- Email: [email protected]
Salmeterol: A real-life effectiveness and cost impact evaluation
Accepted Manuscript Initiating or changing to a fixed-dose combination of Fluticasone propionate/ Formoterol over Fluticasone propionate/Salmeterol: A real-life effectiveness and cost impact evaluation Simon Wan Yau Ming, John Haughney, Iain Small, Stephanie Wolfe, John Hamill, Kevin Gruffydd-Jones, Cathal Daly, Joan B. Soriano, Elizabeth Gardener, Derek Skinner, Martina Stagno d'Alcontres, David B. Price PII:
S0954-6111(17)30183-X
DOI:
10.1016/j.rmed.2017.06.016
Reference:
YRMED 5192
To appear in:
Respiratory Medicine
Received Date: 4 May 2017 Revised Date:
21 June 2017
Accepted Date: 22 June 2017
Please cite this article as: Yau Ming SW, Haughney J, Small I, Wolfe S, Hamill J, Gruffydd-Jones K, Daly C, Soriano JB, Gardener E, Skinner D, Stagno d'Alcontres M, Price DB, Initiating or changing to a fixed-dose combination of Fluticasone propionate/Formoterol over Fluticasone propionate/Salmeterol: A real-life effectiveness and cost impact evaluation, Respiratory Medicine (2017), doi: 10.1016/ j.rmed.2017.06.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Initiating or changing to a fixed-dose combination of Fluticasone propionate/Formoterol
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over Fluticasone propionate/Salmeterol: a real-life effectiveness and cost impact evaluation
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Simon Wan Yau Ming1
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John Haughney2
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Iain Small3
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Stephanie Wolfe4
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John Hamill5
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Kevin Gruffydd-Jones6
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Cathal Daly7
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Joan B Soriano8
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Elizabeth Gardener1
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Derek Skinner9
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Martina Stagno d'Alcontres1
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David B Price1,2
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Observational and Pragmatic Research Institute, Singapore ; 2Academic Primary Care,
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University of Aberdeen, Aberdeen, UK; 3Peterhead Health Centre, Aberdeen, UK; 4Primary
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Research Ltd, Norwich, UK; 5McMullans Pharmacy, Belfast, UK; 6University of Bath, Bath, UK;
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Elmham Surgery, Norfolk, UK; 8Instituto de Investigación Hospital Universitario de la Princesa
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(IISP) Universidad Autónoma de Madrid, Madrid, Spain; 9Optimum Patient Care, Cambridge,
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UK;
25 *Corresponding author: Prof David B Price, Academic Primary Care, Division of Applied
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Health Sciences, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen, UK AB25
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2ZD; Tel +65 6802 9724; Email [email protected]
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Keywords [5-7 not in title]: asthma, cost-effectiveness, fixed-dose combination inhalers,
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Formoterol, GINA, real-life
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Abstract [289 words]
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Objective: Asthma has a substantial impact on quality of life and health care resources. The
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identification of a more cost-effective, yet equally efficacious, treatment could positively
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influence the economic burden of this disease. Fluticasone propionate/Formoterol (FP/FOR) may
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be as effective as Fluticasone Salmeterol (FP/SAL). We evaluated non-inferiority of asthma
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control in terms of the proportion of patients free from exacerbations, and conducted a cost
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impact analysis.
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Methods: This historical, matched cohort database study evaluated two treatment groups in the
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Optimum Patient Care Research Database in the UK: 1) an FP/FOR cohort of patients initiating
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treatment with FP/FOR or changing from FP/SAL to FP/FOR and; 2) an FP/SAL cohort
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comprising patients initiating, or remaining on FP/SAL pMDI combination therapy. The main
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outcome evaluated non-inferiority of effectiveness (defined as prevention of severe
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exacerbations, lower limit of the 95% confidence interval (CI) of the mean difference between
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groups in patient proportions with no exacerbations is -3.5% or higher) in patients treated with
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FP/FOR versus FP/SAL.
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Results: After matching 1:3, we studied a total of 2,472 patients: 618 in the FP/FOR cohort (174
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patients initiated on FP/FOR and 444 patients changed to FP/FOR) and 1,854 in the FP/SAL
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cohort (522 patients initiated FP/SAL and 1332 continued FP/SAL). The percentage of patients
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prescribed FP/FOR met non-inferiority as the adjusted mean difference in proportion of no
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severe exacerbations (95%CI) was 0.008 (-0.032, 0.047) between the two cohorts. No other
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significant differences were observed except acute respiratory event rates, which were lower for
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patients prescribed FP/FOR (rate ratio [RR] 0.82, 95% CI 0.71, 0.94).
56 Conclusions: Changing to, or initiating FP/FOR combination therapy, is associated with a non-
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inferior proportion of patients who are severe exacerbation-free at a lower average annual cost
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compared with continuing or initiating treatment with FP/SAL.
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Introduction
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Asthma is a heterogeneous disease characterised by chronic airway inflammation. The global
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prevalence of this disease has increased by 9.5%, from 334 million affected in 2005 to 358
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million people in 2015 [1, 2]. Asthma has a substantial impact on quality of life and health care
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resources, and its associated burden is high. Treatments aimed at optimal disease control and
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prevention of acute exacerbations are well established in national and international guidelines
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[3]. However, international patient surveys have found that asthma is often uncontrolled,
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underlining the need for optimisation of asthma management [4, 5].
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Inhaled corticosteroids (ICS) have become a mainstay of asthma therapies [6, 7] with a short-acting β2-agonist (SABA) often prescribed for quick symptom relief. However, many
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patients being treated with ICS and SABA do not have fully controlled symptoms [3]. The
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addition of a long-acting β2-agonist (LABA) to increase asthma control as an alternative to
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upward titration of ICS doses is well established [8].
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The co-prescription of ICS with a separate LABA has become an integral part of asthma treatment guidelines [3, 9]. The development and prescription of a fixed-dose combination
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(FDC) ICS/LABA has been shown to improve patient compliance, consequently reducing the
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risk of ICS therapy discontinuation, as well as reducing the health care costs associated with
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separate drug inhalers, and importantly, reducing respiratory-related deaths and life-threatening
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episodes [6, 7, 9-12]. Many different FDC ICS/LABA combination therapies are now available.
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An FDC ICS/LABA composed of Fluticasone propionate (FP) and Formoterol fumarate (FOR)
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has been developed for asthma treatment. FP/FOR combines the anti-inflammatory and
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bronchodilating properties of two effective compounds in a single inhaler. It has been suggested
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that the bronchodilator effects of Formoterol reduce the need for rescue medication and result in
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an increased number of episode-free days compared with patients receiving an alternate LABA,
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Salmeterol [13-15]. Its quick onset of action has a positive impact on patient adherence [16].
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Other FDC therapies, such as FP and Salmeterol (FP/SAL), have also been found to be highly
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effective at maintaining early and sustained improvements in asthma control [17, 18]. There is
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evidence that the safety profile is similar for either Formoterol or Salmeterol combined with
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Fluticasone propionate (i.e. FP/FOR and FP/SAL)[19].
All the above-mentioned factors are recognised by the Global Initiative for Asthma
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(GINA) as being as vital to clinical outcomes as the inhaled drug itself [3]. Asthma care in the
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United Kingdom (UK) costs the National Health Service (NHS) over GBP 1 billion per year
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[20]. The prescription of a more cost-effective, yet equally efficacious, treatment has the
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potential to positively influence the economic burden of asthma care. Within the UK, Seretide®,
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a formulation of FP/SAL, has the greatest volume of prescribed units to treat patients with
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asthma [21]. A recent alternative, Flutiform®, a formulation of FP/FOR, was launched in the UK
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in September 2012 and currently accounts for only 4.6% of overall ICS/LABA units prescribed
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for patients with asthma compared with the 51.8% prescribed Seretide® [21]. Our previous
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studies found that 88.4% of patients that were switched from FP/SAL to FP/FOR remained on
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the new therapy, suggesting a high retention rate for FP/FOR [22]. We also established that
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FP/FOR provides an effective treatment option for patients with asthma [23].
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The objective of this study was to determine non-inferiority of asthma control in patients
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prescribed FP/FOR versus those prescribed FP/SAL, and to conduct a cost impact analysis of
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FP/FOR compared with FP/SAL. Asthma control is defined as the proportion of patients who are
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free from severe exacerbations during the study period.
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106 Methods
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Study design
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This was a historical, matched cohort study comparing patients with asthma prescribed FP/FOR
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(the active comparator) with those prescribed FP/SAL (the reference group). To represent real-
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life treatment pathways, we initially identified patients according to two treatment paths: an
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initiation path comprising those initiating their first FDC ICS/LABA as either FP/FOR or
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FP/SAL on the index date, and a change path, comprising individuals already on FP/SAL who
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either received a repeat prescription for FP/SAL, or changed to FP/FOR on the index date. Thus,
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the final FP/FOR cohort consisted of patients initiating FP/FOR combination therapy and
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changing from FP/SAL to FP/FOR, while the final FP/SAL cohort consisted of patients
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remaining on, or initiating FP/SAL combination therapy. The index date was defined as the date
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when patients received their first prescription of ICS as either FP/FOR or FP/SAL or changed to
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FP/FOR.
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European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP
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number ENCEPP/SDPP/12631) and followed the ENCePP code of conduct.
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Data Source
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The study utilised data from the Optimum Patient Care Research Database (OPCRD) [24]. The
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database has been approved by the Trent Multicentre Research Ethics Committee for clinical
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research use and, as of January 2017, contains anonymous, longitudinal data for over 3 million
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patients from over 580 general practices in the UK. The data includes information on diagnoses,
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prescriptions, investigations, hospital referrals, and admissions. Prescription costs were taken
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from the National Health Service (NHS) Dictionary of Medicines and Devices website [25],
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which contains up-to-date prescription costs. Resource use costs were adapted from the Personal
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Social Services Research Unit (PSSRU) 2015 document [26].
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Patient Population
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Patients eligible for the study were aged between 12 and 80 years, had a coded diagnosis
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compatible with asthma, and at least 2 years of continuous practice data comprising 1 baseline
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year and 1 outcome year. Patients were excluded from the analysis if their records contained
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diagnostic codes for a chronic respiratory illness other than asthma. Patients with more severe
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exacerbations who were prescribed maintenance oral steroids were excluded. In addition,
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patients from practices in the FP/FOR cohort where fewer than 5 patients changed therapy were
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excluded, as the change would more likely be precipitated by poor asthma control rather than
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wholesale change for cost reasons. Inclusion and exclusion criteria are specified in online
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supplementary material (Table S1).
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Study Outcomes
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The primary outcome included patients with asthma experiencing no severe exacerbations in the
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outcome period and compared the proportion of those who were prescribed FP/FOR with those
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prescribed FP/SAL (non-inferiority analysis with a priori limit for the difference in proportions
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set at 3.5%).
