Elsevier

The Lancet

Volume 387, Issue 10030, 30 April–6 May 2016, Pages 1817-1826
The Lancet

Articles
Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial

https://doi.org/10.1016/S0140-6736(16)30069-1Get rights and content

Summary

Background

Chronic obstructive pulmonary disease (COPD) often coexists with cardiovascular disease. Treatments for airflow limitation might improve survival and both respiratory and cardiovascular outcomes. The aim of this study was to assess whether inhaled treatment with a combined treatment of the corticosteroid, fluticasone furoate, and the long-acting β agonist, vilanterol could improve survival compared with placebo in patients with moderate COPD and heightened cardiovascular risk.

Methods

In this double-blind randomised controlled trial (SUMMIT) done in 1368 centres in 43 countries, eligible patients were aged 40–80 years and had a post-bronchodilator forced expiratory volume in 1 s (FEV1) between 50% and 70% of the predicted value, a ratio of post-bronchodilator FEV1 to forced vital capacity (FVC) of 0·70 or less, a smoking history of at least 10 pack-years, and a score of 2 or greater on the modified Medical Research Council dyspnoea scale. Patients had to have a history, or be at increased risk, of cardiovascular disease. Enrolled patients were randomly assigned (1:1:1:1) through a centralised randomisation service in permuted blocks to receive once daily inhaled placebo, fluticasone furoate (100 μg), vilanterol (25 μg), or the combination of fluticasone furoate (100 μg) and vilanterol (25 μg). The primary outcome was all-cause mortality, and secondary outcomes were on-treatment rate of decline in forced expiratory volume in 1 s (FEV1) and a composite of cardiovascular events. Safety analyses were performed on the safety population (all patients who took at least one dose of study drug) and efficacy analyses were performed on the intention-to-treat population (safety population minus sites excluded with Good Clinical Practice violations). This study is registered with ClinicalTrials.gov, number NCT01313676.

Findings

Between Jan 24, 2011, and March 12, 2014, 23 835 patients were screened, of whom 16 590 were randomised. 16 485 patients were included in the intention-to-treat efficacy population; 4111 in the placebo group, 4135 in the fluticasone furoate group, 4118 in the vilanterol group, and 4121 in the combination group. Compared with placebo, all-cause mortality was unaffected by combination therapy (hazard ratio [HR] 0·88 [95% CI 0·74–1·04]; 12% relative reduction; p=0·137) or the components (fluticasone furoate, HR 0·91 [0·77–1·08]; p=0·284; vilanterol, 0·96 [0·81–1·14]; p=0·655), and therefore secondary outcomes should be interpreted with caution. Rate of decline in FEV1 was reduced by combination therapy (38 mL per year [SE 2·4] vs 46 mL per year [2·5] for placebo, difference 8 mL per year [95% CI 1–15]) with similar findings for fluticasone furoate (difference 8 mL per year [95% CI 1–14]), but not vilanterol (difference −2 mL per year [95% CI −8 to 5]). Combination therapy had no effect on composite cardiovascular events (HR 0·93 [95% CI 0·75–1·14]) with similar findings for fluticasone furoate (0·90 [0·72–1·11]) and vilanterol (0·99 [0·80–1·22]). All treatments reduced the rate of moderate and severe exacerbation. No reported excess risks of pneumonia (5% in the placebo group, 6% in the combination group, 5% in the fluticasone furoate group, and 4% in the vilanterol group) or adverse cardiac events (17% in the placebo group, 18% in the combination group, and 17% in the fluticasone furoate group, and 17% in the vilanterol group) were noted in the treatment groups.

Interpretation

In patients with moderate COPD and heightened cardiovascular risk, treatment with fluticasone furoate and vilanterol did not affect mortality or cardiovascular outcomes, reduced exacerbations, and was well tolerated. Fluticasone furoate, alone or in combination with vilanterol, seemed to reduce FEV1 decline.

Funding

GlaxoSmithKline.

