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A comparison of once-daily triple therapy with once-daily dual therapy in the treatment of symptomatic COPD—the IMPACT trial
Approximately 3 million people in the UK have chronic obstructive pulmonary disease (COPD), with only one-third having a formal diagnosis.1 The mortality rate is high, with around 30,000 people dying each year in the UK as a result of COPD.1 One out of eight hospital admissions is due to an exacerbation of COPD, resulting in ill health and a poor quality of life for patients, as well as a large cost to the NHS.2 The economic burden associated with COPD rises as the frequency of exacerbations and the level of dyspnoea increases.3 The best predictor of future exacerbations, regardless of disease severity, is a history of exacerbations.4
One of the management aims of COPD (as per GOLD 2019) is reducing the severity and frequency of exacerbations, which is key to improving patient quality of life and to reducing mortality, as well as minimising associated healthcare costs.5–7
Classification of COPD
Chronic obstructive pulmonary disease is classified according to the severity of airway limitation, as measured using the forced expiratory volume in 1 second (FEV1) after a bronchodilator is given:8,9
- mild (stage 1): FEV1≥80% of the predicted value
- moderate (stage 2): FEV1 = 50–79% of the predicted value
- severe (stage 3): FEV1 = 30–49% of the predicted value
- very severe (stage 4): FEV1 < 30% of the predicted value.
Guidance from GOLD classifies COPD into four groups (A, B, C, and D) based on assessment of the patient’s symptoms or dyspnoea, and their history of moderate and severe exacerbations.9
Pharmacological treatment can reduce symptoms and the risk of future exacerbations.9 The GOLD strategy recommends that treatment is individualised to the patient and guided by the severity of symptoms, risk of exacerbations, side-effects, co-morbidities, drug availability, and cost, while taking into account the patient’s response to treatment, preference, and ability to use different drug delivery systems.9
Recently updated, GOLD 2019 suggests that highly symptomatic patients who are at risk of exacerbations (GOLD Group D) can start on a long-acting muscarinic antagonist (LAMA), a LAMA and long-acting beta2 -agonist (LABA), or an inhaled corticosteroid (ICS) and LABA, depending on their symptom burden or eosinophil score.9 Blood eosinophil levels are increasingly understood to be a biomarker for ICS sensitivity and effectiveness in reducing exacerbation rates.10 Treatment can then be escalated depending on whether the patient is predominantly dyspnoeic or exacerbating. Both the exacerbating and dyspnoeic patient can be eligible for triple therapy (LAMA/LABA/ICS) if they continue to exacerbate despite dual therapy.9
While GOLD gives suggestions for treatment strategies for patients in GOLD Groups C and D (see Figure 1),9 more evidence is needed to fully support these recommendations.
The InforMing the PAthway of COPD Treatment (IMPACT) trial published in April 2018 compared the use of a once-daily single-inhaler triple therapy with a once-daily single-inhaler dual therapy in patients with symptomatic COPD and a history of exacerbations in the previous year.11
IMPACT was a randomised 52-week trial involving 10,355 patients across three treatment groups:11
- a once-daily triple therapy containing an ICS (fluticasone furoate), a LAMA (umeclidinium) and a LABA (vilanterol) (FF/U/V; n=4151)
- or a once-daily dual therapy containing an ICS and a LABA (FF/V; n=4134)
- or a once-daily dual therapy containing a LAMA and a LABA (U/V; n=2070).
