O4. Inhaled combination therapy

O4.1 Inhaled glucocorticoids and long-acting beta-agonists in combination

A systematic review of six randomised controlled trials involving 4,118 participants of combined glucocorticoid and long-acting beta₂-agonists in one inhaler (Nannini et al., 2004) for COPD reached the following conclusion: Compared with placebo, combination therapy led to clinically meaningful differences in quality of life, symptoms and exacerbations. There was also a statistically significant difference in lung function. There was a statistically significant reduction in exacerbation rate for budesonide and formoterol, or fluticasone and salmeterol when compared to placebo, rate ratio 0.76 (95% CI 0.68, 0.84). There was a significant difference in the change from baseline in pre-dose FEV₁, weighted mean difference 160mls (95% CI 120-200, 697 participants). There were conflicting results for quality of life and symptom scores for both treatment comparisons and combinations (budesonide and formoterol, or fluticasone and salmeterol).

Possible explanations for these conflicts include study design and differential drop outs for interventions between studies. More recent data from Kliber (Kliber et al., 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. Nannini (Nannini et al., 2004) found a statistically significant lower exacerbation rate for combination therapy compared to long-acting beta₂-agonists, rate ratio 0.85 (0.77, 0.95) but not for combination therapy compared to inhaled glucocorticoids. However, a more recent systematic review of eighteen trials involving 12,446 participants comparing combined glucocorticoid and long-acting beta₂-agonists with long-acting beta₂-agonists alone did not confirm this benefit (Rodrigo et al., 2009). They found no significant benefit for combined therapy for severe exacerbations (hospitalisation or withdrawal), relative risk 0.91 (95% CI 0.82, 1.01) or all cause mortality but did for moderate exacerbations (requiring systemic glucocorticoids), relative risk 0.84 (95% CI 0.74, 0.96). Combination therapy did not change mortality but did significantly improve quality of life and FEV₁.

Compared to placebo, combination therapy did not significantly increase adverse events, but oral candidiasis was significantly more common, (NNH 16 [8-36], 1436 participants). Combination therapy was not associated with more adverse effects compared to long-acting beta₂-agonists. Chen et al (Chen et al., 2011) conducted a retrospective cohort study of Veterans Affairs (VA) patients with COPD who were admitted for pneumonia. Prior use of inhaled glucocorticoids 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 glucocorticoids were flunisolide and triamcinolone. [evidence level III-2]. Recent studies by Calverley (Calverley et al., 2007) and Kardos(Kardos et al., 2007) have found an increased rate of pneumonia (defined on clinical grounds) in the inhaled glucocorticoid arms, and this was also found in the Rodrigo systematic review, NNH = 48 (95% CI 31, 85) (Rodrigo et al., 2009). These results contrast with the reductions in exacerbation rates induced by these drugs. A nested case control study from Canada (Ernst et al., 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 glucocorticoids and that this appeared dose-related. In the two year RCT of salmeterol/fluticasone vs. tiotropium (Wedzicha et al., 2008), the number of de novo pneumonias not preceded by symptoms of exacerbations was similar between the two treatment groups.(Calverley et al., 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.