Chronic Obstructive Pulmonary Disease (COPD) is a progressive life-threatening lung disease that causes breathlessness (initially with exertion) and predisposes affected individuals to exacerbations and serious illness. The Global Burden of Disease Study reports a prevalence of 251 million cases of COPD worldwide in 2016. Globally, it is estimated that 3.17 million deaths were caused by the disease in 2015, which accounted to 5% of all deaths globally in that year.1 In the United States almost 15.7 million Americans (6.4%) reported that they have been diagnosed with COPD, while more than 50% of adults with low pulmonary function were not aware that they had COPD, so the actual number may be higher.2
Once a patient has been diagnosed with COPD, the primary therapeutic goals are to reduce risk and symptoms. Risk reduction includes slowing the progression of the disease, preventing and minimizing exacerbations and managing exacerbations when they do occur, ultimately reducing mortality from COPD.3 Other components of disease management include providing relief from COPD symptoms, enhancing the patient’s activity and exercise tolerance, and optimizing their overall health status.3,4 Although treatment guidelines are available, practitioners still need practical information that translates guidelines and other evidence to better diagnose and manage this disease state. This paper endeavors to help primary care clinicians consider evidence, devices, adherence, and cost in differentiating available single-inhaler triple therapies for COPD.
Pharmacologic Treatment of COPD
Pharmacologic treatment selection is based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) group (A, B, C, or D), with the drug classes consisting of short-acting beta-2 agonists (SABA) (e.g., albuterol), long-acting beta-2 agonists (LABAs [e.g., salmeterol and formoterol]), short-acting muscarinic antagonists (SAMA)/anticholinergics (e.g., ipratropium), long-acting muscarinic antagonists/anticholinergics (LAMAs [e.g., tiotropium and umeclidinium]), inhaled corticosteroids (ICS) (e.g., fluticasone and budesonide), N-acetylcysteine, phosphodiesterase-4 inhibitors (e.g., roflumilast), maintenance oral antibiotics (azithromycin), and oral corticosteroids.5,6 (Figure 1)
Treatment escalation should be considered when response is not optimal and should be based on the prevalent trait: dyspnea or exacerbation. In instances when patients present with both exacerbations and dyspnea, exacerbation should be addressed first. (Figure 2) As COPD progresses, patients may require more than one inhaled medication.
Several combination inhalers available in the US include two drugs, and there are currently two approved single-inhaler triple therapy products available in the US, budesonide/glycopyrrolate/formoterol (marketed as Breztri™) and fluticasone/umeclidnium/vilanterol (marketed as Trelegy™). (Table 1)
Key Studies Evaluating Single-Inhaler Triple Therapy
As more data has become available, the GOLD guidelines have increased the included information on use of triple therapy in patients with COPD. Earlier trials included triple therapy administered via multiple inhalers, but more recent publications addressed use of single-inhaler triple therapy. Key publications have been summarized to facilitate primary care providers’ review of available evidence around the safety and efficacy of single-inhaler triple therapy. (Table 2)
This publication collated data from two identical, 12-week, randomized, double-blind, placebo-controlled studies evaluating the efficacy and safety of two doses of umeclidinium added to fluticasone furoate/vilanterol. Triple therapy resulted in significant improvements in lung function than dual therapy, as measured by forced expiratory volume in one second on Day 85 (range: 0.111–0.128 L, all p < 0.001). Additionally, patients using triple therapy used fewer doses of rescue inhaler than dual therapy. Adverse events were similar across treatment groups. Although the included trials were relatively short at 12 weeks, these data provided some initial evidence that single-inhaler triple therapy conferred therapeutic benefit in individuals with COPD.7
The FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) trial was a randomized, double-blind study comparing once-daily triple therapy with twice-daily inhaled corticosteroid/long-acting beta agonist therapy. Patients with advanced, symptomatic COPD who are at risk of exacerbations were randomized to daily fluticasone/umeclidinium/vilanterol (fluticasone triple therapy) or twice-daily budesonide/formoterol for 24 weeks. Triple therapy or corresponding placebo was delivered via the Ellipta® inhaler and dual therapy or corresponding placebo was delivered via the Turbuhaler™ device. A subgroup of patients remained on blinded treatment and was followed for 52 weeks to evaluate enduring benefits as well as longer-term safety of triple therapy. Results of the trial showed that once-daily fluticasone triple therapy offered significant improvements in lung function of 171 mL and health-related quality of life scores on the St. George’s Respiratory Questionnaire compared with budesonide/formoterol at week 24. Reported adverse events were similar between groups at both time points. The FULFIL study confirmed that including LAMA therapy in COPD regimens provides additional benefit beyond ICS/LABA therapy.8
