Tiotropium for COPD
Bandolier
looked at tiotropium for COPD (Bandolier 98) when the first two large trials
were published. It reduced exacerbations and hospital admissions. Four years on
we have a new systematic review [1], and it is interesting to see what has
changed.
Systematic review
The
review [1] used five search strategies, including Cochrane, and searching was
up to the first quarter of 2006, making the review current. It also looked at
bibliographies and requested studies from manufacturers. The review included
studies in adults with stable COPD satisfying US and European criteria, where
tiotropium was compared with placebo or long acting beta-agonists, that were
randomised, and where the outcomes included exacerbations, hospital admission,
and mortality. Only full publications were accepted.
Results
Thirteen
studies with 6,078 patients were available, with 11 coming from the
manufacturer (86% of patients). Most patients were men (80%), with FEV
1
between 34% and 43% of predicted. Almost all studies used tiotropium at an 18
μg dose inhaled once a day. Trials were as short as one week and as long
as one year, and all but one had reasonably high reporting quality, and all
were described as both randomised and double blind.
Eight
trials compared tiotropium with placebo (Figure 1). Overall there were fewer
exacerbations with tiotropium (relative risk 0.83; 95% confidence interval 0.76
to 0.91), and the number needed to treat to prevent one exacerbation was 21
(Table 1). The NNT was similar for three large trials lasting six months or
longer, and five small trials lasting six weeks or less (Table 1), but event
rates were much lower in the shorter trials. However, the average number of
exacerbations per week with placebo was consistent between trials at about 1.3
(Figure 2).
Figure 1: Exacerbations in individual trials comparing tiotropium with placebo
Table 1: Results of trials comparing tiotropium with placebo, with outcomes of exacerbations, and of hospital admissions
| Outcome | (95% CI) |
||||
| Exacerbations (all trials) | |||||
| Large trials ≥6 months | |||||
| Small trials ≤6 weeks | |||||
| Hospital admissions | |||||
Figure 2: The mean number of exacerbations per week of trials for placebo in individual trials. Symbol size is related to the number given placebo
Tiotropium
also reduced hospital admissions in the three larger studies of at least six
months duration (Table 1), with a similar NNT to prevent one hospital
admission, of 20 (14 to 34). In trials of six months or longer, mortality was
1.7% for both tiotropium and placebo.
Most
other outcomes were recorded in only a few trials, though spirometric testing
in most trials consistently showed slight but significant improvement with
tiotropium over placebo.
Comparison
with long acting beta-agonists in two or three trials showed no significant
difference for exacerbations, but lower hospital admissions with tiotropium,
with an NNT to prevent one admission of 33 (17-1000), and significantly better
results for spirometry.
Dry
mouth was significantly more common with tiotropium than placebo or long acting
beta agonist.
Comment
The
estimates of efficacy from this review are broadly similar to those found in
the original trials, despite there being five times more patients for the
comparison with placebo. Tiotropium reduces exacerbations and hospital
admissions compared with placebo, and probably against long acting
beta-agonists. We could do with more comparisons with the latter to prove the
point.
What
was interesting was the comparison between larger, longer, trials, and smaller,
shorter, trials. This could have been a source of clinical heterogeneity, or
possible lack of validity, but actually the studies had a consistent rate of
exacerbations with placebo, of about 1.3 per week, with only small studies
varying much (Figure 2). This can provide a benchmark for knowing whether COPD
candidates are like the patients in the studies.
For
collectors of examples of how duplicate studies can creep into systematic
reviews, this paper describes how subjects in six trials excluded from this
review were included at least twice in a previous review.
Reference:
- GJ Rodrigo, LJ Mannini. Tiotropium for the treatment of stable chronic obstructive pulmonary disease: a systematic review with meta-analysis. Pulmonary Pharmacology & Therapeutics 2006 [epub ahead of print].