Symptom relief
Inhaled bronchodilators
Short-acting bronchodilators
Regular short-acting beta-agonists improve lung function and daily
breathlessness scores. A systematic review of randomised controlled trials43
found a significant increase in post-bronchodilator spirometry when compared
to placebo; weighted mean difference = 140mls (95% CI 40 to 250) for FEV1
and 300mls (95% CI 20 to 580) for FVC. There were also improvements in
post-bronchodilator morning and evening PEF: weighted mean difference =
29.17 l/min (95% CI 0.25 to 58.09) for morning and 36.75 l/min (95% CI 2.57
to 70.94) for evening measurements. The relative risk of dropping out of the
study was 0.49 (95% CI 0.33 to 0.73), giving a number needed to treat of 5
(95% CI 4 to 10) to prevent one treatment failure. There was no significant
benefit on functional capacity, measured by walking tests, or symptoms other
than breathlessness, although one randomised controlled trial has found a
significant improvement in six-minute walking distance and quality of
life.40 Short-acting beta-agonists are now usually prescribed for use as
“rescue” medication, i.e. for relief of breathlessness, rather than for
regular use.
The duration of action of short-acting anticholinergics is greater than
short-acting beta-agonists. A systematic review of randomised controlled
trials comparing ipratropium bromide alone, or in combination with
short-acting beta-agonists, against short-acting beta-agonists alone found
significant benefits for regimens containing ipratropium bromide.44
Ipratropium bromide improved pre-drug spirometry over short-acting
beta-agonists alone, weighted mean difference = 30mls (95% CI 0 to 60) for
FEV1 and 70mls (95% CI 10 to 140) for FVC, although there was no significant
difference between peak post-drug measurements. Ipratropium bromide improved
quality of life, with a statistically significant improvement in all domains
of the Chronic Respiratory Disease Questionnaire. These benefits occurred
with fewer adverse drug effects, Peto odds ratio = 0.71 (95% CI 0.53 to
0.97), number needed to harm = 32 (95% CI 20 to 316). There was a lesser
need to add or increase the dose of oral corticosteroids for participants
receiving ipratropium bromide, Peto odds ratio = 0.52 (95% CI 0.37 – 0.74),
with 15 (95% CI 12 – 28) people requiring treatment with ipratropium bromide
to prevent one receiving additional oral corticosteroids.
For combination therapy with ipratropium bromide and short-acting
beta-agonists, there was no significant difference in pre-drug spirometry
compared to ipratropium bromide alone. There was a significant benefit for
the combination for post-drug spirometry measurements; weighted mean
difference = 70 mls (95% CI 50 to 90) for FEV1 and 120mls (95% CI 80 to 160)
for FVC. There was no significant difference between interventions for
quality of life or adverse drug effects, but combination treatment decreased
the need to add or increase oral corticosteroids compared to ipratropium
bromide alone, Peto odds ratio = 0.69 (95% CI 0.50 to 0.94), number needed
to treat = 20 (95% CI 12 to 108).
In summary, short-acting bronchodilators, either beta-agonists or
ipratropium bromide, significantly increase lung function measurements in
COPD. Ipratropium bromide has a significantly greater effect on lung
function compared to beta-agonists, in addition to improving quality of life
and decreasing need for oral corticosteroid treatment. These benefits
occurred with a decreased risk of adverse drug effects.
Long-acting bronchodilators
Long-acting beta-agonists (eg salmeterol, eformoterol) cause prolonged
bronchodilatation, for at least 12 hours, and can thus be administered twice
daily. A systematic review of randomised controlled trials45
found that compared to placebo, long-acting beta-agonists used for at least
four weeks produce statistically significant benefits in lung function,
quality of life, use of ‘reliever’ short-acting bronchodilators and acute
exacerbations. This review compared different drugs and doses independently,
the commonest being salmeterol 50 mcg daily which involved up to 3363
participants.
The review did not find evidence
that higher doses of salmeterol were
more beneficial than 50mcg/day.
Fewer studies of the effect of
eformoterol were included and they
were not combined in a
meta-analysis, but some benefits
similar to those of salmeterol were
seen for a range of outcomes across
a range of doses. Adverse drug
effects were not reported.
The efficacy of long-acting beta-agonists compared to ipratropium
bromide, alone or in combination, have also been combined in a systematic
review.44 Comparisons of
monotherapy found a greater increase in FEV1, weighted mean difference = 60 mls (95% CI 0 to 110), and morning PEF, weighted mean difference = 10.96
l/min (95% CI 5.83 to 16.09) for salmeterol over ipratropium bromide. There
were no significant differences between interventions for quality of life,
functional capacity, symptoms, acute exacerbations or adverse events.
Comparisons of the combination of ipratropium bromide and salmeterol with
ipratropium bromide alone showed varying effects on lung function and
symptoms, but a small, significant reduction in reliever use; weighted mean
difference = -0.67 puffs/day (95% CI -1.11 to -0.23).
Tiotropium is a long-acting anticholinergic agent with duration of action
of over 24 hours and is used once daily. Two systematic reviews of
randomised controlled trials of its clinical effects have been published.46,47 These had differing inclusion criteria,
particularly the duration of treatment, and consequently slightly different
results. Compared to placebo, the reviews found tiotropium produced a
significant increase in FEV1 in the order of 130mls and improved
quality of life, decreasing the mean St George’s Respiratory Questionnaire
by about 3 units. Tiotropium had a beneficial effect on acute exacerbations,
odds ratio of 0.75, and hospitalisation, odds ratio 0.64. These effects came
at the cost of an increased risk of adverse drug effects, particularly dry
mouth which is 4-5 times more likely with tiotropium. Comparisons of
tiotropium with ipratropium bromide or long-acting beta-agonists are limited
by scanty data, producing conflicting results.
In summary, long acting bronchodilators produce significant improvements
in lung function, symptoms and quality of life, as well as decrease
exacerbations. Tiotropium increases the likelihood of developing hoarseness,
while adverse effects associated with long-acting beta-agonists were not
well reported.
Theophyllines
Theophylline has a modest effect
on FEV1 and FVC and
slightly improves arterial blood gas
tensions in moderate to severe COPD.
However, theophyllines are rarely used
because of their narrow therapeutic
index and potential for significant
side effects48,
49
[evidence level I]. Some patients with
disabling breathlessness may derive
benefit from their use.50,
51, 52
Theophyllines may have an
anti-inflammatory effect or reduce
muscle fatigue.53,54Evidence supports only the
slow-release formulation.
Theophylline is effective in COPD
but due to its potential toxicity,
inhaled bronchodilators are
preferred when available.
9
Recent placebo-controlled studies of
members of the phosphodiesterase-4
inhibitor family (cilomilast and
roflumilast) up to six months
duration, suggest these drugs may
decrease time to first exacerbation,
as well as improving lung function
and quality of life. However, more
clinical data are awaited before any
recommendations can be made as to
the role, if any, of these drugs in
the management of COPD.55-57