Triple Therapy in COPD: What We Know and What We Don't

ABSTRACT

Triple inhaled therapy for chronic obstructive pulmonary disease (COPD) consists of an inhaled corticosteroid (ICS), a long-acting β₂-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) taken in combination. Triple therapy is recommended by the Global initiative for Chronic Obstructive Lung Disease (GOLD) for patients who experience recurrent exacerbations despite treatment with either a dual bronchodilator (preferred initial therapy) or LABA/ICS combination (alternative initial therapy). Although there is evidence for the greater efficacy of triple therapy compared with LABA/ICS and LAMA monotherapy with regards to improved lung function, health status, and exacerbation rate, the efficacy of triple therapy when compared with dual bronchodilation (LABA/LAMA) is as yet unknown. As ICS use is associated with an increased risk of developing pneumonia, it is important to assess the risk/benefit ratio of triple therapy on an individual basis, and identify patients most likely to benefit. The role of elevated blood eosinophils as a biomarker for the identification of candidates for ICS treatment is currently debated, and further prospective evidence is required. This review assesses evidence for the efficacy and safety of triple therapy and postulates on the prospective evidence from ongoing studies. The potential for treating patients who experience further exacerbations on dual bronchodilation according to phenotype is also considered, as well as withdrawal of ICS from triple therapy in patients who are unlikely to benefit.

KEYWORDS:

• dual bronchodilation
• exacerbations
• inhaled corticosteroids
• long-acting bronchodilators
• phenotype
• pneumonia

Introduction

Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality worldwide, with its burden increasing due to an ageing population and continued exposure to risk factors (1). Bronchodilators, which are effective and well tolerated in patients with stable disease, are the cornerstone of the pharmacological management of COPD (1).

In the past, inhaled corticosteroids (ICS) in combination with long-acting β₂-agonists (LABA) were recommended for the treatment of patients at high risk of exacerbation, following evidence for their efficacy in preventing COPD exacerbations and hospitalizations, and improving quality of life (2–5). However, effective long-acting muscarinic antagonists (LAMAs) such as tiotropium emerged, demonstrating similar benefits to LABA/ICS regarding exacerbation prevention (6). In addition, evidence began to accumulate suggesting an association between ICS-containing regimens and increased pneumonia risk (7–9). These developments, coupled with the emergence of effective dual bronchodilator therapies (LABA/LAMA), led to revisions in the Global initiative for chronic Obstructive Lung Disease (GOLD) recommendations for the management of patients with COPD (1,10). Patients with COPD commonly receive a LABA/ICS combined with a LAMA (11,12); however, clearer guidance is required regarding when treatment escalation is necessary and in which patients this should be considered.

GOLD currently recommends triple therapy (ICS plus LABA plus LAMA) for high-risk patients with severe symptoms (GOLD Group D) who develop further exacerbations on dual bronchodilation (preferred initial therapy) or LABA/ICS (alternative initial therapy) (1). This recommendation is based on studies that applied former GOLD recommendations for the identification of ‘high-risk’ patients (severe-to-very severe airflow limitation or an exacerbation history) (13). In GOLD 2017, only exacerbation history is taken into account when assessing patients for exacerbation risk and data using the GOLD 2017 classification system are limited. There are recommendations to restrict triple therapy use further, to only patients who are likely to respond to ICS (such as those with asthma-COPD overlap or elevated blood eosinophils) (14,15).

There is a clear need for better evidence upon which to base treatment recommendations. In this review, we discuss published studies that examine the efficacy of triple therapy in COPD management. We also discuss evidence for the withdrawal of ICS from triple therapy, as a tool for identifying appropriate patients for triple therapy treatment. Our intention is to clarify what we know with certainty and highlight those areas where further evidence is needed to inform the management of patients with COPD.

Evidence for triple therapy: efficacy and safety

Several studies have demonstrated the superiority of triple therapy over LABA/ICS and LAMA monotherapy in patients with COPD. We will present these studies in chronological order, and separate them into those published pre-2016 (Table 1) (16–23) and those published from 2016 onwards (Table 2), (24–29) as newer studies utilize more modern and potentially more potent fixed-dose combinations (30–33).

Table 1. Patient disposition/enrollment criteria and key results from initial studies (pre-2016) demonstrating the efficacy of triple therapy combinations of LABA/ICS and LAMA administered using different inhaler devices.

