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Chronic obstructive pulmonary disease hospital admissions and drugs—unexpected positive associations: a retrospective general practice cohort study

Chronic obstructive pulmonary disease hospital admissions and drugs—unexpected positive... www.nature.com/npjpcrm All rights reserved 2055-1010/14 ARTICLE OPEN Chronic obstructive pulmonary disease hospital admissions and drugs—unexpected positive associations: a retrospective general practice cohort study 1 1 2 1 1 Timothy H Harries , Paul T Seed , Simon Jones , Peter Schofield and Patrick White BACKGROUND: Increased prescribing of inhaled long-acting anti-muscarinic (LAMA) and combined inhaled long-acting β -agonist and corticosteroid (LABA+ICS) drugs for the treatment of chronic obstructive pulmonary disease (COPD) has led to hopes of reduced hospital admissions from this disease. AIMS: To investigate the impact of rising primary care prescribing of LAMA and LABA+ICS drugs on COPD admissions. METHODS: This retrospective cohort study of general practice COPD admission and prescribing data between 2007 and 2010 comprised a representative group of 806 English general practices (population 5,264,506). Outcome measures were practice rates of COPD patient admissions and prescription costs of LAMA and LABA+ICS. General practice characteristics were based on the UK quality and outcomes framework. RESULTS: Rates of COPD admissions remained stable from 2001 to 2010. Practice-prescribing volumes of LAMA per practice patient and LABA+ICS per practice patient increased by 61 and 26%, respectively, between 2007 and 2010. Correlation between costs of LAMA and those of LABA+ICS increased year on year, and was the highest in 2010 (Pearson’s r = 0.68; 95% confidence interval (CI), 0.64–0.72). Practice COPD admission rates were positively predicted by practice-prescribing volumes of LAMA (2010: B = 1.23, 95% CI, 0.61–1.85) and of LABA+ICS (2010: B = 0.32, 95% CI, 0.12–0.52) when controlling for practice list size, COPD prevalence and deprivation. CONCLUSION: The increase in the prescribing of LAMA and LABA+ICS inhalers was not associated with the predicted fall in hospital admission rates for COPD patients. The positive correlation between high practice COPD prescribing and high practice COPD admissions was not explained. npj Primary Care Respiratory Medicine (2014) 24, Article number: 14006; doi:10.1038/npjpcrm.2014.6; published online 20 May 2014 INTRODUCTION contraindicated in COPD) reduces the rate of moderate/severe COPD exacerbations and reduces exacerbation-related admissions Chronic obstructive pulmonary disease (COPD) is a leading cause 1,2 when compared with placebo. When compared with LABA, LABA of death and of emergency hospital admissions worldwide. +ICS significantly reduces exacerbations with no difference in The efficacy of COPD drugs in reducing exacerbations and admissions. hospital admissions and improving the quality of life has been 3–6 Despite the benefits of LAMA in reducing the frequency of reported in clinical trials. The success of the three main classes COPD exacerbations, its effect on exacerbation-related admissions of COPD drugs—the inhaled long-acting muscarinic antagonist is less clear. When compared with placebo, the LAMA tiotropium (LAMA) bronchodilator tiotropium, inhaled long-acting β -agonists reduces the proportion of patients with one or more exacerba- (LABAs), and combined LABA and inhaled corticosteroid 11,12 tions requiring hospitalisation. Subgroup analysis by severity (LABA+ICS) inhalers—has transformed the perception of the drug of the UPLIFT trial found this difference to be not significant in treatment of the disease. Drug treatment of COPD is a major cost to the UK National patients with severe/very severe COPD, those most likely to be Health Service (NHS). The LABA+ICS combination inhaler of admitted with exacerbations. Few studies have examined the translation of these findings salmeterol–fluticasone was the single most costly drug product into everyday clinical settings. A meta-analysis of LAMA trials and prescribed by general practitioners in England in 2011. Between a retrospective analysis of COPD prescribing suggested that the January 2007 and January 2011 in England the annual spending on LAMAs increased from £78 million to £130 million, an increase effectiveness of LAMA in reducing COPD admissions in routine practice was at best limited and in other circumstances may have of 65%, and that on LABA+ICS increased from £385 million to £498 10,13 million, an increase of 29% (Appendix), at a time when spending been associated with increased risk. Furthermore, a cost-utility on LABAs fell by 25%. analysis concluded that LAMA had an unfavourable cost- Monotherapy with LAMA or LABA improves respiratory effectiveness ratio. symptoms and quality of life and leads to fewer COPD In the NHS, the majority of prescribing of LAMA and LABA+ICS is 8 15 exacerbations. Treatment with LABA+ICS (ICS monotherapy is undertaken by general practitioners in the community. It was 1 2 King’s College London, King’s Health Partners, Division of Health and Social Care Research, London, UK and Department of Health Care Management and Policy, University of Surrey, Guildford, Surrey, UK. Correspondence: TH Harries (timothy.harries@kcl.ac.uk) Received 19 October 2013; revised 10 January 2014; accepted 8 February 2014 © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited Association between COPD drugs and hospital admissions TH Harries et al hoped that these drugs would reduce the risk of admission from Inclusion criteria COPD and consequently reduce the healthcare-related costs of Practices were included if complete data had been obtained on 16,17 the disease. prescriptions for inhaled remedies dispensed by pharmacists for at least 3 of the 4 years from 2007 to 2010 and complete COPD admission data for The aim of this study was to determine whether the increasing at least 8 of the 10 years from 2001 to 2010. At no point were more than 23 rates of use of LAMA and LABA+ICS in the NHS were reflected in a practices (2.9%) missing from the data analysis. No allowance was made in reduction in the rate of admissions for COPD and whether general the analysis for missing data. practices with higher rates of prescribing of these drugs had fewer COPD admissions compared with low-prescribing practices. LABAs Admissions data were excluded from the analysis because their prescription We obtained anonymised patient-level data on COPD patient admissions declined throughout the study. from the NHS Information Centre Hospital Episodes Statistics database (Appendix). A primary diagnosis field captured all patient admissions in England from 2001 to 2010 with a primary diagnosis of COPD (ICD-10 MATERIALS AND METHODS codes J40-J44) for patients within practices in the selected PCTs. We Study design undertook analysis by patient admitted per year rather than by each We conducted a retrospective cohort study of general practice COPD admission per year to avoid the potential distortion that would be admissions and inhaler use in the English NHS using data from two associated with multiple admissions of the same patient. independent sources: the NHS Information Centre and the NHS Business Services Authority (NHSBSA). Unit of analysis was NHS general practice. Prescribing data We sought prescribing data from the NHSBSA for all practices within the 15 Participating practices PCTs. Data were obtainable from 2007 to 2010 and not available prior to At the time of this study, general practices in England were grouped in 2007. We based our assessment on prescription costs as these were the Primary Care Trusts (PCTs), managerial groupings comprising around