COPD Exacerbation Costs in the IMPACT Study: A Within-Trial Analysis

May 6, 2020
Michael R. Bogart, PharmD

,
Sari D. Hopson, PhD, MSPH

,
Huai-Che Shih, PhD

,
Richard H. Stanford, PharmD, MS

,
Anna D. Coutinho, PhD, BPharm

Volume 26, Issue 05

Treatment with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) compared with FF/VI or UMEC/VI reduced exacerbation-related costs associated with chronic obstructive pulmonary disease (COPD) in the US healthcare system.

ABSTRACT

Objectives: Exacerbations account for the greatest proportion of costs associated with chronic obstructive pulmonary disease (COPD). Here we aimed to evaluate, from the US payer perspective, the costs associated with moderate and severe COPD exacerbation events for patients treated with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) compared with FF/VI or UMEC/VI.

Study Design: This post hoc, within-trial economic analysis used data derived from the InforMing the PAthway of COPD Treatment (IMPACT) study (NCT02164513).

Methods: Treatment groups within the IMPACT trial received either triple therapy with FF/UMEC/VI (100/62.5/25 mcg) or dual therapy (FF/VI [100/25 mcg] or UMEC/VI [62.5/25 mcg]). The primary end point for this IMPACT post hoc analysis was cost differences between the treatment arms related to 1-year on-treatment combined moderate and severe COPD exacerbation events.

Results: The final study sample for this within-trial analysis consisted of 10,355 patients, 49% of whom experienced an on-treatment moderate or severe exacerbation during the study. The mean 1-year on-treatment cost estimate associated with combined moderate and severe exacerbations was highest with UMEC/VI and lowest with FF/UMEC/VI ($6205 vs $4913, respectively). Mean cost differences were statistically significant for all pairwise comparisons of FF/UMEC/VI with FF/VI or UMEC/VI (−$549 [95% CI, −$565 to −$533] and −$1292 [95% CI, −$1313 to −$1272], respectively; both P <.0001).

Conclusions: Treatment with FF/UMEC/VI compared with FF/VI or UMEC/VI in the US healthcare system resulted in lower exacerbation-related costs for combined moderate/severe exacerbation events, as well as moderate and severe exacerbations separately.

Am J Manag Care. 2020;26(5):e150-e154. https://doi.org/10.37765/ajmc.2020.43157

Takeaway Points

In patients with moderate and severe chronic obstructive pulmonary disease exacerbation events, treatment with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) compared with FF/VI or UMEC/VI resulted in lower exacerbation-related costs for combined moderate/severe exacerbation events, as well as moderate and severe exacerbations separately, in the US healthcare system.

  • This was a within-trial economic analysis of data from the large, prospective IMPACT study.
  • The mean 1-year on-treatment cost estimate associated with combined moderate and severe exacerbations was highest with UMEC/VI and lowest for patients who received FF/UMEC/VI.
  • Mean cost differences were statistically significant for all pairwise comparisons of FF/UMEC/VI with FF/VI or UMEC/VI.

Chronic obstructive pulmonary disease (COPD), a progressive and debilitating respiratory condition, resulted in more than 3 million deaths worldwide in 2012.1 A surveillance summary of COPD conducted in the United States between 1971 and 2000 suggested that approximately 24 million US adults show evidence of impaired lung function.2 The cost of COPD, the third most common cause of death in the United States, was estimated to be approximately $50 billion in 2010, which consisted of $20 billion in indirect costs and $30 billion in direct healthcare costs.3 COPD exacerbations, which are defined as an acute worsening of respiratory symptoms that results in a requirement for additional therapy, account for the greatest proportion of costs associated with COPD.1 Moreover, as the US population ages and continues to be exposed to risk factors for COPD, the incidence of this disease and its associated costs are also projected to increase.4

The InforMing the PAthway of COPD Treatment (IMPACT; NCT02164513) trial was a phase 3, randomized, double-blind, parallel-group, multicenter trial, the protocol and principal findings of which have been previously published.5,6 The primary objective of IMPACT was to evaluate the effects of 52 weeks of once-daily, single-inhaler triple combination therapy versus dual therapy on the rate of moderate or severe exacerbations in patients with symptomatic COPD and a history of exacerbations. In this study of triple therapy containing an inhaled corticosteroid (ICS) together with a long-acting β2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA), treatment consisted of a combination of fluticasone furoate (FF; 100 mcg), umeclidinium (UMEC; 62.5 mcg), and vilanterol (VI; 25 mcg) compared with dual therapy with either FF/VI (100/25 mcg) or UMEC/VI (62.5/25 mcg). The findings of the study revealed a statistically significant reduction in moderate or severe exacerbations in those patients randomized to receive FF/UMEC/VI compared with either FF/VI or UMEC/VI. Moreover, the rate of COPD-related hospitalization among those treated with FF/UMEC/VI was numerically lower compared with those who received FF/VI and statistically significantly lower compared with UMEC/VI.

