Health and cost impact of stepping down asthma medication for UK patients, 2001-2017: A population-based observational study.

BACKGROUND: Guidelines recommend stepping down asthma treatment to the minimum effective dose to achieve symptom control, prevent adverse side effects, and reduce costs. Limited data exist on asthma prescription patterns in a real-world setting. We aimed to evaluate the appropriateness of doses prescribed to a UK general asthma population and assess whether stepping down medication increased exacerbations or reliever use, as well as its impact on costs. METHODS AND
FINDINGS: We used nationwide UK primary care medical records, 2001-2017, to identify 508,459 adult asthma patients managed with preventer medication. Prescriptions of higher-level medication: medium/high-dose inhaled corticosteroids (ICSs) or ICSs + add-on medication (long-acting β2-agonist [LABA], leukotriene receptor antagonist [LTRA], theophylline, or long-acting muscarinic antagonist [LAMA]) steadily increased over time (2001 = 49.8%, 2017 = 68.3%). Of those prescribed their first preventer, one-third were prescribed a higher-level medication, of whom half had no reliever prescription or exacerbation in the year prior. Of patients first prescribed ICSs + 1 add-on, 70.4% remained on the same medication during a mean follow-up of 6.6 years. Of those prescribed medium/high-dose ICSs as their first preventer, 13.0% already had documented diabetes, cataracts, glaucoma, or osteopenia/osteoporosis. A cohort of 125,341 patients were drawn to assess the impact of stepping down medication: mean age 50.4 years, 39.4% males, 39,881 stepped down. Exposed patients were stepped down by dropping their LABAs or another add-on or by halving their ICS dose (halving their mean-daily dose or their inhaler dose). The primary and secondary outcomes were, respectively, exacerbations and an increase in reliever prescriptions. Multivariable regression was used to assess outcomes and determine the prognostic factors for initiating stepdown. There was no increased exacerbation risk for each possible medication stepdown (adjusted hazard ratio, 95% CI, p-value: ICS inhaler dose = 0.86, 0.77-0.93, p < 0.001; ICS mean daily = 0.80, 0.74-0.87, p < 0.001; LABA = 1.01, 0.92-1.11, p = 0.87, other add-on = 1.00, 0.91-1.09, p = 0.79) and no increase in reliever prescriptions (adjusted odds ratio, 95% CI, p-value: ICS inhaler dose = 0.99, 0.98-1.00, p = 0.59; ICS mean daily = 0.78, 0.76-0.79, p < 0.001; LABA = 0.83, 0.82-0.85, p < 0.001; other add-on = 0.86, 0.85-0.87, p < 0.001). Prognostic factors to initiate stepdown included medication burden, but not medication side effects. National Health Service (NHS) indicative prices were used for cost estimates. Stepping down medication, either LABAs or ICSs, could save annually around £17,000,000 or £8,600,000, respectively. Study limitations include the possibility that prescribed medication may not have been dispensed or adhered to and the reason for stepdown was not documented.
CONCLUSION: In this UK study, we observed that asthma patients were increasingly prescribed higher levels of treatment, often without clear clinical indication for such high doses. Stepping down medication did not adversely affect outcomes and was associated with substantial cost savings.

Introduction

Over the past 4 decades, the use of inhaled corticosteroids (ICSs) and, subsequently, long-acting β2-agonists (LABAs) have resulted in extraordinary improvements in outcomes for people with asthma [1,2]. Since the mid-1990s, asthma guidelines and strategies (including Global Initiative for Asthma [GINA], National Asthma Education and Prevention Program Expert Panel Report, and British Thoracic Society/Scottish Intercollegiate Guidelines Network [BTS/SIGN]) have offered a coherent, evidenced-based, stepwise approach for pharmacological management that can be used within primary and specialist care settings [3-5]. These guidelines strongly advocate finding the minimum effective treatment dose that can achieve symptom control. Indifference to this recommendation increases the risk of serious adverse medication effects because of the chronicity of treatment and unquestionably increases medication costs. The ongoing improvement in asthma care, alongside a higher disease prevalence and rapid growth of more expensive newer drugs, has led to ever-increasing total medication costs across many countries [6-8]. For example, in the UK, asthma costs are over £1.1 billion, of which around 80% is for drug costs, and in the United States, the cost of asthma is around $80 billion annually, of which nearly two-thirds is for prescriptions [6].

The GINA 2019 guidelines recommend a paradigm shift in asthma treatment, advising all asthma patients to receive ICSs, starting with low-dose ICSs or as-needed low-dose ICS–formoterol in the GINA guidelines, and escalating as necessary. For the majority of patients, 80%–90% of the therapeutic benefit of ICSs are obtained with low doses [9,10]. Prolonged use and higher doses of ICS are associated with a progressive risk of systemic adverse effects, including adrenal suppression, diabetes, cataracts, glaucoma, osteoporosis, and fractures. Unlike the plateau effect of efficacy outcomes, which occurs with higher ICS doses, there is no plateau to the risk of adverse effects [11]. Community studies from Australia and Scotland suggest patients are often inappropriately prescribed, and remain on, high doses of ICSs [12,13]. International and national guidelines recommend stepping down treatment once asthma is controlled to prevent accumulating adverse effects, yet it is thought to be an uncommon practice [3,14], even though the majority of asthma patients seldom exacerbate [15].

In this study, using nationally representative primary care data from across the UK, we first evaluated the temporal pattern of preventer prescriptions (prevalent and incident prescriptions), the associated patient characteristics, and the frequency of medication step change. We then focused on patients that were stepped down to evaluate any associated health and cost impact.

Methods

Ethical approval

The protocol for this research was approved by the Independent Scientific Advisory Committee (ISAC) for MHRA Database Research (protocol number 18_120) and is available alongside the STROBE checklist for observational studies (S1 STROBE Checklist & S1 Study Protocol). This study is based, in part, on data from the Clinical Practice Research Datalink (CPRD) obtained under licence from the UK Medicines and Healthcare products Regulatory Agency. The data are provided by patients and collected by the National Health Service (NHS) as part of their care and support. Linked pseudonymised data were provided for this study by CPRD. Data are linked by NHS Digital, the statutory trusted third party for linking data, using identifiable data held only by NHS Digital. Select general practices consent to this process at a practice level, with individual patients having the right to opt-out. The Office for National Statistics (ONS) was the provider of the ONS data contained within the CPRD data. The interpretation and conclusions contained in this study are those of the authors alone.

Data sources

We used the CPRD-GOLD, a nationally representative database of deidentified UK primary care electronic medical records. CPRD holds information on diagnoses, symptoms, and prescriptions on more than 11 million patients [16]. It is one of the largest longitudinal healthcare databases worldwide and has been validated extensively [16]. Secondary care information was obtained from the Hospital Episode Statistics (HES) database. HES only covers English NHS hospitals, so around 60% of CPRD practices have individual level HES linkage, socioeconomic data (using the Index of Multiple Deprivation), and mortality data (ONS).

In the UK, each single inhaler prescribed should last one month if taken as per manufacturer intended dose (usually as 2 puffs twice a day). A new prescription is recorded for every successive inhaler, and more than one of the same inhaler can be prescribed on the same day (and is recorded as such).

