Combo Therapy Surpasses Single Drug for Severe COPD

By Judith Groch
LONDON, Dec. 28 -- Combination drug therapy with salmeterol (Serevent), a long-acting inhaled bronchodilator, and fluticasone (Flovent) improved survival and led to fewer treatment withdrawals compared with single-drug therapy in severe COPD. A multicenter head-to-head study found a 52% reduction in the risk of all-cause mortality at any time during the study for the combo treatment compared with single-drug treatment, Jadwiga A. Wedzicha, M.D., of Royal Free & University College Medical School here, and colleagues reported in the first January issue of the American Journal of Critical Care Medicine Significantly, however, exacerbations, which are key drivers of morbidity and mortality, were similar for the two regimens, the researchers reported.
The study, Investigating New Standards for Prophylaxis in Reducing Exacerbations (INSPIRE), compared the relative efficacy of the combination treatment with monotherapy with the long-acting bronchodilator tiotropium (Spiriva).
In a two-year, double-blind, double-dummy parallel study, 1,323 patients (mean age, 64, post-bronchodilator FEV1, 39% predicted) were randomized to receive either the combination of salmeterol/ fluticasone (50/500 μg twice daily) or tiotropium (18 μg once daily).
The probability of withdrawing from the study was 29% greater with tiotropium than with salmeterol and fluticasone (P=0.005).
Mortality was significantly lower for the combination treatment patients: 21 (3%) patients in this group died compared with 38 (6%) in the tiotropium group (P=0.032).
The exacerbation rates between the two groups were statistically indistinguishable, the researchers said. The modeled annual exacerbation rate was 1.28 per year in the salmeterol/fluticasone group and 1.32 in the tiotropium group (rate ratio: 0.967, 95% confidence interval: 0.836 to 1.119, P=0.656).
Although exacerbation rates were similar, there were differences in the treatment required. Oral corticosteroids were used more often to treat the tiotropium patients, whereas the combination patients required antibiotics more frequently, the researchers said.
Health status, measured by the St. George's Respiratory Questionnaire (SGRQ) total score, found a small but statistically significant beneficial effect at two years for the combination patients compared with those given tiotropium (difference: 2.1 units, 95% CI: 0.1 to 4.0; P=0.038).
At the end of the study, both treatments largely maintained the improvement in lung function (FEV1) achieved during the run-in period.
Although overall health status did not worsen, twice as many pneumonias were reported for the salmeterol/fluticasone patients than for those taking tiotropium (eight patients versus four, hazard ratio: 1.94, P=0.008).
The exact nature of these episodes and why they occurred is being evaluated further and remains to be determined, the researchers said.
This study raises several important questions, they noted: Why is there a difference in the nature of the exacerbations between the two treatments? What is the biological basis of the differential effect on exacerbations, and is it related to the difference in mortality between the two treatments?
Finally, the researchers said, there may be potential advantages from combining salmeterol/fluticasone and tiotropium, and this should be formally tested in adequately powered trials against other active comparators.
The two treatments achieved similar exacerbation rates with different mechanisms, as shown by the difference in the use of corticosteroids and antibiotics to treat exacerbation, and this resulted in different outcomes. "We believe that this has important implications for the choice of therapy in the management of COPD," they concluded.
This study was supported by GlaxoSmithKline, maker of salmeterol (Serevent) and fluticasone (Flovent).
Dr. Wedzicha reported receiving research funding from GlaxoSmithKline, Boehringer Ingelheim, and AstraZeneca, and also, honoraria from GlaxoSmithKline and Novartis, and lecture fees from GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca, and Novartis.
Co-author Gerry Hagan has been an employee of the sponsor, GlaxoSmithKline, since 1996 and holds stock options in different formats. Zainab Ansari, another co-author, was a full-time employee of GlaxoSmithKline from October 2002 to November 2006.
Primary source: American Journal of Respiratory and Critical Care MedicineSource reference:Wedzicha JA, et al "The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide" Am J Respir Crit Care Med 2008; 177: 19-26.