O4. Combination therapies and biologic therapies

O4.1 Inhaled corticosteroids and long-acting beta₂-agonists in combination (ICS/LABA)

A systematic review of 19 randomised controlled trials involving 10,400 COPD patients of combined corticosteroids and long-acting beta₂-agonists in one inhaler (Nannini 2013a) [evidence level I] found that, compared with placebo, both fluticasone/salmeterol and budesonide/formoterol reduced the rate of exacerbations (rate ratio 0.73; 95% CI 0.69 to 0.78). It was estimated that treatment with combined therapy would lead to a reduction of one exacerbation every two to four years. The three-year number needed to treat for an additional beneficial outcome (NNTB) with fluticasone/salmeterol to prevent one extra death was estimated at 42 (95% CI 24 to 775). Combined treatments improved health status to a small extent and improved lung function. Increased risk of pneumonia was observed with combined treatments compared with placebo (OR 1.62, 95% CI 1.36 to 1.94), with a three-year NNTH for one additional case of pneumonia estimated to be 17. However, exacerbations, hospitalisations or deaths did not increase. Overall, the authors concluded that there were no major differences between combined inhalers in terms of benefits, but the evidence was currently not strong enough to demonstrate that all are equivalent. Data from Kliber (Kliber 2010) [evidence level I] in 30,495 patients with COPD enrolled in trials of six months or greater duration found combination therapy, compared with placebo, was associated with a reduction in all cause mortality, relative risk 0.80 (95% CI 0.69, 0.94).

Studies have found conflicting results when the different combination therapies were compared with the mono-components alone. A systematic review by Nannini et al (Nannini 2012) of 14 studies (11,784 participants) found low quality evidence for reduced exacerbation rates (rate ratio 0.76; 95% CI 0.68 to 0.84) with ICS/LABA versus LABA alone [evidence level I]. There was no statistically significant difference in hospitalisations or mortality. ICS/LABA improved quality of life and FEV₁ to a small extent, compared to LABA alone. High attrition rates from the studies limited the confidence in the results, except the mortality result. Pneumonia was observed more commonly with ICS/LABA use (OR 1.55; 95% CI 1.20 to 2.01) with an annual risk of 4% on combination treatment, compared to 3% on LABA alone. A network meta-analysis of 21 clinical trials of ICS/LABA demonstrated that these combinations, except budesonide/formoterol and beclometasone/formoterol, reduced moderate-to-severe exacerbations as compared with placebo and LABA; however, none of the combinations reduced severe exacerbations (Oba 2014) [evidence level I]. In 2012, Sharafkaneh et al reported that budesonide/formoterol 320/9 mg compared with formoterol alone prolonged the mean time to first exacerbation (277.9 days versus 249.8 days; p= 0.029). Higher pneumonia rates were noted with budesonide/formoterol 320/9 mg 6.4% compared with 2.7% for formoterol alone (Sharafkhaneh 2013).   In a RCT of 26 weeks (Ferguson 2017) [evidence level II], twice daily budesonide/formoterol pMDI 320/9 mcg resulted in a 24% reduction in exacerbation rate (rate ratio 0.76, 95% CI 0.62 to 0.92; P = 0.006) and a 22% reduction in time to first exacerbation (hazard ratio 0.78; 95% CI 0.64 to 0.96; P = 0.0164) compared with twice daily formoterol DPI 9 mcg. The study did not show any important difference between the groups in their safety profile, including incidence of pneumonia (1% versus 0.5%).

A systematic review of 15 randomised controlled trials involving 7,814 COPD patients of combined corticosteroids and long-acting beta2-agonists in one inhaler versus inhaled steroids alone (Nannini 2013b) [evidence level I] found that, compared with inhaled steroids, exacerbation rates were significantly reduced with combination therapies (rate ratio 0.87, 95% CI 0.80 to 0.94). Mortality was lower with combination therapy (odds ratio 0.78, 95% CI 0.64 to 0.94), mainly due to results from the TORCH study. There was a small improvement in lung function and health-related quality of life (HRQoL). The authors concluded that combination ICS/LABA inhalers offer some clinical benefits in COPD compared with ICS alone, especially for reduction in exacerbations. The review did not support the use of ICS alone when LABAs are available.

Compared to placebo, combination therapy did not significantly increase other adverse events, but oral candidiasis was significantly more common, (NNH 16 [8-36], 1,436 participants). Combination therapy was not associated with more adverse effects compared to long-acting beta₂-agonists. Chen et al (Chen 2011) conducted a retrospective cohort study of Veterans Affairs (VA) patients with COPD who were admitted for pneumonia. Prior use of inhaled corticosteroids was associated with significantly reduced 30- and 90-day mortality and need for mechanical ventilation. The analysis adjusted for age, gender, race, marital status, primary care, classes of medications, smoking, comorbidities etc. However, the patients were 98% male and the most common inhaled corticosteroids were flunisolide and triamcinolone [evidence level III-2]. Studies by Calverley (2007) and Kardos (2007) have found an increased rate of pneumonia (defined on clinical grounds) in the inhaled corticosteroid arms, and this was also found in the Rodrigo systematic review, NNH = 48 (95% CI 31, 85) (Rodrigo 2009). These results contrast with the reductions in exacerbation rates induced by these drugs. A nested case control study from Canada (Ernst 2007) [evidence level III-2] using databases linking hospitalisations and drug dispensing information also found an increased risk of pneumonia and hospitalisation from pneumonia in those prescribed and dispensed inhaled corticosteroids and that this appeared dose-related. In the two-year RCT of salmeterol/fluticasone versus tiotropium (Wedzicha 2008), the number of de novo pneumonias not preceded by symptoms of exacerbations was similar between the two treatment groups (Calverley 2011). However, unresolved exacerbations preceding pneumonia were more common in the salmeterol/fluticasone-treated patients (32 exacerbations in 658 patients), compared to the tiotropium-treated group (7 exacerbations in 665 patients) [evidence level II]. Further prospective studies using objective pneumonia definitions may clarify the situation. Meantime, increased vigilance and patient education about prompt treatment of infections would seem prudent. A network meta-analysis of 71 RCTs of 73,062 patients with COPD showed that quality of life and lung function improved most with combination ICS/LABA inhalers, with LABA or LAMA inhalers next in efficacy, and ICS alone least effective (Kew 2014a). Many of the patients in these studies had FEV₁<50% predicted.

