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Evidence Update - The IMPACT trial

Trelegy ▼ Ellipta (fluticasone furoate/umeclidinium/vilanterol 92/55/22 mcg) is indicated as maintenance treatment in adult patients with moderate to severe chronic obstructive pulmonary disease (COPD) who are not adequately treated by a combination of an inhaled corticoteroid (ICS) and a long-acting β2 -agonist (LABA) or a combination of a long-acting β2- agonist (LABA) and a long-acting muscarinic antagonist (LAMA).

Relvar Ellipta (fluticasone furoate/vilanterol 92/22 mcg) is indicated for the symptomatic treatment of adults with COPD with a forced expiratory volume in one second (FEV1) <70% predicted normal (post-bronchodilator) with an exacerbation history despite regular bronchodilator therapy.

Anoro ▼ Ellipta (umeclidinium/vilanterol 55/22 mcg) is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD.

“Inhaled pharmacotherapy for COPD has changed considerably since the last update of the NICE COPD guidelines (2010). As a result of this time lapse, most regional areas have developed their own local COPD guidelines and prescribing practices. During this time, we have seen an increasing trend to base these local guidelines on the international GOLD COPD treatment algorithms, which are updated annually. GOLD and NICE COPD guidelines have both recently been updated, with GOLD released early November and NICE released in early December.

There has been a considerable change to the landscape of inhaled therapy over the past five years, with the advent of LABA/LAMA combination therapy, as well as increasing recognition of the risks of ICS—and potential biomarkers such as blood eosinophil count—that may help direct ICS treatment. This raises the question of who may benefit from triple inhaled therapy (ICS/LABA/LAMA) above dual combination therapy, and when. Decisions to alter treatment are now recommended to be based on symptoms (e.g. breathlessness) or exacerbation prevention, rather than severity of airflow obstruction.

Evidence from the IMPACT trial can be appreciated alongside the new NICE and GOLD algorithms and will help decision making. The primary outcome of IMPACT was exacerbation reduction, rather than changes in FEV1, which helps direct application of its findings to real-world decision making. While NICE did not review the role of triple inhaled therapy, it is recommended as step-up therapy from combination therapy. The IMPACT trial will help inform which patients may, or may not, have increased benefit on triple inhaled therapy.

NICE supports the use of LABA/LAMA therapy in those with symptoms or exacerbations without features of asthma/steroid responsiveness (secure diagnosis of asthma, or atopy, high blood eosinophil count, or lung function variability) and suggests ICS/ LABA therapy in those with features of asthma/steroid responsiveness. IMPACT included pre-defined analysis based on blood eosinophil and showed greater reduction in exacerbations in those with blood eosinophilia, supporting NICE recommendations. However, improvements were seen in the non-eosinophilic group, suggesting that triple inhaled therapy may still have a role in non-eosinophilic disease, although less pronounced.

Overall, the IMPACT trial will aid UK implementation of both national and international guidelines, particularly on for whom triple inhaled therapy may be best prescribed.”

Dr Neil Greening
Associate Professor (Clinical)/Honorary Consultant Physician
Glenfield Hospital, Leicester

FEV1 =forced expiratory volume in 1 second; ICS=inhaled corticosteroid; LABA=long‑acting β2 -agonist; LAMA=long-acting muscarinic antagonist

A comparison of once-daily triple therapy with once-daily dual therapy in the treatment of symptomatic COPD—the IMPACT trial

IMPACT provides clinically important outcomes to inform treatment decisions when a symptomatic, exacerbating population of COPD patients is managed with GOLD recommended treatment options

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

Treatment options

Figure 1. GOLD (2019)

Figure 1

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.

IMPACT trial

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

Trial participants

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

Figure 2 Annual rate of moderate:severe exacerbations of COPD

Figure 2

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

Secondary endpoints

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

Lung function

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

Pneumonia

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

Conclusion

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.

References

  1. British Lung Foundation. Key facts about COPD.www.blf.org.uk/support-for-you/copd/key-facts (accessed 8 May 2018).
  2. Suh E-S, Mandal S, Hart N. Admission prevention in COPD: non-pharmacological management. BMC Medicine 2013; 11: 247.
  3. 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.
  4. 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.
  5. Mapel D, Roberts M. New clinical insights into chronic obstructive pulmonary disease and their implications for pharmacoeconomic analyses. Pharmacoeconomics 2012; 30 (10): 869–885.
  6. 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.
  7. 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.
  8. NICE. Chronic obstructive pulmonary disease in over 16s: diagnosis and management. Clinical Guideline 101. NICE, 2010. Available at: www.nice.org.uk/guidance/cg101
  9. 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).
  10. 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.
  11. 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.

UK/TLY/0040/18e

Date of preparation: January 2019

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This Guidelines supplement has been commissioned by GlaxoSmithKline. The views and opinions in this supplement are not necessarily those of GlaxoSmithKline or of Guidelines, its publisher, advisers, or advertisers. The copyright of Guidelines (including the Guidelines brand, logo, and the design and format of the book) rests with MGP Ltd unless otherwise stated. No part of this publication may be reproduced in any form without the permission of the publisher.