Cardiovascular outcomes with an inhaled beta2-agonist/corticosteroid in patients with COPD at high cardiovascular risk

Abstract

Objectives: Cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD) often coexist. We assessed the effect of inhaled COPD treatments on CVD outcomes and safety in patients with COPD and at heightened CVD risk.

Methods: The SUMMIT (Study to Understand Mortality and MorbidITy) was a multicentre, randomised, double-blind, placebo-controlled, event-driven trial in 16 485 patients with moderate COPD who had or were at high risk of CVD. Here, we assessed the prespecified secondary endpoint of time to first on-treatment composite CVD event (CVD death, myocardial infarction, stroke, unstable angina or transient ischaemic attack (TIA)) by Cox regression and by clinician-reported CVD adverse events across the four groups: once-daily inhaled placebo (n=4111), long-acting beta2-agonist (vilanterol (VI) 25 µg; n=4118), corticosteroid (fluticasone furoate (FF) 100 µg; n=4135) and combination therapy (FF/VI; n=4121).

Results: Participants were predominantly middle-aged (mean 65 (SD 8) years) men (75%) with overt CVD (66%). The composite CVD endpoint occurred in 688 patients (first event: sudden death (35%), acute coronary syndrome (37%) and stroke or TIA (23%), and was not reduced in any treatment group versus placebo: VI (HR 0.99, 95% CI 0.80 to 1.22), FF (HR 0.90, 95% CI 0.72 to 1.11) and their combination (HR 0.93, 95% CI 0.75 to 1.14). Outcomes were similar among all subgroups. Adverse events, including palpitations and arrhythmias, did not differ by treatment.

Conclusions: In patients with COPD with moderate airflow limitation and heightened CVD risk, treatment with inhaled VI, FF or their combination has an excellent safety profile and does not impact CVD outcomes.

Trial registration number: NCT01313676.

Keywords: cardiovascular disease; inhaler therapies; pulmonary disease.

Conflict of interest statement

Competing interests: RDB, PMAC, BRC, FJM, JV and DEN are external members of the SUMMIT Steering Committee. JAA, CC and JY are employed by GSK and are members of the SUMMIT Steering Committee. MAD and SM are members of the SUMMIT Clinical Endpoint Committee, and SR is a member of the SUMMIT Independent Data Monitoring Committee.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Figures

Figure 1

Risks of adjudicated composite CV endpoints in patients treated with combination therapy versus placebo Kaplan-Meier graph for the time to first adjudicated on-treatment composite CVD event (CVD death, myocardial infarction, stroke, unstable angina or TIA) for patients on treatment with combination therapy (VI plus FF) versus placebo. CV, cardiovascular; CVD, cardiovascular disease; FF, fluticasone furoate; TIA, transient ischaemic attack; VI, vilanterol.

Figure 2

Risks of adjudicated composite CV endpoints for all treatment groups. Kaplan-Meier graph for the time to first adjudicated on-treatment composite CVD event (CVD death, myocardial infarction, stroke, unstable angina or TIA) for patients on treatment with VI, FF, combination therapy and placebo. CV, cardiovascular; CVD, cardiovascular disease; FF, fluticasone furoate; TIA, transient ischaemic attack; VI, vilanterol.

Figure 3

Risks of adjudicated composite CV endpoints in subgroups treated with combination therapy versus placebo forest plot of the HRs and 95% CIs for the adjudicated composite CV endpoint in subgroups of patients on treatment with combination therapy versus placebo. Cardiovascular entry criteria with CVD defined as at least one of the following: coronary artery disease, peripheral arterial disease, previous stroke, previous MI or diabetes mellitus with target organ disease. Regions are defined in online supplementary table 3. Ischaemic heart disease indicator defined as previous MI or previous revascularisation of any type; vascular disease indicator defined as previous TIA, stroke, arterial bruits, or medication and/or surgery for carotid or aortofemoral vascular disease. ‘n’ represents number of patients in combined FF/VI and placebo arms shaded regions show overall 95% CI. CV, cardiovascular; CVD, cardiovascular disease; FF, fluticasone furoate; MI, myocardial infarction; TIA, transient ischaemic attack; VI, vilanterol.

Figure 4

Risks of reported adverse cardiovascular events among treatment groups. Kaplan-Meier graph for time to first reported on-treatment (A) adverse and (B) serious adverse cardiac events of special interest in patients on treatment with VI, FF, combination therapy and placebo. Cardiovascular adverse events of special interest are defined as any untoward medical occurrence falling within Standardised MedDRA (Medical Dictionary for Regulatory Activities) Queries of cardiac arrhythmias, hypertension, cardiac failure, ischaemic heart disease, or central nervous system haemorrhages and cerebrovascular conditions. Details are provided in online supplementary table 1. Serious cardiovascular adverse events of special interest are defined as above as those that also result in death or are life threatening or require hospitalisation or result in disability. Details are provided in online supplementary table 2. FF, fluticasone furoate; VI, vilanterol.