Recent studies

Five large placebo-controlled trials have recently been conducted — one 6-month study and four studies lasting 3 years. Crude results are shown in Table 10.1.

Paggiaro et al. [12] showed an effect of inhaled fluticasone on FEV1, respiratory symptoms, and severity of exacerbations in patients with well-defined COPD; however, the study only lasted 6months, which limits its value for assessing long-term effects.

The Copenhagen City Lung Study (CCLS) [13] included 290 subjects with predominantly mild COPD from an ongoing epidemiological study in which almost 10000 subjects were screened using spirometry. Patients were recruited as non-asthmatic subjects with a decreased ratio between FEV1 and vital capacity (VC); i.e. FEV1/VC < 0.7. Eligible patients had to be irreversible to oral prednisolone and inhaled terbutaline—i.e. have an increase in FEV1 less than 15% of baseline; only 5% were reversible to prednisolone. A total of 290 patients were randomized to receive either budesonide, 800 + 400 |mg daily for 6 months followed by 400 |mg twice daily for 30months, or placebo for 36 months. The study drug and placebo were given in a multidose powder inhaler, the Turbuhaler. The mean age of the patients was 59years, 40% were women, and 77% were present smokers. The mean FEV1 was 2.37L or 86%

Fig. 10.1 Crude mean change from baseline forced expiratory volume in 1s (FEVj) in the Copenhagen City Lung Study. Reprinted with permission from [13].

Fig. 10.1 Crude mean change from baseline forced expiratory volume in 1s (FEVj) in the Copenhagen City Lung Study. Reprinted with permission from [13].

12 15 18 21 Months

of predicted. The main outcome parameter was FEVj decline, and crude FEVj declines turned out to be slightly smaller than expected—41.8mL/year in the placebo group and 45.1mL/year in the budesonide group. Post-bronchodilator FEVj over the course of the study is shown in Fig. 10.1. Using a regression model in the intention-to-treat population, patients in the placebo group had an FEVj decline of 49.1 mL/year, in contrast to 46.0mL/year in the budesonide group; the estimated difference was 3.1 mL/year (95% confidence interval, 12.8 to 19.0) was both statistically and clinically insignificant (P=0.70). There was no initial rise in FEVj in the budesonide group. Before the study, the minimal relevant difference was decided as 20 mL/year; this difference was outside the two-sided 95% confidence interval. Secondary effect parameters were respiratory symptoms and number of exacerbations, and no effect of inhaled budesonide was seen on either of these outcomes.

The European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOP) study [14] was a European multicentre study in which 39 study centres in nine countries participated. EUROSCOP included patients with mild COPD who continued to smoke in spite of a 3-month smoking cessation program including nicotine gum. A total of 1277 current smokers were randomized to either budesonide 400 |mg b.i.d. or placebo, both given in the Turbuhaler. The patients' mean age was 52.5 years, 73% were men, and the mean postbronchodilator FEV1 was 79.7% of predicted. There was a significant initial effect of inhaled budesonide on lung function; in the first 6 months, the placebo group experienced a rapid decline in FEV1, 81 mL/year, whereas the budesonide group had an increase in FEVj of 17mL/year. From 9 to 36months, both groups declined in FEVj, 69m/year in the placebo group and 57mL/year in the budesonide group. The difference was not statistically significant (P=0.39). After substratification according to pack-years of smoking, there was a tendency towards an effect of budesonide in subjects with < 36 pack-years, but the difference in decline from 9 to 36

months did still not reach statistical significance. No information on symptoms or exacerbations is given in the report [14], but from early presentations of the study it seemed that no differences in the number of exacerbations were found. Side effects and safety were well documented. There was a statistically significant difference in the occurrence of skin bruises larger than 50 mm in diameter on the volar side of the forearms — 10% in the budesonide group and 4% in the placebo group (P < 0.001). Apart from this, treatment was well tolerated.

The third study is the Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study [15]. ISOLDE is the only study that has included patients with severe COPD, the mean FEV1 being 50% of predicted. A total of 751 patients were included and randomized to either fluticasone 500 |mg in me-tered-dose inhaler (MDI) via a Volumatic spacer twice daily, or placebo MDI via Volumatic spacer. All patients were immediately after randomization offered 2weeks of treatment with oral prednisolone, 0.6mg/kg once daily. The main effect parameter was FEVj decline; secondary effect parameters were exacerbations, symptoms, and health status, the latter evaluated using the St George's Respiratory Health Questionnaire. Only 219 patients in the fluticasone group and 182 in the placebo group completed the study; patients with more than three exacerbations within a 3-month period were excluded throughout the study, and this led to significantly more patients being excluded from the placebo arm than the fluticasone arm of the study. The course of lung function over the 3-year study is shown in Fig. 10.2 and was almost similar to that seen in the EUROSCOP study, except for the short effect of the oral prednisolone. There was an overall reduction in the number of exacerbations from 1.32 to 0.99 per year (P=0.03). Most significantly, the gradual loss in health status was slowed down in the fluticasone group, from 3.2 units per year in the placebo group to 2.0 units per year in the fluticasone group (P= 0.004). These findings may be linked, as exacerbations are associated with loss of health status [16]. From preliminary reporting, it seems that the effect of fluticasone on exacerbations was mainly seen in those with low FEV1, which in the ISOLDE study was the tertile with FEVj < 1.25 L and virtually ab

-2 -1 PS 0 3 6 9 12 15 18 21 24 27 30 33 36 Month

Fig. 10.2 Crude change from forced expiratory volume in 1s (FEVj) at randomization in the Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study. The box illustrates the time of prednisolone. Modified from [15].

sent in the tertile with the best FEV1. In the recruitment phase, a number of subjects were taken off ICS when entering the run-in period of the ISOLDE study, an 8-week wash-out period in which eligible subjects were followed without ICS. Thirty-eight percent of those taken off ICS experienced an exacerbation during the run-in, in contrast to only 6% of those entering run-in without previous treatment with ICS [17]. These findings have subsequently been confirmed in an American study in which withdrawal of inhaled steroids was associated with worsening of dyspnoea and a drop in FEV1 [18].

Finally, the results of the Lung Health Study II have been published, to some extent confirming the findings of the previous studies [19]. Whereas Lung Health Study I [20] included both smoking cessation and usual care with or without an inhaled anticholinergic, Lung Health Study II (LHSII) was a pure controlled trial of inhaled triamcinolone. A total of 1116 patients with mild to moderate COPD were randomized in this multicentre trial, including 10 clinical centres in the USA and Canada. As in the previous studies, no effect of inhaled steroids was seen on FEVj decline; FEVj decline was 47 ± 3 mL/year in the placebo group and 44 ± 3mL/year in the triamcinolone group. Exacerbations were not a predefined end-point, but as in the ISOLDE study, an effect was seen on effect parameters associated with exacerbations. Both hospital-izations and unscheduled outpatient visits for respiratory causes were reduced by approximately 50% in the triamcinolone group.

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