KRONOS was a randomized, double-blind, parallel- group, phase 3 randomized controlled trial which evaluated triple therapy budesonide/glycopyrrolate/formoterol (budesonide triple therapy) versus dual therapies of glycopyrrolate/formoterol or budesonide/formoterol. Approximately 1900 patients were randomized to budesonide triple therapy, glycopyrrolate/formoterol, budesonide/formoterol, or open-label budesonide/formoterol. Results of the trial demonstrated that triple therapy improved FEV1 AUC0-4 versus both doses of budesonide/formoterol, with improvements of approximately 90 – 100 mL. Reported overall adverse events were similar across groups, range 56-61%, and rates of confirmed pneumonia were 1–2%. Over 80% of study participants were symptomatic patients with moderate to very severe COPD who were not at high risk of exacerbations, a population that may be better representative of many clinical practice settings. The results of this study suggest that a broad patient population could realize improvements in lung function from triple fixed-dose combination therapy.9
The Informing the Pathway of COPD Treatment (IMPACT) was a phase 3, randomized, double-blind, parallel-group, multicenter trial comparing the effects of fluticasone triple therapy once-daily to fluticasone/vilanterol and umeclidinium/vilanterol. Over 10,000 patients were randomized to fluticasone triple therapy, fluticasone/vilanterol, or umeclidinium/vilanterol. Results of this study demonstrated that triple therapy with fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate/vilanterol or umeclidinium/vilanterol, with rate reductions of 15% and 25% respectively. Triple therapy also resulted in a 34% lower rate of hospitalization due to COPD than umeclidinium–vilanterol. All-cause mortality, although not a primary outcome, was lower with triple therapy than with umeclidinium/vilanterol. All groups treated with fluticasone had a higher incidence of pneumonia than the umeclidinium/vilanterol group; other adverse events were comparable between groups. Similar to the KRONOS and ETHOS trials, the IMPACT trial demonstrated that triple therapy improves outcomes in COPD patients.10
This study performed a post-hoc analysis of data from the IMPACT trial, following up to confirm the reported impact on all-cause mortality and also evaluating the impact of stepping down from triple therapy to dual therapy. The authors noted that some data were not included in all-cause mortality improvements reported in the IMPACT trial; this study included additional vital status information. Triple therapy was associated with a reduction in all-cause mortality versus dual therapy with umeclidinium/vilanterol, hazard ratio 0.72 (95% confidence interval, 0.53–0.99; p = 0.042). Authors were able to assess therapy step down due to the randomization scheme of IMPACT, where 40% of the patients who entered the trial on triple therapy were switched to dual therapy with fluticasone/vilanterol and 20% were changed to umeclidinium/vilanterol. Although statistical significance was not reached, the group maintained on triple therapy had a lower incidence of all-cause mortality than either group stepped down to dual therapy. This study confirmed the impact of triple therapy on all-cause mortality initially seen in the IMPACT trial and also suggests a benefit of continuing on triple therapy once it is started.11
The Efficacy and Safety of Triple Therapy in Obstructive Lung Disease (ETHOS) trial was a phase 3, randomized, double-blind, parallel-group trial evaluating the efficacy and safety of triple therapy at two doses of inhaled glucocorticoid in patients with moderate-to-very-severe COPD and at least one exacerbation in the past year. Just over 8,500 patients were randomized to twice daily doses of budesonide triple therapy (at either the 160-mcg or 320-mcg glucocorticoid dose), glycopyrrolate/formoterol, or budesonide/formoterol. Results of the trial demonstrated that twice-daily budesonide triple therapy (at either the 160-mcg or 320-mcg dose) resulted in a significantly lower rate of moderate or severe COPD exacerbations than glycopyrrolate/formoterol or budesonide/formoterol, with rate reductions of 24% and 13% respectively. As a notable secondary outcome, both doses of triple therapy reduced the risk death from any cause compared to either dual therapy although statistical significance was only reached for triple therapy versus glycopyrrolate/formoterol. No significant difference was noted in all reported adverse events between treatment groups (range, 61.7 to 64.5%). Confirmed pneumonia was documented more often in the inhaled glucocorticoid groups (range, 3.5 to 4.5%) than in the glycopyrrolate/formoterol group (2.3%).12 Although this trial was not powered to determine a difference between the triple-dose regimens, a favorable trend was noted in reducing severe exacerbations with the 320 mcg budesonide dose. The ETHOS trial expands on data from the KRONOS trial to show the benefits of triple therapy in reducing exacerbation risk in patients with COPD.13
Current guidelines include single-inhaler triple therapy as a therapeutic option for patients with COPD who continue to experience symptoms and suffer exacerbations despite use of LABA/LAMA or LABA/ICS. Although there are no published head-to-head trials, reported evidence supports that single-inhaler triple therapy results in a lower rate of moderate or severe COPD exacerbations. Single-inhaler triple therapy also resulted in a lower rate of hospitalization due to COPD than dual therapy. Available evidence summarizes use of these agents in patients up to 52 weeks, suggesting that benefits of use continue long term. Additionally, the safety profile of single-inhaler triple therapy is predictable, with reported adverse events resembling those expected with dual therapies.