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Secondary outcomes were assessed using previously described composite measures [27-
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30]. Briefly, these included a comparison of: the rate of exacerbations; the proportion of patients
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with frequent exacerbations (defined as ≥2 per year); risk domain asthma control (defined by the
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absence of lower respiratory-related hospital attendance or admission, emergency department
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(ED) attendance, primary care physician consultation for lower respiratory tract infections, or
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acute oral steroids); the acute respiratory event rate (defined as the prescription of antibiotics or
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oral steroids in a lower respiratory primary care consultation or hospital or ED attendance with a
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lower respiratory code); overall asthma control (defined by the presence of risk domain asthma
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control and >200µg/day SABA use); SABA use; treatment stability; and the number of lower
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respiratory-related hospitalisations.
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incidence of oral thrush in treatment groups.
Cost impact outcomes included health care resource use, prescriptions for respiratoryrelated conditions, and combined costs. The total respiratory-related drug costs included
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prescriptions for ICS, LABA, long-acting muscarinic antagonists (LAMA), leukotriene receptor
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antagonists (LTRA), short-acting muscarinic antagonists (SAMA), FDC ICS/LABA,
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theophylline, antibiotic and oral steroids linked with a lower respiratory consultation. Lower
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respiratory-related health care resources consisted of combined and disaggregated primary care
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physician consultations, nurse asthma reviews, ED attendance, and hospital admissions with a
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lower respiratory-related diagnostic code.
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Sample Size
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A sample size calculation was set a priori to determine our primary objective of evaluating non-
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inferiority of FP/FOR compared with FP/SAL in preventing exacerbations, assessed in this study
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by comparing the proportion of patients who were free of severe asthma exacerbations during a
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one-year follow-up. The term exacerbation is used based on the American Thoracic
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Society/European Respiratory Society (ATS/ERS) Joint Taskforce definition: an asthma-related
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hospital admission, emergency department attendance, or an acute course of oral corticosteroids
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[31]. Preliminary data from a historical, matched database study showed that the difference in
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proportions of patients with no severe exacerbations was 4.5% [32]. For the purposes of this
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study, a more stringent non-inferiority limit of 3.5% was chosen for the upper limit of the 95%
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confidence interval (CI) for the mean difference in primary outcomes. With a minimum of 511
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patients with asthma treated with FP/FOR and 2,044 treated with FP/SAL, this study provided
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90% power to reject the null hypothesis that FP/FOR and FP/SAL are non-inferior in terms of
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the proportion of patients with no exacerbations.
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185 Statistical analysis
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Statistical analysis was carried out using SPSS Statistics version 22 (IBM SPSS Statistics,
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Feltham, Middlesex, UK), and SAS version 9.3 (SAS Institute, Marlow, Buckinghamshire, UK).
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Demographic and clinical characteristics, comorbidities, and previous asthma
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exacerbations with p<0.05 were considered as potential confounders during modelling. In the
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event of significant differences within the cohorts for certain variables, an assessment was made
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for clinical relevance by a panel of medical experts and the relevant variable was considered for
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matching criteria.
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The final matching criteria were cohort path type (initiation or change), age, gender,
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number of asthma exacerbations, SABA daily dose (0-150 µg, 151-300 µg, 301-450 µg, 451-600
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µg, >600 µg), ICS daily dose (0-250µg, 251-500 µg, >500µg), smoking status, and rhinitis
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diagnosis. Exact matching for categorical variables and coarsened exact matching for numeric
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variables were used to match patients using a ratio of 1:3 nearest neighbour matching between
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treatment arms without replacement. We used a ratio of 1:3 to improve the power of the study
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with minimal loss of patients in the intervention arm. Conditional logistic regression was used for the primary, non-inferiority analysis of the
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proportion of patients experiencing no severe asthma exacerbations, and for the secondary
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outcomes of the proportion of patients with frequent asthma exacerbations (defined as ≥2 per
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year), risk domain asthma control, overall asthma control and treatment stability. Conditional
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Poisson regression was used to compare rate ratios of severe asthma exacerbations, clinical
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asthma exacerbations and hospitalisations between cohorts. Conditional ordinal regression was
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used for SABA use. Minimal adjustment for residual confounding was made in each of the fitted
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models. Adjustment for residual confounding was based on non-collinear predictors of outcomes
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determined from multivariable analyses on the unmatched sample and the balance of cohorts
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after matching, together with clinical input. A p-value lower than 0.05 was considered to be
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statistically significant.
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Results
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We identified a total of 671 eligible patients in the FP/FOR group (203 initiated FP/FOR
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combination therapy; 468 changed from FP/SAL to FP/FOR) and 67,054 in the FP/SAL group
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(25,719 initiated FP/SAL combination therapy; 41,335 remained on FP/SAL) that met the
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inclusion criteria (Figures S1 and S2).
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Matching resulted in 2,472 unique patients: 618 in the FP/FOR cohort who were matched
1:3 with 1,854 in the FP/SAL cohort (Table S2). The mean age (SD) was 50 years (18) and 62% were female for both matched groups. The percent predicted peak flow reading was 76% for both FP/FOR and FP/SAL. Each final
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cohort was composed of 55% non-smokers, 21% current smokers and 24% ex-smokers. Active
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rhinitis, defined by the use of rhinitis drugs and a physician diagnosis, was 18% in both cohorts
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(Table 1).
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At baseline, a higher percentage of patients in the FP/FOR cohort were found to have
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better asthma control compared with the FP/SAL group, 57% vs. 53%, p=0.005 (Table 1).
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Age, mean (SD)* Female sex, n (%)* Initiation or Change path*, n (%) Initiation Change
Smoking status*, n (%)
Total (n=2,472)
p value
50.0 (18.3)
49.9 (18.1)
49.9 (18.1)
n/a
384 (62.1)
1,152 (62.1)
1,536 (62.1)
n/a
174 (28.2)
522 (28.2)
696 (28.2)
n/a
444 (71.8)
n/a
n/a
1,332 (71.8)
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Characteristic
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Table 1 Baseline matched demographics and clinical characteristics.
390 (21.0)
520 (21.0)
149 (24.1)
447 (24.1)
596 (24.1)
339 (54.9)
1,017 (54.9)
1,356 (54.9)
413 (66.8)
1,266 (68.3)
1,679 (67.9)
76.3 (19.2)
75.5 (19.0)
75.7 (19.0)
0.213
2013 (0.5)
2008 (3.1)
2009 (3.4)
<0.001
0 (0–1)
0 (0–1)
0 (0–1)
0.353
0, n (%)
430 (70)
1,290 (70)
1,720 (70)
n/a
1, n (%)
120 (19)
360 (19)
480 (19)
n/a
>2, n (%)
68 (11)
204 (11)
272 (11)
n/a
Ex-smokers Non-smokers
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Current smokers
n/a
Percent predicted peak flow readings N (% non-missing)
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Mean (SD)
Index year, mean (SD)
Exacerbations (ATS/ERS definitiona), median (IQR)*
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Acute respiratory eventsb, median (IQR)
0 (0–1)
0 (0–1)
Mean (SD)
0.7(1.1)
0.8(1.1)
0.8(1.1)
0, n (%)
354 (57)
978 (53)
1,332 (54)
1, n (%)
148 (24)
504 (27)
652 (26)
>2, n (%)
116 (19)
372 (20)
488 (20)
0 (0–1)
0 (0–1)
0, n (%)
431 (70)
1,299 (70)
1, n (%)
119 (19)
360 (19)
>2, n (%)
68 (11)
195 (11)
Risk domain asthma controlc
Uncontrolled, n (%) Overall asthma controld Controlled, n (%) Uncontrolled, n (%)
0 (0–1)
0.965
1,730 (70) 479 (19)
0.090
263 (11)
1,332 (54) 0.005
264 (43)
876 (47)
1,140 (46)
172 (28)
455 (25)
627 (25)
446 (72)
1,399 (76)
1,845 (75)
0 (0–1)
0 (0–1)
0 (0–1)
0.003
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Lower respiratory tract infection consultations resulting in script for antibiotics, median (IQR)
978 (53)
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Controlled, n (%)
0.013
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Acute oral steroid courses, median (IQR)
0.004
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0 (0–1)
0.016
1 (1–2)
1 (1–3)
1 (1–3)
0.002
Asthma-review consultations, mean (SD)
1.2 (0.9)
0.9 (1.0)
1.0 (1.0)
<0.001
Primary care consultations
8.7 (7.0)
8.9 (7.5)
8.9 (7.4)
0.394
5.3 (4.5)
5.0 (4.7)
5.0 (4.6)
0.012
110 (17.8)
330 (17.8)
440 (17.8)
n/a
0, n (%)
617 (99.8)
1,838 (99.1)
2,455 (99.3)
>1, n (%)
1 (0.2)
16 (0.9)
17 (0.7)
0, n (%)
617 (99.8)
1,836 (99.0)
2,453 (99.2)
>1, n (%)
1 (0.2)
18 (1.0)
19 (0.8)
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Asthma consultations, median (IQR)
SABA scripts, mean (SD)
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Rhinitis diagnosis and drugs*, n (%) Hospital inpatient admissions
0.098
ED attendance
0.072
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*
Matching criteria
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a
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asthma OR use of acute courses of oral steroids OR primary care physician consultations for lower respiratory tract
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infection.
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b
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or ED attendance with a lower respiratory code.
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c
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consultation for lower respiratory tract infections or acute oral steroids.
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d
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SD=standard deviation; IQR=interquartile range; ATS/ERS=American Thoracic Society/European Respiratory
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Society; SABA=short-acting beta agonist; FP/FOR=Fluticasone propionate/Formoterol; FP/SAL=Fluticasone
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propionate/Salmeterol.
Defined as an occurrence of an unscheduled hospital admission / ED Attendance / out of hours attendance for
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Defined as the prescription of antibiotics or oral steroids in a lower respiratory primary care consultation or hospital
Defined by the absence of asthma related hospital attendance or admission, ED attendance, primary care physician
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Defined by the presence of risk domain asthma control and no treatment change.
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Main analysis: Primary Outcome – proportion of ‘no exacerbations’
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The matched combined FP/FOR cohort was found to be non-inferior for FP/FOR compared with
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FP/SAL, in terms of the proportion of patients with no severe exacerbations [0.008 (-0.032,
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0.047)] using the non-inferiority boundary of -3.5% (Table 2).
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Table 2 Primary outcome results.
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Treatment group
FP/FOR (n=618)
FP/SAL (n=1,854)
Mean difference in proportion of ‘no exacerbations’ (FP/FOR-FP/SAL), % (95% CI)
Non-inferiority met? (Lower 95% CI >3.5%)
No, n (%)
458 (74)
1,372 (74)
0.008 (-0.032, 0.047)
-3.5%: MET
Yes, n (%)
160 (26)
482 (26)
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Matched cohort Exacerbations (ATS/ERS definition)
n/a
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Abbreviations: ATS/ERS, American Thoracic Society/European Respiratory Society; FP/FOR, Fluticasone
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propionate/Formoterol; FP/SAL, Fluticasone propionate/Salmeterol; CI, confidence interval.
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The acute respiratory event rate was significantly lower for the combined FP/FOR cohort
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compared with the combined FP/SAL cohort ([RR] 0.82, 95% CI 0.71–0.94). Other secondary
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outcomes were not significantly different between the two cohorts (Table 3).
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Table 3: Summary of secondary outcomes.
