CLINICAL IMPACT RATINGS

THERAPEUTICS GM A
PM

In uncontrolled asthma, adding a LAMA to ICS plus LABA

improved lung function at 6 mo and reduced exacerbations at 1 y
Virchow JC, Kuna P, Paggiaro P, et al. Single inhaler extrafine triple therapy in uncontrolled asthma (TRIMARAN and TRIGGER): two double-blind,
parallel-group, randomised, controlled phase 3 trials. Lancet. 2019;394:1737-49.

Question: In uncontrolled asthma, does adding a long-acting muscarinic
antagonist (LAMA) to an inhaled corticosteroid (ICS) and long-acting b 2-
agonist (LABA) combination improve lung function and reduce exacerbations?
Design: 2 randomized controlled trials (RCTs) (Triple in Asthma With
Uncontrolled Patients on Medium Strength of ICS + LABA [TRIMARAN]; Triple in
Asthma High Strength Versus ICS/LABA HS and Tiotropium [TRIGGER]).
Blinding: Treatment allocation concealed; blinded (patients, investigators,
and center and sponsor staff)*.
Setting: Multiple centers in 16 (TRIMARAN) and 17 (TRIGGER) countries.
Patients: Patients 18 to 75 years of age (TRIMARAN n = 1155, TRIGGER
n = 1437; mean age 53 y; 61% women) who had uncontrolled asthma;
≥ 1 exacerbation in the past year treated with systemic corticosteroids,
hospitalization, or emergency department visit; and ≥ 4 weeks of ICS plus
LABA treatment before enrollment. Key exclusions: previous near-fatal
asthma or ICU admission for asthma, severe exacerbation in the past 4
weeks, or other substantial lung disease.
Interventions: Single-inhaler extrafine triple therapy with a LAMA
(glycopyrronium, 10 mcg, in both trials), an ICS (beclomethasone
dipropionate: TRIMARAN 100 mcg, TRIGGER 200 mcg), and a LABA
(formoterol fumarate, 6 mcg in both trials), 2 inhalations twice daily
(TRIMARAN n = 579, TRIGGER n = 573); or double therapy with an ICS and
LABA (TRIMARAN n = 576, TRIGGER n = 576). Results for a tiotropium-
based group in TRIGGER are not reported here.
Funding: Chiesi Farmaceutici.
*See Glossary.

Results: Single-inhaler triple (LAMA + ICS + LABA) vs double (ICS + LABA) therapy in uncontrolled asthma (intention-to-treat analysis)
Outcomes Trial Adjusted† mean change scores At 26 wk
Bottom line:
Triple therapy Double therapy Adjusted† mean difference (95% CI)
In uncontrolled asthma,
Change in predose FEV1 (mL) TRIMARAN 185 127 57 (15 to 99) single-inhaler extrafine
TRIGGER 229 157 73 (26 to 120) triple therapy with a
LAMA, ICS, and LABA
Adjusted‡ annualized rate per Adjusted‡ rate ratio reduction (CI) NNT (CI)§ improved lung function
patient at 1 y at 1 y at 6 months and
Moderate or severe exacerbation TRIMARAN 1.83 2.16 15% (1 to 27) 16 (9 to 135) reduced exacerbations
at 1 year compared
TRIGGER 1.73 1.96 12% (−3 to 25) 13 (8 to 38) with an ICS and LABA.
ICS = inhaled corticosteroid; LABA = long-acting b 2-agonist; LAMA = long-acting muscarinic antagonist; other abbreviations defined in Glossary. Primary outcomes are
indicated by boldface type.
†Adjusted for visit, treatment x visit interaction, country, baseline value, and baseline x visit interaction.
‡Adjusted for country, number of exacerbations in the past year, and log-time in study.
§NNT and CI based on proportion of patients with an event and calculated from data in article (hazard ratio, CI, and event rate in the double-therapy group).

Commentary: The RCTs reported by Virchow and colleagues show that a
LAMA, when added in a single inhaler to moderate- or high-dose ICS/LABA
(Global Initiative for Asthma [GINA] Step 4 or 5) (1), reduces asthma
exacerbations and improves lung function. By using broad inclusion
criteria, the trials extend the evidence for LAMAs to all patients with
asthma who do not achieve control with ICS/LABAs. In previous trials that
found benefit with the combination of ICS, LABA, and LAMA over the
combination of ICS and LABA, patients had to have persistent
postbronchodilator obstruction (2), raising a question about whether some
had chronic obstructive pulmonary disease (COPD) or asthma–COPD
overlap. Subgroup analyses of patients in TRIMARAN and TRIGGER with or
without a postbronchodilator FEV1–FVC ratio < 0.70 would have been of
interest.
These trials are the first to study a LAMA other than the tiotropium soft-
mist inhaler in asthma. The finding that glycopyrronium performed indistin-
guishably from open-label tiotropium confirms that LAMA benefits in
asthma are a class effect, thereby expanding medication and inhaler device
options for asthma. The trials also provide validation for the efficacy of sin-
gle-inhaler triple therapy in asthma, although it failed to show a benefit
over open-label triple therapy given in 2 inhalers in TRIGGER, suggesting
that the convenience of a single inhaler might be overrated. Double-blind,
real-world effectiveness trials are needed to test this further.
Where GINA step 4 treatment fails in asthma, current recommendations
favor increasing the ICS dose (1). Adding a LAMA would now seem to be
an alternative, but which is more effective is unknown and should be
tested in a future trial. Similarly, we have no direct evidence comparing
the addition of a LAMA vs a biologic after failure of GINA Step 5 treatment.
LAMAs are more convenient to administer than biologics and less
expensive. However, in patients with asthma who are dependent on oral
steroids, LAMAs have not yet been studied as steroid-sparing agents,
whereas biologics have proven steroid-sparing effects and thus may be
preferred in such patients.
Matthew B. Stanbrook, MD, PhD
Toronto Western Hospital, University of Toronto
Toronto, Ontario, Canada
Disclosures: The commentator has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/
authors/icmje/ConflictOfInterestForms.do?msNum=M19-3040.
References
1. Global Initiative for Asthma. Global strategy for asthma management and prevention, 2019.
Available from www.ginasthma.org (accessed 18 Dec 2019).
2. Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard
combination therapy. N Engl J Med. 2012;367:1198-207.

doi:10.7326/ACPJ202003170-028

JC28 Annals of Internal Medicine
Vol. 172 No. 6
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