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A review of the TORCH study.

Calverley PMA et al for the TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775-89. It has been over a year since the influential TORCH study was published. Nevertheless, the editors thought it appropriate to provide a critical review of the data since there is a great deal of useful information that can still be gleaned from this paper. Mortality was the chief endpoint of the TORCH study, which is very significant since COPD will be the third most common cause of death by 2020. 6112 patients were randomised and double-blinded into four treatment groups: salmeterol 50 mcg plus fluticasone propionate at a dose of 500 mcg twice daily administered via a single inhaler discus (SAL/FP); placebo; salmeterol (SAL) alone; or fluticasone (FP) alone. Treatment was for a period of three years. The primary outcome was death from any cause. Other outcomes included exacerbations (defined as a symptomatic deterioration requiring treatment with antibiotic agents, systemic corticosteroids, hospitalisation, or a combination of these), health status assessed by the St. George’s Respiratory Questionnaire, and spirometry. Recruited patients were current or former smokers with at least a 10 pack-year history, aged 40-80, with a previous diagnosis of COPD. The pre-bronchodilator FEV1 had to be <60% of predicted, with a ratio FEV1/FVC < 0.70. The post400 mcg albuterol FEV1 could not increase more than 10%. Before the two-week run-in period, all use of corticosteroids and inhaled long-acting bronchodilators was stopped, but patients could continue other medications for COPD (note that this study predated the availability of tiotropium). Patients were seen every 12 weeks, with health status and post-bronchodilator spirometry done every 24 weeks. There were 875 deaths – 12.6% in the combination therapy group, 15.2% in the placebo group, 13.5% in the salmeterol group and 16% in the fluticasone group. The hazard ratio for death in the combination-therapy vs the placebo group, was 0.825 (95% confidence interval [CI], 0.681 to 1.002; P=0.052, adjusted for the interim analyses), corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5%. The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo. This p value (0.052) was not considered statistically significant, but there was a 17.5% relative reduction in mortality and 2.6% absolute reduction in mortality. Analysis of all-cause mortality with 3-year interaction tests showed that there was no interaction between survival and multiple factors, including smoking status, region, predicted FEV1 (%), age, gender, ethnic origin, or body mass index (BMI). Thus, the survival benefit seen in the TORCH trial is similar regardless of any of these interactions. The combination regimen reduced the annual rate of exacerbations from 1.13 (placebo group) to 0.85, and improved health status and spirometric values (P<0.001 for all comparisons with placebo). A safety sub-study at 88 sites in the USA – with annual assessments of bone mineral densitometry, slit-lamp eye examination and cortisol secretion – was carried out in 658 patients, and showed no differences between the placebo and treatment arms. There seemed to be a higher rate of pneumonia in all groups using fluticasone (19.6% in Sal/FP and 18.3% in the FP groups vs placebo (12.3%, P<0.001). It should be noted that pneumonia did not have to be proven by chest radiography, so some of these ‘pneumonia’ episodes were likely exacerbations, and the rate of exacerbations (and mortality) was clearly lower.