https://orcid.org/0000-0002-1281-5296
Abstract
Recent reports provide evidence-based guidelines for the withdrawal of inhaled corticosteroids (ICS) in COPD, but data on patients treated with ICS-based triple therapy are sparse and contradictory. We assessed the effect of ICS discontinuation on the incidence of severe exacerbation and pneumonia in a real-world population of patients with COPD who initiated triple therapy. We identified a cohort of patients with COPD treated with LAMA-LABA-ICS triple therapy during 2002–2018, age 50 or older, from the UK’s CPRD database. Subjects who discontinued ICS were matched 1:1 on time-conditional propensity scores to those continuing ICS and followed for one year. Hazard ratios (HR) of severe exacerbation and pneumonia were estimated using Cox regression. The cohort included 42,667 patients who discontinued ICS matched to 42,667 who continued ICS treatment. The hazard ratio of a severe exacerbation with ICS discontinuation relative to ICS continuation was 0.86 (95% CI: 0.78–0.95), while for severe pneumonia it was 0.96 (95% CI: 0.88–1.05). The incidence of severe exacerbation after ICS discontinuation was numerically higher than after continuation among patients with two or more exacerbations in the prior year (HR 1.09; 95% CI: 0.94–1.26) and among those with FEV1 <30% predicted (HR 1.29; 95% CI: 1.04–1.59). This large real-world study in the clinical setting of COPD treatment suggests that certain patients on triple therapy can be safely withdrawn from ICS and remain on bronchodilator therapy. As residual confounding cannot be ruled out, ICS discontinuation is not warranted for patients with multiple exacerbations and with very severe airway obstruction.
Introduction
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends to initiate maintenance treatment of chronic obstructive pulmonary disease (COPD) with long-acting bronchodilators, namely long-acting muscarinic antagonists (LAMAs) and long-acting beta2-agonists (LABAs), alone or in combination [Citation1]. Treatment is intensified to triple therapy by adding inhaled corticosteroids (ICS) when patients incur frequent COPD exacerbations and significant dyspnea [Citation1]. However, despite these specific guidelines, the use of ICS in clinical practice was shown to be inappropriate for a large proportion of patients with COPD [Citation2–4]. This is a particular concern because of its various adverse effects, including the risk of pneumonia [Citation5].
The 2019 GOLD recommendations thus introduced a guidance for ICS withdrawal and stepping down to long-acting bronchodilators for patients inefficiently treated with ICS-based therapy [Citation6]. Additionally, the European Respiratory Society Task Force produced evidence-based guidelines for ICS withdrawal in COPD [Citation7]. The evidence was based on four randomized trials on the safety of ICS withdrawal in COPD [Citation8–11] and is supported in several commentaries [Citation12–14].
Recent trials have focused specifically on the question of withdrawing ICS in patients on triple therapy, with conflicting results. The SUNSET trial found no difference overall on the rate of exacerbation after withdrawing ICS compared with continuing ICS, though the rate was higher after ICS withdrawal among patients with blood eosinophil count ≥300 cells/μl at baseline [Citation11]. A subgroup analysis of the patients on triple therapy at baseline in the WISDOM trial found no difference on the rate of exacerbation with ICS withdrawal compared with ICS continuation [Citation15]. In contrast, a similar subgroup analysis of patients already on triple therapy at baseline in the InforMing the PAthway of COPD Treatment (IMPACT) trial found that the rate of exacerbation was significantly increased by 43% with ICS withdrawal compared with continuation on triple therapy [Citation16].
To date, only one study recently evaluated the effect of withdrawing ICS among patients on triple therapy in a real-world context finding that, in most patients, discontinuation of ICS was not associated with an increased risk of exacerbation [Citation17]. In this paper, we assess the effectiveness and safety of ICS discontinuation in a general practice cohort of patients with COPD, who all initiated triple therapy, on the incidence of COPD exacerbation and pneumonia.
Methods
Data sources
We used the Clinical Practice Research Datalink (CPRD), a primary care database from the United Kingdom (UK) that contains primary care medical records for over 50 million people enrolled in more than 1800 general practices. Participating general practitioners in the CPRD’s GOLD and Aurum networks provide extensive medical information, including demographic data, lifestyle factors, medical diagnoses recorded using Read and SNOMED codes, and prescriptions. Over 85% of the CPRD practices can be linked to the Hospital Episodes Statistics (HES) database and the Office for National Statistics (ONS) that provides electronic death certificates data. The CPRD population is representative of the overall population and these data sources have been validated [Citation18–20]. In particular, the information on medications and diagnoses has been validated and shown to be of high quality [Citation18, Citation19, Citation21]. These databases have been used extensively for studies of COPD [Citation22–27].