The aim of this post hoc, within-trial economic analysis using data derived from IMPACT was to evaluate the costs associated with moderate and severe COPD exacerbation events for patients treated with FF/UMEC/VI compared with FF/VI or UMEC/VI from a US healthcare payer perspective.

METHODS

Patients

The patient population for this analysis consisted of the intent-to-treat (ITT) population of patients enrolled in the global, multicenter phase 3 IMPACT study.6 As previously described, eligible patients were men or women 40 years and older with symptomatic COPD, current or former smokers with a smoking history of at least 10 pack-years, who had (1) a postbronchodilator forced expiratory volume in 1 second (FEV1) less than 50% predicted together with a documented history of at least 1 moderate or severe COPD exacerbation in the previous 12 months or (2) a postbroncho&shy;dilator FEV1 at least 50% but less than 80% predicted and a documented history of at least 1 severe (hospitalized) or at least 2 moderate COPD exacerbations in the previous 12 months. Exclusion criteria included a current diagnosis of asthma or a respiratory disorder other than COPD, lung resection in the 12 months prior to screening, the presence of risk factors for pneumonia, a respiratory tract infection that had not resolved 7 or more days prior to screening, a requirement for long-term oxygen therapy, and pulmonary rehabilitation.

Study Design

This was a post hoc retrospective economic analysis conducted from the payer perspective of the US healthcare system using within-trial data derived from the IMPACT randomized controlled clinical trial (ClinicalTrials.gov identifier, NCT02164513; GlaxoSmithKline plc study number CTT116855).6 Patients were expected to contribute 52 weeks’ study time, giving this economic analysis a time horizon of approximately 1 year.

Mean unit costs of COPD events (per-event costs) were applied to patient-level moderate and severe exacerbation events from IMPACT to understand differences in cost of exacerbation events among the 3 study treatment groups. Unit cost estimates were obtained from a retrospective database analysis using the Optum Research Database to provide claims data from July 1, 2015, to June 30, 2017, derived from a population of patients with COPD with a history of at least 1 moderate or severe exacerbation in the previous year who were receiving inhaled maintenance treatment. The Optum Research Database is a large US healthcare claims database containing information for commercial and Medicare Advantage plan enrollees. Direct medical and pharmacy costs relating to COPD exacerbation events only, and not to maintenance treatment, were provided from the US payer perspective. Patients with COPD were identified using International Classification of Diseases, Ninth Revision, Clinical Modification and Tenth Revision, Clinical Modification diagnosis codes.7 Costs related to COPD exacerbations included costs for exacerbations requiring an inpatient hospital stay with a primary discharge diagnosis of COPD; costs for exacerbations requiring outpatient care, urgent care, or an emergency department visit with a primary diagnosis code for COPD; and costs for oral or parenteral corticosteroids occurring within 5 days of a COPD claim. All costs were adjusted to 2017 US dollars using the Consumer Price Index.8 The mean (SD) unit cost was $22,729 ($26,663) for a severe exacerbation and $2107 ($4865) for a moderate exacerbation.

Study End Points

The primary end point for this analysis was the incremental cost differences among the treatment groups within the IMPACT trial (FF/UMEC/VI, FF/VI, or UMEC/VI) related to 1-year on-treatment combined moderate and severe COPD exacerbation events.

Secondary end points included the incremental cost differences among the IMPACT treatment groups related to 1-year on-treatment moderate COPD exacerbation events and the cost differences among the IMPACT treatment groups related to 1-year on-treatment severe COPD exacerbation events. A moderate exacerbation was defined as an exacerbation leading to treatment with antibiotics or systemic glucocorticoids. A severe exacerbation was defined as an exacerbation resulting in hospitalization or death.

