Mortality risk reduction with budesonide/glycopyrrolate/formoterol fumarate versus fluticasone furoate/umeclidinium/vilanterol in COPD: a matching-adjusted indirect comparison based on ETHOS and IMPACT

Figures & data

Figure 1. Network of studies for ETHOS and IMPACT.

BFF, budesonide/formoterol fumarate; BGF, budesonide/glycopyrrolate/formoterol fumarate; FF, fluticasone furoate; GFF, glycopyrrolate/formoterol fumarate; ITC, indirect treatment comparison; MAIC, matching-indirect treatment comparison; UMEC, umeclidinium; VI, vilanterol

Table 1. Summary of primary MAIC and sensitivity analyses.

Analysis category	Analysis technique	Dataset
Unanchored methods
Primary analysis	MAIC analysis (selected baseline covariates^a), Unadjusted analysis (supplementary)	Final retrieved dataset^b, on- and off-treatment^c (ITT)
Sensitivity analysis of dataset	MAIC analysis (selected baseline covariates^a), Unadjusted analysis (supplementary)	Original dataset^d, on- and off-treatment^c (ITT)
Sensitivity analysis of dataset	MAIC analysis (selected baseline covariates^a), Unadjusted analysis (supplementary)	On-treatment^c^,e (final retrieved BGF dataset and original FF/UMEC/VI dataset^d)
Sensitivity analysis of covariates	MAIC analyses: Only significant covariate effects^f Baseline covariates^a + age Baseline covariates^a + CAT score Baseline covariates^a + FEV1 (instead of COPD categories) Baseline covariates^a + severe/moderate exacerbation history (instead of severe exacerbation history) Baseline covariates^a + CV conditions^g	Final retrieved dataset^b, on- and off-treatment^c (ITT)

^a Primary analysis baseline covariates: sex, body mass index, smoker, race (White, Asian, Other), severe exacerbation history in last 12 months, bronchodilator reversibility, and COPD severity (moderate, severe, very severe).

^b Final retrieved datasets included the original datasets plus additional data retrieved for patients missing Week 52 vital status, resulting in data for 99.6% of the ITT populations for each study.

^c A death was defined as “on-treatment” in IMPACT if the date of death occurred ≤7 days after the last treatment day and was considered “off-treatment” if the date of death occurred >7 days after the last treatment day of treatment and up to within 7 days of the projected Week 52 date [24]. In ETHOS, time to all-cause death was a prespecified secondary endpoint and was assessed in the ITT population using the treatment policy estimand, which included all randomized patients who received any amount of study drug and all observed data within 52 weeks of randomization regardless of whether patients remained on randomized treatment [23]. Data from within 52 weeks of randomization was used for the on- and off-treatment analyses.

^d Dataset established at database lock.

^e A 7-day data cut-off from ETHOS for on-treatment sensitivity analysis was used to be consistent with the definition in IMPACT.

^f Significant covariates (as measured by a standardized mean difference >0.1): sex, body mass index, bronchodilator reversibility, and COPD severity category (moderate, severe, very severe).

^g CV condition covariates: angina, myocardial infarction, hypertension, hypercholesterolemia, diabetes mellitus.

BGF, budesonide/glycopyrrolate/formoterol fumarate 320/18/9.6 µg; CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; FEV₁, forced expiratory volume in 1 s; FF/UMEC/VI, fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 μg; ITC, indirect treatment comparison; ITT, intention-to-treat; MAIC, matching-adjusted indirect comparison.

Figure 2. Kaplan–meier curves and hazard ratios for all-cause mortality (MAIC^a,b and unadjusted analyses) for BGF from ETHOS versus FF/UMEC/VI from IMPACT over 52 weeks (ITT population^c).

^aBGF was adjusted according to aggregate FF/UMEC/VI data from IMPACT for sex, body mass index, smoking status, race (Asian, White, Other), severe exacerbation history in the last 12 months, bronchodilator reversibility, and COPD severity (moderate, severe, very severe).