Base cohort
We first identified all adults with a new diagnosis of COPD during 1995–2017 who received their first prescription for a LABA, LAMA, or an ICS from January 2002 (market entry for LAMAs) onwards. To increase the likelihood of identifying COPD, the subjects had to be 50 years of age or older on the date of their diagnosis. Only patients from CPRD practices linked to the HES were included. We then formed the base cohort of patients initiating triple therapy, defined by the first occurrence of triple therapy with LAMA-LABA-ICS (as two or three separate inhalers) prescribed on the same day, which marked the base cohort entry date. All patients required at least one year of medical history prior to base cohort entry to identify the initiation of triple therapy. Subjects were followed up until death, November 2018, or the end of coverage in the practice, whichever was first.
Study design
We first defined continuous ICS use within the base cohort. Thus, starting with the first occurrence of triple therapy, continuous use was defined by successive prescriptions of ICS, each lasting 30 days, separated by a grace period of at most 60 days after the end of the previous one. Discontinuation of ICS was defined as no subsequent prescription for ICS in that span. We defined the group of ICS discontinuers as those who discontinued ICS and had at least one prescription for a LAMA or LABA during the ICS discontinuation period.
The prevalent new-user design was then used to construct the study cohort by first identifying the group of ICS discontinuers in the base cohort [Citation28]. Starting chronologically with the first subject discontinuing ICS, we identified a matched reference subject who was still continuing ICS treatment at the same time since the initiation of triple therapy. The matched reference subject was selected from the corresponding time-based exposure set of all subjects in the base cohort who continued their ICS-based treatment, namely those who received an ICS prescription within the period defining discontinuation along with at least one prescription for a LAMA or LABA.
The matching was done on data source (GOLD/Aurum) and prior asthma diagnosis, as well as time-conditional propensity scores (TCPS), computed as a function of time-dependent covariates measured at the time of the matched set [Citation28]. The covariates included age, sex, body mass index (BMI), smoking status, excessive alcohol consumption, as well as measures of COPD severity and comorbidity. COPD severity was assessed by the frequency of moderate and severe COPD exacerbations, presence of pneumonia and respiratory drugs during the one-year period prior to the matched set. In particular, moderate exacerbations were defined by prescriptions of prednisolone while severe exacerbations were hospitalizations for COPD. Co-morbidity in the year prior to the matched set date was measured using diagnoses and prescriptions for conditions often present with COPD, including cardiovascular disease, diabetes, thyroid disease, renal failure, and cancer. The TCPS of discontinuation of ICS was applied to the entire matched exposure set, with the ICS-continuing subject with the closest propensity score to the ICS discontinuer selected as the matched comparator. The date defining ICS discontinuation, namely the end of the 60-day grace period, and the corresponding date for the matched ICS continuer reference subject defined study cohort entry for each pair of subjects. Study subjects were followed for one year after the study cohort entry date, death or the end of coverage in the practice.
Outcome events
The effectiveness outcome was the occurrence of a first severe COPD exacerbation during follow-up, defined as a hospitalization with a primary diagnosis of COPD (ICD-10 J41-J44). The safety outcome was the first severe pneumonia defined by a hospitalization for community-acquired pneumonia (ICD-10 J10.0, J11.0, J12-J18, J22, J69, J85.0, J85.1, J86). These diagnostic codes have been shown to have good accuracy and were used in several studies of COPD using the CPRD [Citation25, Citation29–32].
Data analysis
We used descriptive statistics, including standardized mean differences, to summarize and compare the patient characteristics of the matched groups. Incidence rates of exacerbation and pneumonia were analyzed using the Poisson distribution.
The primary analysis was as-treated, where follow-up for ICS discontinuers was censored at a restart of ICS while for ICS continuers it was censored at ICS discontinuation. The hazard ratios (HR) and corresponding 95% confidence intervals (CI) of severe exacerbation and pneumonia associated with ICS discontinuation versus continuation were estimated using a Cox proportional hazards regression model. For the outcome of severe exacerbation, subjects were also censored at the occurrence of a moderate exacerbation, defined by a new prescription for prednisolone. Thus, inverse probability of censoring weights was used to account for potential informative censoring from of ICS restart or discontinuation, as well as from a moderate exacerbation.