				Inclusion/exclusion criteria
Study name						Number/
and patient	Run-in			Airflow		severity of	Prior
number	treatment	Duration	Comparators	limitation	Symptoms	exacerbations	medication	Key results
OPTIMAL (16) (N = 449)	N/A	52 weeks	SFC 25/250 µg two puffs BID plus TIO 18 µg QD TIO 18 µg QD plus SAL 25 µg two puffs BID TIO 18 µg QD	Post-bronchodilator FEV1 <65% predicted Post-bronchodilator FEV1/FVC <0.7	N/A	≥1 exacerbation requiring treatment with ICS or antibiotics in the previous 12 months	N/A	Primary outcome: No significant difference in the proportion of patients who experienced ≥1 COPD exacerbation (60.0%, 64.8% and 62.8% of patients in SFC + TIO, TIO + SAL and TIO groups, respectively) Secondary outcomes: No significant difference in TDI total score (mean scores 1.84, 1.40 and 1.78 units, respectively), rate of exacerbations (mean exacerbations per patient year 1.37, 1.75 and 1.61, respectively) or time-to-first exacerbation (217, 128 and 130 days, respectively) Triple therapy, compared with TIO, significantly improved pre-bronchodilator FEV1 (increase of 86 mL vs 27 mL;  p = 0.049) and SGRQ total score (change in score –8.6 units vs. –4.5 units; p = 0.01)
Singh et al. (17) (N = 41)	N/A	13 weeks	SFC 50/500 µg BID TIO 18 µg QD SFC 50/500 µg BID plus TIO 18 µg QD In a crossover study	Post-bronchodilator FEV1 30–75% predicted Post-bronchodilator FEV1/FVC 0.7	mMRC dyspnea scale minimum score of ≥2	Patients with COPD exacerbations were excluded	Patients who had used systemic CS within 4 weeks, or antibiotics within 8 weeks prior to randomization were excluded	Primary outcome: Triple therapy significantly improved AUC0–4h sGaw compared with TIO (ratio 1.22; 97.5% CI: 1.10–1.35;  p < 0.001) and SFC (ratio 1.27; 97.5% CI: 1.14–1.42;  p < 0.001) Secondary outcomes: Triple therapy significantly improved trough FEV1 (between-treatment differences: 212 mL; p < 0.001 and 110 mL; p = 0.017, respectively) and significantly reduced rescue medication use (1.0 occasion less; p < 0.001, and 0.6 of an occasion less; p = 0.013, respectively) compared with TIO and SFC
CLIMB (18) (N = 660)	TIO 18 µg QD plus reliever medication (2 weeks)	12 weeks	BUD/FOR 320/9 µg BID plus TIO 18 µg QD TIO 18 µg QD	Pre-bronchodilator FEV1 <50% predicted FEV1/FVC <0.7	N/A	≥1 exacerbation in the previous 12 months requiring treatment with systemic steroids and/or antibiotics Patients eligible for LABA/ICS combination therapy	Patients who had used ICS within 2 weeks or systemic CS within 4 weeks prior to visit 2 were excluded	Primary outcome: Triple therapy significantly improved pre-dose FEV1 compared with TIO (6% increase [65 mL]; p < 0.001) Secondary outcome: Triple therapy significantly improved post-dose FEV1 (11% increase [123 and 131 mL at 5 and 60 min post-dose, respectively]; both  p < 0.001) and reduced exacerbation rate vs TIO (rate ratio, 0.38; 95% CI: 0.25–0.57;  p < 0.001) Triple therapy significantly improved SGRQ total score (mean difference:  –2.3 units; p = 0.023) and symptoms (as measured by GCSQ [mean difference in scores for chest tightness and breathlessness ranging from –0.104 to –0.185 at 5 min and 15 min post-dose; all p < 0.05] and COPD symptoms rating scale [mean difference in scores ranging from –0.142 to –0.161 for breathlessness, chest tightness, nighttime awakenings and cough; all p < 0.001]) vs. TIO
Hoshino and Ohtawa (19) (N = 30)	N/A	12 weeks	SFC 50/250 µg BID plus TIO 18 µg QD TIO 18 µg QD	Post-bronchodilator FEV1/FVC <0.7	N/A	Patients with >1 exacerbation in the 12 weeks prior to the study were excluded	N/A	Primary outcome: Triple therapy significantly decreased airway wall area corrected for body surface area; percentage wall area and absolute wall thickness (p < 0.05;  p < 0.01 and p < 0.01, respectively) and increased luminal area corrected for body surface area (p < 0.01) Secondary outcome: Triple therapy significantly improved SGRQ total score vs. TIO
Hanania et al. (20) (N = 342)	Open-label TIO 18 µg QD (4 weeks)	24 weeks	SFC 50/250 µg BID plus TIO 18 µg QD TIO 18 µg QD	Post-bronchodilator FEV1 40–80% predicted Post-bronchodilator FEV1/FVC <0.7	N/A	<7% of patients suffered from >1 exacerbation in the previous 12 months	N/A	Primary outcome: Triple therapy significantly improved pre-dose FEV1 compared with TIO (LSM difference: 115 mL; p < 0.001) Secondary outcome: Triple therapy significantly improved rescue medication use compared with TIO (LSM difference: −0.6 [SE 0.24]; p  =  0.01) There were no significant differences in health status (LSM differences in CRQ-SAS domain scores ranging from 0.02 to 0.2) or exacerbation rate (0.14 vs. 0.17 for SFC + TIO and TIO, respectively)
Jung et al. (21) (N = 479)	Treatment not specified (2 weeks)	24 weeks	SFC 50/250 µg BID plus TIO 18 µg QD TIO 18 µg QD	Post-bronchodilator FEV1 <65% predicted Post-bronchodilator FEV1/FVC <0.7	N/A	N/A	Patients were excluded if they had used systemic CS or immuno-suppressants ≤ 4 weeks prior to study entry	Primary outcome: Triple therapy significantly improved pre-bronchodilator FEV1 vs. TIO (90 mL vs. 38 mL; p = 0.005) Secondary outcome: Triple therapy significantly improved SGRQ-C scores vs TIO (mean change in score: −6.6 units vs. −1.5 units; p =  0.001)
NHS database study (22) (N = 2,853)	N/A	5 years	ICS plus LABA plus TIO ICS plus LABA	Post-bronchodilator FEV1 < 80% predicted (77) Post-bronchodilator FEV1/FVC <0.70 (77)	Dyspnea, chronic cough or sputum production, and/or a history of exposure to disease risk factors (77)	N/A	N/A	Triple therapy has benefits in reducing all-cause mortality (HR 0.65; 95% CI: 0.57–0.75; p < 0.001) and hospital admissions (HR 0.85; 95% CI: 0.73–0.99; p  =  0.04) compared with LABA/ICS
GLISTEN (23) (N = 773)	SFC 50/500 µg BID (one week)	12 weeks	SFC 50/500 µg BID plus GLY 50 µg QD SFC 50/500 µg BID plus TIO 18 µg QD SFC 50/500 µg BID	Post-bronchodilator FEV1 30– <80% predicted Post-bronchodilator FEV1/FVC <0.7	N/A	Patients were excluded if they experienced a COPD exacerbation within 6 weeks before screening		Primary outcome: GLY + SFC was non-inferior to TIO + SFC in terms of trough FEV1 Secondary outcome: Compared with SFC plus placebo, triple therapy with SFC plus GLY significantly improved trough FEV1 (101 mL increase; p < 0.001), SGRQ total score (LSM treatment difference: −2.15 units; p = 0.02) and rescue medication use (between-group mean difference: −0.72 puffs/day; p < 0.001) No significant differences in SGRQ total score (LSM treatment difference: −1.1 units) or rescue medication use (between-group mean difference: 0.098 puffs/day) were reported between SFC plus GLY and SFC plus TIO groups

 

AUC, area under the curve; BID, twice daily; BUD, budesonide; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CRQ-SAS, Chronic Respiratory Disease Questionnaire-Self-Administered Standardized; CS, corticosteroids; FEV₁, forced expiratory volume in 1 second; FEV₁/FVC, forced expiratory ratio; FOR, formoterol; GCSQ, Global Chest Symptoms Questionnaire; GLY, glycopyrronium; HR, hazard ratio; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LSM, least squares mean; mMRC, modified Medical Research Council dyspnea scale; N/A, not applicable/not reported; NHS, National Health Service; QD, once daily; SAL, salmeterol; SE, standard error; SFC, salmeterol/fluticasone; sGaw, specific airway conductance; SGRQ, St George's Respiratory Questionnaire; SGRQ-C, St George's Respiratory Questionnaire for COPD patients; TDI, Transition Dyspnea Index; TIO, tiotropium

Table 2. Patient disposition/enrollment criteria and key results from modern recent studies (2016 onwards), and studies yet to be published, demonstrating the efficacy of fixed-dose triple therapy combinations.