best estimate of the volume of prescriptions dispensed. Costs of drugs 50–60 practices. Selection of study practices was limited by constraints were stable and uniform within the NHS and more accurately reflected the imposed by the NHSBSA, which provided prescription-dispensing data in volume of drug dispensed than the item issued, which did not include the response to requests made under the Freedom of Information Act 2000. volume or amount of drug. We chose not to use Specific Therapeutic To obtain a representative sample of practices with respect to COPD group Age-sex weightings Related Prescribing Units as our unit of prevalence, we stratified each PCT in England by mean COPD prevalence in prescribing as prescribing for COPD is predominantly in patients over patients aged ⩾ 45 years within their respective practices and by 45 years of age. Instead, we controlled for list size, COPD prevalence and deprivation using the mean Index of Multiple Deprivation (IMD) score. practice deprivation in the analysis. IMD is a multidimensional score based on decennial national census data Total costs of NHS prescriptions dispensed presented as Net Ingredient and annual local authority population data reflecting deprivation specific Cost were calculated by the NHSBSA for each practice. Net Ingredient to a geographical area based on the practice address. We made a random Cost was the cost to the NHS of each LAMA and of each LABA+ICS selection of 50 PCTs representing the distribution of characteristics by drug dispensed by pharmacists from prescriptions from the study which all PCTs were stratified. From this selection the NHSBSA made a practices (Appendix). Costs and dates of dispensing of each item were pragmatic selection of 15 PCTs based on the availability of dispensing data. aggregated by general practice and by PCT. Aggregated prescribing data could only be obtained from the NHSBSA through freedom of These were data on prescriptions dispensed for which community pharmacists were reimbursed by the NHS. information enquiries. Access to data was restricted. Size limits were imposed on each enquiry, necessitating our making 10 separate requests to the NHSBSA between January 2011 and August 2012. Data on most Practice characteristics small practices were withheld by the NHSBSA to prevent the identification We obtained characteristics of selected practices from the NHS Information of individual prescribers, an action that would contravene the Data Centre Quality and Outcomes Framework (QOF) database for the years Protection Act. The data we obtained were made available online on the 2006–2010 (Appendix). QOF is the basis of a financial incentive system NHSBSA website (Appendix). Prescribing data obtained were independent that was applied to general practices in the form of clinical and of underlying disease and may have represented use among asthmatic as administrative performance points. QOF data, to which there is open well as COPD patients. access, included practice list size, prevalence of diagnosed COPD, IMD scores and overall and COPD treatment-related QOF points awarded. Statistical methods These demographic and performance characteristics were collected to We based prescribing analysis on the annual prescription (dispensing) adjust for their effect in the analysis of the relationship between COPD costs of LAMA and LABA+ICS per registered practice patient (2007–2010). prescribing and admissions. Figure 1. Identification of practices for inclusion in the study. npj Primary Care Respiratory Medicine (2014) 14006 © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited Association between COPD drugs and hospital admissions TH Harries et al We based hospital admission analysis on the annual rate of patients Table 1. Study practices (806) compared with all other practices in admitted with a COPD exacerbation (2001–2010) per 10,000 registered England (7,439): characteristics drawn from QOF data set 2010 practice patients. We sought correlations between general practices’ prescription costs per Practice Mean (s.d.) Difference between practice patient for LAMA and their prescription costs per practice patient characteristic means (± 95% CI) for LABA+ICS from 2007 to 2010. To correct for possible spurious correlation, we calculated the coefficients of the logged costs of LAMA Practice list size 22,23 and of LABA+ICS, controlling for the log of practice list size. Study 6,517 (3,780) −166 (−133.1 to 444.7) We used multiple linear regression to examine the relationship in each England 6,683 (4,228) year between the prescription costs of each drug per practice patient and the rate of COPD patients admitted per 10,000 practice patients. We Males (%) controlled for the prevalence of diagnosed COPD, IMD score and the Study 50.7 (2.6) 0.4 (0.2–0.6) practice performance indicators obtained from QOF. We expressed both England 50.3 (2.9) predictors and outcomes as rates per practice patient, and included a correction using the inverse of the list size (1/list size) according to the Patients aged 45+ (%) method of Kronmal to correct for possible spurious correlation. Study 39.3 (9.5) − 1.2 (−2.0 to -0.6) As confirmatory analysis we fitted a multiple linear regression model, England 40.5 (10.1) correcting for practice list size and COPD prevalence, according to the formula: Patients aged 45–64 (%) Study 24.5 (4.9) − 0.6 (−1.0 to -0.3) log (COPD patient admitted) = log (LAMA cost) + log (LABA + ICS cost) England 25.1 (4.9) + log (practice list size) + log (IMD score) + log (total QOF score) + log (COPD QOF score) + log (COPD registered patients). Patients aged 65–74 (%) Study 7.8 (2.6) − 0.3 (−0.5 to − 0.1) We used the statistical package SPSS version 20 for data analysis. Ethical England 8.1 (3.0) approval was not required for this study as data were at practice level. Patients aged 75+ (%) Study 7.0 (2.7) − 0.3 (−0.5 to −0.1) RESULTS England 7.3 (3.8) Participants We included data from 806 practices (population 5,264,506) Deprivation score Study 33.8 (17.6) 8.0 (6.6–9.2) (Figure 1). We excluded 215 practices because of insufficient data. England 25.8 (17.2) Study practices differed from national practices in their greater deprivation and prevalence of diagnosed COPD, but were no PCT cost of LABA+ICS/patient (£) different in practice size or drug costs (Table 1). Study 9.60 (2.00) 0.57 (−0.77 to 1.90) QOF data were available for 162 of the 215 excluded practices. England 9.03 (2.54) These were significantly smaller (list size mean difference 3,599; 95% confidence interval (CI), 2,991.7–4,206.2), included more PCT cost of LAMA/patient (£) single-handed practices (58.1 vs. 8.7%) (difference 49.4%, 95% CI, Study 2.64 (0.67) 0.26 (−0.19 to 0.71) England 2.38 (0.85) 41.4–57.4) and were more deprived (IMD score mean difference 7.0; 95% CI, 4.0–10.1) than the study practices. Diagnosed COPD prevalence (%) Prevalence of diagnosed COPD in study practices increased by Study 1.93 (0.88) 0.26 (0.19–0.32) 0.13% (95% CI, 0.11–0.16) from 1.79 to 1.92% from 2007 to 2010 England 1.67 (0.97) (Figure 2). Figure 2 includes reference to the predicted national prevalence of COPD (2.58%) in 2010. Prevalence of diagnosed QOF points/available asthma in study practices increased by 0.21% (95% CI, 0.17–0.26) Study 0.948 (0.04) 0.001 (−0.005 to 0.003) England 0.947 (0.05) from 5.93 to 6.14% over this period. COPD points/available Prescribing data Study 0.981 (0.06) 0.008 (0.003–0.012) The annual prescribing cost per practice patient (all patients) of England 0.973 (0.10) LAMA increased by 61% from a mean of £1.81 in 2007 to £2.90 in Smoking points/available 2010 (mean difference £1.09, 95% CI, 1.03–1.16). LABA+ICS cost Study 0.994 (0.04) 0.002 (−0.0036 to 0.0004) increased by 26% from