Study populations and design

Main study population

Inclusion criteria were an asthma diagnosis using a validated algorithm of including asthma clinical codes (with an 86% positive predictive value) [17], no chronic obstructive pulmonary disease (COPD) co-diagnosis [18], ≥18 years old, and ≥1 year of prescription data (Fig 1 & Fig 2). Prescription data were considered eligible for study inclusion (‘eligible prescription date’) from the latest date of the following: January 1st, 2001, research acceptable date (CPRD quality control), continuous records date, 18th birthday, or asthma diagnosis date. Follow-up was censored at the earliest date of the following: January 1st, 2018, date transferred out of CPRD, last data collection, or death.

Fig 1

Study design.

COPD, chronic obstructive pulmonary disease; CPRD, Clinical Practice Research Datalink; HES, Hospital Episode Statistics; ICS, inhaled corticosteroid

Fig 2

Flow diagram for study.

CPRD, Clinical Practice Research Datalink; ICS, inhaled corticosteroid

Prescription analysis (prevalent and incident prescriptions)

To be eligible, patients had to have ≥1 year of follow-up and ≥3 preventer prescriptions (Figs 1 & S1). For the incident (first asthma prescription) analysis, patients were included if they had ≥2 asthma prescriptions within the year after their incident prescription (to exclude patients prescribed a ‘trial’ inhaler; in the UK, trialling an inhaler is often part of the diagnostic pathway to determine whether a patient has asthma or not), ≥1 year of no preventer prescriptions before their incident prescription, and were HES-linked. Patients characteristics in the incident analysis were described to assess their suitability for their level of inhaler and their potential risk of medication adverse effects. A change in prescriptions was described using the 2016 SIGN/BTS stepwise approach [3].

Stepping-down outcomes analysis

To determine the health impact, a cohort of regular preventer users was drawn from the main study population (Fig 1 & S1 Fig). Exposed patients had asthma medication stepped down, and unexposed patients were all other eligible patients. Patients could only enter this cohort once they had been prescribed ≥3 ICSs during a 1-year period after their eligible prescription date and were HES-linked. This cutoff was chosen to include patients with regular inhaler use, potentially suitable for reduction in their treatment level. The ‘step-down date’ was defined as either the date of stepping down (exposed patients) or, if unexposed, the first date after satisfying all eligibility criteria. This cohort was also used to determine the prognostic factors associated with instigating stepping down.

The ‘index date’ for the outcome analysis was then recorded as 2 months from the stepdown date. This time period was set because although a single inhaler prescription should last 1 month, many patients miss doses. In this cohort, patients received a mean of 7 prescriptions per year (IQR 6–9), suggesting each inhaler was used on average for approximately 2 months. Therefore, after this time period, patients were considered to be no longer using their dropped medication; however, a sensitivity analysis was also carried out assuming 1- and 3-month time periods.

Stepping down and medication escalation

Stepping down was based on guideline recommendations and was defined as (1) dropping an add-on therapy (LABA, leukotriene receptor antagonist [LTRA], theophylline, or long-acting muscarinic antagonist [LAMA]), (2) halving the ICS inhaler dose (for example, beclometasone 200 mcg to 100 mcg), or (3) halving the mean-daily ICS dose (stepping down by reducing daily inhalations) [3,4]. Most ICS stepping-down trials used a 50% stepdown [19]; using a lower stepdown would be less likely to identify an effect if there is one. To be included, patients had to have ≥3 inhalers of the stepped-down drug in the year before stepping down. Only the first stepdown that occurred during follow-up was included.

A drop in mean-daily ICS was measured by comparing the mean ICS dose per day in 1 year with the mean ICS dose per day in the first 4 months of the subsequent year (‘assessment year’). The first day of the assessment year was recorded as the index date.

Escalation was defined as the opposite of stepping down (i.e., addition of an add-on therapy or doubling of ICS dose) occurring in the year following the index date.

Outcomes and confounders

The primary outcome was asthma exacerbations. These were identified as previously defined [20], as a short course of oral corticosteroids, an emergency department visit for asthma, a hospital admission, or death secondary to asthma. An exacerbation had to occur within 12 months of the patient’s study entry date. The secondary outcome was a change in reliever prescriptions. This was defined as an increase of ≥1 reliever prescription (short-acting beta-agonist) in the year after the index date compared with the year before. Frequency of SABA is used to help assess asthma control and is often used in observational studies as a proxy for asthma control [21-24]. A history of atopy, gastroesophageal reflux, smoking, anxiety, depression, cataracts, pneumonia, diabetes, osteopenia, osteoporosis, and arrhythmia was recorded using appropriate Read codes (see S1 CPRD_medcodes). Variables defined only using data from the year prior to the index date were ‘ICS stability’ (binary variable; defined as change or no change in ICS inhaler prescription dose or type), ‘maximum ICS dose’ (categorical variable [low, medium, or high]); maximum dose of ICS prescription), ‘ICS frequency’ (categorical variable (0–3, 4–6, 7–10, ≥11); number of ICS prescriptions) and reliever frequency (binary variable (<3, ≥3); number of short-acting beta-agonist canisters). Also, using only data from the previous year, nonpharmacological management was assessed using appropriate Read codes for the occurrence of the following within primary care: patient given an asthma management plan, annual asthma review, or inhaler technique check. Patients prescribed LABA–ICS were categorised by combination inhaler or not (this variable was included as a secondary analysis, after a reviewer’s suggestion). ICS dose was categorised using the 2016 SIGN/BTS guidelines, based on fine-dose beclometasone dipropionate equivalent: low dose (≤799 mcg), medium dose (800–1,599 mcg), and high dose (≥1,600 mcg) [3]. The cutoff for an infrequent ICS prescription was defined as ≤2 prescriptions per year, based on the distribution across the whole cohort.

Statistical analysis

For prevalent prescriptions, the maximum therapy level per patient each calendar year was determined. To evaluate change in prescriptions from the first (incident) preventer medication prescribed, a single prescription increase/decrease during a patient’s total follow-up was recorded as a change. The effect of stepping down on exacerbations was analysed in an intention-to-treat Cox proportional hazards model adjusted for sex, age, body mass index (BMI), smoking, socioeconomic class, gastroesophageal reflux, anxiety, depression, annual asthma review, inhaler technique check, asthma management plan, exacerbations, reliever use, maximum ICS dose, ICS frequency, ICS stability, and add-on therapies using complete case analysis. Patients were censored on their first exacerbation or 1 year after the index date. Schoenfeld residuals were found not to violate the proportional hazards assumption [25]. The effect of stepping down on reliever use was analysed in an intention-to-treat logistic regression model adjusted for the same variables as the Cox model. The association between potential prognostic factors and initiating stepdown was assessed using multivariable mixed-effects logistic regression models, using GP practice as the random intercept. Several sensitivity and subgroup analyses were performed (1) using a 6-month (instead of 12-month) outcome window after the index date, (2) defining the date of stepping down at 1 month and at 3 months after the last prescription date (instead of 2 months), (3) stratifying patients by presence of exacerbations in the year prior to the index date, and (4) analysing the effect on exacerbations using an as-treated approach (censoring stepped-down patients on date of escalation, if within 1 year of the index date). To further diminish the effect of selection bias, an additional analysis using inverse-probability–weighted propensity score methodology was used; the average treatment time for the first exacerbation was compared between each stepdown and no stepdown. All statistical analyses were performed using STATA 14.2.