Treatment group
FP/FOR (n=618)
Matched cohort Exacerbation rate (ATS/ERS definition)
Median (IQR)
FP/SAL (n=1,854)
0.4 (0.8)
0.4 (0.8)
0 (0, 1)
0 (0, 1)
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Mean (SD)
≥2, n (%)
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Frequent Exacerbation (ATS/ERS Definition)c
61 (10)
Controlled, n (%)
Uncontrolled, n (%)
Median (IQR)
0.97a (0.82–1.14)
174 (9) 1.11c (0.91–1.37)
383 (62)
1,115 (60)
235 (38)
739 (40) 0.82d (0.71–0.94)
Acute respiratory event rate Mean (SD)
RR/OR* (95% CI)
0.99b (0.72–1.36)
Risk domain asthma control
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0.6 (1.0) 0 (0–1)
0.7 (1.2) 0 (0–1) 1.21e (0.97–1.52)
Overall asthma control Controlled, n (%)
180 (29)
463 (25)
Uncontrolled, n (%)
438 (71)
1,391 (75)
Effectiveness and cost impact of FP/FOR and FP/SAL April 2017
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0.95f (0.78–1.16)
SABA use (daily dose) ≤200 mcg, n (%)
245 (40)
695 (37)
>200 & ≤400 mcg, n (%)
167 (27)
522 (28)
>400 mcg, n (%)
206 (33)
637 (34)
RI PT
1.10g (0.89–1.35)
Treatment stability Yes, n (%)
342 (55)
990 (53)
No, n (%)
276 (45)
864 (47)
2.07h (0.83–5.16)
Hospitalisations
No, n (%)
610 (99)
259
14 (1)
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8 (1)
1,840 (99)
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Yes, n (%)
260
*
261
a
262
use (categorised) and baseline LTRA use. Unadjusted result rate ratio 0.97 (95% CI, 0.82–1.15).
263
b
264
baseline SAMA use, gender, baseline ICS daily dose (categorised), NSAID use and baseline LTRA use. Unadjusted
265
odds ratio 1.06 (0.79, 1.41).
266
c
267
diagnosis, smoking status, LTRA use, gender, rhinitis diagnosis and paracetamol use. Unadjusted odds ratio 1.08
268
(0.90, 1.29).
269
d
270
(ATS definition), GINA control code, baseline LTRA use and baseline SAMA use. Unadjusted rate ratio 0.88 (0.77
271
to 1.00).
272
e
273
and CCI score (categorised). Unadjusted odds ratio 1.23 (1.04 to 1.47).
274
f
275
Unadjusted odds ratio 0.93 (0.82 to 1.05).
Comparison is FP/FOR versus FP/SAL.
Rate ratio: adjusted for baseline ICS daily dose, baseline acute oral steroid courses (categorised), baseline SAMA
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Odds ratio: logistic regression adjusted for GERD diagnosis, baseline acute oral steroid courses (categorised),
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Odds ratio: adjusted for baseline asthma exacerbations (clinical definition), ICS daily dose, cardiovascular
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Rate ratio: adjusted for gender, heart failure diagnosis, NSAIDS use, rhinitis diagnosis, baseline exacerbations
Odds ratio: adjusted for baseline exacerbations (clinical definition), baseline SABA dose, cardiovascular diagnosis
Odds ratio: adjusted for baseline antibiotics, baseline SABA dose, CCI score (categorised), age and smoking status.
Effectiveness and cost impact of FP/FOR and FP/SAL April 2017
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276
g
277
gender, smoking status, number of GP consultations (categorised) and LTRA use. Unadjusted odds ratio 1.08 (0.90,
278
1.29).
279
h
280
Abbreviations: IQR, interquartile range; ATS/ERS, American thoracic society/European Respiratory Society;
281
SABA, short-acting beta agonist; CI, confidence interval; FP/FOR, Fluticasone propionate/Formoterol; FP/SAL,
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Fluticasone propionate/Salmeterol; SAMA, short-acting muscarinic antagonist; GERD, gastro-oesophageal reflux
283
disease; LTRA, leukotriene receptor antagonist; NSAID; nonsteroidal anti-inflammatory drug; ICS, inhaled
284
corticosteroid; CCI, Charlson comorbidity index
Odds ratio: adjusted for baseline exacerbations (clinical definition), rhinitis diagnosis, GINA control code, age,
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Odds ratio: adjusted for index year and baseline number of antibiotics. Unadjusted odds ratio 1.72 (0.72, 4.15)
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285 286
Exploratory outcomes Prescription of FP/FOR compared to FP/SAL is associated with a greater medication possession (p=0.017) and controller to reliever ratio (p<0.001) (Table S3). The number of
288
associated lower respiratory consultations was lower for the FP/FOR group compared with the
289
FP/SAL group (p<0.001). Other exploratory outcomes were non-significant between cohorts.
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290 Health care costs
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Lower respiratory-related drug costs (including prescriptions for all SABA, SAMA, ICS,
293
ICS/LABA, LABA, LAMA, LTRA, theophylline, lower respiratory-related antibiotics or oral
294
corticosteroid prescriptions) were significantly reduced in the FP/FOR cohort compared with the
295
FP/SAL cohort (median of GBP 316 versus GBP 360 per annum p<0.001) (Table 4, Figure 1).
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Lower respiratory-related health care resource costs were significantly decreased for the
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FP/FOR cohort compared with the FP/SAL cohort, although in terms of clinical relevance there
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was no difference (Table 4, Figure 1).
299
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The total respiratory-related health care costs (the aggregate of drug costs and resource costs) were significantly different: costs were lower for the FP/FOR cohort (median of GBP 351
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versus GBP 399 per annum, p<0.001) (Table 4, Figure 1).
303
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Table 4 Cost impact in GBP of prescribed medications, resource use and total cost.
Characteristic
FP/FOR (n=618)
FP/SAL (n=1,854)
Total (n=2,472)
p-valuea
316 (198–493)
360 (219–557)
352 (215–544)
<0.001
Asthma-related drug cost (GBP) Median (IQR) Asthma-related resource cost (GBP)
Effectiveness and cost impact of FP/FOR and FP/SAL April 2017
<0.001
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Median (IQR)
14 (14–42)
14 (0–56)
14 (14–56)
351 (228–557)
399 (248–638)
385 (242–614)
All asthma-related medical costs (GBP) Median (IQR)
<0.001
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304 305
a
306
errors adjusted for matching.
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Abbreviations: FP/FOR, Fluticasone propionate/Formoterol; FP/SAL, Fluticasone propionate/Salmeterol.
p-value obtained from fitting a generalised linear model using Gamma distribution and log link, with standard
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Figure 1: Median asthma-related costs in GBP of prescribed medications, resource use, and total
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cost.
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Medical
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Drug
£400
£300
£200
£100
£0
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FP/FOR
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£0
£100
£200
£300
£400
FP/SAL
Abbreviations: FP/FOR, Fluticasone propionate/Formoterol; FP/SAL, Fluticasone propionate/Salmeterol.
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The matched combined FP/FOR asthma cohort was non-inferior compared with the combined
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FP/SAL asthma cohort in terms of the proportion of patients with no severe exacerbations.
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Using exacerbation prevention (ATS/ERS definition) and secondary care as the measure of
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treatment effectiveness the observed similarity is not unexpected, given that the active
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preventative medication was FP in both prescription cohorts.
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The total number of acute respiratory events in the outcome period was significantly
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different between the two cohorts. This indicates that prescription of FP/FOR may be associated
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with fewer lower respiratory primary care consultations, where the patient presents with a
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condition requiring antibiotics or oral corticosteroids, as compared with FP/SAL. Alternative
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explanations for the observed difference include individual prescribing preferences of primary
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care physicians, differences in the coding system used, and the use of different codes to record
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events. The observed reduction in the number of associated lower respiratory primary care
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consultations in the outcome period for the FP/FOR cohort strengthens this hypothesis.
327
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Furthermore, the acute respiratory event rate was found to be significantly lower for the combined FP/FOR cohort compared with the combined FP/SAL cohort. Although superiority of
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this outcome was not the aim of the study, one possible explanation for the reduced acute
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respiratory event rate in the FP/FOR cohort may be that patients do not present to their primary
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care physician as often for respiratory conditions owing to improved symptom control with
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Formoterol as with Salmeterol. Alternatively, the difference in average index date between the
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cohorts (2013 for FP/FOR and 2008 for FP/SAL) may indicate an increased awareness of
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effective asthma treatment and less reliance on antibiotic prescription in patients prescribed
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FP/FOR owing to improved disease management. The large difference in index year (2013 for
336
FP/FOR compared with 2008 for FP/SAL) reflects the later licensing of FP/FOR (from
337
September 2012). SABA daily dose was similar for FP/FOR and FP/SAL patients, which may
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indicate comparable day-to-day symptom control when the disease is controlled. Other
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differences between the two cohorts, such as better risk domain asthma control in the FP/FOR
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cohort, are also potentially related to the difference in index year as a result of improved data
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recording practices or changes in management guidelines. Although there were many statistically
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significant differences in the baseline characteristics between the groups, the magnitude of most
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was not clinically meaningful.
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Our real-world study supports findings reported in a randomised controlled trial (RCT) where FP/FOR was found to be comparable to FP/SAL in terms of improvements in lung
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function and measures of asthma control [14]. The authors of this study, in accordance with other
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researchers, found FP/FOR to have a more rapid onset of action and suggest that if patients
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perceive the benefits of FP/FOR more rapidly than FP/SAL, this could have a positive impact on
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adherence [13, 14]. This correlates with a study by Bender et al., who found that patients
350
expressed a wish for more immediate symptom relief [33].
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This study found that the cost impact of FP/FOR was lower than that of FP/SAL and is
352
driven by the associated lower total respiratory drug cost. The exploratory lower resource cost
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analysis also indicates that there are fewer demands on health care resources irrespective of drug
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costs. This was reiterated in a recent budget analysis where FP/FOR was revealed to be the least
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costly option for the NHS in comparison with FP/SAL [13]. Although a more in-depth health
356
economic analysis would provide a more robust comparison, our cost impact analysis shows that
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the lower current price of FP/FOR is associated with lower overall respiratory-related costs
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compared with FP/SAL prescriptions.
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Our data provide evidence that despite the use of ICS/LABA, there is still a large
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proportion of patients (>70%), in both cohorts, who are uncontrolled and >60% of patients using
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SABA rescue therapy daily. This agrees with previous studies such as Asthma Insights and
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Reality in Europe (AIRE) and the International Asthma Patient Insight Research (INSPIRE)
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study that have shown that only a small proportion of patients achieve guideline targets for
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asthma control [34, 35]. The INSPIRE study found that >70% of patients prescribed ICS/LABA
365
had uncontrolled asthma according to Asthma Control Questionnaire data. Our findings also
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reflect those found in this global study where 74% of patients used their SABA therapy every
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day [35], further demonstrating poor asthma control. Multiple factors have been identified as
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contributors to the lack of control including incorrect diagnosis, sub-optimal inhaler technique,
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poor compliance, smoking and co-morbidities [36], and patient choice [37]. Underestimation of
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disease severity and hence insufficient prescription or therapy-resistant disease is also a prevalent
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problem. Our previous studies including Recognise Asthma and Link to Symptoms and
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Experience (REALISE) [38, 39] and the EUrope and CANada (EUCAN) study
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[40] demonstrated that patients with asthma reported features indicating uncontrolled disease
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though the majority believed to be controlled. This implies that patients have low expectations of
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long-term asthma management. Regardless of the cause, these data show that there is a large
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proportion of patients globally that have suboptimally controlled asthma
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Real-world evidence corroborates and reinforces the results from clinical trials. The use
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of a large database enabled us to analyse data on real-life patients from a high-quality source, the
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OPCRD, which has previously been used in respiratory research [24, 41, 42]. This allowed us to
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include a broad range of patients comparable to those typically examined in primary care
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settings. In addition, we studied outcomes over a full year both before and after the index patient
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review/change to balance seasonal influences and other transient confounders on outcome
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measures. Finally, the matching identified a comparator group that had most key variables
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evenly distributed at baseline.
