Single-inhaler triple therapy in symptomatic COPD patients: FULFIL subgroup analyses

Halpin, David; Birk, Ruby; Brealey, Noushin; Criner, Gerard J.; Hilton, Emma; Lomas, David A.; Zhu, Chang‐Qing; Lipson, David A.

doi:10.1183/23120541.00119-2017

Cited by 18 publications

(9 citation statements)

References 13 publications

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“…In addition, the NNT for 1 year to prevent one additional moderate/severe COPD exacerbation in BGF MDI versus GFF MDI was similar in both subgroups (no prior history: 3; prior history: 2). While other triple therapy studies included patients with differing exacerbation risks (eg 1 versus 2 or more), with the exception of the FULFIL study, 7 , 12 none included patients with no prior exacerbations. 4 , 5 , 8 , 9 The 24-week FULFIL study was conducted in symptomatic patients with moderate-to-very severe COPD and showed that annual moderate/severe exacerbation rates were improved by triple therapy versus ICS/LABA regardless of a history of exacerbations (0/1 moderate exacerbations, ≥2 moderate exacerbations, or ≥1 severe exacerbation).…”

Section: Discussionmentioning

confidence: 99%

“…4,5,8,9 The 24-week FULFIL study was conducted in symptomatic patients with moderate-to-very severe COPD and showed that annual moderate/severe exacerbation rates were improved by triple therapy versus ICS/LABA regardless of a history of exacerbations (0/1 moderate exacerbations, ≥2 moderate exacerbations, or ≥1 severe exacerbation). 12 Approximately one third of patients in the FULFIL study had no documented history of moderate/severe exacerbations in the previous year. 7 ICS-containing regimens are not generally recommended for symptomatic patients who do not report exacerbations.…”

Section: Discussionmentioning

confidence: 99%

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Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Improves Exacerbation Outcomes in Patients with COPD without a Recent Exacerbation History: A Subgroup Analysis of KRONOS

Martínez¹,

Ferguson²,

Bourne³

et al. 2021

COPD

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Purpose In the Phase III, 24-week KRONOS study (NCT02497001), triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) reduced exacerbation rates versus glycopyrrolate/formoterol fumarate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) and no requirement for a history of exacerbations. We report a post hoc analysis investigating whether the benefits observed were driven by patients with ≥1 exacerbation in the 12 months prior to the study. Patients and Methods Patients received BGF MDI 320/18/9.6 µg, GFF MDI 18/9.6 µg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 µg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 µg twice-daily. Post hoc analyses were conducted on exacerbation and lung function results from patients with and without a documented exacerbation in the 12 months prior to the study. Results Overall, 74% (1411/1896) of the modified-intent-to-treat (mITT) population had no moderate/severe exacerbations in the 12 months prior to the study. BGF MDI reduced exacerbation rates versus GFF MDI in the prior (58%; unadjusted p =0.0003) and no prior (48%; unadjusted p =0.0001) exacerbations subgroups. The magnitude of reduction in exacerbation rates was generally similar within subgroups for BGF MDI versus BFF MDI and BUD/FORM DPI. In the prior exacerbations subgroup, risk during treatment for time to first exacerbation was lower with BGF MDI versus GFF MDI ( p =0.0022) and BFF MDI ( p =0.0110); excluding the first 30 days of data yielded similar results. The magnitude of reduction in exacerbation rates for BGF MDI compared with GFF MDI increased with eosinophil count. Conclusion In patients with or without a history of exacerbations in the 12 months prior to the study, BGF MDI reduced exacerbation rates versus GFF MDI, suggesting results observed in the overall population were not driven by the small subgroup with a prior history of exacerbations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Improves Exacerbation Outcomes in Patients with COPD without a Recent Exacerbation History: A Subgroup Analysis of KRONOS

Martínez¹,

Ferguson²,

Bourne³

et al. 2021

COPD

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“…A full-text analysis led to the removal of 90, leaving 15 records (seven abstracts/posters) belonging to six studies for inclusion ( Fig. 1) [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Detailed reasons for exclusion are outlined in Additional file 1: Table S3.…”

Section: Resultsmentioning

confidence: 99%

“…However, the converse was also found in comparisons with LAMA/LABA (TRIBUTE) and LABA/ ICS (IMPACT [21]) where triple therapy demonstrated a higher reduction in the rate of moderate and severe exacerbations in patients who experienced fewer historical exacerbations compared to those with a higher frequency of historical exacerbations. A post-hoc analysis of data from the FULFIL study showed that, compared with LABA/ICS, triple therapy resulted in a significantly higher reduction in moderate and severe exacerbation rates in patients who had experienced ≥1 severe exacerbation, and 0/1 moderate exacerbations; patients who experienced ≥2 moderate exacerbations also experienced a rate reduction but the difference was not statistically significant [20]. There were no data relating to prior exacerbation frequency subgroups in the KRONOS study.…”

Section: Prior Exacerbation Frequency Subgroupmentioning

confidence: 97%

Single-inhaler triple therapy in patients with chronic obstructive pulmonary disease: a systematic review