						Inclusion/exclusion criteria
Study name						Degree of		Number and
and patient			Run-in			airflow		severity of	Prior medication
number			treatment	Duration	Comparators	limitation	Symptoms	exacerbations	use	Key results/primary endpoint
TRILOGY (24) (N = 1,368)			BDP/FOR 100/6 µg two puffs BID (2 weeks)	52 weeks	BDP/FOR/GLY 100/6/12.5 µg two puffs BID BDP/FOR 100/6 µg two puffs BID	Post-bronchodilator FEV1 <50%; Post-bronchodilator FEV1/FVC <0.7	CAT score ≥10 and BDI score ≤ 10	≥1 moderate or severe exacerbation in the previous 12 months	LABA/ICS Or ICS/LAMA Or LAMA monotherapy As open or fixed combinations for ≥2 months prior to screening	Primary outcome: Triple therapy significantly improved pre-dose FEV1 (adjusted mean difference: 81 mL; p < 0.001) and 2-hour post-dose FEV1 (adjusted mean difference: 117 mL; p < 0.001) compared with BDP/FOR Triple therapy did not significantly improve TDI total score compared with BDP/FOR (mean treatment difference: 0.21 units) Secondary outcomes: Triple therapy significantly improved SGRQ total score at Weeks 4, 12 and 52 vs. BDP/FOR (mean treatment difference at Week 52: –1.69 units; p = 0.029) Triple therapy significantly reduced the rate of moderate-to-severe exacerbations vs. BDP/FOR (rate ratio 0.77; 95% CI: 0.65–0.92; p  = 0.005) In patients with >1 exacerbation, triple therapy significantly reduced the rate of moderate-to-severe exacerbation vs. BDP/FOR (rate ratio 0.67; 95% CI: 0.48–0.94; p  =  0.019)
TRINITY (25) (N = 2,691)			TIO 18 µg QD (2 weeks)	52 weeks	BDP/FOR/GLY 100/6/12.5 µg two puffs BID TIO 18 µg QD BDP/FOR 100/6 µg BID plus TIO 18 µg two puffs QD	Post-bronchodilator FEV1 <50% predicted	CAT score ≥10	≥1 moderate or severe exacerbation in the previous 12 months	LABA/ICS Or ICS plus LAMA Or LABA/LAMA Or LAMA monotherapy As open or fixed combinations for ≥2 months prior to screening	Primary outcome: BDP/FOR/GLY significantly reduced the rate of moderate or severe exacerbations compared with TIO (rate ratio 0.80; 95% CI: 0.69–0.92; p  =  0.0025) Secondary outcomes: BDP/FOR/GLY significantly improved pre-dose FEV1 compared with TIO (mean difference 61 mL; p < 0.0001) BDP/FOR/GLY was non-inferior to BDP/FOR plus TIO in terms of lung function (adjusted mean difference –3 mL) BDP/FOR/GLY significantly improved SGRQ total score compared with TIO at all time-points except Week 26 BDP/FOR/GLY and BDP/FOR plus TIO resulted in similar rates of moderate or severe exacerbations (rate ratio 1.01; 95% CI 0.85–1.21) and provided a similar mean change from baseline in SGRQ total score at all time-points except Weeks 26 and 52
FULFIL (26) (N = 1,810)			Medications at screening unchanged (2 weeks)	52 weeks	FF/UMEC/VI 100/62.5/25 µg QD BUD/FOR 400/12 µg BID	Post-bronchodilator FEV1 <50% or 50–80% predicted	CAT score ≥10	2 moderate or 1 severe exacerbation in the previous year	Daily maintenance treatment for COPD for ≥3 months prior to screening	Primary outcome: At Week 24, triple therapy significantly improved trough FEV1 (between- treatment difference: 171 mL; p < 0.001) and SGRQ total score (between-treatment difference:  –2.2 units; p < 0.001) compared with BUD/FOR Secondary outcomes: At Week 52, triple therapy significantly improved trough FEV1 compared with BUD/FOR (between- treatment difference: 179 mL; p < 0.001) No significant difference in SGRQ total score at Week 52 (between-treatment difference:  –2.7 units) Triple significantly reduced the rate of moderate or severe exacerbations (up to 24 weeks and 52 weeks) compared with BUD/FOR (35% reduction in rate; p  = 0.002 and 44% reduction in rate p = 0.006, respectively)
	Studies yet to be completed
IMPACT (27) (N = 10,000^*)			Treatment not specified (2 weeks)	52 weeks	FF/UMEC/VI 100/62.5/25 µg QD UMEC/VI 62.5/25 µg QD FF/VI 100/25 µg QD	Severe COPD Post-bronchodilator FEV1 <50% predicted and a documented history of >1 moderate or severe COPD exacerbation in the previous 12 months (GOLD B) Or post-bronchodilator 50–80% FEV1 predicted and a documented history of >2 moderate exacerbations in the previous 12 months (GOLD D) Or documented history of >1 severe COPD exacerbation in the previous 12 months			Daily maintenance treatment for COPD for ≥3 months prior to screening	Primary outcome: Rate of moderate and severe exacerbations over 52 weeks of treatment Secondary outcomes: Time to first moderate and severe exacerbations Rate of moderate and severe exacerbations in patients with blood eosinophil count ≥150 cells/µL Time to first moderate and severe exacerbation in patients with blood eosinophil count ≥150 cells/µL Change from baseline in trough FEV1 Change from baseline in SGRQ
TRIBUTE (28) (N = 2,192^*)			IND/GLY 85/43 µg QD (2 weeks)	52 weeks	BDP/FOR/GLY 100/6/ 12.5 µg BID IND/GLY 85/43 µg QD	Post-bronchodilator FEV1 <50% predicted Post-bronchodilator FEV1/FVC <0.7	CAT score ≥10	≥1 exacerbation in the previous 12 months	LABA/ICS Or ICS/LAMA Or LABA/LAMA For ≥2 months prior to screening	Primary outcome: Rate of moderate and severe COPD exacerbations over 52 weeks of treatment Secondary outcomes: Time to first moderate or severe exacerbation Rate of severe COPD exacerbations over 52-weeks of treatment Rate of moderate COPD exacerbations over 52-weeks of treatment Change from baseline in trough FEV1
ETHOS (29) (N = 8,000^*)			N/A	52 weeks	BUD/FOR/GLY 320/9.6/ 14.4 µg FOR/GLY 9.6/14.4 µg BUD/FOR 320/9.6 µg (Dosing frequency not specified)	Post-bronchodilator FEV1 <65% predicted Post-bronchodilator FEV1/FVC <0.7	N/A	History of exacerbation	N/A	Primary outcome: Rate of moderate and severe COPD exacerbations over 52 weeks of treatment Secondary outcomes: Time to first moderate or severe exacerbation Change from baseline in rescue medication use Time to death (all cause)