Cost analysis

Cost analyses for the cohort were performed applying drug costs alone. Price per drug was obtained using 2019 indicative prices from the NHS Dictionary of Medicines and Devices to avoid a cost effect due to price changes [26]. Patients prescribed drugs that no longer had a price available were excluded. Individual cost differences were calculated by subtracting the cost of preventer medications prescribed 12 months post-index date from the yearly drug costs pre-index date. The mean of those differences was calculated for the cohort by medication stepped down. The mean cohort costs were used to estimate population-level costs for stepping down LABAs or ICSs using the following assumptions: UK population was 65 million, of whom 80% were adults (based on 2019 ONS data); 7% had asthma [27]; 50% were prescribed LABAs; 40% were prescribed medium- or high-dose ICSs (Fig 1); 15% had a ‘stable’ year; and only half of the eligible population were stepped down (Table 1). A ‘stable’ year was defined as ≥3 ICS prescriptions, no change in preventer medications, or <3 reliever prescriptions and no exacerbations.

Table 1

Change of preventer medication during follow-up from incident prescription.

	Mean Follow-up (95% CI)	No Change (%)	Escalate Only (%)	Stepdown Only (%)	Escalate and Stepdown (%)
Low-dose ICSs	6.6 years (6.5–6.6)	41.7	39.5	*	18.9
Medium/high-dose ICSs	8.1 years (8.0–8.2)	19.5	34.3	14.5	31.7
ICSs + 1 add-on	6.6 years (6.6–6.7)	70.4	6.3	7.8	15.5

*Patients that stopped all preventer medications were not included. Abbreviations: ICS, inhaled corticosteroid.

Results

Prevalent preventer prescriptions

508,459 patients were identified; the proportion on higher-level preventer medications (medium/high-dose ICSs or ICSs and add-on therapy) steadily increased over time (2001 = 49.8%, 2017 = 68.3%; Fig 3).

Fig 3

Prevalent asthma preventer prescriptions from across the UK, 2001–2017.

The light blue area below the dotted line is the percentage of patients prescribed medium-dose or high-dose ICSs that are prescribed an ICS and 1 add-on therapy. Add-on therapy refers to LABA, LTRA, theophylline, or LAMA. ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist.

In 2017, only 31.7% of patients were treated with low-dose ICSs alone. Most patients were managed with ICSs and 1 add-on. Of those prescribed an add-on, 88.3% were prescribed a combination LABA–ICS inhaler, of which 69.6% included medium- or high-dose ICSs.

First-time (incident) preventer prescriptions

107,908 patients were identified for the incident analysis; around one-third were prescribed higher-level medication as their first asthma preventer medication (S1 Fig). Most patients prescribed an add-on were prescribed LABAs (94.0%), of whom 74.6% were prescribed either medium- or high-dose ICSs. Of those prescribed LABA–ICS, 77.2% were prescribed an LABA–ICS combination inhaler throughout the time period, but by 2016 onwards, all LABA–ICS prescriptions were combination inhalers.

In patients prescribed ICSs + 1 add-on, 70.4% did not have their prescription changed during a mean follow-up of 6.6 years (Table 1). Of those prescribed medium- or high-dose ICSs, 54.5% kept the same therapy or escalated during a mean follow-up of 8.1 years.

Of those prescribed higher-level medication as their incident asthma prescription (all steps above low-dose ICSs), 48.4% had no exacerbation or reliever prescriptions in the previous year. The median time since diagnosis before first prescription was 19.2 months, and 13.2% already had a comorbidity that could be worsened by corticosteroids (S1 Table).

Of those prescribed medium- or high-dose ICSs as their incident prescription, 13.0% had known diabetes, cataracts, glaucoma, osteopenia, or osteoporosis at the time of prescription, compared with 11.2% prescribed incident low-dose ICSs (Table 2).

Table 2

Patient characteristics at their first asthma preventer prescription by ICS dose prescribed; low-dose ICSs compared with medium/high-dose ICSs.

	Low-Dose ICSs Incident Prescription	Medium/High-Dose ICSs Incident Prescription
	Median (IQR)	Median (IQR)
Age (years)	48 (35–62)	52 (39–64)
Reliever frequency	1 (0–2)	0 (0–1)
	N (%)	N (%)
Total	68,363 (100%)	39,545 (100%)
Never smoked	22,727 (33.2%)	12,186 (30.8%)
Atopy	32,314 (47.3%)	18,544 (46.9%)
Anxiety	13,016 (19.0%)	7,455 (18.9%)
Reflux	6,993 (10.2%)	4,746 (12.0%)
Bronchiectasis	306 (0.4%)	418 (1.1%)
GP-treated exacerbations	7,666 (11.2%)	5,379 (13.6%)
Hospital exacerbations	883 (1.3%)	885 (2.2%)
IHD	3,181 (4.7%)	2,502 (6.3%)
Hypertension	14,211 (20.8%)	9,073 (22.9%)
Arrhythmia	2,021 (3.0%)	1,536 (3.9%)
Pneumonia	1,812 (2.7%)	1,332 (3.4%)
Comorbidity that could be worsened by corticosteroids	7,674 (11.2%)	5,128 (13.0%)
Glaucoma	862 (1.3%)	639 (1.6%)
Cataracts	2,125 (3.1%)	1,419 (3.6%)
Osteopenia/osteoporosis	1,960 (2.9%)	1,337 (3.4%)
Diabetes	3,875 (5.7%)	2,498 (6.3%)

Abbreviations: GP, general practitioner; ICS, inhaled corticosteroid; IHD, ischaemic heart disease.

Effect of stepping down on exacerbations

125,341 patients (mean age 50.4 years, 39.4% males) satisfied the criteria for the stepping-down analysis: 39,881 were stepped down (ICS mean daily = 26,603, ICS inhaler dose = 6,182, LABA = 4,078, other add-on = 3,018), and 85,460 were not stepped down (Table 3).

Table 3

Patient characteristics of each exposed and unexposed group.