Langham¹,

Lewis²,

Pooley³

et al. 2019

Respir Res

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Background: Guidelines recommend that treatment with a long-acting β 2 agonist (LABA), a long-acting muscarinic antagonist (LAMA), and inhaled corticosteroids (ICS), i.e. triple therapy, is reserved for a select group of symptomatic patients with chronic obstructive pulmonary disease (COPD) who continue to exacerbate despite treatment with dual therapy (LABA/LAMA). A number of single-inhaler triple therapies are now available and important clinical questions remain over their role in the patient pathway. We compared the efficacy and safety of single-inhaler triple therapy to assess the magnitude of benefit and to identify patients with the best risk-benefit profile for treatment. We also evaluated and compared study designs and population characteristics to assess the strength of the evidence base. Methods: We conducted a systematic search, from inception to December 2018, of randomised controlled trials (RCTs) of single-inhaler triple therapy in patients with COPD. The primary outcome was the annual rate of moderate and severe exacerbations. Results: We identified 523 records, of which 15 reports/abstracts from six RCTs were included. Triple therapy resulted in the reduction of the annual rate of moderate or severe exacerbations in the range of 15-52% compared with LAMA/LABA, 15-35% compared to LABA/ICS and 20% compared to LAMA. The patient-based number needed to treat for the moderate or severe exacerbation outcome ranged between approximately 25-50 (preventing one patient from having an event) and the event-based number needed to treat of around 3-11 (preventing one event). The absolute benefit appeared to be greater in patients with higher eosinophil counts or historical frequency of exacerbations and ex-smokers. In the largest study, there was a significantly higher incidence of pneumonia in the triple therapy arm. There were important differences in study designs and populations impacting the interpretation of the results and indicating there would be significant heterogeneity in cross-trial comparisons. Conclusion: The decision to prescribe triple therapy should consider patient phenotype, magnitude of benefit and increased risk of adverse events. Future research on specific patient phenotype thresholds that can support treatment and funding decisions is now required from well-designed, robust, clinical trials. Trial registration: PROSPERO #CRD42018102125.

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“…Singh et al, 2016 (TRILOGY) 67 Vestbo et al, 2017 (TRINITY) 70 Lipson et al, 2017 (FULFIL) 65 Papi et al, 2018 (TRIBUTE) 71 Halpin et al, 2018 (FULFIL) 86 Patients with eosinophils ≥300 cells/mL and a history of ≥ 1 exacerbation in previous year…”

Section: Ics Withdrawalmentioning

confidence: 99%

Inhaled Corticosteroid Treatment in Chronic Obstructive Pulmonary Disease (COPD): Boon or Bane?

Kaplan

2020

J Am Board Fam Med

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Inhaled corticosteroid (ICS)-based therapy is often used for patients with chronic obstructive pulmonary disease (COPD). However, this approach is under scrutiny because of ICS overuse in patients for whom it is not recommended and because of concerns about adverse events, particularly pneumonia, with long-term ICS use. Evidence suggests ICS may be beneficial in specific patients, namely, those with high blood eosinophil counts (eg, ≥300 cells/mL) or who are at a high risk of exacerbations. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 ABCD assessment tool, these patients belong in group D. For these patients, recommended initial treatment includes ICS in combination with long-acting b 2-agonists (LABAs) when blood eosinophil counts are ≥300 cells/mL or LABA 1 long-acting muscarinic antagonist (LAMA) when patients are highly symptomatic, that is, with greater dyspnea and/or exercise limitation. Follow-up treatments for patients with persistent dyspnea and/or exacerbations may include LABA 1 ICS, LABA 1 LAMA, or LABA 1 LAMA 1 ICS, with use of ICS being guided by blood eosinophil counts. In this review, differences in the inflammatory mechanism underlying COPD and asthma and the role of ICS treatment in COPD are summarized. Furthermore, findings from recent clinical trials where use of ICS-based dual or triple therapy in COPD was compared with LABA 1 LAMA therapy and trials in which ICS withdrawal was evaluated in patients with COPD are reviewed. Finally, a step-by-step guide for ICS withdrawal in patients who are unlikely to benefit from this treatment is proposed. A video of the author discussing the overall takeaway of the review article could be downloaded from the link provided: https://www.youtube.com/watch?v=Uq7Sr5jqPDI.

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Single-inhaler triple therapy in symptomatic COPD patients: FULFIL subgroup analyses

Cited by 18 publications

References 13 publications

Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Improves Exacerbation Outcomes in Patients with COPD without a Recent Exacerbation History: A Subgroup Analysis of KRONOS

Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Improves Exacerbation Outcomes in Patients with COPD without a Recent Exacerbation History: A Subgroup Analysis of KRONOS

Single-inhaler triple therapy in patients with chronic obstructive pulmonary disease: a systematic review

Inhaled Corticosteroid Treatment in Chronic Obstructive Pulmonary Disease (COPD): Boon or Bane?

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