 

^*Estimated enrollment. AB,antibiotics, BDP, beclomethasone dipropionate; BDI, baseline dyspnea index; BID, twice daily; CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; CS, corticosteroids; FEV₁, forced expiratory volume in 1 second; FEV₁/FVC, forced expiratory ratio; FF, fluticasone furoate; FOR, formoterol fumarate; GOLD, Global initiative for chronic Obstructive Lung Disease; GLY, glycopyrronium bromide; IND/GLY, indacaterol/glycopyrronium; N/A, not applicable/not reported; QD, once daily; SFC, salmeterol/fluticasone; SGRQ-C, St George's Respiratory Questionnaire for COPD patients; TIO, tiotropium; UMEC, umeclidinium; VI, vilanterol

Initial data (pre-2016), with triple therapy combinations

All triple therapy regimens discussed within this section consist of combinations of LABA/ICS and LAMA administered using different inhaler devices.

The OPTIMAL study investigated the comparative efficacy of triple therapy with salmeterol/fluticasone propionate combination (SFC) 25/250 µg two puffs twice daily (BID) plus tiotropium 18 µg once daily (QD) versus tiotropium 18 µg QD monotherapy (16). While the study also contained a tiotropium 18 µg QD plus salmeterol 25 µg two puffs BID arm, it was not designed or powered to compare the differences between the triple therapy and tiotropium plus salmeterol groups. There were no significant differences between triple therapy and tiotropium monotherapy with regards to the rate of exacerbations or time-to-first exacerbation (of any severity), or Transition Dyspnea Index (TDI) total score over 52 weeks (Table 1) (16). However, triple therapy significantly improved lung function (increase in forced expiratory volume in 1 second [FEV₁]: 27 mL vs. 86 mL, respectively; p = 0.049) and health status (change in St. George's Respiratory Questionnaire [SGRQ] total score: –4.5 units vs. –8.6 units, respectively; p = 0.01) compared with tiotropium monotherapy (16). An important limitation of this study was the high rate of discontinuation amongst patients receiving tiotropium (43%) or tiotropium plus salmeterol (47%), resulting in the under powering and potential bias of results in the intention-to-treat population (16,34). Furthermore, the mean change in pre-bronchodilator FEV₁ within treatment arms was relatively low compared with other studies.

In the CLIMB (Evaluation of Efficacy and Safety of Symbicort as add-on Treatment to Spiriva in Patients with Severe COPD) study, triple therapy with budesonide/formoterol (BUD/FOR) 320/9 µg BID plus tiotropium 18 µg QD significantly improved lung function (65 mL increase in pre-dose FEV₁, and 123 and 131 mL increase in post-dose FEV₁ at 5 and 60 min, respectively; all p < 0.001) versus tiotropium 18 µg QD monotherapy (18). BUD/FOR plus tiotropium also significantly improved health status (mean difference in SGRQ total score: –2.3 units; p = 0.023) and symptoms (mean differences in Global Chest Symptoms scores: p < 0.05; mean differences in COPD symptoms rating scale scores: p < 0.001) compared with tiotropium monotherapy. Further, BUD/FOR plus tiotropium significantly reduced the rate of moderate and severe exacerbations (defined as worsening of COPD leading to treatment with systemic corticosteroids [oral or parenteral] and/or hospitalization/emergency room visits) (rate ratio 0.38; 95% confidence interval [CI]: 0.25–0.57; p < 0.001) compared with tiotropium monotherapy (18). However, interpretation of the CLIMB study is made more difficult by its relatively short duration (3 months). The study indicates an initial benefit of triple therapy on exacerbations (i.e. the intervention worked), but it does not indicate whether this effect is sustained beyond the brief study period, which may not allow for the achievement of maximal responses to treatment. Furthermore, in studies of this kind, seasonality may influence the observed changes in exacerbation rate, as the incidence of exacerbations is higher in winter compared with other seasons (35). One positive feature of this trial was the absence of differential withdrawal between treatment arms, possibly due to the short study duration. Differential dropout rates between study arms can result in a loss of statistical power to detect differences in exacerbation rates (36).

Some support for these observations came from Hanania et al., who found that treatment with SFC 50/250 µg BID plus tiotropium 18 µg QD significantly improved lung function (least squares mean [LSM] difference in trough FEV₁: 115 mL; p < 0.001) and rescue medication use (LSM difference: −0.6 puffs/day; p = 0.01) compared with tiotropium 18 µg QD monotherapy over 24 weeks in patients with moderate-to-severe COPD. No significant between-group differences were observed in dyspnea, health status or exacerbation rate (Table 1) (20).

In the GLISTEN study, SFC 50/500 µg BID plus glycopyrronium bromide 50 µg QD significantly improved lung function (increase in trough FEV₁: 101 mL; p < 0.001), health status (LSM treatment difference in SGRQ total score −2.15 units; p = 0.02) and rescue medication use (between-group mean difference −0.72 puffs/day; p < 0.001) compared with SFC 50/500 µg BID over 12 weeks in patients with moderate-to-severe COPD. Furthermore, improvements in lung function, health status and rescue medication use observed with SFC plus glycopyrronium versus SFC were similar to those seen with SFC 50/500 µg BID plus tiotropium 18 µg QD versus SFC (Table 1) (23).

Additionally, a retrospective cohort study using a National Health Service database of UK patients with COPD supports the idea that the addition of tiotropium to LABA/ICS may confer benefits in reducing all-cause mortality (hazard ratio [HR] 0.65; 95% CI: 0.57–0.75; p < 0.001) and hospital admissions (HR 0.85; 95% CI: 0.73–0.99; p = 0.04) compared with LABA/ICS (22).

Other pre-2016 studies demonstrating the superiority of triple therapy over LABA/ICS and LAMA monotherapy are summarized in Table 1 (17,19,21). All studies listed within this section compared triple therapy administered via different inhalers (usually LABA/ICS plus LAMA) with LABA/ICS or LAMA monotherapy (the dual bronchodilator arm of the OPTIMAL study gave each inhaler separately). Moreover, data from several of these studies were not collected for long enough or in an appropriate population to provide a conclusive answer about the benefit of triple therapy on exacerbations.

