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Personalising add-on treatment with inhaled corticosteroids in patients with chronic obstructive pulmonary disease: a benefit–harm modelling study

Background Since the benefit–harm balance of adding inhaled corticosteroids to long-acting β 2 -agonists (LABA) and long-acting muscarinic antagonists (LAMA) for patients with chronic obstructive pulmonary disease is unclear, we evaluated this addition for a range of patient profiles


Introduction
Inhaled corticosteroids are commonly used in combination with long-acting β 2 -agonists (LABA) and long-acting muscarinic antagonists (LAMA) to prevent moderate-tosevere exacerbations in patients with chronic obstructive pulmonary disease (COPD). 1 The 2020 American Thoracic Society (ATS) evidence-based guide line on COPD drug treatments issued a conditional recommendation to add inhaled cortico steroids to LABA and LAMA in patients with a history of one or more exacerbations in the past year, requiring antibiotics or oral steroids, or admission to and treatment in hospital. 2 With a conditional recommendation, clinicians are advised not to pursue a treat-all strategy but seek a treatment decision that is consistent with the patient's characteristics, values, and preferences. This decision can be challenging because of the interplay of several factors contributing to the risk of exacerbations, harm outcomes, and patient preferences. [3][4][5][6] Processing all relevant factors might be cognitively overwhelming for both patients and clinicians, and unless a more systematic approach is taken, there is a risk of overtreatment or under treatment with inhaled corticosteroids.
To the best of our knowledge, a systematic and quantitative benefit-harm assessment of inhaled corticosteroids, LABA, and LAMA has never been done. We consider it is an ideal time to do so, since additional evidence has become available from recent (published since 2018) randomised controlled trials (RCTs) and observational studies on the benefit and harm of added inhaled corticosteroids, but also on the treatmentmodifying effect of blood eosinophil counts (BEC). 2,5,7 Therefore, our study aimed to: (1) quantitatively assess the net clinical benefit of triple therapy with inhaled corticosteroids, LABA, and LAMA compared with dual therapy with LABA and LAMA for the prevention of moderate-to-severe exacerbations against the harms of severe pneumonia, oropharyngeal candidiasis, and dysphonia; (2) establish the exacerbation risk thresholds, above which the benefits outweigh the harms; and (3) assess the influence of risk thresholds by estimating the proportion of patients with COPD who benefit from adding inhaled corticosteroids to their treatment.

Study design and participants
The target population of this modelling study was patients with COPD at risk of moderate-to-severe exacerbations. Triple therapy with inhaled corticosteroids, LABA, and LAMA was compared with dual therapy with LABA and LAMA. Low (<500 μg fluticasone-equivalent) to moderate (500 to <1000 μg fluticasone-equivalent) inhaled corticosteroid doses combined and stratified as low, moderate, and high (1000 μg or more) daily doses were considered, with high doses considered in a sensitivity analysis.

Benefit and harm outcomes
In the main analysis, we considered the benefit in terms of a reduced risk of moderate-to-severe exacerbations and the harm due to increased risk of severe pneumonia, oropharyngeal candidiasis, and dysphonia (and skin bruising in high doses only). We used an event-based definition of exacerbations as those for which patients required an unscheduled doctor or emergency room visit requiring oral antibiotic or corticosteroid therapy (moderate) or a hospital admission (severe). 8 We defined severe pneumonia as requiring a hospital admission. Outcomes described in observational studies but not reported in RCTs, such as the onset or progression of diabetes, cataract, and fractures, [9][10][11] were included in a sensitivity analysis. All-cause mortality was considered a competing risk.

Data sources Relative effect estimates
We reviewed the availability and examined the applicability of treatment effect estimates for the chosen outcomes. We considered the systematic review by Nici and colleagues, 2 which served as an evidence base for the ATS guideline, to provide the most up-to-date and valid estimates for moderate-to-severe exacerbations and severe pneumonia sourced from RCTs-namely IMPACT, 12 KRONOS, 13 Aaron and colleagues, 14 and TRIBUTE. 15 This particular review did not comprise all outcomes chosen a priori. We thus reviewed eight RCTs and summarised estimates using a pairwise metaanalysis, particularly for oropha ryngeal candidiasis, dysphonia, and skin bruising, to inform our study. Although the main sources of estimates were RCTs, we also included estimates from observational data in sensitivity analyses, mainly on the harm outcomes of candidiasis and severe pneumonia, for which RCTs are often underpowered (table 1, appendix pp 3-4).

