Relatively recent evidence has been produced on the clinical benefit of LABA/ICS combination in COPD. So far, this strategy has been demonstrated to be specifically effective in patients with severe or very severe disease and history of exacerbations.

Budesonide/formoterol combination in COPD
Two 12-month clinical trials with the fixed combination budesonide/formoterol (Symbicort^®) will be described: Calverley et al (2003) and Szafranski et al (2003). These studies demonstrated that the combination (at daily dose of budesonide 800 μg + formoterol 24 μg) significantly reduces the risk of COPD exacerbations requiring medical intervention and provides rapid and sustained improvement in lung function and symptoms relief.

Maintenance therapy with Symbicort^® compared with budesonide and formoterol, in chronic obstructive pulmonary disease
Calverley P.M. et al. Eur Respir J 2003; 22: 912–919 (21)

The study involved 1022 patients with severe COPD (FEV₁ < 50% predicted normal pre-bronchodilator) and a history of exacerbations. Initially treatment was intensified with the oral steroid prednisolone (30 mg once daily) and inhaled formoterol Turbuhaler^® (9 μg twice daily) for two weeks, in an attempt to optimise patients’ health status. Following the intensification period, patients were randomised to receive the fixed combination, Symbicort^®, (320/9 μg, twice daily), budesonide Turbuhaler^® alone (400 μg, twice daily), formoterol alone (9 μg, twice daily), or placebo for one year. All treatments were delivered via Turbuhaler.

Following 1 year of treatment, the budesonide/formoterol combination significantly reduced the time to first exacerbation requiring medical intervention compared with all other treatments and placebo (all p<0.05) (Fig. 14).

Figure 14: Exacerbations during the trial.

The risk of having an exacerbation in the combination group was 23%, 30% and 29% lower compared to patients treated with budesonide, formoterol and placebo, respectively (hazard rate analysis). The budesonide/formoterol combination increased the time to first exacerbation by 100 days compared with formoterol. In addition, the number of exacerbations requiring medical intervention per patient per year was lowest in the combination group (28% reduction compared to formoterol). The number needed to treat (NNT) to avoid one exacerbation in 1 year was 2.1 for combination versus formoterol.

After the treatment optimisation period, the improvement in FEV₁ and morning PEF achieved during run-in was maintained throughout the study in Symbicort-treated patients. In contrast, FEV₁ and morning PEF declined rapidly from the end of run-in and remained low until the end of the study with all other treatments and placebo (Fig. 15).

Figure 15: Mean FEV₁ during the trial.

Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease
Szafranski, W. et al. Eur Respir J 2003; 21: 74-81 (22)

The study involved 812 patients with severe COPD (FEV₁ < 50% predicted normal) and a history of exacerbations. Patients were randomised to receive budesonide/formoterol fixed combination, Symbicort^®, (320/9 μg, twice daily), budesonide alone (400 μg, twice daily), formoterol alone (9 μg, twice daily), or placebo for one year, after a two week run-in period where maintenance medication was withdrawn and only terbutaline was allowed as rescue. All treatments were provided in Turbuhaler^®.

The number of exacerbations requiring medical intervention per patient per year was 1.42, 1.59, 1.84 and 1.87 in the combination, budesonide, formoterol and placebo groups, respectively. Budesonide plus formoterol significantly reduced the rate of exacerbations requiring medical intervention compared with placebo and formoterol (both p<0.05) (Fig. 16).

Figure 16: Exacerbations during the trial.

Budesonide/Formoterol fixed combination increased FEV₁ by 15% compared with placebo (95% CI: 11.0–19.1; p<0.001) and by 9% vs budesonide (95% CI: 5.4–13.1; p<0.001). These improvements were sustained throughout the study period (Fig. 17).

Figure 17: Mean values for forced expiratory volume in one second (FEV₁) measured at clinic visits.