Statistical Analyses

A censored cost-analysis approach was used to adjust for those patients without complete on-treatment follow-up data, using the method of Bang and Tsiatis.9 This method uses inverse probability weighting to estimate mean costs and provides expected costs for a cohort that includes patients with incomplete cost data due to censoring (eg, discontinuing treatment prior to the end of the follow-up period).

Descriptive analyses (mean and SD for continuous measures and frequency distributions for categorical variables) were used to characterize the study sample. All analyses were performed using SAS version 9.4 (SAS Institute Inc; Cary, North Carolina).

For the primary study end point, incremental cost differences and the corresponding 95% CIs were computed. The statistical significance of the differences in mean costs was tested using independent t tests among 1000 bootstrap-generated cost means computed for each treatment group. Differences were calculated as mean costs of the FF/UMEC/VI group minus the mean costs for each comparator group (FF/VI or UMEC/VI). To account for multiple testing (2 pairwise comparisons), P values were adjusted using the Hochberg method.10

RESULTS

Patients

The final study sample for this within-trial analysis consisted of the 10,355 patients who constituted the IMPACT trial ITT efficacy population. Patient demographics are shown in Table 1; the distribution of baseline characteristics was similar across all 3 treatment groups. Mean patient age was 65.3 years; patients were predominantly men (66%) and white (78%).

On-Treatment Exacerbations of COPD

On-treatment exacerbations of COPD were assessed using data derived from the IMPACT trial. Overall, 49% of the ITT population experienced an on-treatment moderate or severe exacerbation event during the course of the study (Table 2). The overall rate of on-treatment moderate or severe exacerbations within the ITT population was 1016 exacerbations per 1000 subject-years. The observed rate of exacerbations was highest in the UMEC/VI group (1148 moderate or severe exacerbations per 1000 subject-years; 946 moderate exacerbations per 1000 subject-years; 201 severe exacerbations per 1000 subject-years) and lowest in the FF/UMEC/VI group (923 moderate or severe exacerbations per 1000 subject-years; 772 moderate exacerbations per 1000 subject-years; 151 severe exacerbations per 1000 subject-years).

Primary End Point

The mean 1-year on-treatment cost estimate associated with combined moderate and severe exacerbations was found to be highest for patients who received UMEC/VI and lowest for patients who received FF/UMEC/VI ($6205 vs $4913, respectively) (Figure 1). Mean cost differences were statistically significant for all pairwise comparisons of FF/UMEC/VI with FF/VI or UMEC/VI (−$549 [95% CI, −$565 to −$533] and −$1292 [95% CI, −$1313 to −$1272], respectively; P <.0001).

Secondary End Points

The mean 1-year on-treatment cost estimate associated with moderate COPD exacerbations was demonstrated to be highest for patients who received UMEC/VI and lowest for patients who received FF/UMEC/VI ($1879 vs $1579, respectively) (Figure 2 [A]). The mean cost differences were statistically significant for all pairwise comparisons of FF/UMEC/VI with FF/VI or UMEC/VI (−$207 [95% CI, −$211 to −$204] and −$300 [95% CI, −$305 to −$295], respectively; P <.0001).

The 1-year on-treatment cost estimate associated with severe COPD exacerbations was examined and found to be highest for patients who received UMEC/VI and lowest for patients who received FF/UMEC/VI ($4296 vs $3330, respectively) (Figure 2 [B]). As observed for moderate exacerbations, the mean cost differences for patients with severe COPD exacerbations were statistically significant for all pairwise comparisons of FF/UMEC/VI with FF/VI or UMEC/VI (−$342 [95% CI, −$358 to −$327] and −$965 [95% CI, −$985 to −$945], respectively; P <.0001).

DISCUSSION

This study was a within-trial economic analysis of the IMPACT phase 3 study conducted from the US payer perspective. It demonstrated that 1-year on-treatment COPD exacerbation event costs for patients with symptomatic COPD who had experienced at least 1 exacerbation in the previous 12 months were significantly lower for patients treated with FF/UMEC/VI compared with either FF/VI or UMEC/VI. These findings were observed both for combined and for separately analyzed moderate and severe exacerbation events.