Research in context
Evidence before this study We searched PubMed on April 4, 2021 for studies published in English using the search terms "inhaled corticosteroids", "ICS", "fluticasone", "budesonide", "beclomethasone", "flunisolide", "benefit-harm", "risk-benefit", "costeffectiveness", "COPD", and "chronic obstructive pulmonary disease". The search resulted in 89 publications. Of these, 56 were cost-effectiveness analyses and 29 were systematic reviews or other types of studies. Although many of the cost-effectiveness analyses were on other forms of long-acting bronchodilator and inhaled corticosteroid combinations, two analyses were on triple therapy with inhaled corticosteroids, long-acting β 2 -agonists (LABA), and long-acting muscarinic antagonists (LAMA) versus dual therapy with LABA and LAMA. Both cost-effectiveness analyses measured quality-adjusted life-years, cost per quality-adjusted life-year, or cost per exacerbation avoided. They did not stratify the outcomes by patient risk spectrum or other granular patient subgroups that would help for personalised treatment decisions. We also found four studies related to benefit-harm assessments. All four were reviews of benefits and harm outcomes, but none of the studies did a quantitative benefit-harm assessment of adding inhaled corticosteroids to LABA and LAMA.

Added value of this study
This is the first study to quantitatively estimate the benefit-harm balance of low-to-moderate doses of inhaled corticosteroids combined with LABA and LAMA, and to identify predictors of net clinical benefit. Identified predictors included the 2-year risk of exacerbations, blood eosinophil counts, and age. On the basis of these predictors and a prognostic model for exacerbations that we additionally validated in a two-country cohort of patients with chronic obstructive pulmonary disease, the proportion of patients who would benefit from inhaled corticosteroids, LABA, and LAMA triple therapy was 68% in the best-case scenario of subgroup combinations.

Implications of all the available evidence
The absence of a personalised approach for adding inhaled corticosteroids to LABA and LAMA probably leads to overtreatment and undertreatment with inhaled corticosteroids. The predictors of the net clinical benefit identified here together with a model for predicting the risk of exacerbations of individuals help to personalise the decision to initiate additional inhaled corticosteroids therapy, thereby increasing the benefit and reducing overtreatment or undertreatment in patients with chronic obstructive pulmonary disease. Low-dose inhaled corticosteroids were less than 500 μg. Moderate-dose inhaled corticosteroids were between 500 μg and less than 1000 μg. High-dose inhaled corticosteroids were 1000 μg or more (all in the form of fluticasone-equivalent). BEC=blood eosinophil count. ICS=inhaled corticosteroids. LABA=long-acting β 2 -agonists. LAMA=long-acting muscarinic antagonists. *Triple therapy with inhaled corticosteroids, LABA, and LAMA versus dual therapy LABA and LAMA. †Triple therapy with inhaled corticosteroids, LABA, and LAMA or inhaled corticosteroids plus LABA and LAMA monotherapy versus LABA and LAMA monotherapy or dual therapy. ‡Observational data that were used in the sensitivity analysis. §Odds ratio relative to the low-dose group. The odds ratio estimates of oropharyngeal candidiasis were converted to risk ratio.  were not available for the chosen outcomes. We, therefore, used generic values that have been applied in other decision problems-namely, a preference weight of 1·000 (on a scale of 0·000 to 1·000) for death (but this endpoint was a competing risk in our analysis), 0·750 for life-threatening outcomes, 0·500 for serious outcomes (severe pneumonia and severe exacerbations), 0·250 for moderate exacerbations, and 0·100 for mild outcomes (candidiasis, dysphonia, and skin bruising). 25 Since 90% of exacerbations are mostly moderate and 10% are serious, 26,27 we used a preference of 0·275 for exacerbations weighted for these distributions (0·500 for serious exacerbations × 10%, and 0·250 for moderate exacerbations × 90%). In addition, the effect of other preference weights for exacerbations and harm outcomes on the benefit-harm balance was assessed.