More recent data (2016 onwards) with fixed-dose triple therapy combinations

All triple therapy regimens discussed in this section consist of fixed-dose combinations of ICS, LABA, and LAMA administered using a single inhaler device.

In the TRILOGY trial, triple therapy with beclometasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FOR/GLY) 100/6/12.5 µg two puffs BID significantly improved pre-dose FEV₁ (adjusted mean difference: 81 mL; p < 0.001) and 2-hour post-dose FEV₁ (adjusted mean difference: 117 mL; p < 0.001; two of three co-primary endpoints) compared with BDP/FOR 100/6 µg two puffs BID after 26 weeks; however, there were no significant improvements in TDI total score (third co-primary endpoint) after 26 weeks (Table 1) (24). The incidence of pneumonia was similar between the two treatment groups (23 and 18 cases in the BDP/FOR/GLY and BDP/FOR groups, respectively; 3% for both).

In the TRINITY trial, triple therapy with BDP/FOR/GLY 100/6/12.5 µg two puffs BID significantly reduced the rate of moderate or severe exacerbations (rate ratio 0.80; 95% CI: 0.69–0.92; p = 0.0025) and improved lung function (mean difference in pre-dose FEV₁: 61 mL; p < 0.0001) compared with tiotropium 18 µg QD monotherapy in symptomatic COPD patients over 52 weeks (25). The incidence of pneumonia was similar between the BDP/FOR/GLY group (28 cases; 3%), the tiotropium group (19 cases; 2%) and the BDP/FOR 100/6 µg two puffs BID plus tiotropium 18 µg QD group (12 cases; 2%) (25).

The interpretation of the TRILOGY and TRINITY studies is somewhat limited by the low incidence of exacerbations in the study population: the mean number of reported exacerbations in the previous 12 months was 1.2 and only approximately 20% of patients had ≥2 exacerbations, or ≥1 hospitalization in that time frame (24,25,37). Furthermore, the rate of moderate and severe exacerbations in the studies were low; for instance, in TRINITY, the combined rate of moderate and severe exacerbations per treatment arm were 0.46 (BDP/FOR/GLY), 0.57 (tiotropium), and 0.45 (BDP/FOR plus tiotropium) exacerbations per year (25). As these patients may not be considered as ‘frequent exacerbators’ at high risk of future exacerbations, it is difficult to draw conclusions on the results of this study in a higher risk population.

The FULFIL (lung FUnction and quality of LiFe assessment in COPD with closed trIpLe therapy) study demonstrated that treatment with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg QD significantly improved lung function compared with BUD/FOR 400/12 µg BID at all time-points over the 24-week treatment period in the intention-to-treat population (between-treatment difference in trough FEV₁ at Week 24: 171 mL; p < 0.001) and in the 52-week extension population (between-treatment difference in trough FEV₁ at Week 52: 179 mL; p < 0.001) (26). FF/UMEC/VI significantly improved health status compared with BUD/FOR at Week 24 (between-treatment difference in SGRQ total score: –2.2 units; p < 0.001), but the treatment difference did not reach statistical significance at Week 52 (between-treatment difference in SGRQ total score: –2.7 units; p  =  0.065). A greater proportion of patients in the FF/UMEC/VI group than the BUD/FOR group experienced a clinically meaningful improvement (≥4 unit decrease from baseline) in SGRQ total score at Week 24 (50% vs. 41% of patients, respectively; odds ratio 1.41; p < 0.001). Furthermore, FF/UMEC/VI significantly reduced the annual rate of moderate and severe exacerbations compared with BUD/FOR based on data up to 24 weeks (35% reduction in rate; p = 0.002). After 24 weeks, the incidence of pneumonia was almost three-fold higher in the FF/UMEC/VI group (20 cases; 2.2%) than the BUD/FOR group (7 cases; 0.8%: p-value not provided); in the 52-week extension population, the incidence of pneumonia was 1.9% and 1.8% (both 4 cases) in the FF/UMEC/VI and BUD/FOR groups, respectively (26).

Studies to date have compared triple therapy with LABA/ICS or LAMA monotherapy. Triple therapy led to improvements in lung function, health status, rescue medication use and exacerbation rate compared with LABA/ICS and LAMA monotherapy, with no significant difference observed in the rate of adverse events between treatment groups. Generally, the incidences of pneumonia were low across the discussed studies, with a slightly higher number of pneumonia cases seen with triple therapy (3%) versus LAMA monotherapy (2%) in TRINITY (24–26). However, the more relevant and informative comparison is triple therapy versus LABA/LAMA. Any benefit seen with triple therapy may be driven mainly by dual bronchodilation; the benefit of adding ICS to LABA plus LAMA is as yet unknown (38,39).

Expected data

All triple therapy regimens discussed within this section consist of fixed-dose combinations of ICS, LABA, and LAMA administered using a single inhaler device, and are yet to report results.

The IMPACT (InforMing the PAthway of COPD Treatment) study will evaluate the efficacy of triple therapy with FF/UMEC/VI 100/62.5/25 µg QD compared with UMEC/VI 62.5/25 µg QD and FF/VI 100/25 µg QD in patients with severe-to-very severe COPD. IMPACT has broad inclusion criteria and enrolled approximately 10,000 patients with a post-bronchodilator FEV₁ <50% predicted and a documented history of ≥1 moderate or severe COPD exacerbation in the previous 12 months; patients with a post-bronchodilator FEV₁ 50–80% predicted and a documented history of ≥2 moderate exacerbations in the previous 12 months; or patients with documented history of ≥1 severe COPD exacerbation in the previous 12 months (27,40). The primary outcome of IMPACT is the rate of moderate and severe exacerbations over 52 weeks of treatment. The rate and time to first moderate-or-severe exacerbation will be analyzed in a subset of patients with a blood eosinophil count ≥150 cells/µL. IMPACT is expected to complete in July 2017.

TRIBUTE will evaluate the efficacy of triple therapy with BDP/FOR/GLY 100/6/12.5 µg BID compared with indacaterol/glycopyrronium (IND/GLY) 85/43 µg QD in approximately 1,500 patients with severe-to-very severe COPD and a history of ≥1 exacerbation in the previous 12 months (28). The primary outcome of TRIBUTE is the rate of moderate and severe COPD exacerbations over 52 weeks of treatment. TRIBUTE is expected to complete in July 2017.

