Large clinical trials for drug registration of tiotropium were performed in multiple countries outside of Canada and at clinical research centres. As part of an ongoing postapproval program, the current trial investigated tiotropium in a Canadian health care setting. The trial confirmed that tiotropium is effective at improving lung function in both current smokers and ex-smokers, even with the placebo group already receiving most elements of usual care.
There was some speculation that current smoking may affect the response to tiotropium, as is seen in previous studies with corticosteroid treatment in asthma (7
) and bronchodilator treatment in COPD (8
), but this was not observed in the current study. This may be due to the substantial differences between the smoker and ex-smoker subgroups, and it would have been better to stratify the patients before randomization to ensure balanced groups. Smoking status was recorded at screening but was not confirmed at study completion by either asking the patient or by measuring serum cotinine levels. This study does show, however, that regardless of ongoing physician attempts to promote smoking cessation, the approximately 100 mL or 10% improvement in lung function with tiotropium in patients already receiving the benefits of usual care will still be realized.
Baseline trough FEV1 and absolute FEV1 were lower in ex-smokers compared with smokers. This may have been due to a form of selection bias in that more severe patients may be more committed to smoking cessation.
The smaller gain in FEV1
with tiotropium in ex-smokers could be attributed to greater disease severity and therefore to less potential for reversibility compared with current smokers. However, this hypothesis has been refuted by Calverley et al (20
), who found that baseline lung function (with FEV1
ranging from 0.5 L to 2.0 L) does not influence the absolute improvement in FEV1
following bronchodilation. Although matching smokers and nonsmokers for disease severity would have been preferable, we believe that the observation that tiotropium is effective in current smokers is valid.
In previous tiotropium studies (9
), the improvement in FEV1
was 120 mL to 150 mL compared with placebo or ipratropium. The mean improvement in FEV1
of approximately 100 mL observed in the present study may reflect the fact that patients in the placebo group were allowed to take LABAs, which were usually excluded in previous studies. In one recent study by Niewoehner et al (13
), which did permit the concomitant use of LABAs, the difference in trough FEV1
between tiotropium and placebo was also 100 mL. The difference between the groups might have been larger if there had been fewer drop outs of sicker patients in the placebo group.
FVC and FEV6
(secondary end points) also improved with tiotropium compared with the placebo group. Again, the mean improvement in FVC (180 mL) was slightly less than the 210 mL to 290 mL improvement found in the placebo- or ipratropium-controlled trials (9
). Swanney et al (21
) showed that FEV6
is more reproducible than FVC and may be more relevant in a standard clinic setting. Unfortunately, the 130 mL improvement in FEV6
cannot be compared with other tiotropium studies, because this is the first time that it has been assessed in a clinical trial with tiotropium and the measurement was only performed at qualified sites as a pilot assessment.
The use of rescue medication provides an indication of the degree of breathlessness experienced by the patient. In the current study, rescue medication use was significantly reduced in the tiotropium group compared with the placebo group. By improving lung function, tiotropium relieves breathlessness. In other studies, tiotropium consistently reduced shortness of breath as measured by the improvement in the transition dyspnea score and decreased use of rescue medication compared with placebo, as demonstrated Brusasco et al (11
) and Vincken et al (10
As with dyspnea, HRQL was better at the end of the one-year trial, with statistically significant improvements in the SGRQ total score as seen by the improvements in the symptoms and impacts domains. The difference between the treatment groups was slightly less than that observed in previous placebo- and ipratropium-controlled studies (3.7 and 3.3 units, respectively) (9
). The difference in SGRQ scores might have been larger if there had been fewer drop outs of sicker patients in the placebo group. However, greater than one-half of the tiotropium patients had a clinically meaningful improvement in the SGRQ total score. This is an important, validated subjective improvement that is comparable with results from other tiotropium studies (9
). The large improvement in the placebo group is certainly more than would be expected. Perhaps this is explained by the halo effect of being in a study with additional monitoring by the clinic staff, enhanced compliance with their concomitant medication (LABA plus inhaled corticosteroids) and, potentially, the poorer responders dropping out. The clinically significant improvement in the SGRQ total score for smokers compared with the ex-smokers is consistent with greater improvement in lung function in smokers.
The observed lack of a significant difference between treatment groups in exacerbation parameters is in direct contrast to the results from the Spiriva (Boehringer Ingelheim Canada) tiotropium clinical trial program to date (9
). There are a number of potential explanations for this finding. The trial was not powered to detect a reduction in exacerbations. In addition, an inclusion criterion was amended to permit patients who were less likely to exacerbate to enter the trial (ie, those patients who had only experienced one COPD exacerbation in the past two years rather than those who had experienced a COPD exacerbation in the past 12 months). Had we realized during enrolment what was recently reported by FitzGerald et al (22
) that 46.9% of Canadian patients with moderate to severe COPD might not have an exacerbation during one year, we would not have allowed the change to the inclusion criteria. Finally, commercial tiotropium became available on the market during the study. This may have contributed to the observed higher discontinuation rate in the placebo group (12.5%) compared with the tiotropium group (7.4%) early on in the study (ie, by day 50) and may have resulted in a selection bias. Because patients in the tiotropium group remained in the trial for a longer duration than the patients in the placebo group, they may have experienced more respiratory events. Adjusting for the length of exposure diminished the apparent difference between the two treatment arms and is indicative of nonrandom discontinuation influencing the results.
The low exacerbation and hospitalization rates in the placebo group in the present study may reflect, in part, participation in a self-management plan, an increasingly popular treatment strategy in Canada with proven efficacy in reducing the utilization of health care services (23
Problems associated with differential discontinuation rates between the active and placebo groups in major COPD trials have been discussed by Decramer et al (24
). They concluded that premature discontinuation is not completely random, with sicker patients discontinuing earlier than less sick patients, thereby enriching the remaining study group with healthier patients. In the current study, a higher percentage of patients in the ‘drop out population’ had a history of cardiac and respiratory disorders, in association with a higher use of both cardiac and respiratory medications at baseline. Additionally, the drop out population had more severe COPD at baseline, as assessed by smoking history, lung function, oxygen use and respiratory medications compared with patients who completed the trial, which may reflect a signal toward selection bias. Given the higher drop out rate in the placebo group, the unintentional enrichment of the healthy patients in this group may, in part, explain the lack of a significant difference between the two treatment groups in terms of exacerbations. In addition, Calverley et al (25
) found that patients withdrawing from their study’s placebo group had a more rapid decline in FEV1
and more exacerbations than the active group. Perhaps if the current placebo group had been followed after study withdrawal, it may have been determined that they too had exacerbations after they dropped out of the study. However, withdrawn patients were not systematically followed up after they dropped out. Therefore, the poststudy exacerbation status was not available for comparison with the patients who remained in the study. This may have permitted an evaluation of any imbalances following premature discontinuation.
The mortality rate in the current placebo group was much lower (0.7% per year) than in the placebo or ipratropium control arms in the pivotal one-year tiotropium studies (1.9% and 1.7%) (9
). As with the issue regarding exacerbations, this large difference probably reflects the early drop out of sicker patients and the fact that the remaining patients in the placebo group had better-controlled disease. The 2.1% mortality rate for the tiotropium group was comparable with that observed in other one-year studies of patients with moderate to severe COPD (2.0 % to 3.5%) (26
), and it was comparable to the rate in other tiotropium studies (1.3% to 2.5%) (9