The trials summarized previously were in many ways more representative of general clinical practice. Patients who are frequently excluded from COPD trials, such as individuals with common co-morbidities or history of asthma, were included in these study populations.8,10,12 Another notable practice allowed in these trials was the continuation of standard-of-care maintenance therapies through the run-in phase; this both simulated medication changes that occur in clinical practice as well as minimized the ICS-withdrawal effect for many patients.8–10,12
Additional evidence demonstrates that triple therapy via multiple devices is effective in improving lung function and reducing the risk of exacerbation in patients with COPD, however this likely means using three different inhalers resulting in the need to wait between inhaled doses and hindering adherence.14 Single-inhaler triple therapies provide an opportunity to improve treatment adherence that often may be negatively impacted because of complexity introduced by multiple inhaler(s).
As noted above, budesonide/glycopyrrolate/formoterol (Breztri™) and fluticasone/umeclidnium/vilanterol (Trelegy™) are the only single-inhaler triple therapy products on the US market. Budesonide triple therapy is available via a proprietary metered dose inhaler (MDI) device called the Aerosphere™. The device allows delivery of a homogenous suspension of all the medications and does not depend on a particular shaking technique. However, as a MDI, the Aerosphere™ requires sufficient breath-inhaler technique.14 Since this is a MDI, patients could use the device with a spacer to minimize dosing errors due to poor technique. The device has a dose indicator that includes number of doses in increments of 20 and an indicator that moves after 10 puffs have been used.15,16
Fluticasone triple therapy is available via proprietary dry powder inhaler (DPI) device called the Ellipta™. The device contains 30 individually sealed doses of medication that are available when the inhaler is activated. Activation includes fully opening the cover until a click is heard, at which time the mouthpiece should be placed in the mouth for medication administration. The device also has a numerical dose counter.17 The device does not depend on breath-inhaler coordination, but a sufficient inspiratory flow rate is necessary to deliver the medication to the small airways.18 No clinical trial data has demonstrated superiority for either MDIs or DPIs. Some factors that providers might consider in selecting a triple therapy inhaler are the differences between MDIs vs DPI. Patients who cannot generate an adequate inspiratory flow rate are likely to respond better to an MDI than a DPI. Conversely, patients who struggle with breath-inhaler coordination may respond better to a DPI than a MDI. This challenge can be eliminated with use of a spacer; however, some patients may be reluctant to use spacers because of their bulk or because of the additional steps in device usage. Other factors include prior device experience since patients who have become comfortable using a particular device might want to continue with that technique. Other adherence considerations include dosing frequency; fluticasone triple therapy is taken once daily, and budesonide triple therapy is taken twice daily. Some data suggest that patients are more successfully adherent to once daily versus twice daily dosing.19
In general, these medications tend to be well tolerated; fluticasone triple therapy is formulated with lactose and is contraindicated in patients with a severe milk protein allergy.16 Reported adverse effects include respiratory complaints such as lower and upper respiratory tract infections, cough, and rhinitis; gastrointestinal effects such as diarrhea and oral candidiasis, and headache. These effects generally occur in less than ten percent of patients.15,16
Drug interactions of note include concomitant administration of potent CYP3A4 inhibitors, such as ritonavir, itraconazole, or erythromycin, due to a potential increased exposure to the inhaled corticosteroid constituents. Other relevant drug interactions include concomitant administration of drugs that might potentiate or antagonize the intended effects of the triple therapy inhalers, such as anticholinergic agents, beta antagonists, xanthine derivatives, or diuretics.5,15,16
Patients with COPD classified as GOLD groups B, C, and D are commonly treated with multiple inhaled medications, specifically combinations of LABA and LAMA. ICS are often added to LAMA or LABA when patients continue to experience exacerbations or when serum eosinophil count exceeds 100 cells/μ. Patients in GOLD group D may benefit from triple therapy with LABA/LAMA/ICS if exacerbations continue despite use of two inhaled medications.5
Compelling data supports the use of triple therapy in these, demonstrating improvements in breathing, reductions in exacerbations and hospitalizations, and decreases in all-cause mortality. Additionally, the studies confirm that the safety profiles of single inhaler triple therapies are predictable based on safety profiles of known inhaled COPD therapies. An individualized patient approach should be taken to maximize benefit and limit potential undesired effects. Primary care providers should consider factors such as patients’ prior experience with similar devices, need for a spacer, dosing frequency, and formulary coverage when initiating single-inhaler triple therapy in patients with COPD.
Funding statement: This article was not funded.