Statistical analysis
A 2-year horizon was used to estimate the cumulative risk of benefit and harm outcomes in patients with COPD. We used the modelling approach by Gail and colleagues, 28 which has been applied in various preventive and therapeutic treatments. 29 The model is described extensively elsewhere, 28 but we have also included some details in the appendix (p 8). In brief, we assumed that the risk of having events related to inhaled corticosteroids was constant over a 2-year period. Cumulative risk of having a benefit or harm event was calculated with a probabilistic exponential model in a theoretical cohort of 1000 patients with COPD given LABA and LAMA. The cumulative risk of the outcomes was again calculated for the same cohort size receiving inhaled corticosteroids, LABA, and LAMA. The risk difference of the outcomes was then calculated from the aforementioned two estimations of cumulative risk with and without inhaled corticosteroids and individually weighted on the basis of patient preferences towards the outcomes. The weighted risk differences of the outcomes were interpreted as fatal-equivalent events. This calculation was done simultaneously for all benefit and harm outcomes and added up to a benefit-harm balance index or a net clinical benefit. The index shows whether the benefits outweighed the harms (positive index) or vice versa (negative index), or whether neither benefits nor harms outweighed the other (index equals zero). The analysis was done stochastically with 100 000 repetitions accounting for the statistical uncertainty of the input estimates to generate a distribution of the net clinical benefit. From the distribution, we calculated the probability that patients given inhaled corticosteroids, LABA, and LAMA would have a net benefit compared with those given LABA and LAMA. Triple therapy was considered to be net beneficial when the probability of net benefit was 60% or above. Thus, the 2-year baseline risk of exacerbations corresponding to the 60% probability was defined as the risk threshold, above which the benefits of triple therapy outweigh its harms. We chose 60% (instead of 50%, a threshold at which expected incremental net benefit is zero) since, when taking a more intensive treatment, it is sensible to be slightly risk averse. 29 We defined more than 40% to less than 60% as an uncertainty zone in which decisions needed to be made with greater caution. Probabilities of less than 40% were interpreted as a net harm. We did the benefit-harm analysis according to age, sex, and BEC, and stratified by inhaled cortico steroids type and dose, when data allowed. Finally, we calculated the proportion of patients in the Dutch and Swiss primary care COPD cohort (International Collaborative Effort on Chronic Obstructive Lung Disease: Exacerbation Risk Index Cohorts [ICE COLD ERIC]) that would benefit from triple therapy. 30 This calculation required a prediction model for exacerbations to estimate the 2-year risk for each patient and to see whether the risk is more than the thresholds of a net benefit. The model by Bertens and colleagues 31 is one of few that allows for estimating the risk of exacerbations in primary care settings. Since we needed to ensure that this model worked well in patients of the ICE COLD ERIC cohort, we first did an external validation of the prediction model, in which we identified the need for a minor  model update (appendix), and subsequently estimated the proportion of patients with COPD who would benefit from the additional inhaled corticosteroids (appendix p 10). All analyses were done in R (version 4.0.2).

Sensitivity analysis
We examined the sensitivity of the net clinical benefit to different preference weights and to baseline incidences for the harm outcomes. We also assessed the effect of estimates from observational data on harm outcomes and types of inhaled corticosteroids, as well as the outcomes of additional harms (particularly diabetes and fracture).
This study was done in accordance with the consolidated standards of reporting quantitative benefitrisk models applied to vaccines guidelines. 32

Role of the funding source
There was no funding source for this study. Figure 1A shows the probability that a patient has a net clinical benefit as a function of their 2-year predicted risk of at least one moderate-to-severe exacerbations (appendix p 11). Weighing the risk of avoided exacerbations against the excess risk of harmful outcomes on  Event risks with or without inhaled corticosteroids, long-acting β 2 -agonists, and long-acting muscarinic antagonists triple therapy were estimated using an exponential model assuming constant exacerbation risk over 2 years, as explained in the methods. The difference of the outcome risks was calculated after adjustment for the preference weights of the individual outcomes. This was done stochastically to generate a distribution of the benefit-harm indices, from which the probability of a net clinical benefit was calculated. ICS=inhaled corticosteroid. RD=risk difference. *Proportion of patients from the Dutch and Swiss Chronic obstructive pulmonary disease cohort (ICE COLD ERIC) with 2-year predicted risk ≤ the probability of net benefit.