The adjusted hazard ratio of a first severe COPD exacerbation was stratified by the number of baseline exacerbations during the year prior to study cohort entry, as well as by the baseline blood eosinophil count and FEV1 percent predicted. We also stratified by the definition of frequent exacerbators commonly used in many randomized trials, namely two or more moderate exacerbations or one severe in the year prior to cohort entry. These stratified analyses were estimated using an interaction term between the stratification factors and ICS discontinuation. In addition, the adjusted hazard ratio of a first severe exacerbation was computed as a function of the one-year follow-up time, using cubic splines.
To address potential immeasurable time bias, we excluded subjects with a hospitalization during the time period to define ICS discontinuation [Citation33]. All analyses were conducted using SAS version 9.4. The study protocol was approved by the Independent Scientific Advisory Committee of the CPRD (Protocol 21_000491) and the Ethics Committee of the Jewish General Hospital (JGH Protocol #18-026), Montreal, Quebec, Canada.
Results
The base cohort included 125,441 patients newly diagnosed with COPD, aged 50 years or older, who initiated triple therapy between 2002 and 2018 (). There were 42,667 ICS discontinuers at some point during follow-up who were matched to 42,667 ICS continuers. The baseline characteristics of these patients are displayed in , showing good balance between the two groups, with discontinuation of ICS use occurring 16.3 months on average after initiation of triple therapy. The ICS discontinuers received a LABA (1.4%), a LAMA (89%) or both (9.5%) during the 90-day period defining discontinuation. During the one-year follow-up, 74% of the discontinuers reinitiated ICS use while 16% of the ICS continuers discontinued ICS.
Figure 1. Flowchart of cohort selection.
Table 1. Baseline characteristics of the study cohort, comparing patients on triple therapy who discontinued ICS with those continuing ICS, after matching on time-conditional propensity scores, with corresponding standardized mean differences.
The crude cumulative incidence of a first severe exacerbation at 1 year is 6.3% for ICS discontinuers and 7.6% for continuers (). The adjusted hazard ratio of a first severe exacerbation with ICS discontinuation relative to ICS continuation is 0.86 (95% CI: 0.78–0.95), while for severe pneumonia it is 0.96 (95% CI: 0.88–1.05) ().
Figure 2. One-year cumulative incidence of severe exacerbation comparing patients on triple therapy who discontinued ICS with those continuing ICS, after matching on time-conditional propensity scores.
Table 2. Crude and adjusted hazard ratios of a first severe COPD exacerbation and severe pneumonia comparing ICS discontinuation with continuation in patients with COPD treated with triple therapy.
shows that the comparative incidence of severe exacerbation is not affected by the blood eosinophil count. On the other hand, the incidence of severe exacerbation for ICS discontinuers was lower than for continuers among patients with no prior asthma diagnosis (HR 0.82; 95% CI: 0.73-0.92), but was not different among patients with an asthma diagnosis (HR 0.98; 95% CI: 0.82-1.18). The HR of severe exacerbation for ICS discontinuers versus continuers increased numerically with the number of prior exacerbations (). The HR also varies by FEV1, particularly elevated among patients with % predicted FEV1 < 30% (HR 1.29; 95% CI: 1.04-1.59). The adjusted hazard ratio of a first severe exacerbation is no different from 1 in the first seven months of follow-up and decreases thereafter ().
Figure 3. Adjusted hazard ratio of severe exacerbation (solid line) comparing patients on triple therapy who discontinued ICS with those continuing ICS and 95% confidence intervals (dashed lines) as a function of follow-up time, fit by cubic splines.
Table 3. Crude and adjusted hazard ratios of a first severe COPD exacerbation comparing ICS discontinuation with continuation in patients with COPD treated with triple therapy, stratified by prior asthma diagnosis, number of prior exacerbations, baseline FEV1 percent predicted and blood eosinophil count.
Stratification by the definition of exacerbators commonly used in many randomized trials, namely two or more moderate exacerbations or one severe in the year prior to cohort entry, produced the same results as for the stratification by the number of exacerbations. The estimates remained similar after the exclusion of subjects hospitalized during the time period to define ICS discontinuation and thus not affected by potential immeasurable time bias.