a mean of £7.87 in 2007 to £9.89 in 2010 England 0.992 (0.03) (mean difference £2.02, 95% CI, 1.89–2.15; Figure 3). The median (interquartile range) cost per practice patient in the same period Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmon- increased from £1.59 (1.01–2.37) to £2.66 (1.82–3.69) for LAMA and ary disease; LABA+ICS, combined inhaled long-acting β -agonist and corticosteroid; LAMA, long-acting anti-muscarinic; PCT, Primary Care Trust; from £7.44 (5.35–10.11) to £9.79 (7.10–12.34) for LABA+ICS. QOF, Quality and Outcomes Framework. Admissions data The annual rate of COPD patients admitted per 10,000 practice 2010 are shown in Figure 4. Reference to the year of publication patients increased from a mean (s.d.) of 15.7 (10.2) in 2001 to 18.3 (February 2003) of the first study on the efficacy of the combination (10.2) in 2010 (mean difference 2.6 patients per 10,000 practice of salmeterol–fluticasone in improving exacerbations in COPD is patients, 95% CI, 1.8–3.3). The median (interquartile range) of 3 included. This date was close to that of the introduction of COPD patients admitted per 10,000 practice patients varied tiotropium in the United Kingdom (September 2002). between a minimum of 13.7 (8.6–20.4) in 2001 and a maximum of 16.1 (9.9–23.5) in 2003 with an annual average median Prescribing correlations (interquartile range) of 15.5 (10.0–22.4) over 10 years. To demonstrate the difference between COPD patients admitted The correlations between the prescribing costs of LAMA per and COPD admissions, means of both, including CIs, from 2001 to practice patient and those of LABA+ICS per practice patient are © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited npj Primary Care Respiratory Medicine (2014) 14006 Association between COPD drugs and hospital admissions TH Harries et al Table 2. Correlation between rates of practice prescribing cost per practice patient of LAMA and LABA+ICS (with partial correlation of log of the cost of LAMA and the log of the cost of LABA+ICS when controlling for the log of the practice list size) Rate LAMA versus Log LAMA cost versus Predicted COPD prevalence, England 2010 (Nacul et al., 2011) Year Rate LABA+ICS Log LABA+ICS cost R (±95% CI) R (±95% CI) 1 2 2007 (n= 798) 0.52 (0.47–0.57) 0.56 (0.52–0.61) Diagnosed COPD (study practices) 2008 (n= 801) 0.60 (0.55–0.64) 0.63 (0.59–0.67) 2009 (n= 804) 0.63 (0.59–0.67) 0.67 (0.63–0.71) 2010 (n= 796) 0.68 (0.64– 0.72) 0.73 (0.69–0.76) R is Pearson’s correlation (unadjusted for practice list size). R is Partial 1 2 0 correlation (adjusted for log practice list size). n is number of practices. Abbreviations: CI, confidence interval; LABA+ICS, combined inhaled long- 2007 2008 2009 2010 acting β -agonist and corticosteroid; LAMA, long-acting anti-muscarinic. Year Figure 2. Prevalence (% ± 95% confidence interval) of diagnosed chronic obstructive pulmonary disease (COPD) in study practices Confirmatory analysis to exclude spurious correlation was 2007–2010 (dashed line shows predicted prevalence of COPD in 24 carried out using a log transformation model of prescribing to 2010). predict the log (base 10) of the hospital admission rate (Table 4). A significant increase in admissions was observed with greater prescribing of LAMA between 2008 and 2010 and with greater prescribing of LABA+ICS in 2007 and 2009. LABA+ICS DISCUSSION Main findings Practices that were high prescribers of LAMA and LABA+ICS drugs had higher rates of COPD admission compared with low- prescribing practices. This relationship was observed during a time of significant increase in national prescribing of both drug classes and unchanging rates of COPD admissions. Practice rates LAMA of prescribing of LAMA and LABA+ICS were strongly correlated. There was no evidence of reciprocal prescribing between these two groups of drugs whose effects on COPD in clinical trials were similar. There was considerable variation in prescribing across practices. The rates of prescribing of LAMA and LABA+ICS in those practices within the lowest quartile were respectively less than 2007 2008 2009 2010 Year half and almost half of those practices within the highest quartile. The small changes in the diagnosed prevalence of COPD and Figure 3. Annual rates (mean ± 95% confidence interval) of LAMA asthma were unlikely to be responsible for the increased and LABA+ICS prescribing costs per practice patient (all patients). prescribing of these drugs. There was no evidence of a change Costs expressed based on all patients on the practice list to in true prevalence of COPD and hence it is probable that the small standardise prescribing rates. The unit cost to the NHS of LAMA fell increase in diagnosed prevalence of COPD resulted from by 7.3% and the unit cost to the NHS of LABA+ICS fell by up to 4.5% between 2007 and 2010 (BNF.org). LAMA, long-acting anti-muscari- improved recognition of the disease or changes in clinical nic; LABA+ICS, combined inhaled long-acting β -agonist and 2 recording practice. corticosteroid; NHS, National Health Service. Strengths and limitations of this study The pattern of increasing inhaled medication prescription volume shown in Table 2. To test for spurious correlation, partial and unchanging rate of COPD patient admissions and the correlations of the log of the cost of LAMA and log of the cost consistency of the relationship between practice-level prescribing of LABA+ICS, controlling for the log of practice list size, are and COPD admissions throughout the study were striking. included. Prescribing data were based on NHS prescriptions dispensed, a better reflection of the true impact of the drugs compared with Regression and sensitivity analyses prescribers’ records, which would reflect prescriber intentions Estimates for the association between prescribing costs and COPD rather than patient use. Study practices did not differ from the patient admission rates (2007–2010) are shown in Table 3. Results practices in England other than their being situated in more were adjusted for COPD prevalence, IMD score, QOF points (total deprived areas, the most likely explanation for their high COPD and COPD specific) and inverse of practice size (1/practice size), prevalence. The increase in the prescribing of COPD drugs in study which were significantly associated with COPD admissions in practices from 2007 to 2010 matched that in England. It is likely univariate analysis. that the study findings reflected the pattern of care in England. Numbers in the table can be interpreted as additional Concerns regarding the accuracy of routinely collected data admissions/10,000 patients/£ spent on the drug per practice sources, including Hospital Episodes Statistics admissions data, patient. have been ameliorated by improvements in quality over recent npj Primary Care Respiratory Medicine (2014) 14006 © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited Mean prescribing cost per patient (£) Mean prevalence of COPD (%) Association between COPD drugs and hospital admissions TH Harries et al 30 30 Admissions 20 20 Patients admitted 10 10 TRISTAN study published 0 0 2000 2002 2004 2006 2008 2010 Year Figure 4. Annual rates (mean ± 95% confidence interval) of chronic obstructive pulmonary disease (COPD) patients admitted and of all COPD admissions per 10,000 practice patients. Table 3. Association of practice rates of prescribing of LAMA and LABA+ICS with practice rates of patients admitted for COPD Associations with COPD patients admitted/10,000 patients on the list (multiple linear regression) Predictor variable 2007 (n = 787) 2008 (n = 790) 2009 (n = 797) 2010 (n = 783) LAMA cost/practice patient, β-statistic (±95% CI) 0.37 (−0.22 to 0.97) 1.24 (0.58–1.91) 1.12 (0.55–1.70) 1.23 (0.61–1.85) LABA+ICS cost/practice patient, β-statistic (±95% CI) 0.39 (0.22–0.56) 0.28 (0.08–0.48) 0.23 (0.05–0.41) 0.32 (0.12–0.52) Adjusted for COPD prevalence, local deprivation (Index of Multiple Deprivation score), clinical and administrative performance (Quality and Outcomes Framework points), and inverse of list size (1/practice size). Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; LABA+ICS, combined inhaled long-acting β -agonist and corticosteroid; LAMA, long-acting anti-muscarinic. Table 4. Association between prescribing costs and COPD patient admission rates (2007–2010) using a log-transformation model to predict the log (base 10) of the hospital admission rate Regression outcome 2007–2010 (±95% CI) Predictor variable 2007 2008 2009 2010 Log10 LAMA cost, β-statistic (±95% CI) 0.02 (−0.05 to 0.09) 0.22 (0.13–0.30) 0.19 (0.10–0.28) 0.29 (0.19–0.40) Log10 LABA+ICS cost, β-statistic (±95% CI) 0.20 (0.13–0.28) 0.07 (−0.03 to 0.16) 0.11 (0.01–0.21) 0.10 (−0.01 to 0.22) Dependent variable: Log10 COPD patients admitted. Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; LABA+ICS, combined inhaled long-acting β -agonist and corticosteroid; LAMA, long-acting anti-muscarinic. years. The relative stability of annual admission rates in our data individual patients. Disease severity is an important example. and the consistency of the relationship between admissions and Another possible confounder is the actual level of use of prescribing gave cause for confidence. medication by individuals. The advantage of being able to analyse Analysing data at a practice level rather than at patient level has a large cohort of practices as we have done here is that the large the disadvantage in a study with an ecological element such as number of COPD admissions observed has given us the power to this of missing possible explanatory variables that are exclusive to examine the relationship between prescribing and admissions, © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited npj Primary Care Respiratory Medicine (2014) 14006 COPD patients admitted (mean/10,000 practice patients) COPD admissions (mean/10,000 practice patients) Association between COPD drugs and hospital admissions TH Harries et al which would be impossible at individual practice level. As is a huge financial burden to the UK taxpayer from the widespread admissions occur mainly among the most severely affected COPD use of prescription drugs, the extent of effectiveness of which in patients it may be surmised that the patients admitted were COPD is uncertain. 4,27 predominantly those with severe disease. We cannot assume that it was for these patients that LAMA and LABA+ICS were ACKNOWLEDGEMENTS prescribed. However, the positive association between prescribing and admissions was strong throughout the study when control- The authors thank Hannah Thornton and Helen Booth for their help with the initial data analysis and Mark Ashworth and Martin Gulliford for their assistance in ling for prevalence, deprivation, prescribing of the other drug type reviewing the draft paper. and practice performance data. It would seem perverse to suggest that the significant increase in prescribing took place only in those patients who were not at risk of admission. CONTRIBUTIONS The association between high practice rates of prescribing of PW and THH devised the study and all authors contributed to its design. PW, LAMA and LABA+ICS and high practice rates of COPD admission THH and SJ contributed to data collection. PW, THH, PTS and PS contributed to may be explained by larger numbers of severely affected COPD data analysis. PW and THH wrote the first draft. All authors commented and patients being found in high prescribing practices. If this was the contributed to the final paper. case it would suggest that the drugs were ineffective at reducing admissions, as rates of COPD admission have not fallen following the introduction and progressive increase in rates of prescribing of COMPETING INTERESTS these drugs. An increased rate of prescription of LABA+ICS to PW has received project grants, consultancy fees, speaker fees and support for patients with asthma may have contributed to the increasing rate attending conferences from a number of pharmaceutical company manufac- of prescribing of these drugs within the practices. turers of respiratory drugs, but has no other financial relationships with any organisations that might have an interest in the submitted work. The remaining Interpretation of findings in relation to previously published work authors declare no conflict of interest. The reduction in the frequency of COPD exacerbations seen in clinical trials of LAMA and LABA+ICS has raised the hope that prescribing of these drugs in patients with severe and very severe FUNDING COPD would reduce COPD admissions, leading to substantial cost 4,28,29 This study is the independent work of the authors. THH was supported by a savings. The lack of evidence for their effect in reducing 30 National Institute for Health Research In-Practice fellowship. No other funding COPD admissions resonates with concerns of Suissa about was provided. underestimates of the number needed to treat in clinical trials of LABA+ICS, which assessed outcome in terms of frequency of acute exacerbations of COPD assessed. REFERENCES The positive association between prescribing costs and admis- 1 The Burden of Lung Disease. 2nd Edn. A Statistics report from the BTS. http:// sions is unlikely to represent a causal relationship as there is no www.brit-thoracic.org.uk/Portals/0/Library/BTS%20Publications/burdeon_of_ evidence from clinical trials of such adverse effects. A second lung_disease2007.pdf, 2006. possible explanation might be that patients started using these 2 NICE. 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The images prepared for the department for constitutional affairs. http://webarchive.natio- or other third party material in this article are included in the article’s Creative Commons nalarchives.gov.uk/%2B/http:/www.dca.gov.uk/foi/reference/foi-independent- license, unless indicated otherwise in the credit line; if the material is not included under review.pdf, 2006. the Creative Commons license, users will need to obtain permission from the license 20 Payne RA, Abel GA. UK indices of multiple deprivation—a way to make holder to reproduce the material. To view a copy of this license, visit http:// comparisons across constituent countries easier. Health Stat Q 2012; 53: creativecommons.org/licenses/by-nc-nd/4.0/ 22–37. 21 Data Protection Act 1998. http://www.legislation.gov.uk/ukpga/1998/29/contents. APPENDIX 22 Kim HJ. Spurious correlation between ratios with a common divisor. Stat Prob Lett 1999; 44: 383–386. The drug prescribing data from the NHSBSA used during the study 23 Kronmal RA. Spurious correlation and the fallacy of the ratio standard revisited. are available online. J R Stat Soc 1993; 156:379–392. https://www.ppa.org.uk/foiRequest/foiRequestList.do (Request 24 Nacul L, Soljak M, Samarasundera E, Hopkinson NS, Lacerda E, Indulkar T et al. reference number 512422). COPD in England: a comparison of expected, model-based prevalence and https://www.ppa.org.uk/NHSBSA_foiRequest/foiRequestList.do observed prevalence from general practice data. J Public Health (Oxf) 2011; 33: (Request reference numbers: 516980, 520125, 520258, 520918, 108–116. 521923, 522492, 522931, 2643 and 2805). 25 Welsh EJ, Cates CJ, Poole P. Combination inhaled steroid and long-acting Health & Social Care Information Centre: http://www.ic.nhs.uk/. beta2-agonist versus tiotropium for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2010; 5: CD007891. Hospital Episodes Statistics: http://www.hesonline.nhs.uk/Ease/ 26 Improving data quality in the NHS: 2010 - Audit Commission. http://www.audit- servlet/ContentServer?siteID = 1937. commission.gov.uk/2010/08/improving-data-quality-in-the-nhs-2010/. British National Formulary: http://www.bnf.org/bnf/index.htm. © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited npj Primary Care Respiratory Medicine (2014) 14006 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Primary Care Respiratory Medicine Springer Journals

