Discussion
exacerbations, right heart dysfunction, RV dysfunction, exacerbation-prone COPD, ECOPD, COPD, shortness of breath
RHD, COPD
In this post-hoc analysis of the BLOCK-COPD trial, we found that patients with P-pulmonale assigned to treatment with metoprolol were at increased risk of ECOPD of any severity. In addition, metoprolol assignment was associated with worsening in respiratory symptoms in the P-pulmonale group that was both statistically and clinically significant (minimal clinically indicated differed: change in CAT > 2) with no observed change in symptoms in participants without P-pulmonale [Our findings of increased CAT scores and exacerbation risk in those with P-pulmonale assigned to metoprolol highlight the importance identifying concomitant RHD in COPD. Overall, these findings suggest that including P-pulmonale in the risk assessment for metoprolol therapy may be helpful in this select group of COPD patients. While speculative, it is possible that metoprolol use in COPD patients with ECG signs of RHD could lead to a decrease in both inotropy and chronotropy which would reduce heart function andmanifest clinically as increased shortness of breath, a key symptom of ECOPD [Previous investigators have demonstrated that the presence of PH in COPD has functional and prognostic implications and is associated with adverse COPD outcomes, increased risk for exacerbations, and more rapid lung function decline [The parent BLOCK-COPD trial demonstrated that metoprolol does not reduce ECOPD risk in exacerbation-prone COPD patients with no guideline-based indication for beta-blocker therapy. In fact, metoprolol led to an increased risk of hospitalized or mechanically ventilated exacerbations as well as increased respiratory symptoms. The reasons for these findings remain unclear with subsequent post-hoc analyses of BLOCK-COPD revealing no explanatory worsening in lung function with metoprolol treatment [While there has been significant progress in understanding the heart-lung interface, much remains unknown. Structural and mechanical changes in pulmonary vasculature in COPD can increase right ventricular (RV) afterload and, in some cases, subsequently result in RV dysfunction [A better understanding of RV mechanics overall would allow for utilization of multimodal assessments of RV function and morphology and the identification of individuals at heightened risk of COPD morbidity and mortality. This would also allow for targeted investigations of PH therapies in a population enriched for individuals most likely to receive benefit.Our study has several limitations. When compared to right heart catheterization, echocardiography, or cardiac magnetic resonance imaging (cMRI), ECG changes are insensitive to identifying RHD and PH. We focused our analysis on P-pulmonale as it has been shown to be prevalent and have a strong association with PH based on existing literature, but our lack of utilization of more sensitive measures of PH and RHD could lead to some persons with PH being incorrectly analyzed in the ‘no PH’ group which would bias our estimates towards the null. Second, only ECGs obtained at baseline were analyzed which precluded evaluation for longitudinal changes in cardiac conduction, particularly during the an exacerbation; however, this allowed us to standardize for ECGs being obtained only when patients were several weeks exacerbation free and not on study drug. Third, ECG data were analyzed retrospectively, and while observers were well qualified, blinded to patient outcomes, and utilized an electronic caliper system, there may be varying interrater assessment of our ECG indicator of PH, P-pulmonale, which may affect our results. However, in our measurement of interrater reliability, there was strong agreement in P-pulmonale classification between observers. Finally, our study differed from the parent study findings in that metoprolol was associated with an increased risk of severe and very severe exacerbations in BLOCK-COPD; whereas, in our study, we additionally found an association between metoprolol and all exacerbations in individuals with P-pulmonale. We did not find that metoprolol was associated with a greater risk of severe exacerbations in those with p-pulmonale compared to those without p-pulmonale. However, in our analysis a relatively small number of participants with P-pulmonale experienced severe/very severe exacerbations limiting our statistical power to detect associations with this outcome.In conclusion, we found that metoprolol is associated with an increased risk of exacerbation and worsening COPD symptoms in individuals with P-pulmonale. Further investigations are needed using widely available and novel tools targeted at the impact of right heart dysfunction in COPD.