Large prospective randomized clinical trials are designed to report their pre-specified outcomes in the recruited population. However, clinicians are also interested in whether treatment responses vary within specific subsets of patients which, in the case of COPD, have been defined in terms of the post-bronchodilator FEV1
thresholds used in the GOLD guidelines. Indeed guidelines require this type of post-hoc analysis since they encourage more targeted therapy to specific patient groups. Based on the size of studies like TORCH and UPLIFT [10
], there is reasonable power to conduct exploratory post-hoc analysis of secondary outcomes. In the case of TORCH, where approximately one-third of the TORCH study population fell into the GOLD stage II category, the present post-hoc analysis demonstrates that SFC improved SGRQ, reduced exacerbations and improved lung function when compared with placebo. SFC was also associated with reduced mortality in GOLD stage II patients, compared with placebo.
TORCH recruited patients with a history of COPD, reversibility to salbutamol of < 10% of predicted FEV1
and excluded patients with a diagnosis of asthma. Reversibility to bronchodilation has been shown to be variable within COPD patients and the presence or absence of reversibility on a single test is not an important criterion to predict response to ICS [12
]. A very small number of patients in TORCH (16 patients) were protocol violators on the reversibility entry criterion.
The primary purpose of the TORCH trial was to determine whether SFC reduced all-cause mortality compared with placebo treatment (effectively regular short-acting bronchodilator therapy). As discussed elsewhere [2
], TORCH was probably underpowered to show this difference in a 4-arm study design and so particular caution is needed when interpreting mortality data between GOLD stage subgroups in this post-hoc analysis. However, while patients showed an increased risk of dying as their baseline spirometry worsened, there was a lower mortality with SFC treatment even in those with GOLD stage II disease. Clearly this finding should be confirmed by further prospective studies.
As expected, the burden of disease increased with severity regardless of the endpoint measured (mortality, exacerbations, FEV1, and AEs). All subgroup analyses should be treated with caution. However, treatment to prevent exacerbations seemed just as effective whatever the GOLD stage. The exacerbation frequency on placebo was lowest in GOLD stage II, but was not negligible with a rate of 0.82 events per year. We observed the same proportionate reduction in events with SFC therapy in GOLD stage II patients suggesting that treatment would be worthwhile for these patients. Deterioration in health status was seen over 3 years in the placebo arm in patients with GOLD stages III and IV, but those in GOLD II showed a small improvement. SFC improved health status by approximately the same amount from baseline in all three GOLD stages. In patients with more severe disease, the main effect of SFC appears to be to slow the rate of progression relative to placebo. However, it is clear that patients in GOLD stage II do have better health status when treated with SFC compared with placebo, with a change of over two units in total score maintained over the 3 years of study.
The treatment effects on post-bronchodilator FEV1
followed a similar pattern across all GOLD stages. The rate of decline in FEV1
tended to be slightly lower in GOLD stage IV than in stage II. SFC reduced the rate of FEV1
decline by 16 ml/year versus placebo in GOLD stage II patients versus 11 ml/year in stage IV patients which is comparable to the result reported in the overall population [13
In our study, the incidence and severity of AEs was generally comparable across treatment arms, regardless of GOLD stage. Increased incidence of pneumonia has previously been reported with the use of ICS-containing therapy [2
] and whilst this was observed, the probability of pneumonia with SFC in GOLD stage II patients was lower than that observed in the overall population. Further study is required however, to determine the exact mechanisms involved. There were too few on-treatment deaths from pneumonia to analyze these by GOLD stage.
It is important to note that, although GOLD stage II is defined by a post-bronchodilator FEV1
> 50% but < 80% predicted [1
], the upper limit for eligibility to the TORCH study was pre-bronchodilator FEV1
< 60% predicted; therefore most patients would be expected to fall into the more severe end of stage II COPD, which was indeed found to be the case. The majority of patients who were diagnosed with GOLD stage II COPD had a baseline post-bronchodilator FEV1
of 50% to < 60% (1360 patients [64%], while 646 patients [30%] had a FEV1
60% to < 70% and only 122 [6%] had a FEV1
70% to < 80%). This distribution appears to be similar to the FEV1
% predicted distribution of stage II COPD patients from a 2005–2007 UK General Practice Research Database population-based cohort study [GSK Worldwide Epidemiology (WEUSKOP2207) Final study report, May 2009. Data on file] and the demographics of the TORCH GOLD stage II population is also similar to that of the UPLIFT clinical trial [10
]. The majority of patients were also sufficiently symptomatic, as indicated by high baseline SGRQ total score, to have presented and been diagnosed with COPD, most likely as a result of exacerbations.
This analysis provides key information on pharmacotherapy in patients presenting with milder COPD and such data are lacking in the current literature and guidelines. Calverley and colleagues [5
] performed a similar post-hoc analysis of the TRISTAN trial, but divided patients into FEV1
< 50% predicted and ≥ 50% predicted and explored treatment differences by severity as a continuous variable. Lung function was found to improve with active treatment, irrespective of FEV1
, with greatest improvements reported for patients treated with SFC. In contrast to the findings reported here, only patients with more severe disease reported significantly reduced exacerbations; however health status and breathlessness both improved with active treatment irrespective of FEV1
. The present findings provide further evidence that SFC can be used in patients with milder COPD.
Inevitably a post-hoc analysis of this type has limitations. The study was not designed to test for differences between GOLD stages or differences between treatment arms within GOLD stages. The numbers of patients in each stage were different and analyses of treatment subgroups within stages are underpowered. However, the size of the study ensured that the baseline characteristics of patients within each treatment arm was similar in each GOLD stage. TORCH recruited patients with a pre-bronchodilator FEV1
of < 60% predicted, but a substantial number of patients fell into GOLD stage II disease, being defined by spirometric severity based on the post-bronchodilator value. It is important to note that all had a clinical diagnosis of COPD and that the mean total SGRQ in stage II patients was 45, indicating that they were a symptomatic group of patients. Finally, we adopted a conservative criterion with respect to study entry based on the former European Respiratory Society reversibility criterion of a change in FEV1
of less than 10% predicted. This is likely to have limited our ability to show changes in post-bronchodilator spirometry compared with studies where no reversibility limitation was present [8
]. However, this is not likely to impact on our data for health status or exacerbations, which are unrelated to reversibility status [12