Chronic obstructive pulmonary disease hospital admissions and drugs—unexpected positive associations: a retrospective general practice cohort study

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www.nature.com/npjpcrm All rights reserved 2055-1010/14 ARTICLE OPEN Chronic obstructive pulmonary disease hospital admissions and drugs—unexpected positive associations: a retrospective general practice cohort study 1 1 2 1 1 Timothy H Harries , Paul T Seed , Simon Jones , Peter Schofield and Patrick White BACKGROUND: Increased prescribing of inhaled long-acting anti-muscarinic (LAMA) and combined inhaled long-acting β -agonist and corticosteroid (LABA+ICS) drugs for the treatment of chronic obstructive pulmonary disease (COPD) has led to hopes of reduced hospital admissions from this disease. AIMS: To investigate the impact of rising primary care prescribing of LAMA and LABA+ICS drugs on COPD admissions. METHODS: This retrospective cohort study of general practice COPD admission and prescribing data between 2007 and 2010 comprised a representative group of 806 English general practices (population 5,264,506). Outcome measures were practice rates of COPD patient admissions and prescription costs of LAMA and LABA+ICS. General practice characteristics were based on the UK quality and outcomes framework. RESULTS: Rates of COPD admissions remained stable from 2001 to 2010. Practice-prescribing volumes of LAMA per practice patient and LABA+ICS per practice patient increased by 61 and 26%, respectively, between 2007 and 2010. Correlation between costs of LAMA and those of LABA+ICS increased year on year, and was the highest in 2010 (Pearson’s r = 0.68; 95% confidence interval (CI), 0.64–0.72). Practice COPD admission rates were positively predicted by practice-prescribing volumes of LAMA (2010: B = 1.23, 95% CI, 0.61–1.85) and of LABA+ICS (2010: B = 0.32, 95% CI, 0.12–0.52) when controlling for practice list size, COPD prevalence and deprivation. CONCLUSION: The increase in the prescribing of LAMA and LABA+ICS inhalers was not associated with the predicted fall in hospital admission rates for COPD patients. The positive correlation between high practice COPD prescribing and high practice COPD admissions was not explained. npj Primary Care Respiratory Medicine (2014) 24, Article number: 14006; doi:10.1038/npjpcrm.2014.6; published online 20 May 2014 INTRODUCTION contraindicated in COPD) reduces the rate of moderate/severe COPD exacerbations and reduces exacerbation-related admissions Chronic obstructive pulmonary disease (COPD) is a leading cause 1,2 when compared with placebo. When compared with LABA, LABA of death and of emergency hospital admissions worldwide. +ICS significantly reduces exacerbations with no difference in The efficacy of COPD drugs in reducing exacerbations and admissions. hospital admissions and improving the quality of life has been 3–6 Despite the benefits of LAMA in reducing the frequency of reported in clinical trials. The success of the three main classes COPD exacerbations, its effect on exacerbation-related admissions of COPD drugs—the inhaled long-acting muscarinic antagonist is less clear. When compared with placebo, the LAMA tiotropium (LAMA) bronchodilator tiotropium, inhaled long-acting β -agonists reduces the proportion of patients with one or more exacerba- (LABAs), and combined LABA and inhaled corticosteroid 11,12 tions requiring hospitalisation. Subgroup analysis by severity (LABA+ICS) inhalers—has transformed the perception of the drug of the UPLIFT trial found this difference to be not significant in treatment of the disease. Drug treatment of COPD is a major cost to the UK National patients with severe/very severe COPD, those most likely to be Health Service (NHS). The LABA+ICS combination inhaler of admitted with exacerbations. Few studies have examined the translation of these findings salmeterol–fluticasone was the single most costly drug product into everyday clinical settings. A meta-analysis of LAMA trials and prescribed by general practitioners in England in 2011. Between a retrospective analysis of COPD prescribing suggested that the January 2007 and January 2011 in England the annual spending on LAMAs increased from £78 million to £130 million, an increase effectiveness of LAMA in reducing COPD admissions in routine practice was at best limited and in other circumstances may have of 65%, and that on LABA+ICS increased from £385 million to £498 10,13 million, an increase of 29% (Appendix), at a time when spending been associated with increased risk. Furthermore, a cost-utility on LABAs fell by 25%. analysis concluded that LAMA had an unfavourable cost- Monotherapy with LAMA or LABA improves respiratory effectiveness ratio. symptoms and quality of life and leads to fewer COPD In the NHS, the majority of prescribing of LAMA and LABA+ICS is 8 15 exacerbations. Treatment with LABA+ICS (ICS monotherapy is undertaken by general practitioners in the community. It was 1 2 King’s College London, King’s Health Partners, Division of Health and Social Care Research, London, UK and Department of Health Care Management and Policy, University of Surrey, Guildford, Surrey, UK. Correspondence: TH Harries (timothy.harries@kcl.ac.uk) Received 19 October 2013; revised 10 January 2014; accepted 8 February 2014 © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited Association between COPD drugs and hospital admissions TH Harries et al hoped that these drugs would reduce the risk of admission from Inclusion criteria COPD and consequently reduce the healthcare-related costs of Practices were included if complete data had been obtained on 16,17 the disease. prescriptions for inhaled remedies dispensed by pharmacists for at least 3 of the 4 years from 2007 to 2010 and complete COPD admission data for The aim of this study was to determine whether the increasing at least 8 of the 10 years from 2001 to 2010. At no point were more than 23 rates of use of LAMA and LABA+ICS in the NHS were reflected in a practices (2.9%) missing from the data analysis. No allowance was made in reduction in the rate of admissions for COPD and whether general the analysis for missing data. practices with higher rates of prescribing of these drugs had fewer COPD admissions compared with low-prescribing practices. LABAs Admissions data were excluded from the analysis because their prescription We obtained anonymised patient-level data on COPD patient admissions declined throughout the study. from the NHS Information Centre Hospital Episodes Statistics database (Appendix). A primary diagnosis field captured all patient admissions in England from 2001 to 2010 with a primary diagnosis of COPD (ICD-10 MATERIALS AND METHODS codes J40-J44) for patients within practices in the selected PCTs. We Study design undertook analysis by patient admitted per year rather than by each We conducted a retrospective cohort study of general practice COPD admission per year to avoid the potential distortion that would be admissions and inhaler use in the English NHS using data from two associated with multiple admissions of the same patient. independent sources: the NHS Information Centre and the NHS Business Services Authority (NHSBSA). Unit of analysis was NHS general practice. Prescribing data We sought prescribing data from