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Footnotes

• * Denotes patients with suboptimal peak inspiratory flow (sPIF), which is a measure of a patient’s inspiratory effort, or ability to inhale. In this study, suboptimal PIF was defined as ≤60 L/min.^4,6
• ^† Retrospective chart review of 123 patients hospitalised for acute exacerbation of COPD. Disease severity based upon GOLD classification; patients across all ranges of severity were included.⁴ A retrospective analysis of hospitalised patients enrolled in an AECOPD care plan was performed. Data analysed included PIF, age, sex, length of stay, Charlson Comorbidity Index, COPD Assessment Test Score, Modified Medical Research Council Score, percent predicted FEV₁, FVC and inspiratory capacity. A PIF ≤60 L/min was defined as suboptimal (sPIF). Outcome measures included 30- and 90- day COPD and all cause readmissions and days to next COPD and all cause readmission. Of the 123 subjects, 52% had sPIF. PIF was the only variable (p=0.041) that predicted days to COPD readmission in a multivariate model incorporating age, sex, percent predicted FEV₁, Charlson Comorbidity Index and inspiratory flow group.⁴
• ^‡ sPIF has been observed in 19–78% of stable outpatients and 32–52% of inpatients before discharge from the hospital after treatment for COPD exacerbation.³⁵
• ^§ mMRC ≥2. Calculation performed using the percentage of patients in each group (>80%, <80%, >50% and <50%).⁵
• ^¶ In asthma patients – statement drawn from typical scintigraphic images in one patient comparing drug deposition profiles. Mean percentage of the dose deposited in the lungs of 14 asthma patients. For the comparison of RESPIMAT® vs TURBOHALER® with fast inhaled flow rate: p<0.001; BECLOFORTE® pMDI: p<0.001.⁹
• Test drug inhaled:⁹
  • From RESPIMAT® and TURBOHALER®: budesonide
  • From pMDI: beclomethasone dipropionate
• ** Consider if highly symptomatic (e.g. CAT >20).¹
• ^†† The decision to use LAMA/LABA as initial treatment should be guided by the level of symptoms as an advantage of LAMA/LABA over LAMA for exacerbation prevention has not been consistently demonstrated.¹
• ^‡‡ Consider if blood eosinophil count ≥300 cells/μL or in patients with a history of asthma.¹
• ^# ICS-containing therapies are not recommended for the majority of COPD patients as initial treatment, but can be considered if eosinophil count is ≥300 cells/μL.¹
• ^## GOLD 2020 recommends LAMA/LABA as a first line treatment option in symptomatic COPD patients with severe breathlessness regardless of exacerbation risk (consider if highly symptomatic e.g. CAT >20); the decision to use LAMA/LABA as initial treatment should be guided by the level of symptoms as an advantage of LAMA/LABA over LAMA for exacerbation prevention has not been consistently demonstrated.¹ ATS 2020 recommends LAMA/LABA over LAMA or LABA monotherapy in patients with COPD and dyspnoea or exercise intolerance.¹²
• *** Improvement in FEV1 AUC_0-24h²⁹
• ^††† Odds ratio.
• ^‡‡‡ No fixed dose combination of LAMA/LABA/ICS was available during the WISDOM trial. Triple therapy refers to an open combination.³¹
• ^¶¶ In WISDOM, a 12 month, double-blind, parallel-group trial, 2485 patients with severe-to-very-severe COPD and a history of ≥1 documented exacerbation during the past 12 months before screening received triple therapy consisting of once daily tiotropium 18 μg via HandiHaler ®, twice daily salmeterol 50 μg, and the inhaled glucocorticoid, twice daily fluticasone propionate 500 μg, during a 6 week run in period. Patients were then randomly assigned to continued triple therapy or withdrawal of fluticasone propionate in 3 steps over a 12 week period. Stepwise withdrawal of fluticasone propionate over 12 weeks was as follows: 500 μg twice daily at screening, reduced to 250 μg twice daily at time of randomisation, 100 μg twice daily at 6 weeks, and placebo at 12 weeks. The primary endpoint was the time to the first moderate to severe COPD exacerbation.³¹
• ^§§ ENERGITO recruited COPD patients with moderate-to-severe pulmonary impairment who received once-daily tiotropium + olodaterol (5/5 μg and 2.5/5 μg) via Respimat® and twice daily salmeterol + fluticasone propionate (50/500 μg and 50/250 μg) via Accuhaler® for 6 weeks.²⁹ FLAME recruited COPD patients with a history of ≥1 exacerbation during the previous year, randomly assigned to receive, by inhalation, either the LABA indacaterol (110 μg) plus the LAMA glycopyrronium (50 μg) (N=1680) once daily or the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg) twice daily (N=1682).³⁰
• ^### In WISDOM, 2485 patients with a history of exacerbation of COPD received triple therapy of tiotropium (at a dose of 18 μg once daily), salmeterol (50 μg twice daily), and the fluticasone propionate (500 μg twice daily) during a 6 week run in period, before randomisation to triple therapy or withdrawal of fluticasone over a 12 week period.³¹ TRIBUTE compared single inhaler triple therapy (glycopyrronium bromide, formoterol fumarate and beclomethasone dipropionate), twice daily, vs dual LAMA/LABA bronchodilator combination (glycopyrronium plus indacaterol) on the rate of COPD exacerbations over 52 weeks in 1532 COPD patients with severe to very severe airflow limitation and at ≥1 moderate-to-severe exacerbation in the previous year.³² IMPACT compared single inhaler triple therapy (umeclidinium, vilanterol and fluticasone furoate) with its two dual drug inhaler comparators, LABA/ICS (vilanterol and fluticasone furoate) and LAMA/LABA (umeclidinium and vilanterol) over 52 weeks in 10,355 COPD patients with moderate to severe airflow limitation and a recent history of exacerbations.³² Suissa et al. monitored 1977 initiators of LABA LAMA matched with 1977 initiators of LABA ICS from the United Kingdom’s Clinical Practice Research Datalink for the occurrence of moderate or severe exacerbation.³³
• ^‖ ENERGITO recruited COPD patients with moderate-to-severe pulmonary impairment who received once-daily tiotropium + olodaterol (5/5 μg and 2.5/5 μg) via Respimat® and twice daily salmeterol + fluticasone propionate (50/500 μg and 50/250 μg) via Accuhaler® for 6 weeks.²⁹ FLAME recruited COPD patients with a history of ≥1 exacerbation during the previous year, randomly assigned to receive, by inhalation, either the LABA indacaterol (110 μg) plus the LAMA glycopyrronium (50 μg) (N=1680) once daily or the LABA salmeterol (50 μg) plus the inhaled glucocorticoid fluticasone (500 μg) twice daily (N=1682).³⁰
• ^¶¶¶ Administrative healthcare claims and laboratory results data from the HealthCore Integrated Research Database were evaluated for COPD patients initiating treatment wit Tio/Olo versus LABA/ICS during January 2013-March 2019. A Cox proportional hazard regression model was performed as an as treated analysis to assess risk of escalation to triple therapy or adverse outcome. Potential imbalance of confounding factors between cohorts was handled using fine stratification and reweighting of the exposure propensity score (high-dimensional).³⁴
• ^‖‖ GOLD Group B: For patients with severe breathlessness initial therapy with two bronchodilators may be considered.¹

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