Fluticasone/salmeterol combination in COPD
The efficacy of the fixed combination fluticasone/salmeterol (Seretide^®/Advair^®) in COPD patients has been studied in three pivotal trials: a 12-month clinical trial, by Calverley et al. (Tristan study, 2003), and two 6-month trials, by Hanania et al. (2003) and Mahler et al (1999). All the studies showed the combination to provide a significant improvement in lung functions (primary outcome) when compared to single agents. The only trial (Tristan study) powered to detect - even if as secondary endpoint - an effect on exacerbations requiring medical intervention, did not show significant differences between the fluticasone/salmeterol combination and monotherapy. However, there was a trend in favour of the combination group, which became more pronounced with increasing COPD severity.

Effectiveness of Fluticasone Propionate and Salmeterol Combination Delivered via the Diskus^® Device in the Treatment of Chronic Obstructive Pulmonary Disease
Mahler, D. A. et al. Am J Respir Crit Care Med 2002; 166: 1084–1091 (23)

The study involved 691 COPD patients with baseline FEV₁ of less than 65% of predicted (mean value 41%). History of exacerbations was not listed among eligibility requirements. Patients began 2-week, single-blind, run-in period during which they received albuterol on an as-needed basis. After the run-in period, eligible patients were randomised as follows: fluticasone alone (500 μg twice daily); salmeterol alone (50 μg twice daily); fluticasone plus salmeterol “Seretide^®” (500/50 μg, twice daily), or placebo for 24 weeks. All treatments were delivered via Diskus^®. Patients were also given as-needed albuterol.

The primary efficacy measures were:

• Pre-dose FEV₁
  • Combination vs. salmeterol (to assess the anti-inflammatory contribution of fluticasone in the reduction of airway obstruction
• 2 hour post-dose FEV₁
  • Combination vs. fluticasone (to assess the bronchodilatory contribution of salmeterol)

Pre-dose FEV₁
A significantly greater increase in pre-dose FEV₁ improvements was observed after treatment with the combination (156 mL) compared with salmeterol (107 mL) and placebo (-4 mL) (Fig. 18):

Figure 18: Improvement in predose FEV₁ with FSC () compared with the individual components and placebo (). Values from weeks 1-24 are mean + SEM. a = FSC versus placebo, p < 0.001. b = FSC versus S () p = 0.012. c = FSC versus F () p = 0.038. d = S versus placebo, p < 0.001. e = F versus placebo, p < 0.001.

Post-dose FEV₁
A significantly greater increase in 2-hour post-dose FEV₁ at the endpoint was observed after treatment with the combination (261 mL) compared with fluticasone (138 mL) and placebo (28 mL) (Fig. 19).

Figure 19: Improvement in 2-hour postdose FEV₁ with FSC () compared with the individual components and placebo (). Values from weeks 1-24 are mean + SEM. a = FSC versus placebo, p < 0.001. c = FSC versus F () p < 0.001. d = S () versus placebo, p < 0.001. e = F versus placebo, p < 0.001.

In addition, following 6 months of therapy, there were no statistically significant differences between treatment groups in time to exacerbation. However, according to the authors, the sample size was inadequate to discern significant treatment differences.

The Efficacy and Safety of Fluticasone Propionate (250 μg)/Salmeterol (50 μg) Combined in the Diskus^® Inhaler for the Treatment of COPD
Hanania, N. A. et al. CHEST 2003; 124: 834–843 (24)

Apart from the dose, the design of the study is similar to the Mahler et al study. This trial involved 723 COPD patients with baseline FEV₁ of less than 65% of predicted (mean value 42%). History of exacerbations was not listed among eligibility requirements. Patients began a 2-week, single-blind, run-in period during which they received albuterol on an as-needed basis. After the run-in period, eligible patients were randomised as follows: fluticasone alone (250 μg twice daily); salmeterol alone (50 μg twice daily); fluticasone plus salmeterol, Seretide^®, (250/50 μg, twice daily), or placebo for 24 weeks. All treatments were delivered via Diskus^®. Patients were also given as-needed albuterol.

