Higher chronotropic index during the 6-minute walk (CI-6MW) test was shown to be independently associated with a decreased risk for acute exacerbations of chronic obstructive pulmonary disease (AECOPD), according to study results published in the Annals of the American Thoracic Society. Additionally, the use of metoprolol among patients with COPD may be risky, particularly among those individuals with a higher CI-6MW prior to the initiation of the agent.

Researchers conducted a secondary analysis of the Beta-Blockers for the Prevention of Acute Exacerbations of COPD (BLOCK COPD; ClinicalTrials.gov Identifier: NCT02587351). They sought to evaluate the link between the CI-6MW and AECOPD to establish whether higher CI-6MW is associated with a lower risk for AECOPD and whether CI-6MWD is a marker of susceptibility to the adverse effects of metoprolol in patients with COPD.

The BLOCK-COPD secondary analysis 532 exacerbation-prone patients with COPD who were randomly assigned to metoprolol succinate or to placebo. Study inclusion criteria were being between 40 and 85 years of age; having moderate COPD (ie, forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] of <0.7 and FEV1 of <80% of the predicted normal); and having 10 or more pack-years of smoking history.

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Of the 532 participants in BLOCK COPD, 90% (477 of 532) were included in the current analysis. Among these individuals, 238 were assigned to the metoprolol group and 239 were assigned to the placebo group. The mean participant age was 65.1±7.8 years. The mean FEV1 percent predicted was 40.9%±16.2% and the mean pack-years of smoking were 50.4±29.6. Median CI-6MW prior to study randomization was 0.25 (range, 0.15- 0.34). Current smokers had lower median CI-6MW values than did former smokers (0.21 vs 0.26; P value by Mann-Whitney test, <.001).

Higher baseline CI-6MW was associated with a significantly lower risk for AECOPD of any severity (adjusted hazard ratio [aHR], 0.88; 95% CI, 0.80-0.96; P =.005). No significant interaction was observed, however, between assignment to metoprolol and CI-6MW with respect to risk for AECOPD (ratio of metoprolol and placebo aHRs, 1.16; 95% CI, 0.99-1.35; P =.07).

When CI-6MW was treated as a time-varying covariate, study results showed no significant relationship between CI-6MW and time to severe COPD (aHR, 0.91; 95% CI, 0.77-1.06; P =.22). Further, the interaction between assignment to metoprolol therapy and CI-6MW per time-varying analysis was similar to that in the baseline analysis (aHR, 1.40; 95% CI, 1.05-1.88; P =.02).

A major limitation of the current analysis was the fact that chronotropic index was evaluated during 6MW, as opposed to cardiopulmonary exercise test (CPET) — the gold standard. Since 6MW is not a maximal test and it has no measure of exercise intensity, the researchers were not able to establish whether pulmonary, cardiac, effort, or other limitations were responsible for the decreased chronotropic response observed.

The investigators concluded that additional studies are warranted to validate the current findings and to determine whether clinical trials that target chronotropic insufficiency in patients with COPD should be conducted.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


MacDonald DM, Helgeson ES, Adabag S, et al. Chronotropic index and acute exacerbations of COPD: a secondary analysis of BLOCK COPD. Ann Am Thorac Soc. Published online March 30, 2021. doi:10.1513/AnnalsATS.202008-1085OC