The Global Initiative for Chronic Obstructive Lung Disease has noted that the healthcare costs associated with COPD escalate with increased disease severity.1 Therefore, those patients who have advanced symptomatic disease represent a high-cost subset of the patient population with COPD. For such patients, who remain symptomatic despite the use of established dual treatment regimens consisting of an ICS in combination with a LABA or a LAMA in combination with a LABA, triple therapy with an ICS, a LAMA, and a LABA is the recommended regimen.1

The rate of moderate or severe exacerbations experienced by patients who received FF/UMEC/VI in the IMPACT study was lower than in patients treated with FF/VI or UMEC/VI (0.91 vs 1.07 and 1.21 per year, respectively; both comparisons P <.001; modeled rates).6 Moreover, significantly lower rates of hospitalization due to severe exacerbations of COPD were observed in patients who received FF/UMEC/VI compared with patients who received UMEC/VI (0.13 vs 0.19 per year; rate ratio, 0.66; 95% CI, 0.56-0.78; P <.001; modeled rates).6 These findings suggest that the cost savings observed in this economic analysis were driven by the lower hospitalization rates observed within the IMPACT study itself for patients who were treated with FF/UMEC/VI. This hypothesis aligns with the results from an earlier analysis of healthcare resource utilization conducted using data derived from the Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease With Closed Triple Therapy (FULFIL) study (NCT02345161).11 The within-study analysis of FULFIL concluded that the use of FF/UMEC/VI, rather than the ICS/LABA combination of budesonide and formoterol (BUD/FOR), could offer long-term cost advantages, probably owing to a reduction in the number of healthcare provider visits made by patients receiving FF/UMEC/VI compared with BUD/FOR.12

The use of triple-inhaler therapeutic regimens for patients with symptomatic COPD is not only recommended in treatment guidelines1 but also has clear clinical benefits, as demonstrated in a recent meta-analysis.13 This treatment approach has been demonstrated to reduce the rate of COPD exacerbations experienced by patients.6,11,14,15 Despite higher drug acquisition costs for FF/UMEC/VI compared with either FF/VI or UMEC/VI, the reduced exacerbation rate in patients receiving FF/UMEC/VI has been shown to result in overall cost savings.12

Strengths and Limitations

Strengths of this study include the large randomized patient population and the 52-week follow-up period for outcome assessment. In addition, this economic analysis is based on the findings of the primary end point of a randomized clinical trial (the IMPACT study), which mitigates the effects of confounding that can be observed with economic studies conducted in nonrandomized patient populations. Potential limitations of this study include its focus on costs relating to exacerbation events only, which does not consider any differences in acquisition costs for routine maintenance treatment among the 3 arms of the study; these might, in part, offset the observed differences in costs related to exacerbation events. It should also be noted that the cost per COPD exacerbation was obtained from a large US healthcare claims database and subsequently applied to exacerbation events across all trial participants, regardless of country of residence; data were pooled for the costing analysis, and any geographic differences in costs were not assessed. As in many other randomized clinical trials, the patient population and care received during the study are not necessarily representative of treatment received by the general patient population with COPD nor of the typical care received in each study region or in community practice settings.

CONCLUSIONS

The findings of this study demonstrate that treatment with FF/UMEC/VI resulted in a reduction in exacerbation events (moderate and severe) and associated costs compared with FF/VI or UMEC/VI from the perspective of the US healthcare system. The estimated costs for both moderate and severe exacerbations (when assessed either together or separately) were highest for the UMEC/VI group, followed by the FF/VI group, and lowest for the FF/UMEC/VI group. Lower COPD exacerbation costs associated with treatment with FF/UMEC/VI compared with either FF/VI or UMEC/VI were driven by lower rates of COPD hospitalizations observed in the clinical trial in this specific patient population with COPD.Author Affiliations: US Value Evidence and Outcomes, GlaxoSmithKline plc (MRB, RHS), Research Triangle Park, Durham, NC; Xcenda LLC (SDH, HCS, ADC), Palm Harbor, FL.

Source of Funding: The IMPACT study (CTT116855; ClinicalTrials.gov identifier, NCT02164513) and this post hoc analysis (study 207107) were funded by GlaxoSmithKline plc.

Editorial support (in the form of writing assistance, assembling tables and figures, collating author comments, grammatical editing and referencing) was provided by Sarah Birch, PhD, of Gardiner-Caldwell Communications, Macclesfield, UK, and funded by GlaxoSmithKline plc.