Table 3: Net clinical benefit and predicted risk of exacerbation over 2 years by 2-year baseline risk of moderate-to-severe exacerbations
For the R Project for Statistical Computing see https://www.rproject.org/ the same scale, low-to-moderate doses of inhaled corticosteroids with LABA and LAMA showed a net clinical benefit in patients with a 2-year baseline risk of exacerbations between 54% and 83%. The rate of incremental net benefit increased at a decreasing rate up to the 2-year baseline risk of 72% and began to decrease. The proportion of patients in ICE COLD ERIC cohort with a baseline risk between the thresholds was 30%. Tables 3 and 4 show a summary of a net clinical benefit and the expected events of each benefit and harm outcome. For example, consider 1000 patients with a predicted 2-year exacerbation risk of 28% given inhaled cortico steroids, LABA, and LAMA for 2 years. On average, 70 moderate-to-severe exacerbations would be averted compared with patients given LABA and LAMA only, but the patients would have an excess 21 cases of severe pneumonia, 86 of oropharyngeal candidiasis, and 36 of dysphonia. Applying the preference weights, this corresponds to avoiding 19 fatal-equivalent exacerbations, at the cost of 23 fatal-equivalent harm events per 1000 patients (ten pneumonia, nine oropharyngeal candidiasis, and four dysphonia; tables 3 and 4). This shows that patients with a 28% 2-year exacerbation risk are less likely to have a net clinical benefit from inhaled  Events per 1000 patients (2·5th and 97·5th centiles). Event risks with or without inhaled corticosteroids, long-acting β 2 -agonists, and long-acting muscarinic antagonists triple therapy were estimated using an exponential model assuming constant exacerbation risk over 2 years. The difference of the outcome risks was calculated after adjustment for the preference weights of the individual outcomes. This was done stochastically to generate a distribution of the benefit-harm indices, from which the probability of a net clinical benefit was calculated. ICS=inhaled corticosteroid. RD=risk difference.

Table 4: Predicted risk of harm outcomes over 2 years by 2-year baseline risk of moderate-to-severe exacerbations
corticosteroids, compared with those at a higher risk of exacerbations. For example, patients with a 68% 2-year exacerbation risk would expect to avoid 34 fatalequivalent exacerbations in 1000 patients, while having a similar harm risk as above (23 fatal-equivalent harm events), and thus more benefits than harms. For this scenario, the risk without inhaled corticosteroids for harm outcomes was assumed to be the same regardless of an increased risk of exacerbations. Dose and patient subgroups, including baseline exacerbation risk, BEC, and age, were important predictors of net benefit each independently, and even more so in combination. Low doses of inhaled corticosteroids showed a net clinical benefit at a 2-year exacerbation risk between 40% and 91% but not at higher doses, regardless of higher baseline risks (figure 1B). The benefit for patients with a BEC of less than 150 cells per µL was unlikely to outweigh harms at low and moderate doses, and at all exacerbation risks (figure 1C). Patients with baseline BEC of 150 cells per µL or more were more likely to have a net clinical benefit from low-to-moderate inhaled corticosteroid dose at 41-91% 2-year risk of exacerbations. Stratified by dose, patients with a BEC of 150 cells per µL or more would have a net clinical benefit from a low dose of inhaled corticosteroids at 32-95% baseline exacerbation risk in those aged 40-79 years and a 41-93% risk in those older than 80 years. Moderate-dose inhaled corticosteroids were also asso ciated with a net benefit at baseline risks of 52-86% only in patients younger than 80 years with a BEC of 150 cells per µL or more. The thresholds for all subgroups are presented in the appendix (p 12).
Age affected the net clinical benefit of inhaled corticosteroids independent of BEC as a function of difference in the risk of severe pneumonia, which offset the benefit of inhaled corticosteroids. Other harm risks might also play a role, but no age-specific baseline risks were available. The net clinical benefit at a low-tomoderate dose of inhaled corticosteroids was a 2-year baseline risk of 50-84% only in patients younger than 80 years ( figure 1D). The lower risk of severe pneumonia in men also led to a more favourable benefit-harm balance index for men than for women, with a net benefit shown as a 2-year baseline risk of 51-85% for men and 62-76% for women (appendix p 13).
