O1. Inhaled bronchodilators
01.1 Short-acting bronchodilators
O1.1.1 Short-acting beta-agonists
Regular short-acting beta-agonists improve lung function and daily
breathlessness scores. A systematic review of randomised controlled trials49
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.46 Short-acting beta-agonists are now usually prescribed for use as
“rescue” medication, i.e. for relief of breathlessness, rather than for
regular use.
O1.1.2 Short-acting anticholinergics
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.50
Ipratropium bromide improved 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,. 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, Number Needed to Harm (NNH) = 32 (95% CI 20 to 316). There was a lesser
need to add or increase the dose of oral glucocorticoids for participants
receiving ipratropium bromide
with 15 (95% CI 12 – 28) people requiring treatment with ipratropium bromide
to prevent one receiving additional oral glucocorticoids.
Ipratropium bromide is associated
with an increased risk of adverse
cardiovascular effects.51,52
A nested case-control study51
[evidence level III-2] found an
increased risk of cardiovascular
death associated with the
prescription of ipratropium, OR 1.34
(95% CI 1.22 to 1.47). A
meta-analysis of randomised
controlled trials52
found an increased risk for a
combined cardiovascular endpoint of
cardiovascular death, myocardial
infarction and stroke, estimated NNH
for cardiovascular death 40 (95% CI
18 to 185) per year. The consistent
finding across these studies
suggests the cardiovascular adverse
effects are likely to be real
[evidence level I].
O1.1.3 Short-acting bronchodilator combinations
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.50 There was a significant benefit for
the combination in 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 glucocorticoids compared to ipratropium
bromide alone, 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 alone; 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. Combining two
classes of bronchodilator may provide added benefits without compounding
adverse effects.
O1.2 Long-acting bronchodilators
Long-acting bronchodilators produce significant improvements in lung
function, symptoms and quality of life, as well as decreasing exacerbations.
These benefits come at a cost of increased adverse effects, which are
generally of mild to moderate severity.
O1.2.1 Long-acting anticholinergics
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.53,54
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. The number of patients
needed to treat (NNT) with tiotropium for one year were 14 (95% CI 11 to 22)
to prevent one exacerbation and 30 (95% CI 22 to 61) to prevent one
hospitalisation compared to placebo or ipratropium.
The beneficial effects come at a
cost of increased adverse drug
effects. A pooled study of placebo
controlled trials55
found an increased risk of dry mouth
(RR=3.60; 95% CI, 2.56 to 5.05) and
urinary retention (RR=10.93, 95% CI,
1.26 to 94.88), although the latter
occurred infrequently.55
These effects have been confirmed in
a large four-year randomised-controlled
trial56
which found no increase in death
from any cause, RR 0.89 (95% CI 0.79
to 1.02) [evidence level II]. There
was a decreased rate of serious
adverse cardiac events in patients
randomised to tiotropium compared to
placebo.
O1.2.2 Long-acting beta-agonists
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 trials57
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. It would be necessary to treat 24 (95% CI 14 to 98) patients
with salmeterol to prevent one exacerbation.
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.
O1.2.3 Long-acting bronchodilator combinations
The efficacy of long-acting beta-agonists compared to ipratropium
bromide, alone or in combination, have also been combined in a systematic
review.50 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).
O1.3 Assessment of response and continuation of bronchodilator therapy
In some patients a response to bronchodilator therapy may require
treatment for up to two months. Symptomatic and
functional benefits can often be demonstrated in the absence of an increase
in FEV1. Other objective measurements, such as an increase in exercise
capacity (e.g., six-minute walk distance) or an increased inspiratory
reserve capacity, may be useful indicators of physiological improvement.
Subjective measurements, such as quality of life, breathlessness and
functional limitation (e.g., MRC Dyspnoea Scale), can determine the
patient’s perception of benefit.
If there is no improvement:
- check inhaler technique;
- consider psychosocial issues and deconditioning; and
- exclude other causes of exercise impairment (consider specialist
referral or a cardiopulmonary exercise test).
O2. Oral bronchodilators
O2.1 Methylxanthines
Theophylline has a modest effect on FEV1 and FVC58
and slightly improves arterial blood gas tensions in moderate to severe COPD.
However, theophyllines have gone out of favour in many countries because of
their narrow therapeutic index and potential for significant side effects.59,60
Some patients with disabling breathlessness may, however, derive benefit
from their use.61-63
Theophyllines may have an anti-inflammatory effect or reduce muscle fatigue.64,65
Recent studies have suggested lower dose preparations than had previously
been used (achieving plasma levels of 5-10mg/L) may have anti-inflammatory
or immuno-modulatory effects.66,67
A randomised placebo controlled trial in China demonstrated that doses of
100mg twice daily reduced exacerbations compared with placebo.68
Evidence supports only the slow-release formulation. Theophylline is
effective in COPD but due to its potential toxicity (the most common adverse
reactions being gastric irritation, nausea, vomiting, anorexia, epigastric
pain, reactivation of peptic ulcer, gastro-oesophageal reflux, haematemesis,
tachycardia, palpitations, headache, CNS stimulation, reflex
hyperexcitability, insomnia and tremor69),
inhaled bronchodilators are preferred when available.11
Theophylline has an extensive drug interaction profile that may present
potential adverse effects in patients on some multi-medication regimens. The
macrolide antibiotics, particularly erythromycin and quinolone antibiotics
when used concurrently can lead to increased theophylline plasma
concentrations and reduced antibiotic concentrations.
O2.2 Phosphodiesterase type-4 inhibitors
Inhibitors of phosphodiesterase type-4 (PDE-4) act by increasing
intracellular concentrations of cyclic adenosine monophosphate and causing a
range of anti-inflammatory effects. Two drugs, cilomilast and roflumilast,
have been developed, but neither has been approved for use in Australia or
New Zealand at this time. Placebo controlled studies up to six months
duration70,71
have found that PDE-4 inhibitors attenuate decline in lung function and
quality of life, and decrease acute exacerbations when compared to placebo
[evidence level II]. PDE-4 inhibitors significantly increase the FEV1, by an
order of 40 - 100ml, compared to placebo. They improve quality of life,
measured by the SGRQ total score, by 1.6 - 4.1 units compared to placebo,
but the changes did not reach statistical significance in all studies. PDE-4
inhibitors significantly reduced acute exacerbations, whether measured by
the mean number of exacerbations or exacerbation-free survival. Drug related
adverse effects mainly affected the gastrointestinal system; diarrhoea,
abdominal pain, nausea and vomiting, and were approximately twice as common
in subjects taking PDE-4 inhibitors as in those taking placebo. PDE-4
inhibitors are promising candidates for the treatment of chronic obstructive
pulmonary disease. Further research is required to determine their long-term
impact and role when used with other treatments including glucocorticoids
and long-acting bronchodilators.