Discussion
This real-world observational study in over 85,000 patients with COPD who all initiated LAMA-LABA-ICS triple therapy found that the incidence of a severe COPD exacerbation requiring hospitalization was reduced in those who discontinued ICS treatment compared with those who continued. However, there was no reduction in the incidence of severe exacerbation with ICS discontinuation in patients with a history of frequent exacerbations or a history of asthma. Furthermore, ICS discontinuation was not associated with a lower incidence of severe pneumonia requiring hospitalization.
The question of withdrawing ICS in patients with COPD treated with triple therapy has been receiving increased attention because of the large gap between the various treatment recommendations and real-world clinical practice. This divergence resulted in a global phenomenon of substantial inefficient overuse of ICS in COPD. For example, in the United Kingdom, 63% of newly diagnosed GOLD A/B patients received ICS-containing inhalers instead of the recommended long-acting bronchodilators without ICS [Citation2]. While ICS are indicated for frequent exacerbators, the Phenotypes of COPD in Central and Eastern Europe (POPE) study found that over 50% of non-exacerbators were using ICS, including 37% on triple therapy [Citation3]. In the United States, the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) found that 50% of patients were treated with non-indicated ICS-containing regimens [Citation4]. A major concern around such non-indicated ICS overuse is the increased risk of pneumonia and of other adverse events associated with ICS [Citation5].
Several randomized trials specifically evaluated the effects of ICS withdrawal in COPD [Citation8–11]. Some of these focused on withdrawing ICS in patients on triple therapy. The SUNSET trial found no difference on the rate of exacerbation after withdrawing ICS compared with continuing ICS over 6 months (rate ratio 1.08; 95% CI: 0.83–1.40) [Citation11]. However, the rate of exacerbation was increased after withdrawing ICS in the subgroup of patients with blood eosinophil count ≥300 cells/μl at baseline (rate ratio 1.86; 95% CI: 1.06–3.29). In the WISDOM trial’s subgroup analysis of patients on triple therapy, those who discontinued the ICS component had similar incidence of moderate or severe exacerbation compared with those who continued (HR 1.05; 95% CI: 0.89–1.25), though it was numerically higher for severe exacerbation (HR 1.23; 95% CI: 0.92–1.64) [Citation15]. In patients with two or more prior exacerbations and blood eosinophil count ≥400 cells/μL, the HR of moderate or severe exacerbation was 1.45 (95% CI: 0.58–3.60).
In contrast, the reanalysis of the IMPACT trial among the subgroup patients already on triple therapy at study entry found that those who discontinued the ICS and received a dual long-acting bronchodilator had a 43% increase in the rate of moderate or severe exacerbations, compared with those continuing on triple therapy (HR 1.43; 95% CI: 1.30–1.59), with similar effects observed for severe exacerbations [Citation16]. Thus, unlike the other trials, this reanalysis of the IMPACT trial data suggests that ICS withdrawal has a significant detrimental effect on exacerbations for all patients on triple therapy. Possible explanations for the drastic differences in results between this and the other trials are the inclusion of patients with a history of asthma in IMPACT, a significant risk factor for moderate and severe COPD exacerbations [Citation34–36], as well as the abruptness of ICS withdrawal in IMPACT, compared with the gradual ICS dose reduction in WISDOM [Citation37].
With respect to the safety outcome, our study found no decrease in the incidence of severe pneumonia with ICS discontinuation (HR 0.96; 95% CI: 0.88–1.05). The only triple therapy trial that reported data on adverse events, the SUNSET trial, found a numerical difference in the incidence of pneumonia with ICS discontinuation (RR 0.67; 95% CI: 0.24–1.86) [Citation11].
This study has several strengths. First, it identified patients at the time they initiated treatment with triple therapy, which inherently controls for the time to discontinuation (mean 16 months) when comparing ICS discontinuation versus continuation, thus attenuating the effect of confounding bias. The use of time-conditional propensity scores to make the two groups comparable on covariates measured at the time of discontinuation also helped to better control for confounding. Second, the outcome definitions for severe exacerbation and pneumonia were based on hospitalization records which are less subject to misclassification. Finally, the sample size was large with over 85,000 patients, thus permitting to estimate small effects in important phenotype subgroups.