the NHSBSA for all practices within the 15 Participating practices PCTs. Data were obtainable from 2007 to 2010 and not available prior to At the time of this study, general practices in England were grouped in 2007. We based our assessment on prescription costs as these were the Primary Care Trusts (PCTs), managerial groupings comprising around best estimate of the volume of prescriptions dispensed. Costs of drugs 50–60 practices. Selection of study practices was limited by constraints were stable and uniform within the NHS and more accurately reflected the imposed by the NHSBSA, which provided prescription-dispensing data in volume of drug dispensed than the item issued, which did not include the response to requests made under the Freedom of Information Act 2000. volume or amount of drug. We chose not to use Specific Therapeutic To obtain a representative sample of practices with respect to COPD group Age-sex weightings Related Prescribing Units as our unit of prevalence, we stratified each PCT in England by mean COPD prevalence in prescribing as prescribing for COPD is predominantly in patients over patients aged ⩾ 45 years within their respective practices and by 45 years of age. Instead, we controlled for list size, COPD prevalence and deprivation using the mean Index of Multiple Deprivation (IMD) score. practice deprivation in the analysis. IMD is a multidimensional score based on decennial national census data Total costs of NHS prescriptions dispensed presented as Net Ingredient and annual local authority population data reflecting deprivation specific Cost were calculated by the NHSBSA for each practice. Net Ingredient to a geographical area based on the practice address. We made a random Cost was the cost to the NHS of each LAMA and of each LABA+ICS selection of 50 PCTs representing the distribution of characteristics by drug dispensed by pharmacists from prescriptions from the study which all PCTs were stratified. From this selection the NHSBSA made a practices (Appendix). Costs and dates of dispensing of each item were pragmatic selection of 15 PCTs based on the availability of dispensing data. aggregated by general practice and by PCT. Aggregated prescribing data could only be obtained from the NHSBSA through freedom of These were data on prescriptions dispensed for which community pharmacists were reimbursed by the NHS. information enquiries. Access to data was restricted. Size limits were imposed on each enquiry, necessitating our making 10 separate requests to the NHSBSA between January 2011 and August 2012. Data on most Practice characteristics small practices were withheld by the NHSBSA to prevent the identification We obtained characteristics of selected practices from the NHS Information of individual prescribers, an action that would contravene the Data Centre Quality and Outcomes Framework (QOF) database for the years Protection Act. The data we obtained were made available online on the 2006–2010 (Appendix). QOF is the basis of a financial incentive system NHSBSA website (Appendix). Prescribing data obtained were independent that was applied to general practices in the form of clinical and of underlying disease and may have represented use among asthmatic as administrative performance points. QOF data, to which there is open well as COPD patients. access, included practice list size, prevalence of diagnosed COPD, IMD scores and overall and COPD treatment-related QOF points awarded. Statistical methods These demographic and performance characteristics were collected to We based prescribing analysis on the annual prescription (dispensing) adjust for their effect in the analysis of the relationship between COPD costs of LAMA and LABA+ICS per registered practice patient (2007–2010). prescribing and admissions. Figure 1. Identification of practices for inclusion in the study. npj Primary Care Respiratory Medicine (2014) 14006 © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited Association between COPD drugs and hospital admissions TH Harries et al We based hospital admission analysis on the annual rate of patients Table 1. Study practices (806) compared with all other practices in admitted with a COPD exacerbation (2001–2010) per 10,000 registered England (7,439): characteristics drawn from QOF data set 2010 practice patients. We sought correlations between general practices’ prescription costs per Practice Mean (s.d.) Difference between practice patient for LAMA and their prescription costs per practice patient characteristic means (± 95% CI) for LABA+ICS from 2007 to 2010. To correct for possible spurious correlation, we calculated the coefficients of the logged costs of LAMA Practice list size 22,23 and of LABA+ICS, controlling for the log of practice list size. Study 6,517 (3,780) −166 (−133.1 to 444.7) We used multiple linear regression to examine the relationship in each England 6,683 (4,228) year between the prescription costs of each drug per practice patient and the rate of COPD patients admitted per 10,000 practice patients. We Males (%) controlled for the prevalence of diagnosed COPD, IMD score and the Study 50.7 (2.6) 0.4 (0.2–0.6) practice performance indicators obtained from QOF. We expressed both England 50.3 (2.9) predictors and outcomes as rates per practice patient, and included a correction using the inverse of the list size (1/list size) according to the Patients aged 45+ (%) method of Kronmal to correct for possible spurious correlation. Study 39.3 (9.5) − 1.2 (−2.0 to -0.6) As confirmatory analysis we fitted a multiple linear regression model, England 40.5 (10.1) correcting for practice list size and COPD prevalence, according to the formula: Patients aged 45–64 (%) Study 24.5 (4.9) − 0.6 (−1.0 to -0.3) log (COPD patient admitted) = log (LAMA cost) + log (LABA + ICS cost) England 25.1 (4.9) + log (practice list size) + log (IMD score) + log (total QOF score) + log (COPD QOF score) + log (COPD registered patients). Patients aged 65–74 (%) Study 7.8 (2.6) − 0.3 (−0.5 to − 0.1) We used the statistical package SPSS version 20 for data analysis. Ethical England 8.1 (3.0) approval was not required for this study as data were at practice level. Patients aged 75+ (%) Study 7.0 (2.7) − 0.3 (−0.5 to −0.1) RESULTS England 7.3 (3.8) Participants We included data from 806 practices (population 5,264,506) Deprivation score Study 33.8 (17.6) 8.0 (6.6–9.2) (Figure 1). We excluded 215 practices because of insufficient data. England 25.8 (17.2) Study practices differed from national practices in their greater deprivation and prevalence of diagnosed COPD, but were no PCT cost of LABA+ICS/patient (£) different in practice size or drug costs (Table 1). Study 9.60 (2.00) 0.57 (−0.77 to 1.90) QOF data were available for 162 of the 215 excluded practices. England 9.03 (2.54) These were significantly smaller (list size mean difference 3,599; 95% confidence interval (CI), 2,991.7–4,206.2), included more PCT cost of LAMA/patient (£) single-handed practices (58.1 vs. 8.7%) (difference 49.4%, 95% CI, Study 2.64 (0.67) 0.26 (−0.19 to 0.71) England 2.38 (0.85) 41.4–57.4) and were more deprived (IMD score mean difference 7.0; 95% CI, 4.0–10.1) than the study practices. Diagnosed COPD prevalence (%) Prevalence of diagnosed COPD in study practices increased by Study 1.93 (0.88) 0.26 (0.19–0.32) 0.13% (95% CI, 0.11–0.16) from 1.79 to 1.92% from 2007 to 2010 England 1.67 (0.97) (Figure 2). Figure 2 includes reference to the predicted national prevalence of COPD (2.58%) in 2010. Prevalence of diagnosed QOF points/available asthma in study practices increased by 0.21% (95% CI, 0.17–0.26) Study 0.948 (0.04) 0.001 (−0.005 to 0.003) England 0.947 (0.05) from 5.93 to 6.14% over this period. COPD points/available Prescribing