The primary efficacy measures were:

• Pre-dose FEV₁
  • Combination vs. salmeterol (to assess the anti-inflammatory contribution of fluticasone in the reduction of airway obstruction)
• 2 hour post-dose FEV₁
  • Combination vs. fluticasone (to assess the bronchodilatory contribution of salmeterol)

Pre-dose FEV₁
A significantly greater increase in pre-dose improvements in FEV₁ was observed after treatment with the combination (165 mL) compared with salmeterol (91 mL) and placebo (1 mL) (Fig. 20).

Figure 20: Mean change in pre-dose FEV₁.

Post-dose FEV₁
A significantly greater increase in 2-hour post-dose FEV₁ at the endpoint was observed after treatment with the combination (281 mL) compared with futicasone (147 mL) and placebo (58 mL) (Fig. 21).

Figure 21: Mean change in 2h post-dose FEV₁.

In addition, following 6 months of therapy, no significant differences were observed among treatment groups in terms of numbers of exacerbations or time to first exacerbation. However, according to the authors, the sample size and duration of the trial were inadequate to discern significant treatment differences.

Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial (TRISTAN)
Calverley, P. et al. The Lancet 2003; 361: 449-456 (25)

TRISTAN trial involved 1465 COPD patients with a baseline FEV₁ before bronchodilation that was 25–70% of predicted (mean value 44%) and history of exacerbations. Patients began a 2-week, run-in period during which they received albuterol on an as-needed basis. After the run-in period, eligible patients were randomised as follows: fluticasone alone (500 μg twice daily); salmeterol alone (50 μg twice daily); fluticasone plus salmeterol, Seretide^®, (500/50 μg, twice daily), or placebo for 52 weeks (1-year). All treatments were delivered via Diskus^®. Patients were also given as-needed albuterol.

The primary outcome was the pre-treatment FEV₁ after 12 months treatment. The three active treatments significantly increased pre-treatment FEV₁ after 12 months compared with placebo (fluticasone/salmeterol combination p<0.0001; salmeterol p<0.0001; fluticasone p=0.0063). The rise in FEV₁ associated with combination therapy was significantly greater than with either of its components separately (p<0.0001 vs. placebo, fluticasone, salmeterol) (Fig. 22).

Figure 22: Mean change in pre-bronchodilator FEV₁.

One of the secondary endpoints of the trial was the number of exacerbations per patient per year. After 1 year of treatment the occurrence of acute exacerbations of COPD (defined a priori as a worsening of COPD symptoms that required treatment with antibiotics, oral corticosteroids, or both) was significantly reduced, compared with placebo, in all active treatments. There were no significant differences between active treatments with respect to their effect on the rate of episodes of symptom exacerbation.

Interestingly, the fluticasone/salmeterol combination effect was more pronounced in patients with severe disease (i.e, a baseline FEV₁<50% of predicted), who showed a 30% reduction compared with placebo, as against a 10% reduction in patients who had a baseline FEV₁ that was greater than 50% of that predicted. However, even in this more severe subgroup, no significant differences for the combination over single medications were noted.

In conclusion, LABA/ICS combinations have demonstrated to improve lung functions and health status and to reduce exacerbations in COPD patients, thus confirming a positive collaboration between the two different receptor systems and corresponding mechanisms of action. Even though many questions remain open on the use of steroids in COPD, it seems not unlikely that combination therapy will be extended to patients with mild-to-moderate disease in the future. The results of the large 3-year clinical trial “TOwards a Revolution in COPD Health” (TORCH), performed with Seretide^® (fluticasone + salmeterol combination), support this (26). Aim of this study was to investigate the potential for combinations to impact long term survival in COPD. Results have demonstrated Seretide^® to reduce by 17,5% all cause mortality in COPD patients compared to placebo (p=0.052): although not statistically significant, such a decrease in mortality rate can be considered relevant from a clinical point of view and could have implications for the future treatment of COPD. There were significant benefits in all other outcomes among these patients.