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As with other observational studies, there is a potential for selection and physician bias and residual confounding. We addressed this by performing a matched analysis, and residual
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confounding was reduced by undertaking adjusted analyses. While the OPCRD is a well
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validated and maintained database [24, 41], we cannot rule out the possibility of inaccurate or
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missing data. To achieve the objectives, only patients with complete data for the study period
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were included, precluding evaluation of asthma-related deaths and other rare adverse effects with
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either inhaler. We relied on prescription information from the OPCRD primary care database,
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thus the data analysed allowed us to identify instances of when prescriptions were written by
393
general practitioners (GPs). It does not include information on whether the prescription was
394
filled and therefore, we are unable to guarantee consumption of the medications in this study.
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Study findings are dependent on the availability and quality of the data in the OPCRD, which
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contains limited information on hospitalisations. Lastly, there are differences in index date
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because FP/FOR was licensed later than FP/SAL in the UK. This may have influenced study
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outcomes due to advances in asthma treatment guidelines.
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Conclusion
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Changing to or initiating patients on FP/FOR rather than FP/SAL for asthma treatment is
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associated with non-inferior clinical outcomes. An exploratory analysis showed that FP/FOR is
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associated with improved prescription possession as well as lower respiratory related medication,
404
health care resource use, and overall aggregated cost in a real-life UK patient population.
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Acknowledgements
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With institutional support from NAPP Pharmaceutical Group Ltd. All named authors meet the
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International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this
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manuscript, take responsibility for the integrity of the work and have given final approval to the
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version to be published. The authors would like to thank Rosalind Bonomally for medical
411
writing support.
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References
413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458
1. 2.
8. 9.
10.
11.
12. 13. 14.
15.
16.
17.
18.
19.
RI PT
SC
7.
M AN U
6.
TE D
5.
EP
4.
AC C
3.
Martinez, F.D. and D. Vercelli, Asthma. Lancet, 2013. 382(9901): p. 1360-72. Disease, G.B.D., I. Injury, and C. Prevalence, Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet, 2016. 388(10053): p. 1545-1602. Global Initiative on Asthma (GINA). Global strategy for asthma management and prevention. 2016 [cited 2017 20th April]; Available from: http://ginasthma.org/. Boulet, L.P., et al., Evaluation of asthma control by physicians and patients: comparison with current guidelines. Can Respir J, 2002. 9(6): p. 417-23. Rabe, K.F., et al., Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys. J Allergy Clin Immunol, 2004. 114(1): p. 40-7. Montuschi, P., Pharmacotherapy of patients with mild persistent asthma: strategies and unresolved issues. Front Pharmacol, 2011. 2: p. 35. Sin, D.D., et al., Pharmacological management to reduce exacerbations in adults with asthma: a systematic review and meta-analysis. JAMA, 2004. 292(3): p. 367-76. Price, D., et al., Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma? NPJ Prim Care Respir Med, 2014. 24: p. 14023. (BTS), B.T.S. BTS/SIGN British guideline on the management of asthma. 2016 [cited 2017 12 April ]; Available from: https://www.brit-thoracic.org.uk/standards-of-care/guidelines/btssignbritish-guideline-on-the-management-of-asthma/. Postma, D.S., H.A. Kerstjens, and N.H. ten Hacken, Inhaled corticosteroids and long-acting betaagonists in adult asthma: a winning combination in all? Naunyn Schmiedebergs Arch Pharmacol, 2008. 378(2): p. 203-15. Rosenhall, L., et al., Budesonide/Formoterol in a single inhaler (Symbicort) reduces healthcare costs compared with separate inhalers in the treatment of asthma over 12 months. Int J Clin Pract, 2003. 57(8): p. 662-7. Bell, A.D. and R.A. McIvor, The SMART study. Can Fam Physician, 2007. 53(4): p. 687-8. Aalbers, R., et al., Onset of bronchodilation with Fluticasone/Formoterol combination versus Fluticasone/Salmeterol in an open-label, randomized study. Adv Ther, 2012. 29(11): p. 958-69. Bodzenta-Lukaszyk, A., et al., Fluticasone/Formoterol combination therapy is as effective as Fluticasone/Salmeterol in the treatment of asthma, but has a more rapid onset of action: an open-label, randomized study. BMC Pulm Med, 2011. 11: p. 28. Condemi, J.J., Comparison of the efficacy of Formoterol and Salmeterol in patients with reversible obstructive airway disease: a multicenter, randomized, open-label trial. Clin Ther, 2001. 23(9): p. 1529-41. Ullman, A., et al., Onset of action and duration of effect of Formoterol and Salmeterol compared to salbutamol in isolated guinea pig trachea with or without epithelium. Allergy, 1992. 47(4 Pt 2): p. 384-7. Aalbers, R., et al., Adjustable maintenance dosing with budesonide/Formoterol compared with fixed-dose Salmeterol/Fluticasone in moderate to severe asthma. Curr Med Res Opin, 2004. 20(2): p. 225-40. Shapiro, G., et al., Combined Salmeterol 50 microg and Fluticasone propionate 250 microg in the diskus device for the treatment of asthma. Am J Respir Crit Care Med, 2000. 161(2 Pt 1): p. 52734. Bodzenta-Lukaszyk, A., et al., Efficacy and safety profile of Fluticasone/Formoterol combination therapy compared to its individual components administered concurrently in asthma: a randomised controlled trial. Curr Med Res Opin, 2013. 29(5): p. 579-88.
Effectiveness and cost impact of FP/FOR and FP/SAL April 2017
25
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24. 25. 26. 27.
28. 29.
30. 31. 32.
33. 34. 35. 36. 37. 38.
RI PT
SC
23.
M AN U
22.
TE D
21.
NHS. An Outcomes Strategy for COPD and Asthma: NHS Companion Document. 2012 [cited 2016 13 Dec 2016]; Available from: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/216531/dh_1 34001.pdf. Farrington, E., et al., FP/FORM Versus FP/SAL Within Clinical Practice: An Updated Budget Impact Analysis in Asthma. Adv Ther, 2016. 33(5): p. 794-806. Daina Lim, I.S., Stephanie Wolfe, John Hamill, Kevin Gruffydd-Jones, Cathal Daly and David Price. Real life effectiveness of changing fixed-dose combination therapy from Seretide® metered dose inhaler (MDI) to Flutiform® in UK patients with asthma. in Respiratory Effectiveness Group (REG) Summit 2014. 2014. London, England. Group, A.o.b.o.t.R.E., Meeting abstracts from the Respiratory Effectiveness Group 2015 Winter Summit - databases and registries around the world: maximizing the yield Pragmatic and Observational Research, 2015. 2016:6: p. 13-38. OPCRD. The Optimum Patient Care Research Database (OPCRD). 2016 [cited 2017 19th April]; Available from: http://optimumpatientcare.org/opcrd/. NHS. Dictionary of Medicines and Devices (dm+d). 2015 [cited 2017 20th April]; Available from: https://apps.nhsbsa.nhs.uk/DMDBrowser/DMDBrowser.do. Unit, P.S.S.R. Unit Costs of Health and Social Care 2015 [cited 2016 13 December]; Available from: http://www.pssru.ac.uk/project-pages/unit-costs/2015/index.php. Barnes, N., et al., Asthma control with extrafine-particle hydrofluoroalkane-beclometasone vs. large-particle chlorofluorocarbon-beclometasone: a real-world observational study. Clin Exp Allergy, 2011. 41(11): p. 1521-32. Colice, G., et al., Asthma outcomes and costs of therapy with extrafine beclomethasone and Fluticasone. J Allergy Clin Immunol, 2013. 132(1): p. 45-54. Price, D., et al., Prescribing practices and asthma control with hydrofluoroalkanebeclomethasone and Fluticasone: a real-world observational study. J Allergy Clin Immunol, 2010. 126(3): p. 511-8 e1-10. Israel, E., et al., Increased Dose of Inhaled Corticosteroid versus Add-On Long-acting beta-Agonist for Step-Up Therapy in Asthma. Ann Am Thorac Soc, 2015. 12(6): p. 798-806. Chung, K.F., et al., International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J, 2014. 43(2): p. 343-73. Price D, S.I., Wolfe S, Hamil J, Gruffydd-Jones K, Daly C, Haughney J, Yau S, Clinical effectiveness and cost impact in UK patients with asthma switching from Fluticasone-propionate/Salmeterol pMDI to Fluticasone-propionate/Formoterol pMDI [Abstract 51]. Primary Care Respiratory Medicine, 2015. 25. Bender, B.G., et al., Factors influencing patient decisions about the use of asthma controller medication. Ann Allergy Asthma Immunol, 2007. 98(4): p. 322-8. Rabe, K.F., et al., Clinical management of asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study. Eur Respir J, 2000. 16(5): p. 802-7. Partridge, M.R., et al., Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study. BMC Pulm Med, 2006. 6: p. 13. Haughney, J., et al., Achieving asthma control in practice: understanding the reasons for poor control. Respir Med, 2008. 102(12): p. 1681-93. Haughney, J., et al., Features of asthma management: quantifying the patient perspective. BMC Pulm Med, 2007. 7: p. 16. Price, D., M. Fletcher, and T. van der Molen, Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim Care Respir Med, 2014. 24: p. 14009.
EP
20.
AC C
459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506
Effectiveness and cost impact of FP/FOR and FP/SAL April 2017
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39. 40. 41. 42.
Price, D., et al., Time for a new language for asthma control: results from REALISE Asia. J Asthma Allergy, 2015. 8: p. 93-103. Sastre, J., et al., Insights, attitudes, and perceptions about asthma and its treatment: a multinational survey of patients from Europe and Canada. World Allergy Organ J, 2016. 9: p. 13. CPRD. The Clinical Practice Research Datalink (CPRD). https://www.cprd.com/home/ 16 Dec 2015 [cited 2017 19th April]. Jones, R.C., et al., Opportunities to diagnose chronic obstructive pulmonary disease in routine care in the UK: a retrospective study of a clinical cohort. Lancet Respir Med, 2014. 2(4): p. 26776.
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ACCEPTED MANUSCRIPT Manuscript Number: YRMED-D-17-00404 Manuscript Title: Initiating or changing to a fixed-dose combination of fluticasone propionate/formoterol over fluticasone propionate/salmeterol: a real-life effectiveness and cost impact evaluation Respiratory Medicine.