data Study 0.981 (0.06) 0.008 (0.003–0.012) The annual prescribing cost per practice patient (all patients) of England 0.973 (0.10) LAMA increased by 61% from a mean of £1.81 in 2007 to £2.90 in Smoking points/available 2010 (mean difference £1.09, 95% CI, 1.03–1.16). LABA+ICS cost Study 0.994 (0.04) 0.002 (−0.0036 to 0.0004) increased by 26% from a mean of £7.87 in 2007 to £9.89 in 2010 England 0.992 (0.03) (mean difference £2.02, 95% CI, 1.89–2.15; Figure 3). The median (interquartile range) cost per practice patient in the same period Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmon- increased from £1.59 (1.01–2.37) to £2.66 (1.82–3.69) for LAMA and ary disease; LABA+ICS, combined inhaled long-acting β -agonist and corticosteroid; LAMA, long-acting anti-muscarinic; PCT, Primary Care Trust; from £7.44 (5.35–10.11) to £9.79 (7.10–12.34) for LABA+ICS. QOF, Quality and Outcomes Framework. Admissions data The annual rate of COPD patients admitted per 10,000 practice 2010 are shown in Figure 4. Reference to the year of publication patients increased from a mean (s.d.) of 15.7 (10.2) in 2001 to 18.3 (February 2003) of the first study on the efficacy of the combination (10.2) in 2010 (mean difference 2.6 patients per 10,000 practice of salmeterol–fluticasone in improving exacerbations in COPD is patients, 95% CI, 1.8–3.3). The median (interquartile range) of 3 included. This date was close to that of the introduction of COPD patients admitted per 10,000 practice patients varied tiotropium in the United Kingdom (September 2002). between a minimum of 13.7 (8.6–20.4) in 2001 and a maximum of 16.1 (9.9–23.5) in 2003 with an annual average median Prescribing correlations (interquartile range) of 15.5 (10.0–22.4) over 10 years. To demonstrate the difference between COPD patients admitted The correlations between the prescribing costs of LAMA per and COPD admissions, means of both, including CIs, from 2001 to practice patient and those of LABA+ICS per practice patient are © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited npj Primary Care Respiratory Medicine (2014) 14006 Association between COPD drugs and hospital admissions TH Harries et al Table 2. Correlation between rates of practice prescribing cost per practice patient of LAMA and LABA+ICS (with partial correlation of log of the cost of LAMA and the log of the cost of LABA+ICS when controlling for the log of the practice list size) Rate LAMA versus Log LAMA cost versus Predicted COPD prevalence, England 2010 (Nacul et al., 2011) Year Rate LABA+ICS Log LABA+ICS cost R (±95% CI) R (±95% CI) 1 2 2007 (n= 798) 0.52 (0.47–0.57) 0.56 (0.52–0.61) Diagnosed COPD (study practices) 2008 (n= 801) 0.60 (0.55–0.64) 0.63 (0.59–0.67) 2009 (n= 804) 0.63 (0.59–0.67) 0.67 (0.63–0.71) 2010 (n= 796) 0.68 (0.64– 0.72) 0.73 (0.69–0.76) R is Pearson’s correlation (unadjusted for practice list size). R is Partial 1 2 0 correlation (adjusted for log practice list size). n is number of practices. Abbreviations: CI, confidence interval; LABA+ICS, combined inhaled long- 2007 2008 2009 2010 acting β -agonist and corticosteroid; LAMA, long-acting anti-muscarinic. Year Figure 2. Prevalence (% ± 95% confidence interval) of diagnosed chronic obstructive pulmonary disease (COPD) in study practices Confirmatory analysis to exclude spurious correlation was 2007–2010 (dashed line shows predicted prevalence of COPD in 24 carried out using a log transformation model of prescribing to 2010). predict the log (base 10) of the hospital admission rate (Table 4). A significant increase in admissions was observed with greater prescribing of LAMA between 2008 and 2010 and with greater prescribing of LABA+ICS in 2007 and 2009. LABA+ICS DISCUSSION Main findings Practices that were high prescribers of LAMA and LABA+ICS drugs had higher rates of COPD admission compared with low- prescribing practices. This relationship was observed during a time of significant increase in national prescribing of both drug classes and unchanging rates of COPD admissions. Practice rates LAMA of prescribing of LAMA and LABA+ICS were strongly correlated. There was no evidence of reciprocal prescribing between these two groups of drugs whose effects on COPD in clinical trials were similar. There was considerable variation in prescribing across practices. The rates of prescribing of LAMA and LABA+ICS in those practices within the lowest quartile were respectively less than 2007 2008 2009 2010 Year half and almost half of those practices within the highest quartile. The small changes in the diagnosed prevalence of COPD and Figure 3. Annual rates (mean ± 95% confidence interval) of LAMA asthma were unlikely to be responsible for the increased and LABA+ICS prescribing costs per practice patient (all patients). prescribing of these drugs. There was no evidence of a change Costs expressed based on all patients on the practice list to in true prevalence of COPD and hence it is probable that the small standardise prescribing rates. The unit cost to the NHS of LAMA fell increase in diagnosed prevalence of COPD resulted from by 7.3% and the unit cost to the NHS of LABA+ICS fell by up to 4.5% between 2007 and 2010 (BNF.org). LAMA, long-acting anti-muscari- improved recognition of the disease or changes in clinical nic; LABA+ICS, combined inhaled long-acting β -agonist and 2 recording practice. corticosteroid; NHS, National Health Service. Strengths and limitations of this study The pattern of increasing inhaled medication prescription volume shown in Table 2. To test for spurious correlation, partial and unchanging rate of COPD patient admissions and the correlations of the log of the cost of LAMA and log of the cost consistency of the relationship between practice-level prescribing of LABA+ICS, controlling for the log of practice list size, are and COPD admissions throughout the study were striking. included. Prescribing data were based on NHS prescriptions dispensed, a better reflection of the true impact of the drugs compared with Regression and sensitivity analyses prescribers’ records, which would reflect prescriber intentions Estimates for the association between prescribing costs and COPD rather than patient use. Study practices did not differ from the patient admission rates (2007–2010) are shown in Table 3. Results practices in England other than their being situated in more were adjusted for COPD prevalence, IMD score, QOF points (total deprived areas, the most likely explanation for their high COPD and COPD specific) and inverse of practice size (1/practice size), prevalence. The increase in the prescribing of COPD drugs in study which were significantly associated with COPD admissions in practices from 2007 to 2010 matched that in England. It is likely univariate analysis. that the study findings reflected the pattern of care in England. Numbers in the table can be interpreted as additional Concerns regarding the accuracy of routinely collected data admissions/10,000 patients/£ spent on the drug per practice sources, including Hospital Episodes Statistics admissions data, patient. have been ameliorated by improvements in quality over recent npj Primary Care Respiratory Medicine (2014) 14006 © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited Mean prescribing cost per patient (£) Mean prevalence of COPD (%) Association between COPD drugs and hospital admissions TH Harries et al 30 30 Admissions 20 20 Patients admitted 10 10 TRISTAN study published 0 0 2000 2002 2004 2006 2008 2010 Year Figure 4. Annual rates (mean ± 95% confidence interval) of chronic obstructive pulmonary disease (COPD) patients admitted and of all COPD admissions per 10,000 practice patients. Table 3. Association of practice rates of prescribing of LAMA and LABA+ICS with practice rates of patients admitted for COPD Associations with COPD patients admitted/10,000 patients on the list (multiple linear regression) Predictor variable 2007 (n = 787) 2008 (n = 790) 2009 (n = 797) 2010 (n = 783) LAMA cost/practice patient, β-statistic (±95% CI) 0.37 (−0.22 to 0.97) 1.24 (0.58–1.91) 1.12 (0.55–1.70) 1.23 (0.61–1.85) LABA+ICS cost/practice patient, β-statistic (±95% CI) 0.39 (0.22–0.56) 0.28 (0.08–0.48) 0.23 (0.05–0.41) 0.32 (0.12–0.52) Adjusted for COPD prevalence, local deprivation (Index of Multiple Deprivation score), clinical and administrative performance (Quality and Outcomes Framework points), and inverse of list size (1/practice size). Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; LABA+ICS, combined inhaled long-acting β -agonist and corticosteroid; LAMA, long-acting anti-muscarinic. Table 4. Association between prescribing costs and COPD patient admission rates (2007–2010) using a log-transformation model to predict the log (base 10) of the hospital admission rate Regression outcome 2007–2010 (±95% CI) Predictor variable 2007 2008 2009 2010 Log10 LAMA cost, β-statistic (±95% CI) 0.02 (−0.05 to 0.09) 0.22 (0.13–0.30) 0.19 (0.10–0.28) 0.29 (0.19–0.40) Log10 LABA+ICS cost, β-statistic (±95% CI) 0.20 (0.13–0.28) 0.07 (−0.03 to 0.16) 0.11 (0.01–0.21) 0.10 (−0.01 to 0.22) Dependent variable: Log10 COPD patients admitted. Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; LABA+ICS, combined inhaled long-acting β -agonist and corticosteroid; LAMA, long-acting anti-muscarinic. years. The relative stability of annual admission rates in our data individual patients. Disease severity is an important example. and the consistency of the relationship between admissions and Another possible confounder is the actual level of use of prescribing gave cause for confidence. medication by individuals. The advantage of being able to analyse Analysing data at a practice level rather than at patient level has a large cohort of practices as we have done here is that the large the disadvantage in a study with an ecological element such as number of COPD admissions observed has given us the power to this of missing possible explanatory variables that are exclusive to examine the relationship between prescribing and admissions, © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited npj Primary Care Respiratory Medicine (2014) 14006 COPD patients admitted (mean/10,000 practice patients) COPD admissions (mean/10,000 practice patients) Association between COPD drugs and hospital admissions TH Harries et al which would be impossible at individual practice level. As is a huge financial burden to the UK taxpayer from the widespread admissions occur mainly among the most severely affected COPD use of prescription drugs, the extent of effectiveness of which in patients it may be surmised that the patients admitted were COPD is uncertain. 4,27 predominantly those with severe disease. We cannot assume that it was for these patients that LAMA and LABA+ICS were ACKNOWLEDGEMENTS prescribed. However, the positive association between prescribing and admissions was strong throughout the study when control- The authors thank Hannah Thornton and Helen Booth for their help with the initial data analysis and Mark Ashworth and Martin Gulliford for their assistance in ling for prevalence, deprivation, prescribing of the other drug type reviewing the draft paper. and practice performance data. It would seem perverse to suggest that the significant increase in prescribing took place only in those patients who were not at risk of admission. CONTRIBUTIONS The association between high practice rates of prescribing of PW and THH devised the study and all authors contributed to its design. PW, LAMA and LABA+ICS and high practice rates of COPD admission THH and SJ contributed to data collection. PW, THH, PTS and PS contributed to may be explained by larger numbers of severely affected COPD data analysis. PW and THH wrote the first draft. All authors commented and patients being found in high prescribing practices. If this was the contributed to the final paper. case it would suggest that the drugs were ineffective at reducing admissions, as rates of COPD admission have not fallen following the introduction and progressive increase in rates of prescribing of COMPETING INTERESTS these drugs. An increased rate of prescription of LABA+ICS to PW has received project grants, consultancy fees, speaker fees and support for patients with asthma may have contributed to the increasing rate attending conferences from a number of pharmaceutical company manufac- of prescribing of these drugs within the practices. turers of respiratory drugs, but has no other financial relationships with any organisations that might have an interest in the submitted work. The remaining Interpretation of findings in relation to previously published work authors declare no conflict of interest. The reduction in the frequency of COPD exacerbations seen in clinical trials of LAMA and LABA+ICS has raised the hope that prescribing of these drugs in patients with severe and very severe FUNDING COPD would reduce COPD admissions, leading to substantial cost 4,28,29 This study is the independent work of the authors. THH was supported by a savings. The lack of evidence for their effect in reducing 30 National Institute for Health Research In-Practice fellowship. No other funding COPD admissions resonates with concerns of Suissa about was provided. underestimates of the number needed to treat in clinical trials of LABA+ICS, which assessed outcome in terms of frequency of acute exacerbations of COPD assessed. REFERENCES The positive association between prescribing costs and admis- 1 The Burden of Lung Disease. 2nd Edn. A Statistics report from the BTS. http:// sions is unlikely to represent a causal relationship as there is no www.brit-thoracic.org.uk/Portals/0/Library/BTS%20Publications/burdeon_of_ evidence from clinical trials of such adverse effects. A second lung_disease2007.pdf, 2006. possible explanation might be that patients started using these 2 NICE. 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The images prepared for the department for constitutional affairs. http://webarchive.natio- or other third party material in this article are included in the article’s Creative Commons nalarchives.gov.uk/%2B/http:/www.dca.gov.uk/foi/reference/foi-independent- license, unless indicated otherwise in the credit line; if the material is not included under review.pdf, 2006. the Creative Commons license, users will need to obtain permission from the license 20 Payne RA, Abel GA. UK indices of multiple deprivation—a way to make holder to reproduce the material. To view a copy of this license, visit http:// comparisons across constituent countries easier. Health Stat Q 2012; 53: creativecommons.org/licenses/by-nc-nd/4.0/ 22–37. 21 Data Protection Act 1998. http://www.legislation.gov.uk/ukpga/1998/29/contents. APPENDIX 22 Kim HJ. Spurious correlation between ratios with a common divisor. Stat Prob Lett 1999; 44: 383–386. 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Hospital Episodes Statistics: http://www.hesonline.nhs.uk/Ease/ 26 Improving data quality in the NHS: 2010 - Audit Commission. http://www.audit- servlet/ContentServer?siteID = 1937. commission.gov.uk/2010/08/improving-data-quality-in-the-nhs-2010/. British National Formulary: http://www.bnf.org/bnf/index.htm. © 2014 Primary Care Respiratory Society UK/Macmillan Publishers Limited npj Primary Care Respiratory Medicine (2014) 14006

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npj Primary Care Respiratory MedicineSpringer Journals

Published: May 20, 2014

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