PT - JOURNAL ARTICLE AU - Mingjin Yang AU - Yishi Li AU - Youfan Jiang AU - Shuliang Guo AU - Jian-Qing He AU - Don D Sin TI - Combination therapy with long-acting bronchodilators and the risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis AID - 10.1183/13993003.00302-2022 DP - 2022 Jan 01 TA - European Respiratory Journal PG - 2200302 4099 - http://erj.ersjournals.com/content/early/2022/09/14/13993003.00302-2022.short 4100 - http://erj.ersjournals.com/content/early/2022/09/14/13993003.00302-2022.full AB - Introduction Accumulated high-quality data from randomized controlled trials (RCTs) indicate that long-acting muscarinic antagonist/long-acting β2 agonist (LAMA/LABA) combination therapy significantly improves clinical symptoms, and health status and reduces exacerbation risk of patients with chronic obstructive pulmonary disease (COPD). However, there is a growing concern that LAMA/LABA therapy may increase the risk of cardiovascular disease in patients with COPD. The aim of this paper is to determine whether the use of LAMA/LABA combination therapy modifies the risk of cardiovascular disease in patients with COPD.Methods Two reviewers independently searched EMBASE, PubMed, and Cochrane Library to identify relevant RCTs of LAMA/LABA or LABA/LAMA/inhaled corticosteroids (ICS) for the management of patients with COPD that reported on cardiovascular endpoints. The primary outcome was MACE (major adverse cardiovascular events), which was a composite of cardiovascular death, myocardial infarction (MI), or stroke.Results Fifty-one RCTs enrolling 91,021 subjects were analyzed. Both dual LAMA/LABA (1.6% versus 1.3%; RR, 1.42, 95% CI, 1.11–1.81) and triple therapy (1.6% versus 1.4%; RR, 1.29, 95% CI, 1.03–1.61) significantly increased the risk of MACE compared with ICS/LABA. The excess risk was most evident in RCTs in which the average underlying baseline risk for MACE was >1%/year. Compared with LAMA only, LABA only, or placebo, dual LAMA/LABA therapy did not significantly increase the risk of MACE, though these comparisons may have lacked sufficient statistical power.Conclusion Compared with ICS/LABA, dual LAMA/LABA or triple therapy increases cardiovascular risk in patients with COPD. This should be considered in the context of the incremental benefits of these therapies on symptoms and exacerbation rates in patients with COPD especially in those with a MACE risk of >1%/year.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: : DDS has received honoraria for speaking engagements from GSK, AstraZeneca and Boehringer Ingelheim.Conflict of interest: The other authors declare no conflicts of interest.