Characteristics	Controls/Unexposed		Stepped-Down Drug
	Not Stepped Down		ICSs		LABA		Other Add-on
	N	%	N	%	N	%	N	%
Total	85,460	100.0	32,785	100.0	4,078	100.0	3,018	100.0
ICS stepdown
Mean-daily ICS	–	–	26,603	81.1	–	–	–	–
Inhaler dose	–	–	6,182	18.9	–	–	–	–
Other add-on
LTRA	–	–	.	.	–	–	1,751	58.0
Theophylline	–	–	.	.	–	–	605	20.0
LAMA	–	–	.	.	–	–	662	21.9
Age
18–29	10,936	12.8	4,503	13.7	522	12.8	273	9.0
30–40	13,303	15.6	5,899	18.0	610	15.0	418	13.9
40–50	16,403	19.2	6,984	21.3	710	17.4	594	19.7
50–60	14,603	17.1	5,691	17.4	661	16.2	624	20.7
60–70	14,367	16.8	4,817	14.7	673	16.5	537	17.8
≥70	15,848	18.5	4,891	14.9	902	22.1	572	19.0
Males	34,100	39.9	13,049	39.8	1,465	35.9	1,020	33.8
Socioeconomic status
1 (least deprived)	13,920	16.3	4,884	14.9	637	15.6	411	13.6
2	16,347	19.1	6,555	20.0	811	19.9	593	19.6
3	16,154	18.9	6,565	20.0	779	19.1	539	17.9
4	18,041	21.1	7,191	21.9	881	21.6	632	20.9
5	20,998	24.6	7,590	23.2	970	23.8	843	27.9
BMI
Normal	18,120	23.0	7,350	24.0	873	22.7	630	21.9
Underweight	1,659	2.1	608	2.0	86	2.2	59	2.1
Overweight	32,929	41.8	12,802	41.8	1,544	40.2	1,157	40.3
Obese	26,163	33.2	9,876	32.2	1,335	34.8	1,026	35.7
Smoking history
Never	27,822	32.6	10,799	32.9	1,264	31.0	967	32.0
Current	28,452	33.3	11,383	34.7	1,359	33.3	970	32.1
Ex-smoker	29,186	34.2	10,603	32.3	1,455	35.7	1,081	35.8
Atopy	46,104	53.9	17,917	54.6	2,283	56.0	1,842	61.0
Anxiety	18,836	22.0	6,816	20.8	1,031	25.3	777	25.7
Depression	22,921	26.8	8,582	26.2	1,227	30.1	946	31.3
Reflux	11,787	13.8	4,151	12.7	717	17.6	571	18.9
In year prior to exposure
≥1 exacerbation	8,204	9.6	2,750	8.4	526	12.9	585	19.4
ICS frequency
3	18,328	21.4	6,582	20.1	937	23.0	350	11.6
4–6	37,611	44.0	17,467	53.3	1,924	47.2	1,123	37.2
7–10	19,439	22.7	6,410	19.6	833	20.4	930	30.8
≥11	10,082	11.8	2,326	7.1	384	9.4	615	20.4
Max ICS
Low dose	48,136	56.3	16,266	49.6	1,647	40.4	937	31.0
Medium dose	26,969	31.6	11,295	34.5	1,669	40.9	1,010	33.5
High dose	10,355	12.1	5,224	15.9	762	18.7	1,071	35.5
Stable ICS	68,671	80.4	26,300	80.2	2,875	70.5	2,242	74.3
LABA use	46,256	54.1	15,464	47.2	0	0.0	2,478	82.1
≥2 add-on therapies	686	0.8	185	0.6	23	0.6	528	17.5
Reliever frequency
0–2	27,764	32.5	12,094	36.9	1,560	38.3	809	26.8
3–7	36,874	43.1	15,077	46.0	1,770	43.4	1,177	39.0
≥8	20,822	24.4	5,614	17.1	748	18.3	1,032	34.2
Annual asthma review	45,893	53.7	15,775	48.1	2,136	52.4	1,558	51.6
Inhaler technique	37,633	44.0	13,517	41.2	1,807	44.3	1,246	41.3
Asthma management plan	9,673	11.3	3,080	9.4	479	11.7	297	9.8

Dashes indicate no data/not applicable. Abbreviations: BMI, body mass index; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist.

Stepping down LABA or other add-on medication or ICSs, either by reducing the dose of the inhaler or by reducing the number of puffs, did not significantly increase the risk of an exacerbation in the subsequent year (adjusted hazard ratio, 95% CI, p-value: ICS inhaler dose = 0.86, 0.77–0.93, p < 0.001; ICS mean daily = 0.80, 0.74–0.87, p < 0.001; LABA = 0.99, 0.92–1.11, p = 0.87; other add-on = 0.99, 0.91–1.09, p = 0.79; Table 4). The main findings remained robust in the sensitivity analyses (S2 Table). The stratified analysis by prior exacerbation history showed no significant difference (S3 Table). The treatment effect analysis found negligible difference in days between first exacerbation in patients with stepped-down drug and no stepdown (S4 Table).

Table 4

Risk of an exacerbation by medication stepped down.

	Adjusted HR	95% CI	p-Value
Drug stepped down
None	Reference
ICS: inhaler dose	0.86	0.77–0.93	<0.001
ICS: mean daily	0.80	0.74–0.87	<0.001
LABA	0.99	0.92–1.11	0.871
Other add-on	0.99	0.91–1.09	0.791

Cox proportional hazard regression was used to assess the association between an exacerbation in the year after each stepdown, compared with no stepdown, after adjusting for sex, age, BMI, smoking history, socioeconomic status, atopy, anxiety, depression, gastroesophageal reflux, and in the year prior to exposure: maximum ICS dose, ICS stability, ICS frequency, reliever frequency, LABA use, at least 2 add-on therapies, exacerbations, annual asthma review, inhaler technique check, and asthma management plan. The rate and number of exacerbations (per 10 person years, N) of patients that had an exacerbation by drug stepped down were none (1.23 per 10 person years, N = 9,984), ICS mean daily (0.84 per 10 person years, N = 2,163), ICS inhaler dose (1.13 per 10 person years, N = 720), LABA (1.18 per 10 person years, N = 458), other add-on (2.02 per 10 person years, N = 564). Abbreviations: BMI, body mass index; HR, hazard ratio; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist.

The proportion of unexposed patients that had treatment escalated in the year following the index date was similar to or higher than that for mean-daily ICS or LABA (unexposed = 16.7% [95% CI 16.3–17.0], mean-daily ICS = 16.3% [95% CI 15.8–16.7]; LABA = 11.0% [95% CI 10.1–12.0]; S5 Table). Patients that dropped their ICS inhaler dose, LTRA, LAMA, or theophylline had higher proportions escalate (ICS inhaler dose = 29.5% [95% CI 28.3–30.7], LTRA = 20.5% [95% CI 18.7–22.4], LAMA = 23.2% [95% CI 20.0–26.5], theophylline = 59.8% [95% CI 55.9–63.7]).

Effect on reliever use

Stepping down was not associated with an increase in reliever use (adjusted odds ratio [95% CI, p-value]: ICS inhaler dose = 0.99 [0.98–1.00, p = 0.59], ICS mean daily = 0.78 [0.76–0.79, p < 0.001], LABA = 0.83 [0.82–0.85, p < 0.001], other add-on = 0.86 [0.85–0.87, p < 0.001]; Table 5).

Table 5

Risk of increase in reliever use by medication stepped down.

	Adjusted OR	95% CI	p-Value
Drug stepped down
None	Reference
ICS: inhaler dose	0.99	0.98–1.00	0.594
ICS: mean daily	0.78	0.76–0.79	<0.001
LABA	0.83	0.82–0.85	<0.001
Other add-on	0.86	0.85–0.87	<0.001

Logistic regression analysis was used to assess the association between an increase of one or more reliever inhaler prescription in the year after each stepdown, compared to no stepdown, after adjusting for sex, age, BMI, smoking history, socioeconomic status, atopy, anxiety, depression, gastroesophageal reflux, and in the year prior to exposure: maximum ICS dose, ICS stability, ICS frequency, reliever frequency, LABA use, at least 2 add-on therapies, exacerbations, annual asthma review, inhaler technique check, and asthma management plan. The number of patients that had an increase in reliever by drug stepped down was none (N = 19,027, 22.3%), ICS inhaler dose (N = 2,447, 39.6%), LABA (N = 1,269, 31.1%), other add-on (N = 832, 27.3%). Abbreviations: BMI, body mass index; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist.