The proportion of patients with COPD in the ICE COLD ERIC cohort who would benefit from inhaled corticosteroid, LABA, and LAMA triple therapy based on the calculated thresholds ranged from 0 to 68%, depending on the subgroup and inhaled corticosteroid dose. Approximately 48% of primary care patients in the cohort would benefit from a low dose of inhaled corticosteroids. Of patients with a BEC of 150 cells per µL or more given a low dose of inhaled corticosteroids, 154 (68%) of 227 would benefit, whereas no patients with a BEC of less than 150 cells per µL would. The benefit of inhaled corticosteroids can be optimised by taking combinations of subgroups to some patients who would more likely benefit from inhaled corticosteroids (figure 2).
We extended the analysis to include additional data from observational data, particularly on harm outcomes. Data combined from RCTs and observational studies showed a net clinical benefit from low-to-moderate inhaled corticosteroid doses at a baseline exacerbation risk between 68% and 72% (27-96% for low-dose inhaled corticosteroids), which corroborated the main results based on RCT data. In the analysis by inhaled corticosteroid types, the net clinical benefit differed between budesonide and fluticasone therapies, with thresholds of 40-91% for fluticasone and 23-97% (low dose) and 47-87% (moderate dose) for budesonide (appendix p 14).
In a further analysis to assess the effect of the perceived importance of exacerbations, we found that each 2% increase in its preference weight had a visible effect on the net clinical benefit in favour of the inhaled corticosteroid, LABA, and LAMA triple therapy. For example, when patients considered avoiding exacer bations as the most important treatment goal (ie, a preference close to 1·0), even patients with an exacer bation risk of 14% would have a net clinical benefit from the triple therapy ( figure 3A). Benefit and harm outcomes weighted equally Since we used average rate of severe pneumonia from real-world data in the main model, in a sensitivity analysis we tested other baseline incidences for severe pneumonia to consider other possible rates. The results showed a notable effect on the net clinical benefit. Low-to-moderate doses of inhaled corticosteroids provided a net clinical benefit only if the incidence for severe pneumonia was less than 35 per 1000 person-years ( figure 3B).
The inclusion of all potential harms-eg, diabetes and fracture-had only a slight effect on the benefit-harm balance ( figure 3C). In another analysis with equal preference weights of all outcomes, the results showed an unfavourable benefit-harm balance of the triple therapy ( figure 3D). Figure 2 provides a heuristic summary of the thresholds, focusing on the most important determinant factors and excluding other factors that would have little or no effect on treatment decisions. Low doses of inhaled corticosteroids were generally preferable. BEC and age were important predictors of the net clinical benefit that would help to select patients with COPD for recommendation of inhaled corticosteroid, LABA, and LAMA triple therapy. On the basis of this algorithm, we calculated the proportion of primary care patients in the ICE COLD ERIC cohort who would benefit from adding inhaled corticosteroids, using the cal culated thresholds and the ATS guideline. The overall proportion of patients who would have a net clinical benefit was 37% with the thresholds and 33% with the ATS guideline. However, the proportion of those who would benefit was highly variable according to the inhaled corticosteroid dose and patient factors, which was 68% in the best scenario (ie, for patients aged 40-79 years with a baseline exacerbation risk of 32-95% and a BEC of 150 cells per µL or more given low-dose inhaled corticosteroids). However, the propor tions were qualitatively similar between the subgroups and different inhaled corticosteroid doses using the ATS recommendation.

