The impact of dual bronchodilation on cardiovascular serious adverse events and mortality in COPD: a quantitative synthesis

Abstract

ObjectiveLong-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are burdened by the potential risk of inducing cardiovascular serious adverse events (SAEs) in COPD patients. Since the risk of combining a LABA with a LAMA could be greater, we have carried out a quantitative synthesis to investigate the cardiovascular safety profile of LABA/LAMA fixed-dose combinations (FDCs).MethodsA pair-wise and network meta-analysis was performed by using the data of the repository database ClinicalTrials.gov concerning the impact of approved LABA/LAMA FDCs versus monocomponents and/or placebo on cardiovascular SAEs in COPD.ResultsOverall, LABA/LAMA FDCs did not significantly (P>0.05) modulate the risk of cardiovascular SAEs versus monocomponents. However, the network meta-analysis indicated that aclidinium/formoterol 400/12 µg and tiotropium/olodaterol 5/5 µg were the safest FDCs, followed by umeclidinium/vilanterol 62.5/25 µg which was as safe as placebo, whereas glycopyrronium/formoterol 14.9/9.6, glycopyrronium/indacaterol 15.6/27.5 µg, and glycopyrronium/indacaterol 50/110 µg were the least safe FDCs. No impact on mortality was detected for each specific FDC.ConclusionThis meta-analysis indicates that LABA/LAMA FDC therapy is characterized by an excellent cardiovascular safety profile in COPD patients. However, the findings of this quantitative synthesis have been obtained from populations that participated in randomized clinical trials, and were devoid of major cardiovascular diseases. Thus, post-marketing surveillance and observational studies may help to better define the real impact of specific FDCs with regard to the cardiovascular risk.

POINT: Should LAMA/LABA Combination Therapy Be Used as Initial Maintenance Treatment for COPD? Yes

“…LAMA/LABA FDC therapy is characterized by an excellent cardiovascular safety profile, at least in the patients with COPD who were enrolled in pivotal trials and who were devoid of major cardiovascular diseases. 17 Even more interesting is the documentation that combining a LAMA with a LABA does not amplify the potential cardiovascular severe AEs (SAEs) that characterize LAMAs and LABAs when administered as monocomponents. 10 Surprisingly, some LAMA/LABA combinations seem to reduce cardiovascular risk when compared with monocomponents, at least in this population, 10 which reinforces the concept of starting treatment of COPD with dual bronchodilation.…”

“…Nevertheless, there may be a different cardiovascular response to muscarinic receptor blockade and/or b 2 -adrenoceptor stimulation in individual patients, which is not specific to any LAMA or LABA. 17 Therefore, it will be essential to make all possible efforts to proactively identify patients at increased risk of cardiovascular SAEs when treated with LAMA/LABA FDCs; the same efforts that are used when LAMAs and LABAs are administered as monotherapy. Postmarketing surveillance and observational studies may help to better define the real impact of specific LAMA/LABA FDCs regarding the risk of rare, but potentially serious, cardiovascular AEs.…”

Fixed dose long-acting bronchodilator combinations in chronic obstructive pulmonary disease: safety, effectiveness and cardiovascular system

“…Последний метаанализ фиксированных комбинаций ДДБА/ДДАХП, состоящий из 29 РКИ с участием 26 650 больных ХОБЛ, также не выявил достоверных различий в развитии серьезных нежелательных явлений со стороны сердечно-сосудистой системы у пациентов с ХОБЛ по сравнению с ДДБА и ДДАХП (ФК vs. ДДБА: относительный риск (ОР) 0,98 [95% доверительный интервал (ДИ) 0,72-1,34], I 2 9% и ФК vs. ДДАХП: ОР 0,90, [95% ДИ 0,71-1,13], I 2 0%) [15]. Сравнительных РКИ, направленных на изучение сердечно-сосудистых рисков между фиксированными ДДБД, до настоящего времени не проводилось.…”

12-Hour fixed-dose combination of andrenergic agonist and cholinergic antagonist in a new administration device: analytical review

“…В целом метаанализ показал высокую безопасность всех фиксированных комбинаций бронхолитиков в отношения событий со стороны ССС у больных ХОБЛ. Более точные данные в отношении риска влияния на ССС могут быть получены в наблюдательных постмаркетинговых исследованиях [15].…”