Prognostic factors for initiating stepping down

The factors significantly associated with initiating ICS stepdown included high- or medium-dose ICSs, ≥4 ICS prescriptions, current smoker, LABA use, and ICS stability (S6 Table). Common ICS side effects, diabetes, and cataracts were not associated with initiating stepdown, but osteopenia/osteoporosis was significantly associated with not stepping down. Combination LABA–ICS use, an annual asthma review, past exacerbation, and being older were also significantly associated with not initiating ICS stepdown.

The factors significantly associated with stepping down add-on therapy included using ≥2 add-on therapies, LABA, past exacerbation, high-dose ICSs, older age, ICS stability, history of pneumonia, or arrhythmia (S6 Table).

Cost savings

In the cohort of regular inhaler users, 31,379 patients were stepped down and had available drug costs in 2019. The mean annual saving was highest for LAMAs and LABAs and lowest for ICSs (ICS = £60.30 [95% CI 59.34–61.27], LABA = £126.92 [95% CI 123.61–130.22], LTRA = £108.86 [103.91–113.82], LAMA = £150.38 [139.65–161.12], theophylline = £114.98 [105.12–123.67]), S7 Table. Using the assumptions described in the methods, estimated UK savings from stepping down LABAs from half of the UK’s stable adults treated with LABA–ICS would result in around 340,000 people having 7 fewer preventer prescriptions per year, saving approximately £17,000,000 annually. The equivalent calculations if stepping down ICSs would save around £8,600,000.

Discussion

In a representative UK general asthma cohort, we have shown that between 2001 and 2017, prescription of higher-level preventer medications became increasingly common. There was often no clear clinical requirement for such high doses; one-third of patients had not received a reliever inhaler prior to their first asthma prescription or had an exacerbation. Nearly three-quarters of patients who were prescribed an ICS + 1 add-on as their first medication remained on the same medication for several years. One in 8 patients who were prescribed a medium/high-dose ICS as their first preventer already had known steroid-induced adverse effects. When medication stepdown was initiated, it was found to be safe, with no increase in exacerbations or reliever use, and economical.

In over 0.5 million asthma patients, the proportion prescribed higher-level medications (medium-dose ICSs, high-dose ICSs, or fixed-dose ICSs with add-on therapy) steadily increased over the past 2 decades. By 2017, only one-third of patients were managed on low-dose ICSs alone, in keeping with older UK studies also suggestive of inappropriate prescribing of higher doses of ICSs [28,29]. This pattern may have occurred because firstly, there was a relatively high number of patients, around one-third, who were prescribed their first preventer medication above the initial preventer step recommended by guidelines. Secondly, a high proportion of patients either remained on their incident prescription or had their medication escalated but never stepped down thereafter (including 77% of those prescribed ICSs + 1 add-on). Patients often have treatment stepped up in response to temporary worsening control or an acute exacerbation, but once control is achieved, their medication is not reviewed again [14]. Our study found most patients receiving a higher-level preventer medication as their first asthma medication had not received a prescription for a preventer inhaler in the previous year (guidelines pre-2016 advised reliever therapy alone as the first treatment step [30]) nor experienced an exacerbation. The prescribing of a higher level of medication without clear clinical indication suggests the prescribing physicians were not following guideline recommendations. This is perhaps not a surprising finding because adherence to guidelines in general practice has been shown to be low in many countries [28,29,31-34].

Physicians prescribing higher ICS doses were perhaps also not alert to potential adverse systemic effects because 13% of those prescribed medium- or high-dose ICSs as their first prescription already had known relevant comorbid conditions (i.e., diabetes, cataracts, glaucoma, osteopenia, or osteoporosis) compared with 11% of those prescribed low-dose ICSs. The majority of patients prescribed ICSs and an add-on were prescribed a fixed daily medium-dose or high-dose ICS–LABA combination inhaler. The latest recommendation in GINA for mild and moderate asthma, supported by multiple recent randomised control trials (RCTs) [35-38], is a low-dose ICS-containing inhaler. These latest guidelines should help encourage health professionals to prescribe the minimally effective treatment dose. Furthermore, for most patients, 80%–90% of the therapeutic benefit has been found to occur with low-dose ICSs [9,10].

The most common form of stepdown was halving ICS inhalations, a pragmatic approach that can be readily instigated by patients with or without direction from healthcare professionals. Stepdown did not significantly increase the risk of exacerbations, regardless of which medication was stepped down. Interestingly, there was a slight reduction in exacerbations when stepping down ICSs not seen when stepping down add-on therapies. This could be explained by confounding by indication from an unmeasured variable that led to patient selection only in patients with ICS overtreatment or could be due to increased adherence after medication change from increased medication awareness [39].

Findings remained robust even after all sensitivity analyses. As may be expected, the biggest positive confounding effect was a history of exacerbations in the year prior [15], but even when stratifying by this parameter, there was still no observed increase in exacerbations. This could be explained by patient selection towards the most stable patients, even those that had exacerbated. Another possibility is that this may reflect poor inhaler technique such that stepping down prescriptions did not significantly alter the absorbed dose. Considering stepping down is arguably still important in patients with low medication absorption (from either low adherence or poor technique) in terms of both reducing medication costs and alerting patients and physicians to these potential issues. Lastly, it is likely some patients were misdiagnosed [40], and routinely thinking about stepping down medication (as well as stepping up) as part of an annual asthma review could help identify such patients.

A Cochrane Review, 2017, looked at studies that stepped down ICSs in well-controlled asthma patients [19]. The review found 6 relevant studies; there was no difference in asthma exacerbations, asthma control, side effects, or quality of life. However, the quality of evidence was rated as low or very low. A Cochrane Review, 2015 [41], looked at studies that stopped LABA in well-controlled adults. Five studies were reviewed, with moderate quality of evidence. However, trials were short, with too few exacerbations to assess rates [41]. A small study published since found stopping LABAs was well tolerated [42].

There has only been one previous real-world study comparing stepped-down patients to controls. Using US administrative claims data, the authors identified a smaller cohort of 4,235 eligible patients with a shorter follow-up period and no exact timing of stepdown; this study found stepping down to be safe and highly cost-effective [43].

Around 1 in 6 controls had their treatment escalated in the year after the index date; this number was comparable to those that stepped down their ICS inhalations or their LABAs. A slightly higher number, around 1 in 5, escalated treatment if they had dropped LTRAs, LAMAs, or the ICS inhaler dose. Stepping down did not significantly increase the use of reliever medication, and most patients did not escalate treatment more than the controls; together, these findings suggest stepping down did not have a detrimental effect on patient’s asthma control.