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Efficacious and cost-effective asthma treatment is necessary FP/FOR is associated with non-inferior clinical outcomes compared to FP/SAL Combined health care costs in a real-life UK population decreased with FP/FOR
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Highlights
S0954-6111(17)30183-X
DOI:
10.1016/j.rmed.2017.06.016
Reference:
YRMED 5192
To appear in:
Respiratory Medicine
Received Date: 4 May 2017 Revised Date:
21 June 2017
Accepted Date: 22 June 2017
Please cite this article as: Yau Ming SW, Haughney J, Small I, Wolfe S, Hamill J, Gruffydd-Jones K, Daly C, Soriano JB, Gardener E, Skinner D, Stagno d'Alcontres M, Price DB, Initiating or changing to a fixed-dose combination of Fluticasone propionate/Formoterol over Fluticasone propionate/Salmeterol: A real-life effectiveness and cost impact evaluation, Respiratory Medicine (2017), doi: 10.1016/ j.rmed.2017.06.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
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Initiating or changing to a fixed-dose combination of Fluticasone propionate/Formoterol
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over Fluticasone propionate/Salmeterol: a real-life effectiveness and cost impact evaluation
3 Running head [max. 50 characters]:
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Simon Wan Yau Ming1
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John Haughney2
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Iain Small3
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Stephanie Wolfe4
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John Hamill5
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Kevin Gruffydd-Jones6
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Cathal Daly7
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Joan B Soriano8
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Elizabeth Gardener1
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Derek Skinner9
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Martina Stagno d'Alcontres1
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David B Price1,2
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Observational and Pragmatic Research Institute, Singapore ; 2Academic Primary Care,
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University of Aberdeen, Aberdeen, UK; 3Peterhead Health Centre, Aberdeen, UK; 4Primary
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Research Ltd, Norwich, UK; 5McMullans Pharmacy, Belfast, UK; 6University of Bath, Bath, UK;
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Elmham Surgery, Norfolk, UK; 8Instituto de Investigación Hospital Universitario de la Princesa
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(IISP) Universidad Autónoma de Madrid, Madrid, Spain; 9Optimum Patient Care, Cambridge,
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UK;
25 *Corresponding author: Prof David B Price, Academic Primary Care, Division of Applied
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Health Sciences, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen, UK AB25
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2ZD; Tel +65 6802 9724; Email [email protected]
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Keywords [5-7 not in title]: asthma, cost-effectiveness, fixed-dose combination inhalers,
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Formoterol, GINA, real-life
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Abstract [289 words]
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Objective: Asthma has a substantial impact on quality of life and health care resources. The
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identification of a more cost-effective, yet equally efficacious, treatment could positively
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influence the economic burden of this disease. Fluticasone propionate/Formoterol (FP/FOR) may
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be as effective as Fluticasone Salmeterol (FP/SAL). We evaluated non-inferiority of asthma
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control in terms of the proportion of patients free from exacerbations, and conducted a cost
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impact analysis.
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Methods: This historical, matched cohort database study evaluated two treatment groups in the
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Optimum Patient Care Research Database in the UK: 1) an FP/FOR cohort of patients initiating
42
treatment with FP/FOR or changing from FP/SAL to FP/FOR and; 2) an FP/SAL cohort
43
comprising patients initiating, or remaining on FP/SAL pMDI combination therapy. The main
44
outcome evaluated non-inferiority of effectiveness (defined as prevention of severe
45
exacerbations, lower limit of the 95% confidence interval (CI) of the mean difference between
46
groups in patient proportions with no exacerbations is -3.5% or higher) in patients treated with
47
FP/FOR versus FP/SAL.
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Results: After matching 1:3, we studied a total of 2,472 patients: 618 in the FP/FOR cohort (174
50
patients initiated on FP/FOR and 444 patients changed to FP/FOR) and 1,854 in the FP/SAL
51
cohort (522 patients initiated FP/SAL and 1332 continued FP/SAL). The percentage of patients
52
prescribed FP/FOR met non-inferiority as the adjusted mean difference in proportion of no
53
severe exacerbations (95%CI) was 0.008 (-0.032, 0.047) between the two cohorts. No other
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54
significant differences were observed except acute respiratory event rates, which were lower for
55
patients prescribed FP/FOR (rate ratio [RR] 0.82, 95% CI 0.71, 0.94).
56 Conclusions: Changing to, or initiating FP/FOR combination therapy, is associated with a non-
58
inferior proportion of patients who are severe exacerbation-free at a lower average annual cost
59
compared with continuing or initiating treatment with FP/SAL.
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Introduction
62
Asthma is a heterogeneous disease characterised by chronic airway inflammation. The global
63
prevalence of this disease has increased by 9.5%, from 334 million affected in 2005 to 358
64
million people in 2015 [1, 2]. Asthma has a substantial impact on quality of life and health care
65
resources, and its associated burden is high. Treatments aimed at optimal disease control and
66
prevention of acute exacerbations are well established in national and international guidelines
67
[3]. However, international patient surveys have found that asthma is often uncontrolled,
68
underlining the need for optimisation of asthma management [4, 5].
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Inhaled corticosteroids (ICS) have become a mainstay of asthma therapies [6, 7] with a short-acting β2-agonist (SABA) often prescribed for quick symptom relief. However, many
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patients being treated with ICS and SABA do not have fully controlled symptoms [3]. The
72
addition of a long-acting β2-agonist (LABA) to increase asthma control as an alternative to
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upward titration of ICS doses is well established [8].
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The co-prescription of ICS with a separate LABA has become an integral part of asthma treatment guidelines [3, 9]. The development and prescription of a fixed-dose combination
76
(FDC) ICS/LABA has been shown to improve patient compliance, consequently reducing the
77
risk of ICS therapy discontinuation, as well as reducing the health care costs associated with
78
separate drug inhalers, and importantly, reducing respiratory-related deaths and life-threatening
79
episodes [6, 7, 9-12]. Many different FDC ICS/LABA combination therapies are now available.
80
An FDC ICS/LABA composed of Fluticasone propionate (FP) and Formoterol fumarate (FOR)
81
has been developed for asthma treatment. FP/FOR combines the anti-inflammatory and
82
bronchodilating properties of two effective compounds in a single inhaler. It has been suggested
83
that the bronchodilator effects of Formoterol reduce the need for rescue medication and result in
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an increased number of episode-free days compared with patients receiving an alternate LABA,
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Salmeterol [13-15]. Its quick onset of action has a positive impact on patient adherence [16].
86
Other FDC therapies, such as FP and Salmeterol (FP/SAL), have also been found to be highly
87
effective at maintaining early and sustained improvements in asthma control [17, 18]. There is
88
evidence that the safety profile is similar for either Formoterol or Salmeterol combined with
89
Fluticasone propionate (i.e. FP/FOR and FP/SAL)[19].
All the above-mentioned factors are recognised by the Global Initiative for Asthma
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(GINA) as being as vital to clinical outcomes as the inhaled drug itself [3]. Asthma care in the
92
United Kingdom (UK) costs the National Health Service (NHS) over GBP 1 billion per year
93
[20]. The prescription of a more cost-effective, yet equally efficacious, treatment has the
94
potential to positively influence the economic burden of asthma care. Within the UK, Seretide®,
95
a formulation of FP/SAL, has the greatest volume of prescribed units to treat patients with
96
asthma [21]. A recent alternative, Flutiform®, a formulation of FP/FOR, was launched in the UK
97
in September 2012 and currently accounts for only 4.6% of overall ICS/LABA units prescribed
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for patients with asthma compared with the 51.8% prescribed Seretide® [21]. Our previous
99
studies found that 88.4% of patients that were switched from FP/SAL to FP/FOR remained on
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the new therapy, suggesting a high retention rate for FP/FOR [22]. We also established that
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FP/FOR provides an effective treatment option for patients with asthma [23].
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The objective of this study was to determine non-inferiority of asthma control in patients
103
prescribed FP/FOR versus those prescribed FP/SAL, and to conduct a cost impact analysis of
104
FP/FOR compared with FP/SAL. Asthma control is defined as the proportion of patients who are
105
free from severe exacerbations during the study period.
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106 Methods
108
Study design
109
This was a historical, matched cohort study comparing patients with asthma prescribed FP/FOR
110
(the active comparator) with those prescribed FP/SAL (the reference group). To represent real-
111
life treatment pathways, we initially identified patients according to two treatment paths: an
112
initiation path comprising those initiating their first FDC ICS/LABA as either FP/FOR or
113
FP/SAL on the index date, and a change path, comprising individuals already on FP/SAL who
114
either received a repeat prescription for FP/SAL, or changed to FP/FOR on the index date. Thus,
115
the final FP/FOR cohort consisted of patients initiating FP/FOR combination therapy and
116
changing from FP/SAL to FP/FOR, while the final FP/SAL cohort consisted of patients
117
remaining on, or initiating FP/SAL combination therapy. The index date was defined as the date
118
when patients received their first prescription of ICS as either FP/FOR or FP/SAL or changed to
119
FP/FOR.
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European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP
122
number ENCEPP/SDPP/12631) and followed the ENCePP code of conduct.
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Data Source
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The study utilised data from the Optimum Patient Care Research Database (OPCRD) [24]. The
126
database has been approved by the Trent Multicentre Research Ethics Committee for clinical
127
research use and, as of January 2017, contains anonymous, longitudinal data for over 3 million
128
patients from over 580 general practices in the UK. The data includes information on diagnoses,
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prescriptions, investigations, hospital referrals, and admissions. Prescription costs were taken
130
from the National Health Service (NHS) Dictionary of Medicines and Devices website [25],
131
which contains up-to-date prescription costs. Resource use costs were adapted from the Personal
132
Social Services Research Unit (PSSRU) 2015 document [26].
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Patient Population
135
Patients eligible for the study were aged between 12 and 80 years, had a coded diagnosis
136
compatible with asthma, and at least 2 years of continuous practice data comprising 1 baseline
137
year and 1 outcome year. Patients were excluded from the analysis if their records contained
138
diagnostic codes for a chronic respiratory illness other than asthma. Patients with more severe
139
exacerbations who were prescribed maintenance oral steroids were excluded. In addition,
140
patients from practices in the FP/FOR cohort where fewer than 5 patients changed therapy were
141
excluded, as the change would more likely be precipitated by poor asthma control rather than
142
wholesale change for cost reasons. Inclusion and exclusion criteria are specified in online
143
supplementary material (Table S1).
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Study Outcomes
146
The primary outcome included patients with asthma experiencing no severe exacerbations in the
147
outcome period and compared the proportion of those who were prescribed FP/FOR with those
148
prescribed FP/SAL (non-inferiority analysis with a priori limit for the difference in proportions
149
set at 3.5%).
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Secondary outcomes were assessed using previously described composite measures [27-
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30]. Briefly, these included a comparison of: the rate of exacerbations; the proportion of patients
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with frequent exacerbations (defined as ≥2 per year); risk domain asthma control (defined by the
153
absence of lower respiratory-related hospital attendance or admission, emergency department
154
(ED) attendance, primary care physician consultation for lower respiratory tract infections, or
155
acute oral steroids); the acute respiratory event rate (defined as the prescription of antibiotics or
156
oral steroids in a lower respiratory primary care consultation or hospital or ED attendance with a
157
lower respiratory code); overall asthma control (defined by the presence of risk domain asthma
158
control and >200µg/day SABA use); SABA use; treatment stability; and the number of lower
159
respiratory-related hospitalisations.