Introduction

Chronic obstructive pulmonary disease (COPD) often coexists with other chronic diseases that can contribute to patients' health status and prognosis.1, 2, 3 Impaired pulmonary function is particularly associated with cardiovascular morbidity and mortality, and patients with COPD are at greater risk of cardiovascular disease compared with age-matched and sex-matched individuals without COPD.4, 5, 6, 7 Furthermore, more patients with moderate airflow limitation die from cardiovascular disease and lung cancer than from the respiratory consequences of COPD.8, 9 Several mechanisms have been proposed to link COPD with the increased risk of cardiovascular disease including shared risk factors (eg, smoking), systemic inflammation,10 vascular dysfunction,11 and sedentary activity secondary to the functional consequences of COPD.12 Conversely, treatments that improve lung function and reduce exacerbations would be anticipated to reduce these factors thereby improving both respiratory and cardiovascular outcomes.13

Research in context

Evidence before this study

We searched PubMed and ClinicalTrials.gov up to Nov 18, 2015, for published or ongoing studies examining the treatment of patients with concomitant chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) with inhaled corticosteroids or long-acting β agonists with the following search terms: “COPD”, “cardiovascular disease”, “inhaled corticosteroids”, “long-acting beta-agonists”. The search was restricted to English language. The search also used our familiarity with the medical literature and research in progress within the specialty. There were no adequately powered trials, and only a few post-hoc or subgroup analyses of larger trials, to provide clinicians with evidence to make decisions about the treatment of patients with concomitant COPD and CVD.

Added value of this study

Our findings bridge a crucial gap by providing clinicians with evidence regarding inhaled treatments for patients with concomitant moderate COPD and CVD. In this patient group, combined inhaled corticosteroid and long-acting β-agonist treatment had no effect on overall mortality or cardiovascular events. By contrast with inhaled β-agonist therapy, inhaled corticosteroid treatment was associated with a reduction in the rate of decline of lung function. All treatments reduced the rate of moderate and severe exacerbations.

Implications of all of the available evidence

Treatment with a combination of an inhaled corticosteroid and long-acting β agonist has documented benefits in COPD. In patients with moderate COPD and CVD, these benefits do not extend to reductions in overall mortality or cardiovascular events. However, inhaled corticosteroid therapy does seem to inhibit the rate of decline in lung function.

The current Global Initiative for Chronic Obstructive Lung Diseases (GOLD) strategy document has highlighted the need to assess and treat comorbidities in COPD.1 However, the evidence base is incomplete and most advice comes from expert statements or from secondary analyses of large studies. Indeed, there is disagreement on the potential effects of COPD treatment on cardiovascular outcomes. Some evidence suggests that in patients with COPD, inhaled β-agonist therapy might be associated with adverse cardiovascular outcomes.14 On the other hand, in secondary analyses of the TOwards a Revolution in COPD Health (TORCH) trial,15 there were apparent reductions in respiratory and cardiovascular mortality with inhaled salmeterol and fluticasone propionate. This was the rationale for this study where we address the hypothesis that inhaled corticosteroid and long-acting β-agonist therapy could improve mortality rates in patients with both COPD and cardiovascular disease.

In the Study to Understand Mortality and MorbidITy (SUMMIT), we prospectively assessed whether inhaled treatment with the corticosteroid, fluticasone furoate, and the long-acting β agonist, vilanterol, would improve survival compared with placebo in patients with moderate COPD and heightened cardiovascular risk.

Section snippets

Study design and participants

This prospective double-blind parallel group placebo-controlled event-driven randomised trial was conducted at 1368 centres in 43 countries. Details of the study design and the analysis approach were published previously.13 We recruited patients who were current or former smokers with at least a 10-pack-year history. Eligible patients were aged 40–80 years and had a post-bronchodilator forced expiratory volume in 1 s (FEV1) between 50% and 70% (inclusive) of the predicted value,16 a ratio of

Results

Between Jan 24, 2011, and March 12, 2014, 23 835 patients were screened at 1583 centres in 43 countries and 16 590 underwent randomisation (figure 1). Of these, 22 participants never took study medication and the safety population therefore consists of 16 568 patients. Data from five centres (83 patients) were excluded from the efficacy analysis because of failure to meet the standards of Good Clinical Practice and ethical practice, and were closed before the study ended. Thus, a total of

Discussion

To the best of our knowledge, SUMMIT is the largest survival study to date of an inhaled corticosteroid and long-acting β agonist in patients with COPD and heightened cardiovascular risk. In more than 16 000 patients, treatment with inhaled fluticasone furoate and vilanterol had no significant effect on all-cause mortality or cardiovascular outcomes. Inhaled therapy improved lung function and fluticasone furoate, alone or in combination with vilanterol, was associated with a reduction in the

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