Although the reason for stepping down was not recorded, we were able to evaluate several potential prognostic factors. We found higher levels of medication and prescription stability were associated with instigating stepping down. Use of combination inhalers was associated with reduced odds of stepping down ICSs; however, this is likely to change with the latest GINA guidelines encouraging an as-needed approach. In contrast, common ICS adverse systemic effects, diabetes, cataracts, glaucoma, osteopenia, or osteoporosis were not associated with stepping down ICS. Older age was significantly associated with not having ICSs stepped down but was significantly associated with stepping down LABAs. Yet the older population are at the greatest risk of ICS side effects and are most likely to experience polypharmacy. In the UK, older people have a similar prevalence of asthma as younger adults but are the age group most likely to be prescribed ICSs and most likely to be prescribed medium- or high-dose ICSs instead [27]. It seems that age is a barrier to instigating stepping down, but our analysis found older age did not impact on asthma outcomes. Recently, there has been a drive in older people to rationalise medicines through deprescribing, and patients are keen to engage [44-46]. Notably, asthma-specific clinical practices, including annual reviews and management plans, did not appear to increase the chances of stepping down. A qualitative study of primary care health professionals suggested that key factors why stepping down does not occur are lack of confidence to step down, lack of time to discuss, and resistance from the patients [47].

Our cost analysis found considerable savings covering during just 1 year. The savings from dropping LABAs were almost 4 times that of ICSs and approximately double that of LTRAs. Scaling up the costs to estimate nationwide savings, assuming only half of all stable treated patients are stepped down, could potentially save around £17 million if LABAs were stepped down, equivalent to 2% of the UK’s asthma budget, or £8.6 million if ICSs were stepped down. This large sum is because over 5.4 million people receive asthma treatment in the UK, with asthma medication contributing towards 13% of the total primary care prescribing costs [48] and ICSs being the second most prescribed medication [49]. Many patients prescribed higher doses have suboptimal inhaler technique, and hence, only a small proportion reaches the airways; the money saved on stepping down could instead be spent on improving and adapting education tools for patients and professionals, for example, to cover the continuously expanding inhaler market [50-52].

Strengths and limitations

Major strengths were the use of a nationally representative study population, large sample size, and longevity of the data. Limitations of using routinely collected patient data include lack of information on daily medication use; therefore, to include patients who reduced the number of puffs, we had to calculate mean-daily ICS doses. This could have led to selection bias by excluding patients who decreased, then increased, their puffs again. However, our findings in this group were consistent with patients that had their ICS inhaler dose halved, suggesting this bias had a minimal influence on the effect estimate. It is possible there was selection bias from only including HES-linked patients in the stepping-down analysis because HES is only available for patients using English NHS hospitals. The nature of the data also did not allow us to know precisely why the decision to initiate stepdown was taken; hence, our analysis of potential prognostic factors attempted to investigate this. Although the algorithm used to identify asthma patients has 86% positive predictive value [17], a limitation of the data set is that it does not contain information on diagnostic tests such as lung function tests or airway hyperreactivity measures. Only around 4% of asthma patients are reviewed in secondary care, where such tests are performed in the UK [53]. Mild exacerbations treated only with an increase in ICSs could not be identified, but an annual increase in preventers and relievers was measured. Additionally, prescriptions in the exposed and unexposed may not have been dispensed or adhered to; however, our findings were comparable to the only other study using real-world data, which had access to dispensed data. Lastly, although guidelines suggest stepping down after 3 months of stability, 1 year of stability was used for the cost analysis; therefore, results may be more conservative than would truly occur.

Conclusions

Over time, patients in the UK have been increasingly prescribed higher-level asthma medications with no clear clinical indication for needing higher doses. Worryingly, although stepping down of treatment is recommended by clinical guidelines, we found that it happened infrequently. Stepping down ICSs or add-on therapy did not appear to worsen health outcomes but did appear to result in significant cost savings. Medication burden seemed to be the main driver to stepping down; adverse medication effects were not. In summary, firstly, adverse treatment effects, medication burden, and cost to the health system should be considered when prescribing higher-level asthma medications for well-controlled asthma patients seen in primary care. Secondly, stepping down medication in stable asthma patients appears to be both safe and highly cost-effective.

STROBE checklist for observational studies for the study.

(DOCX)

Click here for additional data file.

Patient characteristics at their first asthma preventer prescription by level of medication prescribed, low-dose ICSs compared to higher-level treatment (medium/high-dose ICSs or ICSs + add-on therapy).

ICS, inhaled corticosteroid

(XLSX)

Click here for additional data file.

Sensitivity analysis, risk of exacerbation after stepdown (a) using a 6-month outcome window (instead of 12 months), (b) using a definition of stepping down starting 1 month or 3 months after the last prescription containing the stepped-down drug, (c) using an as-treated approach.

(XLSX)

Click here for additional data file.

Effect of exacerbation history in year before stepdown.

(XLSX)

Click here for additional data file.

Time effect on first exacerbation of stepdown compared to no stepdown.

(XLSX)

Click here for additional data file.

Percentage of patients that escalated in the outcome year following stepdown.

(XLSX)

Click here for additional data file.

Factors found to be significantly associated with initiating stepdown, either ICSs or LABAs, ordered by strength of association.

Only factors significantly associated (p < 0.05) with initiating stepdown are shown (OR > 1); each variable is adjusted for all variables in the model. The effect estimate shown is the adjusted odds ratio as compared to their reference value. ICS, inhaled corticosteroid; LABA, long-acting β2-agonist.

(XLSX)

Click here for additional data file.

Annual saving from stepping down each drug (including any escalation) in patients with drugs available in 2019, using 2019 NHS indicative prices.

NHS, National Health Service

(XLSX)

Click here for additional data file.

Incident asthma preventer prescriptions from across the UK, 2001–2017.

Add-on therapy refers to LABA, LTRA, theophylline, or LAMA. ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist

(TIF)

Click here for additional data file.

Study protocol for the study.

(DOC)

Click here for additional data file.

CPRD codes for the variables included in the study.

CPRD, Clinical Practice Research Datalink

(PDF)

Click here for additional data file.

10 Jan 2020

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Comments from the reviewers:

*** Reviewer #1:

"Health and cost impact of stepping-down asthma medication: a UK population-based observational study" finds that asthma patients were bring prescribed higher levels of treatment oft without clear clinical indications, from nationwide UK primary care medical records from 2001 to 2017. Further analysis concluded that stepping-down medication to the minimum effective dose did not adversely affect outcomes, and moreover saved on costs. Indeed, stepping-down of ICS in particular consistently reduced hazard ratios (Tables S2/S3).

A major strength of this study would lie in the large number of patients involved (over 100,000 patients for each of the incident prescription/de-escalation analyses), from a cohort of over 500,000 patients from the UK primary care system over 17 years. Findings on the efficacy of stepping-down remained largely unchanged under relevant sensitivity analyses. To the best of our knowledge, there exists no prior study of comparable scale on the impacts of stepping-down asthma medication. Therefore, this study may have significant potential to affect health policy on asthma management, especially with an observed increase in the prescription of higher level medication, and purported insufficient evidence about stepping-down ICS medication as a factor in increased risk of future asthma attacks (e.g. from page 33 of the BTS/SIGN 2019 guidelines).