161 162
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incidence of oral thrush in treatment groups.
Cost impact outcomes included health care resource use, prescriptions for respiratoryrelated conditions, and combined costs. The total respiratory-related drug costs included
164
prescriptions for ICS, LABA, long-acting muscarinic antagonists (LAMA), leukotriene receptor
165
antagonists (LTRA), short-acting muscarinic antagonists (SAMA), FDC ICS/LABA,
166
theophylline, antibiotic and oral steroids linked with a lower respiratory consultation. Lower
167
respiratory-related health care resources consisted of combined and disaggregated primary care
168
physician consultations, nurse asthma reviews, ED attendance, and hospital admissions with a
169
lower respiratory-related diagnostic code.
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Sample Size
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A sample size calculation was set a priori to determine our primary objective of evaluating non-
173
inferiority of FP/FOR compared with FP/SAL in preventing exacerbations, assessed in this study
174
by comparing the proportion of patients who were free of severe asthma exacerbations during a
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one-year follow-up. The term exacerbation is used based on the American Thoracic
176
Society/European Respiratory Society (ATS/ERS) Joint Taskforce definition: an asthma-related
177
hospital admission, emergency department attendance, or an acute course of oral corticosteroids
178
[31]. Preliminary data from a historical, matched database study showed that the difference in
179
proportions of patients with no severe exacerbations was 4.5% [32]. For the purposes of this
180
study, a more stringent non-inferiority limit of 3.5% was chosen for the upper limit of the 95%
181
confidence interval (CI) for the mean difference in primary outcomes. With a minimum of 511
182
patients with asthma treated with FP/FOR and 2,044 treated with FP/SAL, this study provided
183
90% power to reject the null hypothesis that FP/FOR and FP/SAL are non-inferior in terms of
184
the proportion of patients with no exacerbations.
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185 Statistical analysis
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Statistical analysis was carried out using SPSS Statistics version 22 (IBM SPSS Statistics,
188
Feltham, Middlesex, UK), and SAS version 9.3 (SAS Institute, Marlow, Buckinghamshire, UK).
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Demographic and clinical characteristics, comorbidities, and previous asthma
190
exacerbations with p<0.05 were considered as potential confounders during modelling. In the
191
event of significant differences within the cohorts for certain variables, an assessment was made
192
for clinical relevance by a panel of medical experts and the relevant variable was considered for
193
matching criteria.
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The final matching criteria were cohort path type (initiation or change), age, gender,
195
number of asthma exacerbations, SABA daily dose (0-150 µg, 151-300 µg, 301-450 µg, 451-600
196
µg, >600 µg), ICS daily dose (0-250µg, 251-500 µg, >500µg), smoking status, and rhinitis
197
diagnosis. Exact matching for categorical variables and coarsened exact matching for numeric
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198
variables were used to match patients using a ratio of 1:3 nearest neighbour matching between
199
treatment arms without replacement. We used a ratio of 1:3 to improve the power of the study
200
with minimal loss of patients in the intervention arm. Conditional logistic regression was used for the primary, non-inferiority analysis of the
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proportion of patients experiencing no severe asthma exacerbations, and for the secondary
203
outcomes of the proportion of patients with frequent asthma exacerbations (defined as ≥2 per
204
year), risk domain asthma control, overall asthma control and treatment stability. Conditional
205
Poisson regression was used to compare rate ratios of severe asthma exacerbations, clinical
206
asthma exacerbations and hospitalisations between cohorts. Conditional ordinal regression was
207
used for SABA use. Minimal adjustment for residual confounding was made in each of the fitted
208
models. Adjustment for residual confounding was based on non-collinear predictors of outcomes
209
determined from multivariable analyses on the unmatched sample and the balance of cohorts
210
after matching, together with clinical input. A p-value lower than 0.05 was considered to be
211
statistically significant.
212
Results
213
We identified a total of 671 eligible patients in the FP/FOR group (203 initiated FP/FOR
214
combination therapy; 468 changed from FP/SAL to FP/FOR) and 67,054 in the FP/SAL group
215
(25,719 initiated FP/SAL combination therapy; 41,335 remained on FP/SAL) that met the
216
inclusion criteria (Figures S1 and S2).
218 219 220
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Matching resulted in 2,472 unique patients: 618 in the FP/FOR cohort who were matched
1:3 with 1,854 in the FP/SAL cohort (Table S2). The mean age (SD) was 50 years (18) and 62% were female for both matched groups. The percent predicted peak flow reading was 76% for both FP/FOR and FP/SAL. Each final
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221
cohort was composed of 55% non-smokers, 21% current smokers and 24% ex-smokers. Active
222
rhinitis, defined by the use of rhinitis drugs and a physician diagnosis, was 18% in both cohorts
223
(Table 1).
225
At baseline, a higher percentage of patients in the FP/FOR cohort were found to have
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better asthma control compared with the FP/SAL group, 57% vs. 53%, p=0.005 (Table 1).
226
Age, mean (SD)* Female sex, n (%)* Initiation or Change path*, n (%) Initiation Change
Smoking status*, n (%)
Total (n=2,472)
p value
50.0 (18.3)
49.9 (18.1)
49.9 (18.1)
n/a
384 (62.1)
1,152 (62.1)
1,536 (62.1)
n/a
174 (28.2)
522 (28.2)
696 (28.2)
n/a
444 (71.8)
n/a
n/a
1,332 (71.8)
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FP/SAL (n=1,854)
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Characteristic
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Table 1 Baseline matched demographics and clinical characteristics.
390 (21.0)
520 (21.0)
149 (24.1)
447 (24.1)
596 (24.1)
339 (54.9)
1,017 (54.9)
1,356 (54.9)
413 (66.8)
1,266 (68.3)
1,679 (67.9)
76.3 (19.2)
75.5 (19.0)
75.7 (19.0)
0.213
2013 (0.5)
2008 (3.1)
2009 (3.4)
<0.001
0 (0–1)
0 (0–1)
0 (0–1)
0.353
0, n (%)
430 (70)
1,290 (70)
1,720 (70)
n/a
1, n (%)
120 (19)
360 (19)
480 (19)
n/a
>2, n (%)
68 (11)
204 (11)
272 (11)
n/a
Ex-smokers Non-smokers
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130 (21.0)
Current smokers
n/a
Percent predicted peak flow readings N (% non-missing)
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Mean (SD)
Index year, mean (SD)
Exacerbations (ATS/ERS definitiona), median (IQR)*
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Acute respiratory eventsb, median (IQR)
0 (0–1)
0 (0–1)
Mean (SD)
0.7(1.1)
0.8(1.1)
0.8(1.1)
0, n (%)
354 (57)
978 (53)
1,332 (54)
1, n (%)
148 (24)
504 (27)
652 (26)
>2, n (%)
116 (19)
372 (20)
488 (20)
0 (0–1)
0 (0–1)
0, n (%)
431 (70)
1,299 (70)
1, n (%)
119 (19)
360 (19)
>2, n (%)
68 (11)
195 (11)
Risk domain asthma controlc
Uncontrolled, n (%) Overall asthma controld Controlled, n (%) Uncontrolled, n (%)
0 (0–1)
0.965
1,730 (70) 479 (19)
0.090
263 (11)
1,332 (54) 0.005
264 (43)
876 (47)
1,140 (46)
172 (28)
455 (25)
627 (25)
446 (72)
1,399 (76)
1,845 (75)
0 (0–1)
0 (0–1)
0 (0–1)
0.003
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Lower respiratory tract infection consultations resulting in script for antibiotics, median (IQR)
978 (53)
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Controlled, n (%)
0.013
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Acute oral steroid courses, median (IQR)
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0 (0–1)
0.016
1 (1–2)
1 (1–3)
1 (1–3)
0.002
Asthma-review consultations, mean (SD)
1.2 (0.9)
0.9 (1.0)
1.0 (1.0)
<0.001
Primary care consultations
8.7 (7.0)
8.9 (7.5)
8.9 (7.4)
0.394
5.3 (4.5)
5.0 (4.7)
5.0 (4.6)
0.012
110 (17.8)
330 (17.8)
440 (17.8)
n/a
0, n (%)
617 (99.8)
1,838 (99.1)
2,455 (99.3)
>1, n (%)
1 (0.2)
16 (0.9)
17 (0.7)
0, n (%)
617 (99.8)
1,836 (99.0)
2,453 (99.2)
>1, n (%)
1 (0.2)
18 (1.0)
19 (0.8)
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Asthma consultations, median (IQR)
SABA scripts, mean (SD)
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Rhinitis diagnosis and drugs*, n (%) Hospital inpatient admissions
0.098
ED attendance
0.072
228 229
*
Matching criteria
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a
231
asthma OR use of acute courses of oral steroids OR primary care physician consultations for lower respiratory tract
232
infection.
233
b
234
or ED attendance with a lower respiratory code.
235
c
236
consultation for lower respiratory tract infections or acute oral steroids.
237
d
238
SD=standard deviation; IQR=interquartile range; ATS/ERS=American Thoracic Society/European Respiratory
239
Society; SABA=short-acting beta agonist; FP/FOR=Fluticasone propionate/Formoterol; FP/SAL=Fluticasone
240
propionate/Salmeterol.
Defined as an occurrence of an unscheduled hospital admission / ED Attendance / out of hours attendance for
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Defined as the prescription of antibiotics or oral steroids in a lower respiratory primary care consultation or hospital
Defined by the absence of asthma related hospital attendance or admission, ED attendance, primary care physician
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Defined by the presence of risk domain asthma control and no treatment change.
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Main analysis: Primary Outcome – proportion of ‘no exacerbations’
243
The matched combined FP/FOR cohort was found to be non-inferior for FP/FOR compared with
244
FP/SAL, in terms of the proportion of patients with no severe exacerbations [0.008 (-0.032,
245
0.047)] using the non-inferiority boundary of -3.5% (Table 2).
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Table 2 Primary outcome results.
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Treatment group
FP/FOR (n=618)
FP/SAL (n=1,854)
Mean difference in proportion of ‘no exacerbations’ (FP/FOR-FP/SAL), % (95% CI)
Non-inferiority met? (Lower 95% CI >3.5%)
No, n (%)
458 (74)
1,372 (74)
0.008 (-0.032, 0.047)
-3.5%: MET
Yes, n (%)
160 (26)
482 (26)
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Matched cohort Exacerbations (ATS/ERS definition)
n/a
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Abbreviations: ATS/ERS, American Thoracic Society/European Respiratory Society; FP/FOR, Fluticasone
250
propionate/Formoterol; FP/SAL, Fluticasone propionate/Salmeterol; CI, confidence interval.
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The acute respiratory event rate was significantly lower for the combined FP/FOR cohort
255
compared with the combined FP/SAL cohort ([RR] 0.82, 95% CI 0.71–0.94). Other secondary
256
outcomes were not significantly different between the two cohorts (Table 3).
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Table 3: Summary of secondary outcomes.
