measures.101 In this study, Tashkin et al randomized
255 patients with moderate to very severe COPD
to receive either combination therapy comprising
formoterol 12 µg twice daily plus tiotropium 18 µg
or tiotropium 18 µg daily for 3 months. At the end
of 3 months, statistically significant improvements in
area under the curve for FEV1 over the first 4 hours
post dose were observed favoring combination
treatment (340 mL versus 170 mL, P < 0.001). Similarly, trough FEV1 measurements were higher in the
group that received combination therapy (180 mL
versus 100 mL, P < 0.01). Furthermore, symptom
scores, health-related quality of life as measured
by SGRQ, and rescue medication use improved
in the combination therapy group compared with
tiotropium alone.101 In a post hoc analysis of this trial,
the benefits in lung function were shown to be independent of gender, ICS use, smoking status, and
severity of COPD.102 Similar benefits in lung function
and clinical endpoints have been reported when
LABAs were administered by mobilization, instead
of handheld devices, in combination with tiotropium
versus either agent alone.103–105
The 2 combination treatments, LABA/ICS and
LAMA/LABA, were recently compared head to
head in a multicenter, randomized, double-blind
study that included 605 patients with moderately
severe COPD.106 After 6 weeks of treatment, patients who received tiotropium 18 µg daily and formoterol 12 twice daily had superior improvements
in area under the curve for FEV1 at 12 hours post
dose compared with patients who received combination therapy with salmeterol 50 µg twice daily
and fluticasone 500 µg twice daily (mean difference, 78 mL; P = 0.0006).
TRIPLE THERAPY (LABA/ICS/LAMA)
Addition of a LABA/ICS combination to existing
LAMA treatment has been termed triple therapy,
“triple therapy.” As discussed, there is complemen-
tarity in the pharmacodynamic profiles of LABA
and LAMA. Furthermore, addition of LAMA to
LABA/ICS combination may improve the paradoxi-
cal increase in airway resistance, which is specu-
lated to be due to β2-receptor down regulation.107
A 2-week, double-blind, double-dummy 3-way
crossover study showed further improvements in
specific conductance and inspiratory capacity in
patients who received salmeterol/fluticasone plus
tiotropium compared with patients who received
either alone.108 The INSPIRE trial compared the
utility of salmeterol/fluticasone versus tiotropium
in prevention of acute exacerbation of COPD in
1323 patients with severe COPD.109 Although no
difference was observed between the interven-
tion groups, the salmeterol/fluticasone cohort had
acute exacerbations that required antibiotics more
frequently (0.97 versus 0.82/yr, P = 0.028) com-
pared with the tiotropium cohort. In contrast, the
patients in the tiotropium cohort had more exacer-
bations requiring oral corticosteroids (0.85 versus
0.69/yr, P = 0.039), implying potential differences
in the biological nature of exacerbations which may
benefit from combining treatment with tiotropium
and salmeterol/fluticasone.
Despite sound theoretical background, there
are currently only a few high-quality studies that
have examined the utility of “triple therapy” in patients with COPD. The Canadian Optimal therapy
of COPD trial (OPTIMAL trial) randomized 449
patients with moderate to severe COPD to receive tiotropium and placebo, tiotropium and salmeterol, or tiotropium and salmeterol/fluticasone