The study design has several limitations, including the ICS exposure measures that are based on written prescriptions which may not be dispensed or used. However, the continuity of prescriptions suggests that the medications were likely taken. Also, the use of physician diagnoses to identify patients with COPD and those with a history of asthma may have misclassified some patients.
The most important limitation with this study is the potential for residual confounding despite the use of time-conditional propensity scores. While the groups were alike on markers of disease severity at the time of ICS discontinuation, we cannot rule out residual confounding from unmeasured factors. Indeed, the discontinuation of ICS may have been because of unmeasured better controlled disease, which could have resulted in a lower incidence of exacerbation in the discontinuers and a lower hazard ratio with ICS discontinuation. Thus, the resulting underestimate of the effect of ICS discontinuation may have prevented finding a significant increased risk of exacerbation with the discontinuation of ICS, especially among those with a previous asthma diagnosis and with frequent exacerbations. Besides residual confounding, the possible underestimate of the effect of ICS discontinuation may also be due to the reality of the widespread use of ICS in the treatment of COPD, as well as the rarity and brevity of the discontinuation episodes. Indeed, 74% of the discontinuers in the study reinitiated ICS use while 16% of the ICS continuers discontinued ICS.
This is the second observational study addressing the question of ICS withdrawal in patients with COPD treated with triple therapy in a real-world context. The prior study, though based on fewer subjects and using a different approach, also found that discontinuation of ICS was generally not associated with an increased risk of exacerbation [Citation17]. Nonetheless, it found that ICS discontinuation was associated with an increased risk of exacerbation in patients with frequent courses of oral corticosteroids and high blood eosinophil counts. Certainly, more data are needed on ICS withdrawal in patients with stable GOLD 3 COPD, namely with FEV1% predicted between 30% and 50% [Citation38, Citation39]. These should include the important phenotypes that will permit a precision medicine approach to ICS withdrawal [Citation40, Citation41]. This approach will help identify the profiles of patients who will benefit from ICS withdrawal or continuation, thus lowering harms from the side effects of ICS, including pneumonia [Citation5, Citation40]. For example, certain phenotypes for continuation of ICS could include patients with an asthma component, with elevated blood eosinophils, a history of multiple exacerbations, and possibly as well COPD patients suffering from cardiovascular comorbidities [Citation42, Citation43].
In conclusion, the results of this large real-world study in the clinical setting of treatment for COPD generally support the most recent GOLD recommendations and ERS Task Force report on ICS withdrawal in COPD. It suggests that certain patients treated with triple therapy can be safely withdrawn from the ICS component and continue on bronchodilator therapy. It also confirms that ICS withdrawal may not be warranted for patients with multiple exacerbations and very severe airway obstruction.
Authors’ contributions
Dr Ernst participated in study design, data interpretation, and writing of the manuscript. Ms Dell’Aniello participated in study design, data analysis and writing of the manuscript. Dr. Suissa participated in data acquisition, study design, data analysis, data interpretation, writing of the manuscript, and acts as guarantor of this manuscript.
Acknowledgements
This study was not funded but was conducted thanks to infrastructure funding from the Canadian Institutes of Health Research (CIHR) and the Canadian Foundation for Innovation (CFI). Dr. Suissa is the recipient of the Distinguished James McGill Professorship award. These sponsors had not input in the study.
Data sharing statement
This study is based in part on data from the Clinical Practice Research Datalink obtained under license from the UK Medicines and Healthcare products Regulatory Agency. The data are provided by patients and collected by the UK National Health Service as part of their care and support. The interpretation and conclusions contained in this study are those of the author/s alone. Because electronic health records are classified as “sensitive data” by the UK Data Protection Act, information governance restrictions (to protect patient confidentiality) prevent data sharing via public deposition. Data are available with approval through the individual constituent entities controlling access to the data. Specifically, the primary care data can be requested via application to the Clinical Practice Research Datalink (https://www.cprd.com).
Disclosure statement
Dr. Suissa attended scientific advisory committee meetings for Atara, Merck, Pfizer and Seqirus, and received speaking fees from Boehringer-Ingelheim and Novartis. Ms Dell’Aniello and Dr Ernst have no conflict of interest to report.
Funding
The author(s) reported there is no funding associated with the work featured in this article.
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