ETHOS will evaluate the efficacy of triple therapy with BUD/FOR/GLY 320/9.6/14.4 µg compared with FOR/GLY 9.6/14.4 µg and BUD/FOR 320/9.6 µg in approximately 8,000 patients with moderate-to-very severe COPD (dosing frequency of treatment regimens not currently specified but likely to be twice daily). Recruited patients had a post-bronchodilator FEV₁ <65% predicted and a history of exacerbations (29). The primary outcome of ETHOS is the rate of moderate or severe COPD exacerbations over 52 weeks of treatment. ETHOS is expected to complete in December 2018.

In summary, further evidence is required for the efficacy of triple therapy compared with LABA/LAMA, which will be provided by a number of upcoming studies.

Methodological considerations – run-in treatment

Several of the trials described above incorporated a run-in period prior to randomization to study treatment in the study design, to bridge the gap between discontinuation of usual medication and commencement of study treatment. It has been suggested that run-in treatment can introduce bias in favor of the medication/class used in the run-in period, since patients responding to that treatment are more likely to reach randomization than those who do not respond or who worsen following withdrawal of other treatments (41). Several of the triple therapy trials discussed here had a run-in period of open-label LAMA treatment (Tables 1 and 2), requiring patients using ICS or LABA/ICS before entering the trial to discontinue that treatment. In clinical practice it is recommended that ICS are withdrawn in a controlled manner with adequate bronchodilation in place (as discussed below) and it is possible that ICS withdrawal could have increased risk of exacerbations in previously treated patients during the run-in and study treatment periods. Few trials have included analyses to address this potential bias, although in the CLIMB study, which incorporated a 2-week run-in period of open-label tiotropium, no effect of ICS withdrawal on exacerbation rates in the trial was observed (18). Studies using LABA/ICS (24) or LABA/LAMA (28) in the run-in may provide information on potential clinical benefits of stepping up to triple therapy in a way that more closely reflects likely clinical practice (24).

Stepping down from triple therapy to dual bronchodilation

Despite treatment with triple therapy, patients may still experience frequent exacerbations. GOLD recommends stepping down treatment from triple therapy to dual bronchodilation if no benefit of ICS is seen. However, GOLD does not provide guidance regarding how to withdraw ICS and switch treatments in clinical practice, and acknowledges that there is a lack of data in this area.

There is evidence that ICS may be withdrawn from LABA/ICS in patients at low risk of exacerbation, provided they are in receipt of an effective long-acting bronchodilator (42). The INSTEAD (Indacaterol: Switching Non-exacerbating Patients with Moderate COPD From Salmeterol/Fluticasone to Indacaterol) study investigated the effect of switching from SFC 50/500 µg BID to indacaterol monotherapy 150 µg QD in patients with no exacerbations in the previous year, who were receiving treatment with SFC 50/500 µg BID for ≥3 months prior to screening (42). There were no significant differences in terms of lung function, dyspnea, health status, rescue medication use, or exacerbation risk between switching to indacaterol monotherapy or continuing treatment with SFC.

In patients with more severe COPD, evidence suggests that ICS may be withdrawn from triple therapy provided adequate dual bronchodilator therapy is in place. (WISDOM Withdrawal of inhaled glucoorticoids and exacerbations of COPD) investigated the impact of stepwise ICS withdrawal on the risk of moderate or severe COPD exacerbations compared with ICS continuation in patients with severe-to-very severe COPD and ≥1 exacerbation in the previous year (39). All patients received triple therapy with SFC 50/500 µg BID plus tiotropium 18 µg QD during the 6-week run-in period, following which the fluticasone dose was reduced incrementally in the ICS-withdrawal arm over the subsequent 12 weeks. The risk of moderate or severe exacerbations was similar among patients in whom ICS was withdrawn and those who continued ICS therapy. There was a statistically significant difference in FEV₁ after ICS withdrawal in favor of continued ICS treatment, which began in the first week after complete ICS withdrawal and persisted for a further 2 weeks (39). FEV₁ decline stabilized between Week 18 and study end at Week 52 (39,43). During the stabilization phase, FEV₁ slopes were similar between patients who continued ICS treatment and those who withdrew ICS treatment (43).

Further evidence is required for the outcomes of withdrawing ICS from triple therapy. SUNSET will assess the efficacy and safety of SFC 50/500 µg BID plus tiotropium 18 µg QD versus IND/GLY 110/50 µg QD in COPD patients with moderate-to-severe airflow limitation and ≤1 moderate or severe exacerbation in the previous year who had been treated with triple therapy for ≥6 months prior to the study (44). The primary outcome of SUNSET is the mean change from baseline in post-dose trough FEV₁ following 26 weeks of treatment. SUNSET is expected to complete in August 2017.

Currently, GOLD does not provide any recommendations regarding the method of ICS withdrawal in patients with COPD, and there are no head-to-head studies directly comparing abrupt ICS cessation versus stepwise withdrawal. However, a stepwise withdrawal of ICS, such as that conducted in WISDOM, may minimize the potential risk of rebound steroid effects, which are common following abrupt cessation of chronic systemic corticosteroid therapy (45). However, in INSTEAD, in which ICS was withdrawn immediately in patients at low risk of exacerbation, there were no differences in lung function, symptoms, health status and exacerbations between ICS withdrawal and continuation (42).

In light of the available evidence and GOLD recommendations for stepping down from triple therapy, an algorithm is required for the withdrawal of ICS that considers withdrawal method, optimal bronchodilation following withdrawal, risk factors and patient follow-up. Figure 1 presents a flow-chart for ICS withdrawal proposed by Kaplan et al (46); however, the recommendation that an increase in blood eosinophils during stepwise withdrawal supports the re-introduction of ICS is not supported by data. More recently, the International Primary Care Respiratory Group have proposed an algorithm to identify the minority of patients who might benefit from ICS treatment, and provide guidance on how to withdraw ICS in COPD patients in whom it is not needed (47). In practice, many clinicians are reluctant to stop therapy once instituted, even though the patient is stable, as exacerbations are not easily predicted and the next exacerbation may be attributed to treatment change. Whether or not a culture of stepping treatment up and down in patients with COPD can be instituted, with results that reflect those from the studies available, is an unanswered question.

Figure 1. A proposed algorithm for ICS withdrawal adapted from Kaplan A, et al. (46). ACO, asthma-COPD overlap; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist.