The primary aim of the trial was to compare the rate of moderate/severe exacerbations over the course of the trial in patients receiving triple therapy (FF/U/V) with those receiving FF/V and with those receiving U/V.11
For consistency of administration, all therapies were given in the same type of inhaler, with each drug given in the same dose.11
Participants were aged ≥40 years and had GOLD Group D COPD, with a COPD Assessment Test (CAT) score ≥10 and either an FEV1 <50% predicted value and at least one moderate or severe exacerbation in the previous year or an FEV1 of 50–80% of predicted value and at least two moderate exacerbations or one severe exacerbation in the previous year.11
Patients in the three treatment groups had similar demographic characteristics, lung function, numbers of COPD exacerbations, and CAT scores at baseline. The mean age of participants was 65.3 years and two-thirds were men. Baseline blood eosinophil level was recorded and 43% of patients had a level <150 cells/microlitre.11
Before the trial began, 38% of patients were taking ICS/LABA/LAMA, 29% were using an ICS and a LABA, and 8% were using a LAMA and a LABA. Patients continued on their own therapy for 2 weeks before being randomised to one of the three treatment groups.11
A total of 9087 patients completed the trial (88%) and 77% of patients (n=7991) completed the trial taking the therapy assigned to them. A smaller percentage of patients in the FF/U/V group (18%, n=758) discontinued treatment prematurely compared with patients in either the FF/V group (25%, n=1040) or in the U/V group (27%, n=566).11
Primary endpoint: moderate/severe exacerbations
The primary outcome measure of moderate/severe exacerbation rate was found to be significantly lower among patients who were receiving FF/U/V at 0.91 per year, compared with 1.07 per year among those in the FF/V group (rate ratio with FF/U/V, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; p<0.001), and 1.21 per year among those in the U/V group (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; p<0.001) (see Figure 2).11
Exacerbations resulting in hospitalisation
The annual rate of severe exacerbations that resulted in hospitalisation was found to be significantly lower among patients in the FF/U/V group at 0.13 per year, compared with those in the U/V group at a rate of 0.19 per year (rate ratio with FF/U/V, 0.66; 95% CI, 0.56 to 0.78; 34% difference; p<0.001).11
However, the rate was not significantly lower with FF/U/V compared with FF/V, which showed a rate of 0.15 per year (rate ratio with FF/U/V, 0.87; 95% CI, 0.76 to 1.01; 13% difference; p=0.06).11
Time to exacerbation
Time-to-first-event analysis showed a lower risk of having moderate/severe exacerbations for people taking FF/U/V compared with those on FF/V (hazard ratio, 0.85; 95% CI, 0.80 to 0.91; 15% difference; p<0.001), and with those on U/V (hazard ratio, 0.84; 95% CI, 0.78 to 0.91; 16% difference; p<0.001).11
Blood eosinophil level
Patients in the triple therapy group had a lower annual rate of moderate/severe exacerbations than those in either dual therapy group, regardless of their blood eosinophil level. However, a greater reduction was observed in the annual rate of moderate/severe exacerbations in patients with a blood eosinophil level ≥150 cells/microlitre.11
A significant improvement was found in the difference in mean change from baseline in trough FEV1 between FF/U/V and FF/V at 97 ml (95% CI, 85 to 109; p<0.001) and between FF/U/V and U/V at 54 ml (95% CI, 39 to 69; p<0.001).11
Health-related quality of life (HRQoL)
HRQoL was measured using a COPD‑specific version of the St George’s Respiratory Questionnaire (SGRQ). Significant differences were found between those in the FF/U/V group and those in the FF/V and U/V groups in both the mean change from baseline in the SGRQ total score and in the percentage of patients with ≥4 point decrease in SGRQ total score (p<0.001).11
As might be expected, patients in the U/V group had a lower incidence of pneumonia than patients in both the FF/U/V group and the FF/V group10 because ICS use has been shown to increase the risk of pneumonia in patients with COPD.9
The risk of pneumonia in the FF/U/V group was significantly higher than in the U/V group (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; p<0.001).11
The results of the IMPACT trial show that a once-daily combination of fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of:11
- moderate or severe COPD exacerbations and better lung function and health-related quality of life than dual therapy with fluticasone furoate/vilanterol or umeclidinium/vilanterol
- hospitalisation due to COPD than umeclidinium/vilanterol.
- British Lung Foundation. Key facts about COPD. www.blf.org.uk/support-for-you/copd/key-facts (accessed 8 May 2018).
- Suh E-S, Mandal S, Hart N. Admission prevention in COPD: non-pharmacological management. BMC Medicine 2013; 11: 247.
- Punekar YS, Shukla A, Müllerova H. COPD management costs according to the frequency of COPD exacerbations in UK primary care. Int J Chron Obstruct Pulmon Dis 2014; 9: 65–73.
- Hurst J, Vestbo J, Anzueto A et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010; 363 (12): 1128–1138.
- Mapel D, Roberts M. New clinical insights into chronic obstructive pulmonary disease and their implications for pharmacoeconomic analyses. Pharmacoeconomics 2012; 30 (10): 869–885.
- Suissa S, Dell’Aniello S, Ernst P. Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality. Thorax 2012; 67: 957–963.
- Pasquale M, Sun S, Song F et al. Impact of exacerbations on health care cost and resource utilization in chronic obstructive pulmonary disease patients with chronic bronchitis from a predominantly Medicare population. Int J Chron Obstruct Pulmon Dis 2012; 7: 757–764.
- NICE. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. Clinical Guideline 101. NICE, 2010. Available at: www.nice.org.uk/guidance/cg101
- GOLD. Global Strategy for the Diagnosis, Management, and Prevention of chronic obstructive pulmonary disease: 2019 report. Available at: http://goldcopd.org (accessed 9 November 2018).
- Bafadhel M, Peterson S, De Blas MA et al. Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Lancet Respir Med 2018; 6: 117–126.
- Lipson D, Barnhart F, Brealey N et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med 2018; 378: 1671–1680.
Date of preparation: January 2019
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