^bIn the MAIC analysis, absolute risk reduction of BGF versus FF/UMEC/VI at week 52 was 0.009 (95% CI [Greenwood SE]: 0.0016, 0.0164), corresponding to a number needed to treat of 112. MAIC weights were scaled to the original sample size when computing the SE so that they are representative of the quantity of data available.

^cBoth analyses used on- and off-treatment data in the final retrieved data, which included 99.6% of data from the ITT populations of both ETHOS and IMPACT.

BGF, budesonide/glycopyrrolate/formoterol fumarate 320/18/9.6 μg; CI, confidence interval; COPD, chronic obstructive pulmonary disease; FF/UMEC/VI, fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 μg; HR, hazard ratio; ITT, intention-to-treat; MAIC, matching-adjusted indirect comparison; SE, standard error.

Figure 3. Hazard ratios for all-cause mortality (MAIC and unadjusted sensitivity analyses) for BGF from ETHOS versus FF/UMEC/VI from IMPACT (ITT population).

^aSignificant covariates (as measured by a standardized mean difference >0.1): sex, body mass index, bronchodilator reversibility, and COPD severity category (moderate, severe, very severe).

^bBGF was adjusted according to aggregate FF/UMEC/VI data from IMPACT for sex, race (Asian, White, Other), body mass index, smoking status, severe exacerbation history in the last 12 months, bronchodilator reversibility, and COPD severity (moderate, severe, very severe).

^cThe final retrieved datasets included the original datasets plus additional data retrieved for patients missing Week 52 vital status, resulting in data for 99.6% of the ITT populations for each study.

^dA death was defined as “on-treatment” in IMPACT if the date of death occurred ≤7 days after the last treatment day and was considered “off-treatment” if the date of death occurred >7 days after the last treatment day and up to within 7 days of the projected Week 52 date²⁴. In ETHOS, time to all-cause death was a prespecified secondary endpoint and was assessed in the ITT population using the treatment policy estimand, which included all randomized patients who received any amount of study drug and all observed data within 52 weeks of randomization regardless of whether patients remained on randomized treatment²³. Data from within 52 weeks of randomization was used for the on- and off-treatment analyses.

^eDataset established at database lock.

^fA 7-day data cut-off from ETHOS for on-treatment sensitivity analysis was used to be consistent with the definition in IMPACT.

BGF, budesonide/glycopyrrolate/formoterol fumarate 320/18/9.6 μg; CAT, COPD Assessment Test; CI, confidence interval; COPD, chronic obstructive pulmonary disease; FEV₁, forced expiratory volume in 1 second; FF/UMEC/VI, fluticasone furoate/umeclidinium/vilanterol 100/62.5/25 μg; HR, hazard ratio; ITT, intention-to-treat; MAIC, matching-adjusted indirect comparison.

Lipson DA, Crim C, Criner GJ, et al. Reduction in all-cause mortality with fluticasone furoate/umeclidinium/vilanterol in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2020;201(12):1508–1516. doi: 10.1164/rccm.201911-2207OC.

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Martinez FJ, Rabe KF, Ferguson GT, et al. Reduced all-cause mortality in the ETHOS trial of budesonide/glycopyrrolate/formoterol for chronic obstructive pulmonary disease. A randomized, double-blind, multicenter, parallel-group study. Am J Respir Crit Care Med. 2021;203(5):553–564. doi: 10.1164/rccm.202006-2618OC.

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Data availability statement

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Data for studies directly listed on Vivli can be requested through Vivli at www.vivli.org. Data for studies not listed on Vivli could be requested through Vivli at https://vivli.org/members/enquiries-about-studies-not-listed-on-the-vivli-platform/. The AstraZeneca Vivli member page is also available, outlining further details: https://vivli.org/ourmember/astrazeneca/.