnosed Group 3 pulmonary hypertension (PH) associated with COPD.
We concur with the authors that our in‐depth statistical approach provides a robust foundation for future research, including a reliable sample size estimation. While the requirement of 312 patients over 5 years is clinically feasible in terms of recruitment, we acknowledge that the necessary long‐term follow‐up poses a significant logistical challenge for a randomized controlled trial. An investigator‐initiated trial, involving collaborative efforts from both the PH and COPD communities, is warranted to definitively establish a potential causal relationship between RAAS inhibition and improved outcomes in this population.
Regarding class specificity, we agree that the distinct pharmacodynamic and side‐effect profiles of ACE inhibitors and angiotensin II receptor blockers (ARBs), particularly the risk of cough with ACE inhibitors, are clinically relevant. However, given the limited number of patients receiving exclusively ARBs in our cohort (n = 40), we excluded this treatment group from the analysis.
However, existing evidence suggests potential mechanistic overlaps. ARBs have been shown to reduce right ventricular (RV) afterload and pulmonary vascular remodeling, thereby improving RV‐PA coupling and prognosis [1, 2]. While these benefits are largely mediated by reduced afterload rather than direct inotropic effects, the precise impact on myocardial contractility remains a subject of ongoing investigation [3, 4]. Similarly, ACEi have demonstrated comparable effects on pulmonary vascular remodeling in the context of hypoxic PH [5, 6]. Given these mechanistic parallels, prospective studies directly comparing the efficacy and tolerability of ACEi versus ARBs in Group 3 PH are warranted.
In our data set, ARB treatment was associated with a numerically lower hazard ratio (hazard ratio 0.53 [0.23, 1.21]). However, the small number of patients receiving ARBs precludes robust inference beyond our study sample to the broader population.
In conclusion, we thank Drs. Zhang and Bao for their comments, which reinforce our conviction that dedicated prospective trials, informed by evidence from real world analyses, are essential to refine the precision medicine approach for this high‐risk patient population.
Author Contributions
Athiththan Yogeswaran: conceptualization, methodology, investigation, formal analysis, writing – original draft, and review and editing. Khodr Tello: conceptualization, methodology, investigation, formal analysis, and review and editing. Werner Seeger: conceptualization, methodology, investigation, formal analysis, and review and editing.
Ethics Statement
The PVRI GoDeep registry was approved by the University of Giessen Ethics Committee and the relevant local ethics committees (NCT05329714).
Conflicts of Interest
A. Yogeswaran reports nonfinancial support from the University of Giessen during the conduct of the study, research grants from the German Research Foundation, support for attending a meeting from OrphaCare and AOP, and personal fees from MSD and Ferrer outside the submitted work. K. Tello has received personal fees from Bayer, AstraZeneca, and Gossamer. W. Seeger has received consultancy fees from United Therapeutics, Tiakis Biotech AG, Liquidia, Pieris Pharmaceuticals, Abivax, Pfizer, and Medspray BV.
Acknowledgments
This work is funded by the Pulmonary Vascular Research Institute (PVRI) and the Cardiovascular Medical Research and Education Fund (CMREF), NIH.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Werner Seeger had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Werner Seeger had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.