Treatment group
FP/FOR (n=618)
Matched cohort Exacerbation rate (ATS/ERS definition)
Median (IQR)
FP/SAL (n=1,854)
0.4 (0.8)
0.4 (0.8)
0 (0, 1)
0 (0, 1)
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≥2, n (%)
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Frequent Exacerbation (ATS/ERS Definition)c
61 (10)
Controlled, n (%)
Uncontrolled, n (%)
Median (IQR)
0.97a (0.82–1.14)
174 (9) 1.11c (0.91–1.37)
383 (62)
1,115 (60)
235 (38)
739 (40) 0.82d (0.71–0.94)
Acute respiratory event rate Mean (SD)
RR/OR* (95% CI)
0.99b (0.72–1.36)
Risk domain asthma control
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0.6 (1.0) 0 (0–1)
0.7 (1.2) 0 (0–1) 1.21e (0.97–1.52)
Overall asthma control Controlled, n (%)
180 (29)
463 (25)
Uncontrolled, n (%)
438 (71)
1,391 (75)
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0.95f (0.78–1.16)
SABA use (daily dose) ≤200 mcg, n (%)
245 (40)
695 (37)
>200 & ≤400 mcg, n (%)
167 (27)
522 (28)
>400 mcg, n (%)
206 (33)
637 (34)
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1.10g (0.89–1.35)
Treatment stability Yes, n (%)
342 (55)
990 (53)
No, n (%)
276 (45)
864 (47)
2.07h (0.83–5.16)
Hospitalisations
No, n (%)
610 (99)
259
14 (1)
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8 (1)
1,840 (99)
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Yes, n (%)
260
*
261
a
262
use (categorised) and baseline LTRA use. Unadjusted result rate ratio 0.97 (95% CI, 0.82–1.15).
263
b
264
baseline SAMA use, gender, baseline ICS daily dose (categorised), NSAID use and baseline LTRA use. Unadjusted
265
odds ratio 1.06 (0.79, 1.41).
266
c
267
diagnosis, smoking status, LTRA use, gender, rhinitis diagnosis and paracetamol use. Unadjusted odds ratio 1.08
268
(0.90, 1.29).
269
d
270
(ATS definition), GINA control code, baseline LTRA use and baseline SAMA use. Unadjusted rate ratio 0.88 (0.77
271
to 1.00).
272
e
273
and CCI score (categorised). Unadjusted odds ratio 1.23 (1.04 to 1.47).
274
f
275
Unadjusted odds ratio 0.93 (0.82 to 1.05).
Comparison is FP/FOR versus FP/SAL.
Rate ratio: adjusted for baseline ICS daily dose, baseline acute oral steroid courses (categorised), baseline SAMA
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Odds ratio: adjusted for baseline asthma exacerbations (clinical definition), ICS daily dose, cardiovascular
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Rate ratio: adjusted for gender, heart failure diagnosis, NSAIDS use, rhinitis diagnosis, baseline exacerbations
Odds ratio: adjusted for baseline exacerbations (clinical definition), baseline SABA dose, cardiovascular diagnosis
Odds ratio: adjusted for baseline antibiotics, baseline SABA dose, CCI score (categorised), age and smoking status.
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276
g
277
gender, smoking status, number of GP consultations (categorised) and LTRA use. Unadjusted odds ratio 1.08 (0.90,
278
1.29).
279
h
280
Abbreviations: IQR, interquartile range; ATS/ERS, American thoracic society/European Respiratory Society;
281
SABA, short-acting beta agonist; CI, confidence interval; FP/FOR, Fluticasone propionate/Formoterol; FP/SAL,
282
Fluticasone propionate/Salmeterol; SAMA, short-acting muscarinic antagonist; GERD, gastro-oesophageal reflux
283
disease; LTRA, leukotriene receptor antagonist; NSAID; nonsteroidal anti-inflammatory drug; ICS, inhaled
284
corticosteroid; CCI, Charlson comorbidity index
Odds ratio: adjusted for baseline exacerbations (clinical definition), rhinitis diagnosis, GINA control code, age,
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Odds ratio: adjusted for index year and baseline number of antibiotics. Unadjusted odds ratio 1.72 (0.72, 4.15)
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285 286
Exploratory outcomes Prescription of FP/FOR compared to FP/SAL is associated with a greater medication possession (p=0.017) and controller to reliever ratio (p<0.001) (Table S3). The number of
288
associated lower respiratory consultations was lower for the FP/FOR group compared with the
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FP/SAL group (p<0.001). Other exploratory outcomes were non-significant between cohorts.
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290 Health care costs
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Lower respiratory-related drug costs (including prescriptions for all SABA, SAMA, ICS,
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ICS/LABA, LABA, LAMA, LTRA, theophylline, lower respiratory-related antibiotics or oral
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corticosteroid prescriptions) were significantly reduced in the FP/FOR cohort compared with the
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FP/SAL cohort (median of GBP 316 versus GBP 360 per annum p<0.001) (Table 4, Figure 1).
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Lower respiratory-related health care resource costs were significantly decreased for the
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FP/FOR cohort compared with the FP/SAL cohort, although in terms of clinical relevance there
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was no difference (Table 4, Figure 1).
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The total respiratory-related health care costs (the aggregate of drug costs and resource costs) were significantly different: costs were lower for the FP/FOR cohort (median of GBP 351
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versus GBP 399 per annum, p<0.001) (Table 4, Figure 1).
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Table 4 Cost impact in GBP of prescribed medications, resource use and total cost.
Characteristic
FP/FOR (n=618)
FP/SAL (n=1,854)
Total (n=2,472)
p-valuea
316 (198–493)
360 (219–557)
352 (215–544)
<0.001
Asthma-related drug cost (GBP) Median (IQR) Asthma-related resource cost (GBP)
Effectiveness and cost impact of FP/FOR and FP/SAL April 2017
<0.001
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Median (IQR)
14 (14–42)
14 (0–56)
14 (14–56)
351 (228–557)
399 (248–638)
385 (242–614)
All asthma-related medical costs (GBP) Median (IQR)
<0.001
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304 305
a
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errors adjusted for matching.
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Abbreviations: FP/FOR, Fluticasone propionate/Formoterol; FP/SAL, Fluticasone propionate/Salmeterol.
p-value obtained from fitting a generalised linear model using Gamma distribution and log link, with standard
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Figure 1: Median asthma-related costs in GBP of prescribed medications, resource use, and total
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cost.
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Medical
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£400
£300
£200
£100
£0
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FP/FOR
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£0
£100
£200
£300
£400
FP/SAL
Abbreviations: FP/FOR, Fluticasone propionate/Formoterol; FP/SAL, Fluticasone propionate/Salmeterol.
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The matched combined FP/FOR asthma cohort was non-inferior compared with the combined
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FP/SAL asthma cohort in terms of the proportion of patients with no severe exacerbations.
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Using exacerbation prevention (ATS/ERS definition) and secondary care as the measure of
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treatment effectiveness the observed similarity is not unexpected, given that the active
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preventative medication was FP in both prescription cohorts.
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The total number of acute respiratory events in the outcome period was significantly
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different between the two cohorts. This indicates that prescription of FP/FOR may be associated
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with fewer lower respiratory primary care consultations, where the patient presents with a
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condition requiring antibiotics or oral corticosteroids, as compared with FP/SAL. Alternative
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explanations for the observed difference include individual prescribing preferences of primary
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care physicians, differences in the coding system used, and the use of different codes to record
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events. The observed reduction in the number of associated lower respiratory primary care
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consultations in the outcome period for the FP/FOR cohort strengthens this hypothesis.
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Furthermore, the acute respiratory event rate was found to be significantly lower for the combined FP/FOR cohort compared with the combined FP/SAL cohort. Although superiority of
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this outcome was not the aim of the study, one possible explanation for the reduced acute
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respiratory event rate in the FP/FOR cohort may be that patients do not present to their primary
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care physician as often for respiratory conditions owing to improved symptom control with
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Formoterol as with Salmeterol. Alternatively, the difference in average index date between the
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cohorts (2013 for FP/FOR and 2008 for FP/SAL) may indicate an increased awareness of
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effective asthma treatment and less reliance on antibiotic prescription in patients prescribed
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FP/FOR owing to improved disease management. The large difference in index year (2013 for
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FP/FOR compared with 2008 for FP/SAL) reflects the later licensing of FP/FOR (from
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September 2012). SABA daily dose was similar for FP/FOR and FP/SAL patients, which may
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indicate comparable day-to-day symptom control when the disease is controlled. Other
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differences between the two cohorts, such as better risk domain asthma control in the FP/FOR
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cohort, are also potentially related to the difference in index year as a result of improved data
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recording practices or changes in management guidelines. Although there were many statistically
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significant differences in the baseline characteristics between the groups, the magnitude of most
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was not clinically meaningful.
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Our real-world study supports findings reported in a randomised controlled trial (RCT) where FP/FOR was found to be comparable to FP/SAL in terms of improvements in lung
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function and measures of asthma control [14]. The authors of this study, in accordance with other
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researchers, found FP/FOR to have a more rapid onset of action and suggest that if patients
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perceive the benefits of FP/FOR more rapidly than FP/SAL, this could have a positive impact on
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adherence [13, 14]. This correlates with a study by Bender et al., who found that patients
350
expressed a wish for more immediate symptom relief [33].
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This study found that the cost impact of FP/FOR was lower than that of FP/SAL and is
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driven by the associated lower total respiratory drug cost. The exploratory lower resource cost
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analysis also indicates that there are fewer demands on health care resources irrespective of drug
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costs. This was reiterated in a recent budget analysis where FP/FOR was revealed to be the least
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costly option for the NHS in comparison with FP/SAL [13]. Although a more in-depth health
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economic analysis would provide a more robust comparison, our cost impact analysis shows that
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the lower current price of FP/FOR is associated with lower overall respiratory-related costs
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compared with FP/SAL prescriptions.
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Our data provide evidence that despite the use of ICS/LABA, there is still a large
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proportion of patients (>70%), in both cohorts, who are uncontrolled and >60% of patients using
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SABA rescue therapy daily. This agrees with previous studies such as Asthma Insights and
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Reality in Europe (AIRE) and the International Asthma Patient Insight Research (INSPIRE)
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study that have shown that only a small proportion of patients achieve guideline targets for
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asthma control [34, 35]. The INSPIRE study found that >70% of patients prescribed ICS/LABA
365
had uncontrolled asthma according to Asthma Control Questionnaire data. Our findings also
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reflect those found in this global study where 74% of patients used their SABA therapy every
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day [35], further demonstrating poor asthma control. Multiple factors have been identified as
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contributors to the lack of control including incorrect diagnosis, sub-optimal inhaler technique,
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poor compliance, smoking and co-morbidities [36], and patient choice [37]. Underestimation of
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disease severity and hence insufficient prescription or therapy-resistant disease is also a prevalent
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problem. Our previous studies including Recognise Asthma and Link to Symptoms and
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Experience (REALISE) [38, 39] and the EUrope and CANada (EUCAN) study
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[40] demonstrated that patients with asthma reported features indicating uncontrolled disease
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though the majority believed to be controlled. This implies that patients have low expectations of
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long-term asthma management. Regardless of the cause, these data show that there is a large
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proportion of patients globally that have suboptimally controlled asthma
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Real-world evidence corroborates and reinforces the results from clinical trials. The use
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of a large database enabled us to analyse data on real-life patients from a high-quality source, the
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OPCRD, which has previously been used in respiratory research [24, 41, 42]. This allowed us to
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include a broad range of patients comparable to those typically examined in primary care
381
settings. In addition, we studied outcomes over a full year both before and after the index patient
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review/change to balance seasonal influences and other transient confounders on outcome
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measures. Finally, the matching identified a comparator group that had most key variables
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evenly distributed at baseline.