Potential alternatives to triple therapy with LABA/LAMA/ICS

Patients who experience further exacerbations on dual bronchodilation may benefit from additional treatment with a phosphodiesterase-4 (PDE4)-inhibitor or a macrolide instead of ICS; however, few studies have addressed these combinations. GOLD also recommend treatment with mucolytics, such as carbocysteine and N-acetylcysteine, for patients not receiving ICS and who are still experiencing exacerbations, while the European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines for the management of exacerbations provide guidance on the use of oral steroids and antibiotics in ambulatory patients, and on the initiation of pulmonary rehabilitation post-discharge (1,48).

PDE4-inhibitors

When combined with LABA or LAMA, roflumilast significantly improved lung function compared with either agent alone (49). Other studies investigating the use of roflumilast combined with LABA demonstrated significant improvements in lung function and quality of life versus roflumilast monotherapy (50). In spite of this evidence, GOLD currently recommends roflumilast only as an additional treatment in Group D patients with post-bronchodilator FEV₁ <50% predicted and chronic bronchitis who continue to experience exacerbations on triple therapy (1).

REACT (Roflumilast and Exacerbations in patients receiving Appropriate Combination Therapy) investigated the effect of adding roflumilast to triple therapy on exacerbation rate compared with triple therapy alone in patients with severe COPD, chronic bronchitis and a risk of frequent exacerbations, who were receiving LABA/ICS with or without tiotropium for at least 12 months prior to the baseline visit (51). The rate of moderate or severe exacerbations was numerically lower with LABA/ICS plus roflumilast versus LABA/ICS alone following Poisson regression analysis, and was significantly lower following negative binomial regression analysis. Furthermore, LABA/ICS plus roflumilast significantly reduced the rate of severe exacerbations, and exacerbations requiring hospital admission compared with LABA/ICS alone (51). In a post-hoc analysis of RE(2)SPOND (Roflumilast Effect on Exacerbations in Patients on Dual [LABA/ICS] Therapy), roflumilast plus LABA/ICS significantly reduced the rate of moderate or severe exacerbations versus placebo in patients with severe-to-very severe COPD and chronic bronchitis, a history of >3 exacerbations and/or ≥1 hospitalizations in the prior year (52). A further post-hoc analysis of REACT (51) and RE(2)SPOND (52) demonstrated that the rate of moderate or severe exacerbations and severe exacerbations leading to hospitalization and/or death (observed with LABA/ICS ± LAMA plus roflumilast versus LABA/ICS ± LAMA) were considerably reduced in patients with ≥1 COPD-related hospitalization in the previous year versus the overall population (53).

Macrolides

When added to usual care, azithromycin significantly^{Figure 2} delayed the median time to first exacerbation and significantly reduced the frequency of exacerbations compared with usual care alone among patients at risk of exacerbations in a 1-year randomized controlled trial (54). Similar findings were reported in COLUMBUS (COPD: influence of Macrolides on exacerbation frequency in patients): the addition of azithromycin to usual care significantly reduced exacerbation rate and significantly increased the time-to-first exacerbation compared with usual care alone in patients with COPD who had received treatment for ≥3 exacerbations in the previous year despite maximal bronchodilation therapy (55). Similarly, the addition of erythromycin therapy to usual care in patients with moderate-to-severe COPD was associated with a significant reduction in exacerbations over 12 months compared with usual care alone (56).

Further alternatives

The ERS/ATS guidelines advise that the use of antibiotics in patients with exacerbations reduces the risk of treatment failure and prolongs the time to the next exacerbation (48). The guidelines recommend the use of oral corticosteroids in ambulatory patients experiencing a COPD exacerbation, to improve lung function and result in fewer hospitalizations (48). It is also stated that initiation of pulmonary rehabilitation, within 3 weeks of discharge following a COPD exacerbation, reduces hospital admissions and improves patient quality of life (48). GOLD suggests that treatment with mucolytics, such as carbocysteine and N-acetylcysteine, may reduce exacerbations and somewhat improve health status in patients not receiving ICS (1).

Identification of patients who are appropriate for triple therapy

Long-term ICS use is associated with an increased risk of pneumonia and other potential adverse events (7–9,57,58) therefore careful identification of patients who may benefit most from triple therapy is required, with consideration for the risk/benefit balance. Patients at risk of exacerbation differ in terms of phenotype and response to treatment. For example, patterns of biomarkers can be used to identify predefined exacerbation phenotypes (59). INSPIRE demonstrated that patients receiving LABA/ICS suffered less frequently from exacerbations requiring treatment with systemic corticosteroids than patients receiving LAMA monotherapy (6), and this has also been demonstrated versus LABA monotherapy (60).

Local guidelines limit triple therapy to certain populations and phenotypes. For example, the Spanish COPD guidelines (GesEPOC) recommend triple therapy in high-risk patients with asthma-COPD overlap (61). Triple therapy may also be an option for patients with exacerbations and emphysema, or exacerbations and chronic bronchitis (61). Miravitlles and Anzueto propose an algorithm for the management of patients who continue to experience exacerbations despite treatment with a dual bronchodilator, and recommend additional treatment according to phenotype or treatable traits (Figure 2) (14). In the proposed algorithm, patients recommended to receive triple therapy are those with elevated blood eosinophils (14).

Figure 2. A two-step treatment algorithm for the treatment of COPD from Miravitlles and Anzueto. Eur Respir J 2017 (14). Reproduced with permission from the ©ERS 2017. European Respiratory Journal Feb, 2017, 49 (2) 1602200; DOI: 10.1183/13993003.02200–2016, At the Step 2: in patients with >1 exacerbation on LABA/LAMA, comorbidities and compliance to treatment should be assessed in order to determine additional treatment according to individual patient phenotype. COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council dyspnea scale.

Blood eosinophils as a biomarker for ICS use

Post-hoc analyses indicate that patients with elevated blood eosinophils gained a greater benefit from LABA/ICS versus long-acting bronchodilator monotherapy and placebo than patients with lower blood eosinophils (62–64). A post-hoc analysis of two COPD trials (65,66) examined the effect of blood eosinophil levels on exacerbation risk in patients receiving LABA or LABA/ICS (67). The analysis indicated a smaller reduction in exacerbation risk in patients with a high blood eosinophil count who received LABA monotherapy, compared with patients who received LABA/ICS (67). Furthermore, pre-specified subgroup analyses of TRINITY demonstrated that the reductions in the rates of moderate or severe exacerbations with triple therapy versus tiotropium observed in patients with ≥2% blood eosinophils were considerably greater than those observed in the <2% subgroup (25).