Author Disclosures: Dr Bogart is an employee of and owns stock in GlaxoSmithKline, which owns the products Trelegy, Anoro, and Breo; he attended the American Thoracic Society 2019 conference. Drs Hopson, Shih, and Coutinho are employees of Xcenda, which received funding from GlaxoSmithKline to conduct the study but was not paid for development of this manuscript. Dr Shih owns stock in Amerisource Bergen, the parent company of Xcenda. Dr Stanford is a current paid consultant for, a past employee of, and owns stocks in GlaxoSmithKline.

Authorship Information: Concept and design (MRB, SDH, RDS, ADC); acquisition of data (SDH); analysis and interpretation of data (MRB, HCS, RDS, ADC); drafting of the manuscript (MRB, HCS, RDS); critical revision of the manuscript for important intellectual content (SDH, HCS, RDS, ADC); statistical analysis (MRB, SDH, HCS, ADC); obtaining funding (MRB); administrative, technical, or logistic support (MRB); and supervision (MRB, ADC).

Address Correspondence to: Michael R. Bogart, PharmD, US Value Evidence and Outcomes, GlaxoSmithKline plc, 5 Moore Dr, Research Triangle Park, Durham, NC 27709. Email: michael.r.bogart@gsk.com.REFERENCES

1. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease: 2019 report. Global Initiative for Chronic Obstructive Lung Disease website. goldcopd.org/wp-content/uploads/2018/11/GOLD-2019-v1.7-FINAL-14Nov2018-WMS.pdf. Published 2019. Accessed April 22, 2019.

2. Mannino DM, Homa DM, Akinbami LJ, Ford ES, Redd SC. Chronic obstructive pulmonary disease surveillance—United States, 1971-2000. MMWR Surveill Summ. 2002;51(6):1-16.

3. Guarascio AJ, Ray SM, Finch CK, Self TH. The clinical and economic burden of chronic obstructive pulmonary disease in the USA. Clinicoecon Outcomes Res. 2013;5:235-245. doi: 10.2147/CEOR.S34321.

4. Chronic obstructive pulmonary disease (COPD). World Health Organization website. who.int/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease-(copd). Published December 1, 2017. Accessed April 22, 2019.

5. Pascoe SJ, Lipson DA, Locantore N, et al. A phase III randomised controlled trial of single-dose triple therapy in COPD: the IMPACT protocol. Eur Respir J. 2016;48(2):320-330. doi: 10.1183/13993003.02165-2015.

6. Lipson DA, Barnhart F, Brealey N, et al; IMPACT Investigators. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med. 2018;378(18):1671-1680. doi: 10.1056/NEJMoa1713901.

7. Classification of diseases, functioning, and disability. CDC website. cdc.gov/nchs/icd. Accessed April 22, 2019.

8. Consumer Price Index. U.S. Bureau of Labor Statistics. bls.gov/cpi. Accessed November 4, 2019.

9. Bang H, Tsiatis AA. Estimating medical costs with censored data. Biometrika. 2000;87(2):329-343. doi: 10.1093/biomet/87.2.329.

10. Hochberg Y. A sharper Bonferroni procedure for multiple significance testing. Biometrika. 1988;75(4):800-802. doi: 10.2307/2336325.

11. Lipson DA, Barnacle H, Birk R, et al. FULFIL trial: once-daily triple therapy for patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017;196(4):438-446. doi: 10.1164/rccm.201703-0449OC.

12. Ismaila AS, Birk R, Shah D, et al. Once-daily triple therapy in patients with advanced COPD: healthcare resource utilization data and associated costs from the FULFIL trial. Adv Ther. 2017;34(9):2163-2172. doi: 10.1007/s12325-017-0604-x.

13. Calzetta L, Cazzola M, Matera MG, Rogliani P. Adding a LAMA to ICS/LABA therapy: a meta-analysis of triple therapy in COPD. Chest. 2019;155(4):758-770. doi: 10.1016/j.chest.2018.12.016.

14. Kupczyk M, Kuna P. Beclomethasone dipropionate, formoterol fumarate and glycopyrronium bromide as a combination therapy for chronic obstructive pulmonary disease. Expert Rev Respir Med. 2019;13(1):5-11. doi: 10.1080/17476348.2019.1548937.

15. Singh D, Corradi M, Spinola M, et al. Triple therapy in COPD: new evidence with the extrafine fixed combination of beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide. Int J Chron Obstruct Pulmon Dis. 2017;12:2917-2928. doi: 10.2147/COPD.S146822.