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As with other observational studies, there is a potential for selection and physician bias and residual confounding. We addressed this by performing a matched analysis, and residual
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confounding was reduced by undertaking adjusted analyses. While the OPCRD is a well
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validated and maintained database [24, 41], we cannot rule out the possibility of inaccurate or
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missing data. To achieve the objectives, only patients with complete data for the study period
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were included, precluding evaluation of asthma-related deaths and other rare adverse effects with
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either inhaler. We relied on prescription information from the OPCRD primary care database,
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thus the data analysed allowed us to identify instances of when prescriptions were written by
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general practitioners (GPs). It does not include information on whether the prescription was
394
filled and therefore, we are unable to guarantee consumption of the medications in this study.
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Study findings are dependent on the availability and quality of the data in the OPCRD, which
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contains limited information on hospitalisations. Lastly, there are differences in index date
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because FP/FOR was licensed later than FP/SAL in the UK. This may have influenced study
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outcomes due to advances in asthma treatment guidelines.
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Conclusion
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Changing to or initiating patients on FP/FOR rather than FP/SAL for asthma treatment is
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associated with non-inferior clinical outcomes. An exploratory analysis showed that FP/FOR is
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associated with improved prescription possession as well as lower respiratory related medication,
404
health care resource use, and overall aggregated cost in a real-life UK patient population.
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Acknowledgements
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With institutional support from NAPP Pharmaceutical Group Ltd. All named authors meet the
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International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this
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manuscript, take responsibility for the integrity of the work and have given final approval to the
410
version to be published. The authors would like to thank Rosalind Bonomally for medical
411
writing support.
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References
413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458
1. 2.
8. 9.
10.
11.
12. 13. 14.
15.
16.
17.
18.
19.
RI PT
SC
7.
M AN U
6.
TE D
5.
EP
4.
AC C
3.
Martinez, F.D. and D. Vercelli, Asthma. Lancet, 2013. 382(9901): p. 1360-72. Disease, G.B.D., I. Injury, and C. Prevalence, Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet, 2016. 388(10053): p. 1545-1602. Global Initiative on Asthma (GINA). Global strategy for asthma management and prevention. 2016 [cited 2017 20th April]; Available from: http://ginasthma.org/. Boulet, L.P., et al., Evaluation of asthma control by physicians and patients: comparison with current guidelines. Can Respir J, 2002. 9(6): p. 417-23. Rabe, K.F., et al., Worldwide severity and control of asthma in children and adults: the global asthma insights and reality surveys. J Allergy Clin Immunol, 2004. 114(1): p. 40-7. Montuschi, P., Pharmacotherapy of patients with mild persistent asthma: strategies and unresolved issues. Front Pharmacol, 2011. 2: p. 35. Sin, D.D., et al., Pharmacological management to reduce exacerbations in adults with asthma: a systematic review and meta-analysis. JAMA, 2004. 292(3): p. 367-76. Price, D., et al., Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma? NPJ Prim Care Respir Med, 2014. 24: p. 14023. (BTS), B.T.S. BTS/SIGN British guideline on the management of asthma. 2016 [cited 2017 12 April ]; Available from: https://www.brit-thoracic.org.uk/standards-of-care/guidelines/btssignbritish-guideline-on-the-management-of-asthma/. Postma, D.S., H.A. Kerstjens, and N.H. ten Hacken, Inhaled corticosteroids and long-acting betaagonists in adult asthma: a winning combination in all? Naunyn Schmiedebergs Arch Pharmacol, 2008. 378(2): p. 203-15. Rosenhall, L., et al., Budesonide/Formoterol in a single inhaler (Symbicort) reduces healthcare costs compared with separate inhalers in the treatment of asthma over 12 months. Int J Clin Pract, 2003. 57(8): p. 662-7. Bell, A.D. and R.A. McIvor, The SMART study. Can Fam Physician, 2007. 53(4): p. 687-8. Aalbers, R., et al., Onset of bronchodilation with Fluticasone/Formoterol combination versus Fluticasone/Salmeterol in an open-label, randomized study. Adv Ther, 2012. 29(11): p. 958-69. Bodzenta-Lukaszyk, A., et al., Fluticasone/Formoterol combination therapy is as effective as Fluticasone/Salmeterol in the treatment of asthma, but has a more rapid onset of action: an open-label, randomized study. BMC Pulm Med, 2011. 11: p. 28. Condemi, J.J., Comparison of the efficacy of Formoterol and Salmeterol in patients with reversible obstructive airway disease: a multicenter, randomized, open-label trial. Clin Ther, 2001. 23(9): p. 1529-41. Ullman, A., et al., Onset of action and duration of effect of Formoterol and Salmeterol compared to salbutamol in isolated guinea pig trachea with or without epithelium. Allergy, 1992. 47(4 Pt 2): p. 384-7. Aalbers, R., et al., Adjustable maintenance dosing with budesonide/Formoterol compared with fixed-dose Salmeterol/Fluticasone in moderate to severe asthma. Curr Med Res Opin, 2004. 20(2): p. 225-40. Shapiro, G., et al., Combined Salmeterol 50 microg and Fluticasone propionate 250 microg in the diskus device for the treatment of asthma. Am J Respir Crit Care Med, 2000. 161(2 Pt 1): p. 52734. Bodzenta-Lukaszyk, A., et al., Efficacy and safety profile of Fluticasone/Formoterol combination therapy compared to its individual components administered concurrently in asthma: a randomised controlled trial. Curr Med Res Opin, 2013. 29(5): p. 579-88.
Effectiveness and cost impact of FP/FOR and FP/SAL April 2017
25
ACCEPTED MANUSCRIPT
24. 25. 26. 27.
28. 29.
30. 31. 32.
33. 34. 35. 36. 37. 38.
RI PT
SC
23.
M AN U
22.
TE D
21.
NHS. An Outcomes Strategy for COPD and Asthma: NHS Companion Document. 2012 [cited 2016 13 Dec 2016]; Available from: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/216531/dh_1 34001.pdf. Farrington, E., et al., FP/FORM Versus FP/SAL Within Clinical Practice: An Updated Budget Impact Analysis in Asthma. Adv Ther, 2016. 33(5): p. 794-806. Daina Lim, I.S., Stephanie Wolfe, John Hamill, Kevin Gruffydd-Jones, Cathal Daly and David Price. Real life effectiveness of changing fixed-dose combination therapy from Seretide® metered dose inhaler (MDI) to Flutiform® in UK patients with asthma. in Respiratory Effectiveness Group (REG) Summit 2014. 2014. London, England. Group, A.o.b.o.t.R.E., Meeting abstracts from the Respiratory Effectiveness Group 2015 Winter Summit - databases and registries around the world: maximizing the yield Pragmatic and Observational Research, 2015. 2016:6: p. 13-38. OPCRD. The Optimum Patient Care Research Database (OPCRD). 2016 [cited 2017 19th April]; Available from: http://optimumpatientcare.org/opcrd/. NHS. Dictionary of Medicines and Devices (dm+d). 2015 [cited 2017 20th April]; Available from: https://apps.nhsbsa.nhs.uk/DMDBrowser/DMDBrowser.do. Unit, P.S.S.R. Unit Costs of Health and Social Care 2015 [cited 2016 13 December]; Available from: http://www.pssru.ac.uk/project-pages/unit-costs/2015/index.php. Barnes, N., et al., Asthma control with extrafine-particle hydrofluoroalkane-beclometasone vs. large-particle chlorofluorocarbon-beclometasone: a real-world observational study. Clin Exp Allergy, 2011. 41(11): p. 1521-32. Colice, G., et al., Asthma outcomes and costs of therapy with extrafine beclomethasone and Fluticasone. J Allergy Clin Immunol, 2013. 132(1): p. 45-54. Price, D., et al., Prescribing practices and asthma control with hydrofluoroalkanebeclomethasone and Fluticasone: a real-world observational study. J Allergy Clin Immunol, 2010. 126(3): p. 511-8 e1-10. Israel, E., et al., Increased Dose of Inhaled Corticosteroid versus Add-On Long-acting beta-Agonist for Step-Up Therapy in Asthma. Ann Am Thorac Soc, 2015. 12(6): p. 798-806. Chung, K.F., et al., International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J, 2014. 43(2): p. 343-73. Price D, S.I., Wolfe S, Hamil J, Gruffydd-Jones K, Daly C, Haughney J, Yau S, Clinical effectiveness and cost impact in UK patients with asthma switching from Fluticasone-propionate/Salmeterol pMDI to Fluticasone-propionate/Formoterol pMDI [Abstract 51]. Primary Care Respiratory Medicine, 2015. 25. Bender, B.G., et al., Factors influencing patient decisions about the use of asthma controller medication. Ann Allergy Asthma Immunol, 2007. 98(4): p. 322-8. Rabe, K.F., et al., Clinical management of asthma in 1999: the Asthma Insights and Reality in Europe (AIRE) study. Eur Respir J, 2000. 16(5): p. 802-7. Partridge, M.R., et al., Attitudes and actions of asthma patients on regular maintenance therapy: the INSPIRE study. BMC Pulm Med, 2006. 6: p. 13. Haughney, J., et al., Achieving asthma control in practice: understanding the reasons for poor control. Respir Med, 2008. 102(12): p. 1681-93. Haughney, J., et al., Features of asthma management: quantifying the patient perspective. BMC Pulm Med, 2007. 7: p. 16. Price, D., M. Fletcher, and T. van der Molen, Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim Care Respir Med, 2014. 24: p. 14009.
EP
20.
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459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506
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39. 40. 41. 42.
Price, D., et al., Time for a new language for asthma control: results from REALISE Asia. J Asthma Allergy, 2015. 8: p. 93-103. Sastre, J., et al., Insights, attitudes, and perceptions about asthma and its treatment: a multinational survey of patients from Europe and Canada. World Allergy Organ J, 2016. 9: p. 13. CPRD. The Clinical Practice Research Datalink (CPRD). https://www.cprd.com/home/ 16 Dec 2015 [cited 2017 19th April]. Jones, R.C., et al., Opportunities to diagnose chronic obstructive pulmonary disease in routine care in the UK: a retrospective study of a clinical cohort. Lancet Respir Med, 2014. 2(4): p. 26776.
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ACCEPTED MANUSCRIPT Manuscript Number: YRMED-D-17-00404 Manuscript Title: Initiating or changing to a fixed-dose combination of fluticasone propionate/formoterol over fluticasone propionate/salmeterol: a real-life effectiveness and cost impact evaluation Respiratory Medicine.
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Efficacious and cost-effective asthma treatment is necessary FP/FOR is associated with non-inferior clinical outcomes compared to FP/SAL Combined health care costs in a real-life UK population decreased with FP/FOR
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Highlights