There however remain some points that might be clarified:

1. In lines 62-64, The appropriate citations might be provided for the various asthma guidelines (GINA, the Expert Panel Report, BTS/SIGN)

2. From line 126, how was the criteria of >= 3 ICS prescriptions (parallel to infrequent ICS defined as <= 2 prescriptions per year in line 166) decided upon, given the mean of 7 prescriptions per year (line 133)? Data on the distribution of prescriptions/year might be illuminating.

3. On the definition of "stepping-down" (Line 138 onwards) - some possible configurations of medication step-down appear not to be explicitly covered by the chosen definition. For example, in prior work ("Stepping Down Asthma Treatment: How and When", Rogers & Reibman, Curr Opin Pulm Med. 2012 Jan; 18(1): 70-75.), it is claimed that "certain step-down practices such as the complete cessation of ICS to LABA alone was associated with a significant loss of asthma control". How might dropping ICS to an add-on therapy be categorized in the analysis (e.g. in Table 4 & 5)?

4. More generally, how were the stepping-down definitions decided? Is halving dosage, for example, universally accepted practice as opposed to say a reduction of dosage by 25% (it is stated in line 309 that "The most common form of step down was halving ICS inhalations", but this does not seem to preclude other practices)?

5. The incidence rate (N) for the various drug-stepped-down categories might be provided in Tables 4 & 5, for convenience.

6. The definition of reliever prescriptions as a secondary outcome (e.g. line 154) might not be entirely obvious. The authors might consider adding a short description of preventer/reliever usage practices in the Introduction. Further, what is the tradeoff between reduced preventer and increased reliever usage?

7. On the incident analysis, it was stated that (line 229) "Of those prescribed higher level medication as their incident asthma prescription... 48.4% had not excerbation or reliever prescriptions in the previous year (Table 2)"; however, the 48.4% figure is not immediately evident from the presentation of Table 2.

8. Moreover, the authors might consider standardizing the formatting of Tables 2/S1/S4 (i.e. consistently place "N" and "%" as separate columns), and include p-values where appropriate.

9. The characteristics examined for incident vs. step-down analysis (i.e. Table 2 vs. Table 3) are fairly different; for instance, age and socioeconomic status are not considered in the incident analysis, although it is not obvious that they do not affect/correlate with incident prescriptions. The authors might consider briefly discussing the selection of characteristics for each analysis.

10. In line 236, it is stated that "(of) 125,341 patients, 39,897 were stepped-down, and 85,460 were not stepped down". However, the sum of stepped-down and non-stepped-down patients appears to be 125,357 patients.

11. Also, from the definition of stepping-down and the chronological length of the study (17 years), it seems possible that an individual (exposed) patient might step-down (and escalate) medication multiple times, over the full time period. How are such cases, if any, accounted for?

12. From line 292, "Our study found most patients receiving a higher level preventer medication as their first asthma medication had not received a prescription for a preventer inhaler in the previous year (guidelines pre-2016 advised preventer therapy alone as the first treatment step(23))", is "preventer medication" not considered "preventer therapy"?

13. In line 310, it is mentioned that step-down can be instigated by patients, possibly without direction from healthcare professionals. How does this happen in practice? Moreover, for the prescription data used in the analyses, were they taken as prescribed by the primary care health professionals (i.e. possibly not followed up on), or as filled by pharmacists?

14. In line 355, which two studies do "both studies" refer to?

15. The discussion on prior investigations on medication step-down for asthma may be somewhat perfunctory. For example, it is claimed that (line 328) "Several randomised controlled trials of medication step-down have shown no difference in asthma exacerbations, asthma control, side-effects or quality of life"; however, citation (36) alone mentions that "Of 14 randomized controlled studies on step down of asthma medications (follow-up period range, 12-168 weeks), only 4 of them found no significant differences in asthma outcomes compared with patients maintaining their asthma medications".

Therefore, while there appears to be a general consensus from the latest asthma management guidelines on stepping-down controlled asthma cases to a minimal level, the evidence from previous randomized controlled trials appears somewhat mixed, even considering recognized methodological limitations. The authors might consider commenting in greater depth on these previous studies.

16. Finally, there may be some minor grammatical issues, e.g.

Line 39: "A cohort of patients were drawn..." -> "was drawn"

Line 47: "...and no increased in reliever" -> "no increase"

Line 297: "Perhaps not a surprising finding..." -> "This is perhaps not a surprising finding..."

Line 337: "this number was comparative..." -> "was comparable"?

*** Reviewer #2:

This is an excellent study showing that asthma patients in the UK (1) are often initiated on overly intensive therapy, (2) are kept on intensive therapy without attempts to step down (contra guidelines), and (3) have no better outcomes than those whose therapy is stepped down.

Major

1. My biggest concern is with the third finding—that stepping down therapy was not associated with more exacerbations or SABA use than continuation of therapy. As the authors recognize, there is a strong possibility for selection bias. They perform a stratified analysis based on exacerbations in the prior year. They also report in Tables 4 and 5 regression analyses that control for a number of potential confounders. These steps all help address the worry of unmeasured confounding. However, they did not perform the analysis with propensity score matching (or high-dimensional propensity score matching), which may help further allay concerns. In general, I worry that the group whose therapy was stepped down is different in important ways than the group whose therapy was continued.

2. The authors did not report on any difference in the side-effects (diabetes, cataracts, glaucoma, osteopenia, or osteoporosis) in the group of patients who were stepped down compared to those who were not. Was there any improvement in these variables among those who were stepped down (whether fewer new diagnoses or improvement in symptoms [e.g. HgbA1c])?

3. This may be beyond the scope of data, but I wonder what proportion of patients had true asthma. As the authors allude to in the discussion (citing the paper by Aaron SD et al., JAMA 2017), many patients who carry a diagnosis of asthma and are started on inhalers never truly have asthma. What proportion of the patients in the cohort had PFTs or a methacholine challenge confirming a diagnosis of asthma? It is possible, as the authors acknowledge, that many patients did not have asthma—in which case, we would expect that stepping down medications would have no effect. Conversely, perhaps those with true asthma may have had more exacerbations and SABA use after being stepped down.

4. The authors note that, in the 107,908 patients in incident cohort, one-third were on an ICS and add-on, of which 94% were on a LABA. What proportion were on combination ICS-LABA versus two separate inhalers (ICS and LABA)? It would be interesting to examine whether being on a combination product affects the likelihood of being stepped down.

5. Of the 107,908 patients who were on an ICS-LABA combination, how many were on ICS-formoterol? The approach of using Symbicort as needed for mild asthma is new in the guidelines. But I wonder whether some clinicians in the UK were already doing this, in which case some of those on an ICS-LABA may not be getting stepped down because they are already on a low intensity therapy (i.e. ICS-formoterol PRN).

Minor

Line 77: This should be "is obtained with a low-dose" rather than "is obtained with low-dose."

Line 110: This should be: "Prescription data were…" rather than "prescription data was..."

Line 121: Does excluding non-HES linked patients affect the generalizability? Is there any reason to think that non-HES linked patients are different from HES-linked patients? This may be worth commenting on in the limitations.

