Male Sex Is Associated With Severe Pulmonary Hypertension and Worse Outcome in Chronic Obstructive Pulmonary Disease Patients Referred for Right Heart Catheterization

Abbreviations

COPD

chronic obstructive pulmonary disease

PH

pulmonary hypertension

PVR

pulmonary vascular resistance

RHC

right heart catheterization

Dear Editor,

Respected Zeder et al. report an interesting retrospective analysis of chronic obstructive pulmonary disease (COPD) patients with pulmonary hypertension (PH) finding that male sex was independently associated with higher mortality risk [1]. We commend the authors for addressing not differences, but note two methodological issues that merit discussion.

Selection bias and generalizability: The cohort was limited to COPD patients referred for right heart catheterization, a highly selected population (likely enriched for advanced disease) [2]. As Avian et al. observed a referral‐based COPD‐PH cohort “enriched by patients with severe Pulmonary hypertension” may not represent the broader COPD population and this selection bias “may limit the generalizability of the findings” [2]. In similar pulmonary hypertension studies referral bias is a known concern. For example Pi et al. found that patients more likely to benefit from therapy tend to be referred preferentially skewing the sample [3]. In the present study it is unclear how many COPD patients were evaluated or excluded before catheterization. Without a flowchart (as recommended by reporting guidelines) or clearer sampling frame it is difficult to know whether the sex difference extends to unselected COPD‐PH. We suggest the authors clarify that conclusions apply chiefly to the right heart catheterization (RHC)‐referred cohort and consider providing a CONSORT/STROBE style flow diagram of patient selection. This would help readers gauge how referral patterns (e.g., only catheterizing those suspected of PH) might have influenced the observed sex disparity [2, 3]. In sum the sex effect might be exaggerated if men were referred only when PH was more severe. Stating the limits of external validity explicitly that these findings derive from a specialized referral sample would strengthen the interpretation.

Confounding by PH severity: Men in the study had significantly higher pulmonary vascular resistance (median PVR) and a greater prevalence of “severe pulmonary hypertension” (PVR > 5 WU) than women. Importantly severe Pulmonary hypertension itself is a strong independent predictor of mortality. For instance a recent large cohort found that severe pulmonary hypertension (PVR > 5 WU) was associated with a roughly 1.8‐fold higher risk of death in COPD patients [4], even after adjusting for other factors. Thus the worse survival in men may be partly explained by their greater pulmonary hypertension severity. It is unclear whether the Cox model in the study adjusted for PVR or included PH severity as a covariate. We note that stratification or additional adjustment for PH severity might attenuate the sex hazard ratio. At a minimum discussing this potential confounding would add balance: Men's higher mortality may reflect at least in part their higher Pulmonary hypertension burden (a variable known to drive outcomes) rather than sex alone [4]. We encourage future analyses to account for PH severity explicitly for example by adjusting for PVR or using multivariable models that include a severity term to isolate any true sex‐specific effect.

In conclusion Zeder et al.'s findings are provocative but should be interpreted in context. We suggest emphasizing that results pertain to an RHC‐referred COPD cohort with advanced disease, and that the male–female survival gap may be mediated by pulmonary hypertension severity. Transparent reporting of the referral process (e.g., a flow diagram) and consideration of PH severity in the model would help ensure the conclusions are valid and generalizable. Addressing these points could inform readers about the appropriate population for applying the results, and guide future prospective studies on sex differences in COPD‐PH.

Author Contributions

Conceptualization: Syed Sardar Shah, Attiq Ur Rehman, and Safa Amin. Data curation: Syed Sardar Shah, Safa Amin, and Mahnoor Nawaz. Writing original draft: Syed Sardar Shah, Attiq Ur Rehman, and Aqdas Laiba. Review and editing: Safa Amin, Mahnoor Nawaz, and Aqdas Laiba.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.