Fluticasone furoate/vilanterol is a new once daily ICS/LABA combination inhaled medicine. In short term studies of 12 weeks duration, fluticasone furoate/vilanterol had comparable lung function and quality of life effects as fluticasone propionate/salmeterol twice daily (Agusti 2014, Dransfield 2014).  Longer term studies (6 months) have shown that fluticasone furoate/vilanterol improves lung function compared to fluticasone furoate alone or placebo, and was similar in effect to vilanterol (Kerwin 2013, Martinez 2013). Patients with higher blood eosinophil count gain greater benefit from treatment with fluticasone furoate to reduce exacerbation frequency than do those with a low eosinophil count. Reductions in exacerbations with fluticasone furoate and vilanterol, compared with vilanterol alone, were 24% in patients with baseline eosinophil counts of ≥ 2 to <4%, 32% for those with counts of 4 to < 6%, and 42% for those with eosinophil counts of ≥ 6%. In patients treated with vilanterol alone, exacerbation rates increased progressively with increasing eosinophil count percentage category (Pascoe 2015). However, prospective validation is required before routine clinical recommendations can be made.

In a 12-month study of COPD patients with a history of exacerbations, fluticasone furoate/vilanterol reduced the rate of moderate to severe exacerbations by 20 to 30% compared to vilanterol alone, whereas the rate of pneumonia increased approximately 2-fold (Dransfield 2013). The study reported the event-based number needed to treat to prevent a moderate or severe exacerbation per year of 3.3 to 5.6 for the 3 doses of fluticasone furoate/vilanterol used, compared to vilanterol. In comparison, the event-based number needed to harm for pneumonia was 19 to 27 for fluticasone furoate/vilanterol, compared to vilanterol. 8 deaths from pneumonia were observed in the patients treated with fluticasone furoate/vilanterol (7 of whom were in the highest dose of 200/25 mcg), compared to no deaths from pneumonia in the vilanterol group. A higher number of fractures was observed in the fluticasone furoate/vilanterol groups. The study authors advised that clinicians should weigh up the benefit of reduced exacerbations with the risk of pneumonia when considering fluticasone furoate/vilanterol, and recommended that the 100/25 mcg dose be the maximum dose used in future clinical trials.

The SUMMIT study randomised 16,590 COPD patients with post-bronchodilator FEV₁ 50 to 70% predicted, and history or increased risk of cardiovascular disease, to fluticasone furoate/vilanterol, fluticasone furoate, vilanterol or placebo (Vestbo 2016a). Median study exposure was 1.8 years in this event-driven RCT. No benefit for all-cause mortality was seen with any of the active treatments, compared to placebo [evidence level II]. Because this primary outcome was not reached, the secondary outcomes were considered to be descriptive. These included a clinically insignificant reduction (8 ml/year) in the rate of decline of FEV₁ with fluticasone furoate/vilanterol or fluticasone furoate versus placebo (Calverley 2018a).  Fluticasone furoate/vilanterol reduced the rate of exacerbations treated with corticosteroids alone (61% reduction, 95% CI 51 to 69%) or with corticosteroids and antibiotics (45%, 95% CI 38 to 52%), but not those treated with antibiotics alone (-2%, 95% CI -15 to 9%) (Martinez 2016). Rates of pneumonia were similar between fluticasone furoate and placebo groups (Vestbo 2016a, Crim 2017)

Vestbo et al (Vestbo 2016b) performed an open label randomised trial in 75 UK general practices where 2,799 patients were randomised to a combination of fluticasone furoate 100 μg and vilanterol 25 μg or usual care. The trial design was unique in that patients in the control group were permitted to continue their current inhalers rather than all take the same treatment, the trial was performed in general practice and the majority of patients only had contact with study staff at baseline and at 12 months. The rate of moderate or severe exacerbations was 8.4% lower (95% CI 1.1 to 15.2) with fluticasone furoate–vilanterol therapy compared with usual care (P = 0.02). There was no increase in pneumonia.

Addition of fluticasone furoate to vilanterol increased the risk of pneumonia, particularly in patients with more severe airflow limitation (FEV₁/FVC <0.46) and either BMI <19 (HR 7.8, 95% CI 4.7–13.0) or previous history of pneumonia (HR 4.8, 95% CI 3.0–7.7) (DiSantostefano 2014) [evidence level II]. Risk for pneumonia was significantly higher in all fluticasone furoate/vilanterol treatment groups (fluticasone furoate/vilanterol 50 mcg/25 mcg, 100 mcg/25 mcg and 200 mcg/25 mcg) compared with the vilanterol 25 mcg group when administered once daily in the morning. Factors associated with at least a twofold increase in risk of pneumonia were low BMI (<25 kg/m²), 30% ≤ FEV₁<50% predicted, age >65 years, a prior exacerbation history, being a current smoker, and having a prior pneumonia event (Crim 2015).