A post-hoc analysis of WISDOM demonstrated that in patients with ≥4% and ≥5% blood eosinophils, the rate of moderate or severe exacerbations was higher following ICS withdrawal versus ICS continuation (68). In further post-hoc investigations, WISDOM data were stratified according to blood eosinophil levels in combination with prior exacerbations (69). The analysis found that ICS withdrawal was only associated with an increased exacerbation rate versus ICS continuation in patients with both ≥2 exacerbations in the previous year and elevated blood eosinophils (≥300 cells/µL). Although a significant effect was seen in patients with ≥300 cells/µL blood eosinophils, this was more pronounced in patients with ≥400 cells/µL blood eosinophils (69). However, it should be noted that the numbers of patients with high blood eosinophils decreased as the threshold increased, and that this was a post-hoc analysis of a subgroup, therefore caution is required when interpreting the results.

Additionally, a prospective analysis of FLAME demonstrated that LAMA/LABA was superior to LABA/ICS in the prevention of COPD exacerbations regardless of baseline eosinophil level (70,71). There was a trend between increasing blood eosinophil count and increased response to LABA/ICS treatment (71). However, LABA/ICS was not significantly superior to LABA/LAMA at any cut off (71). The potency of the dual bronchodilator used may have ‘overpowered’ the effect of SFC even in patients with high blood eosinophil counts (72). In addition, a post-hoc analysis of ISOLDE demonstrated that ICS significantly reduced the rate of exacerbations versus placebo in patients with <2% blood eosinophils at baseline compared with patients with ≥2% blood eosinophils at baseline (73).

One potential drawback of blood eosinophils as a biomarker for ICS efficacy is the variability of blood eosinophils over time (25,62,73,74). In their analysis, Pascoe et al. found that 33% of patients with blood eosinophils <2% at screening had blood eosinophils ≥2% at Week 52 (62). Singh et al. also identified an “intermittent” subgroup of patients (49%) with variable eosinophil levels that oscillated above and below 2% (74). Furthermore, Oshagbemi, et al. demonstrated that the stability of blood eosinophils was higher in COPD patients with baseline eosinophil count <340 cells/µL versus those with ≥340 cells/µL (75).

Further prospective research is required to validate the use of blood eosinophils to predict relative ICS efficacy, and if successful, to determine the most appropriate blood eosinophil threshold for ICS use. To date, only the FLAME study has prospectively investigated the role of blood eosinophils in stratifying treatment response. This hypothesis will be explicitly tested as a pre-specified secondary endpoint in IMPACT (27); although, ‘real world’ studies will be needed to determine whether blood eosinophil-directed treatment choices are useful for individual patients.

Based on what we already know, blood eosinophils (in conjunction with exacerbation history) might also help to identify patients in whom ICS withdrawal may lead to an increased exacerbation rate (69).

Reducing exposure to ICS and associated risks

In patients who require ICS, there is a need for further insight into how to reduce the risks associated with long-term ICS use. GOLD suggest that the long-term safety (>3 years) of ICS in patients with COPD is unclear and requires further investigation (1). The seasonality of exacerbations is one potential area for further research; there is a higher incidence of exacerbations in winter compared with other seasons (35). The exact causes of this seasonality are unknown, but are thought to include increased exposure to viral infections and increased host susceptibility, possibly caused by reduced vitamin D levels or increased airway inflammation (76).

Conclusions

The evidence currently available for the efficacy of triple therapy is in comparison with LABA/ICS and LAMA monotherapy. However, the publication of several studies that examine the efficacy and safety of triple therapy versus LABA/LAMA, a more relevant comparison, is imminent. Patients who are in receipt of triple therapy unnecessarily face the risks associated with ICS use, without the benefits, as well as increased treatment costs.

Furthermore, patients may continue to experience exacerbations on triple therapy. In these patients, GOLD recommend additional therapy on top of triple therapy, or withdrawal of the ICS component (1). WISDOM provides evidence for the withdrawal of ICS from triple therapy, without increased risk of exacerbation (39). However, further evidence is required, and further guidance is needed as to how and when ICS should be withdrawn and appropriate follow-up with patients (46,47).

Individualized treatments and patient phenotyping are recognized as important areas for further research; the determination of predictive markers could aid clinical decision making by identifying patients most likely to benefit from ICS treatment (14,61). Blood eosinophils may help to identify patients who would benefit from the addition of ICS to dual bronchodilation, although further evidence from prospective studies is required for this comparison. In patients who require ICS, steps may be taken to reduce long-term exposure to ICS.

In light of the evidence to date, we believe that patients on LABA/LAMA who still experience exacerbations and have elevated blood eosinophils may benefit from triple therapy; however, a clear threshold for elevated blood eosinophils is yet to be defined. Personalized therapy based on patient phenotype may help address unmet needs in COPD and help to optimize patient outcomes; however, we acknowledge that gaps in knowledge remain with regards to triple therapy and its relative efficacy versus dual bronchodilation, answers which will hopefully be provided by ongoing clinical trials.

Declaration of Interest

The authors were assisted in the preparation of the manuscript by Emily Fisher and Hannah Birchby, professional medical writers at CircleScience, an Ashfield Company, part of UDG Healthcare plc (Tytherington, UK). Medical writing support was funded by Novartis Pharma AG (Basel, Switzerland).

Peter M.A. Calverley has received speaker fees from Boehringer Ingelheim, AstraZeneca and Recipharm and consulting fees from Boehringer Ingelheim, GSK, Recipharm and Zambon.

Marc Miravitlles has received speaker fees from Boehringer Ingelheim, AstraZeneca, Chiesi, GlaxoSmithKline, Menarini, Teva, Grifols and Novartis, and consulting fees from Boehringer Ingelheim, GlaxoSmithKline, Gebro Pharma, CLS Behring, Cipla, MediImmune, Mereo Biopharma, Teva, Novartis and Grifols.

Helgo Magnussen has received speaker fees from Boehringer Ingelheim, Astra Zenaca, Menarini and Novartis, and consulting fees from Boehringer Ingelheim, Astra Zeneca, Novartis and GSK.

Jadwiga A. Wedzicha has not received any speaker or consulting fees since January 2015. She has received research grants from GSK, Vifor Pharma, Johnson and Johnson, and Takeda.

Acknowledgments

The authors were assisted in the preparation of the manuscript by Emily Fisher and Hannah Birchby, professional medical writers at CircleScience, an Ashfield Company, part of UDG Healthcare plc (Tytherington, UK).