Discussion
This quantitative benefit-harm assessment showed that inhaled corticosteroid, LABA, and LAMA triple therapy was more likely to yield a net clinical benefit for patients with COPD with a 2-year moderate-to-severe exacerbation risk between 54% and 83% than was LABA and LAMA dual therapy. However, the net clinical benefit differed by inhaled corticosteroid dose and between patient characteristics, such as baseline exacerbation risk, BEC, and age, yielding opportunities for personalised decision making.
The 2020 ATS guideline is not based on a quantitative benefit-harm assessment and was not based on predicted risk for exacerbations. 2 As a proxy for an increased exacerbation risk, the ATS guideline referred to one or more exacerbations in the previous year to recommend patients for inhaled corticosteroid, LABA, and LAMA triple therapy. This guideline corresponded to a 71% average expected risk over 2 years (figure 2), as calculated from the ICE COLD ERIC cohort based on the prediction model that we validated. 31 This risk value was within our calculated thresholds. The overall proportion of patients who would benefit from the added inhaled corticosteroids was also similar between the ATS and thresholds approaches. However, granulating the recommendations according to patient characteristics showed greater differences between the two approaches. Although the net clinical benefit for low doses of inhaled corticosteroids based on our calculated thresholds was driven primarily by a higher baseline BEC and a younger age, the ATS approach was equally applicable to all patients. For example, the proportion of patients who would benefit from inhaled corticosteroids in those with a BEC of 150 cells per µL or more and less than 150 cells per µL was similar at 34% using the ATS guideline, whereas the average 2-year exacerbation risk was greatly different, at 71% for those with a BEC of 150 cells per µL or more and 46% for those with a BEC of less than 150 cells per µL (figure 2). These results could lead to treatment misclassification, resulting in undertreatment in patients with more eosinophil counts and overtreatment in those with fewer.
Exacerbation history might not guide treatment decisions well and therefore predicted exacerbation risk, baseline BEC, and age would better personalise the treatment decision for low and moderate doses of inhaled corticosteroids added to LABA and LAMA. Baseline BEC is an important predictor of response to inhaled corticosteroid treatment, as shown in ETHOS, a meta-analysis of several RCTs, INCONTROL, and other meta-analyses. 5,7,16,33 The Global Initiative for Chronic Obstructive Disease guidelines also recommend inhaled corticosteroids in patients with an increased BEC. 34 But even for patients with a higher BEC, a one-size-fitsall strategy is not appropriate, since the baseline exacerbation risk still needs to be considered, as we showed in this study. In the ICE COLD ERIC cohort, 57% of patients had a BEC of 150 cells per µL or more, but only 68% of these patients would be recommended for triple therapy on the basis of our calculated thresholds. In terms of age, the benefits of additional inhaled corticosteroids were generally more favourable for younger people than for older people, because of the higher baseline risks of harm outcomes in older patients that counterbalance the potential benefit of inhaled corticosteroids.
The net benefit of inhaled corticosteroids was also dose dependent. The lower the dose, the more favourable the benefit-harm balance. This effect was because of the dose-related excess risk of harm outcomes. 4,6,[13][14][15][17][18][19][20][21][22] Increasing the dose of inhaled corticosteroids confers little additional benefit in terms of reducing exacerbations, but substantially increases harm risks. 4 As such, as shown in this analysis, reducing the inhaled corticosteroid dose appears to be a preferable therapeutic option for many patients with COPD.
In most results, the rate of incremental net benefit or marginal net benefit was not linear. Rather, it increased at a decreasing rate over a range of exacerbation risks, depending on the subgroups, and subsequently decreased. The expected exacerbation risk over the 2-year horizon increased in patients given the triple and dual therapies, but the difference in cumulative risk decreased over time. These results are attributed to the model property that the cumulative risk of events over a restricted time horizon cannot exceed 100%, regardless of higher baseline risks. The diminishing benefit at high exacerbation risks could thus be interpreted analogously to the law of diminishing marginal utility, but here, net clinical benefit, rather than utility. 35 However, this finding could change if the risk of harm outcomes (such as pneumonia) are not the same across the exacerbation risk spectrum.
Although we did a rigorous analysis to assess the benefit-harm balance of triple therapy with a transparent model, the study was not without its limitations. The findings could be more highly stratified than we presented. Data were not available for important factors, such as body-mass index, smoking, or the method of inhaled corticosteroid delivery. 3,4,6 In addition, the model might not cover all scenarios in clinical practice. For example, it cannot control for uncertainty around the predicted exacerbation risk, BEC stability, treatment compliance, the recurrence of outcome events and their distribution over time, and the benefit and harm outcomes of treatments that might be prescribed for inhaled corticosteroid-related harms. We did not elicit preferences from the patients, but took generic weights that were applied in other decision problems. 25 However, it should be noted that average estimates from preference surveys might not always be relevant. Preference could be patient-dependent because of differences in treatment goals between individuals in terms of social, psychological, and functional health. In such cases, decision aids could be of great help to better personalise decisions, instead of taking average estimates, for which individual patient preferences could be considered and individual risks could be estimated using predictive models (eg, Bertens and colleagues 31 and ACCEPT 36 ).
This study shows that the benefit-harm balance of LABA and LAMA varies greatly according to the 2-year risk of baseline exacerbations, BEC, age, and inhaled corticosteroid dose, on the basis of which more granular treatment decisions are needed. With the use of these factors and a model for predicting exacerbation risk, the uncertainty about when to prescribe inhaled corticosteroids and at what dose can be substantially reduced, and overtreatment and undertreatment with inhaled corticosteroids minimised.

Contributors
All authors contributed substantially to the content and writing of this article. HGY and MAP conceptualised the study. HGY collected the data and MAP, DM, GtR, MS, and JB accessed and verified the data. HGY did the benefit-harm analysis. JB validated the COPD prediction model. MAP, DM, GtR, and MS reviewed the analysis and results. HGY drafted the manuscript. All authors reviewed and edited the manuscript, and approved the final version.

Declaration of interests
We declare no competing interests.

Data sharing
Extracted data are available within the publication and its appendix. Codes can be accessed from the corresponding author upon request with a signed data access agreement.