Line 286: This should be "…a higher number of patients, around one-third, who were prescribed…" rather than "a higher number of patients, around one-third, that were prescribed…"

Line 297: This should be "Perhaps this is not a surprising finding…" rather than "Perhaps not a surprising finding…"

Line 373: This should be: "…excluding patients who decreased…" rather than "…excluding patients that decreased…"

*** Reviewer #3:

This is an analysis of the Clinical Practice Research Datalink (UK). The authors used observational data to describe asthma medication patterns with a focus on health outcomes and costs of stepping down asthma medications. The primary conclusion is that higher doses and numbers of asthma medications were prescribed in the UK from 2001-2017, and that most patients can safely reduce them, at a high cost savings.

Major comments:

1-One of the most interesting questions related to step down that was not considered in this analysis is listed as an asterisk in Table 1 (patients that stop all preventer meds were not included). Why not? I could not find in the methods section where this choice is explained. Stopping all controller meds (especially ICS) is probably the highest risk step down (see, for example, recent GINA guideline summarizing these risks). Also, it is potentially very relevant to new recommendations which suggest all asthma patients should use some level of ICS (intermittent or continuous). Without information on this step down risk, it is difficult to broadly state that step down moves do not adverse affect outcomes. I think the authors either need to analyze this group or be more precise in describing which step down types are likely low risk, and which were not analyzed.

2-I think the following variables should be defined more clearly, as in how they were identified within the dataset and what they mean: "asthma management plan, annual asthma review, and inhaler technique check." I also wonder if having seen a specialist is another variable that should be included.

3-The final concluding statement (lines 391-394) which follows "In summary" focuses on not stepping up (which was a descriptive trend finding) and I think most of the analysis is related to outcomes of stepping down. Therefore, the authors may consider a summary statement that includes stepping down.

4-How to accomplish stepping down (i.e. how to solve this problem) is not clear from their data. Having annual visits, checking inhaler technique, and an asthma management plan do not seem to be related to step down. Are there any patterns from their data that suggest a solution? Are there signs of stepping down to ICS PRN and that this could be a successful strategy?

Other comments:

1-Introduction section is concise and clear.

2-Sensitvity analyses are appropriate

3-Line 154-155--is there validation or a reference to justify 1 or more relievers as cut off?

4-Supplementary Figure 2 is very helpful. I suggest the authors consider moving this to the main document.

***

Any attachments provided with reviews can be seen via the following link:

[LINK]

6 Apr 2020

Submitted filename: SteppingDown_ResponseToReviewers_5April2020.docx

Click here for additional data file.

1 May 2020

Dear Dr. Bloom,

Thank you very much for re-submitting your manuscript "Health and cost impact of stepping-down asthma medication: a UK population-based observational study, 2001 - 2017" (PMEDICINE-D-20-00031R2) for consideration at PLOS Medicine.

I have discussed the paper with editorial colleagues and our academic editor, and it was also seen again by three reviewers. I am pleased to tell you that, provided the remaining editorial and production issues are fully dealt with, we expect to be able to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

Our publications team (plosmedicine@plos.org) will be in touch shortly about the production requirements for your paper, and the link and deadline for resubmission. DO NOT RESUBMIT BEFORE YOU'VE RECEIVED THE PRODUCTION REQUIREMENTS.

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Please let me know if you have any questions. Otherwise, we look forward to receiving the revised manuscript shortly.

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Richard Turner, PhD

Senior Editor, PLOS Medicine

rturner@plos.org

------------------------------------------------------------

Requests from Editors:

Please note in your competing interest statement that AS is a member of PLOS Medicine's Editorial Board. Also, please add a few words to explain whether CIB has received grant funding, for example, from AstraZeneca etc.

Your data statement mentions that "code lists will be provided on request", which I'm afraid is not consistent with PLOS Medicine's data policy. Please provide these in a supplementary document to be published with the manuscript. An alternative would be to deposit these in a public repository.

We ask you to adapt the title slightly to: "Health and cost impact of stepping-down asthma medication for UK patients, 2001 - 2017: a population-based observational study".

Around line 45, please quote the number or proportion of patients stepped-down.

At line 52 in your abstract and all other instances, please quote p<0.001 or exact values.

At line 59, please make that "Study limitations included the possibility that prescribed medication ..." or similar.

At lines 62 and 472, please adapt the text to "patients in the UK", or similar to indicate where the study was done.

At line 91, please remove "this one of the largest studies".

At lines 134-135, please add call-outs to the attached protocol and STROBE documents (e.g., "See S1_STROBE_Checklist").

Please make that "data are" at line 137.

Please remove the copyright information at line 143 (the sentence can be truncated at "... within the CPRD data.".

Please substitute "sex" for "gender" where appropriate (e.g., in the legend for table 4).

Please add full access details to reference 26, and any other references that lack it.

Please remove the header "Page number" from the rightmost column of your attached STROBE checklist, and the numbers below if these are page numbers (which generally change in the event of publication). Please restructure this column to provide section details (e.g., "Methods") and paragraph numbers.

Comments from Reviewers:

*** Reviewer #1:

The authors have adequately responded to all points previously raised, in their response. However, it seems that some line numbers referred to in the author response may have shifted (perhaps after further editing as additional points were addressed?); in particular, the response for Point 4 on "most randomised controlled trials used 50% step-down and a larger step-down would be more likely to identify an effect if there as one" was not readily encountered in the text. Other than these, there are no further concerns on our part.

*** Reviewer #3:

The authors are responsive to reviewer feedback. Overall, the methods, interpretation, and communication of the findings are excellent.

A few additional points to consider:

1. The propensity score analysis strengthens the conclusion. I was able to find a description of the methods for the PS, but I did not find the PS in Table S5 as suggested in the authors' responses. I could not find this info listed in a table. I apologize if I missed this. Can the authors please double check to confirm they included this information?

2. I disagree with the authors' decision not to consider the outcomes when patients completely stop ICS, an event that is more likely to result in increased exacerbation than a decrease in controller meds (high level evidence from meta-analysis). Seeing this group and showing a negative outcome would increase the validity of using the dataset for outcome assessment. The argument that these patients are judged not to have asthma is an assumption that may hold for a fraction of patients who completely stop controller medications. However, many others likely stop on their own (without provider direction) or revert back to SABA prn approaches, an accepted GL management option for intermittent asthma prior to GINA 2019 GL release.

3. I agree with the choice not to analyze step down to LABA monotherapy, as this is not an accepted or GL recommended asthma therapy.

***

Any attachments provided with reviews can be seen via the following link:

[LINK]

9 Jun 2020

Dear Dr Bloom,

On behalf of my colleagues and the academic editor, Dr. Aaron Kesselheim, I am delighted to inform you that your manuscript entitled "Health and cost impact of stepping-down asthma medication for UK patients, 2001-2017: population-based observational study" (PMEDICINE-D-20-00031R3) has been accepted for publication in PLOS Medicine.

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Thank you again for submitting the manuscript to PLOS Medicine. We look forward to publishing it.

Best wishes,

Richard Turner, PhD

Senior Editor

PLOS Medicine

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