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Treating COPD: combining tiotropium with salmeterol seretide

Peter Burrill summarises a study on tiotropium in combination with placebo, salmeterol or fluticasone-salmeterol for treatment of COPD(1)

Peter Burrill
BPharm(Hons)
MRPharmS DipPresSci
FCPP FFPMM
Specialist Pharmaceutical Adviser for Public Health Derbyshire County PCT

Treatment for chronic obstructive pulmonary disease (COPD) is focused on minimising risk factors, improving symptoms and preventing exacerbations. Physicians use multiple medications to manage COPD, but many combinations are unstudied. The aim of this trial was to determine whether combining tiotropium with salmeterol or seretide produces greater improvements in clinical outcomes for adults with moderate or severe COPD compared with tiotropium alone.

Method

  • Eligible patients had to have had at least one exacerbation of COPD that had required treatment with systemic steroids or antibiotics within the 12 months before randomisation.

  • Additional inclusion criteria were age older than 35 years, a history of 10 pack-years or more of smoking, FEV1/FVC ratio less than 0.70 and a postbronchodilator FEV1 less than 65% of the predicted value.

  • 449 patients were randomised to one of three treatment arms for 52 weeks: tiotropium 18mcg once daily plus placebo inhaler, two puffs twice daily (T/P); tiotropium plus salmeterol 25mcg/puff, two puffs twice daily (T/S); or tiotropium plus fluticasone-salmeterol 250/25mcg/puff, two puffs twice daily (T/S/F). Tiotropium was administered by using a Handihaler device and other study drugs via a pMDI (metered-dose inhaler) with spacer device. The MDIs containing placebo, salmeterol, and fluticasone-salmeterol were identical in appearance and taste.

  • All patients were provided with prn salbutamol for symptom relief. Any previous treatment with inhaled corticosteroids (ICS), long-acting ß2-agonists (LABAs), and anticholinergics was discontinued on entry into the study.

  • The primary outcome was the proportion of patients in each treatment group who experienced a COPD exacerbation with 52 weeks of randomisation.

  • The study was designed and powered to compare T/P with the other two treatment arms, and not to compare differences between T/S and T/S/F.

  • Secondary outcomes included hospitalisations for COPD, dyspnoea and changes in the SGRQ score.

  • The final analysis was conducted on an intention-to-treat basis.

  • The trial was supported by the Canadian Institutes of Health Research and the Ontario Thoracic Society and not by the pharmaceutical industry.

Results

  • The proportion of patients with at least one exacerbation during the trial was not significantly different between the groups - T/P 62.8%, T/S 64.8%, and T/S/F 60.0%.

  • The mean number of exacerbations per patient-year was not significantly different between the groups.

  • The median time to first exacerbation was not significantly different between the groups.

  • Patients treated with T/S/F had lower rates of severe exacerbations requiring hospitalisation than patients treated with T/P, rate ratio 0.53 (CI 0.33 to 0.86), p=0.01. Significant benefits were not seen for T/S compared with T/P.

  • The SGRQ changes were as follows: -4.5 for T/P, -6.3 for T/S (p=0.02), and -8.6 for T/S/F (p=0.01).

  • Dyspnoea scores improved over one year, but did not significantly differ among the treatment groups.

  • All-cause deaths - T/P 2.6%, T/S and T/S/F 4.1% (no p-values given).

  • Total adverse events - T/P 23.7%, T/S 21.6% and T/S/F 30.3% (no p-values given).

  • 47% of the T/P group discontinued use of study medications before completing one year of therapy, compared with 43% in the T/S group (p=0.54) and 26% in the T/S/F group (p

    Discussion/implications
    There was no significant difference in the primary endpoint. NICE Clinical Guideline 12 suggests that a LABA and tiotropium can be used together to reduce exacerbations, although no trials had investigated this combination at that time.2 This trial does not support the use of the combination of salmeterol and tiotropium.
    Although some secondary endpoints for T/S/F have moderate statistical significance compared with T/P, the failure of the primary outcome to reach significance arguably renders secondary outcomes irrelevant. At best, they provide hypotheses for further studies with these as primary outcomes.
    This trial does not alter the position of an ICS in COPD management and the criteria in the NICE guideline should be followed when considering adding ICS to bronchodilator therapy.

    FEV1 = Forced expiratory volume in 1 second, an important measure of pulmonary function

    FVC = Forced vital capacity. The volume change of the lung between a full inspiration to total lung capacity and a maximal expiration to residual volume

    Peter is a pharmaceutical adviser of many years standing and provides strategic input into the prescribing and clinical effectiveness agenda for the Derbyshire Public Health Network. He is involved with the appraisal of evidence, evaluation of new drugs and guidelines development, and facilitates the Derbyshire Joint Area Prescribing Committee. Peter also trains health professionals in the principles of critical appraisal and evidence-based medicine.

    This article is one of many that Peter will be contributing to NiP over the coming issues. In each Peter will summarise the results of a recent drug study relevant to primary care.

    References
    1. Aaron SD, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of COPD. Ann Intern Med 2007;146:545-55.
    2. NICE. Clinical guideline 12. Chronic obstructive pulmonary disease. London: NICE; 2004.