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LAMAs Carry Risk of Cardiac Adverse Events

<乌鸦传媒 class="dek">—Data from the FDA adverse event reporting system were reviewed to investigate reports of cardiovascular adverse events observed in patients receiving treatment with long-acting muscarinic receptor antagonists.

By Erin M. Burns, PhD, MSPH

Inhaled long-acting muscarinic receptor antagonists (LAMAs) are not free from the risk of cardiac adverse events (AEs), which may be reduced when patients with chronic obstructive pulmonary disease (COPD) are treated with dual bronchodilators or triple therapy, a recent study suggests.1

鈥淎lthough pivotal clinical trials have provided much of the current information indicating that LAMAs appear to be safe even in patients with heart disease, the AE rates seen in such trials may not reflect those seen in real-world practice,鈥� corresponding author Mario Cazzola, MD, Unit of Respiratory Medicine, Department Experimental Medicine, University of Rome 鈥淭or Vergata,鈥� Rome, Italy, told 乌鸦传媒. 

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鈥淭herefore, we reviewed data from the [US Food and Drug Administration (FDA) adverse event reporting system] FAERS to examine reports of CV AEs observed in the real-world during treatment with aclidinium, tiotropium, glycopyrronium, and umeclidinium alone or in combination with a LABA and, in the context of triple therapy, with the addition of an [inhaled corticosteroid].鈥�

The study was published in the April 2024 issue of Lung.

Study design and population

The research team included reports from the FAERS database submitted between January 2020 and September. There was a total of 18,208 AE reports that occurred in patients treated with a LAMA, with most of these (n=12,472) attributed to tiotropium. More AEs were reported in women than men (9832 vs 6231) and in patients aged 65 to 85 years than those aged younger than 65 years (5771 vs 5054). 

In terms of cardiovascular AEs, a total of 2261 were reported, with more events reported in men than women (1055 vs 940) and in patients aged 65 to 85 years compared with those younger than 65 years (941 vs 702).

The association between LAMAs and cardiovascular AEs

Tiotropium was associated with fewer reports of cardiovascular AEs compared with ipratropium, with a reported odds ratio (a disproportionate measure based on the ratio of the odds in reports for a certain drug to the odds in reports where the drug is not present in the FAERS database) of 0.53 (95% CI 0.48-0.58). 

Other LAMAs also had an increased likelihood of association with reports of cardiovascular AEs compared with tiotropium, where the reported odds ratio was the ratio of the number of cardiovascular events associated with tiotropium to the odds associated with other LAMAs. Aclidinium (reported odds ratio 1.60; 95% CI 1.36-1.89), glycopyrronium (reported odds ratio 2.26; 95% CI 1.99-2.57), and umeclidinium (reported odds ratio 1.95; 95% CI 1.73-2.19) had a higher likelihood of reported cardiovascular AEs. 

Dual bronchodilators and triple combinations vs LAMA monotherapy

The combinations of glycopyrronium/indacaterol (reported odds ratio 0.79; 95% CI 0.64-0.97) and glycopyrronium/indacaterol/mometasone (reported odds ratio 0.62; 95% CI 0.37-1.02) were associated with fewer reports of cardiovascular AEs compared with glycopyrronium monotherapy. Similar results were seen with the combination of glycopyrronium and formoterol (reported odds ratio 0.12; 95% CI 0.06-0.20) and with the umeclidinium/vilanterol (reported odds ratio 0.35; 95% CI 0.30-0.41) and umeclidinium/vilanterol/fluticasone furoate (reported odds ratio 0.20; 95% CI 0.18-0.23). 

When considering the impact of each LAMA on the main cardiovascular AE subgroups of arrhythmia, heart failure, and ischemic heart disease, the lowest percentage of arrhythmia events was associated with aclidinium and more than 50% of events were associated with umeclidinium treatment. When considering events in the ischemic heart disease subgroup, the lowest percentage of events was associated with umeclidinium, and the highest percentage was associated with aclidinium treatment. 

鈥淲e were pleased to see that our previous documentation that the addition of a LABA to a LAMA reduces the likelihood of reported cardiac events,2 even though the data analyzed were mainly derived from patients selected for enrolment in randomized controlled trials, who generally do not have severe cardiovascular morbidity, was confirmed by data collected in the real world,鈥� Dr. Cazzola stated.

Putting it into practice

These authors demonstrated that LAMA use is associated with reports of cardiac AEs despite evidence emphasizing cardiovascular safety. 鈥淚t's noteworthy that the risk tends to be significantly mitigated when patients with COPD undergo treatment with dual bronchodilators or triple therapy,鈥� said Dr. Cazzola. 鈥淭his observation underscores the importance of considering the specific context of COPD management when evaluating the safety profile of LAMAs.鈥� 

Limitations of this study include the bias resulting from the FAERS spontaneous mechanism of reporting, the lack of medical review and the subsequent potential misclassification of cases, and the use of reported odds ratios. 

鈥淐linicians should carefully weigh the risks and benefits of various treatment options for COPD patients, considering both pulmonary and cardiovascular considerations,鈥� Dr. Cazzola concluded. 鈥淥bviously, further research, including pragmatic randomized controlled trials, may be warranted to elucidate the comparative safety and efficacy profiles of different therapeutic approaches in this patient population, ultimately informing evidence-based decision-making in clinical practice.鈥�

Published:

Erin Burns has 9 years of academic research experience, including postdoctoral research in microbiology and photocarcinogenesis. She writes about various areas of science and medicine.

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