Off-label use of inhaled bronchodilators in hospitalised patients in Spain: a multicentre observational study

Abstract

Background

Off-label prescription of inhaled bronchodilators (IB) is frequent, despite the fact that they can be ineffective and increase avoidable healthcare costs.

Objective

To analyse the frequency of off-label prescription of IB in hospitalised patients. Indications and level of evidence, involved drugs, medical specialties prescribing off-label IB and patients’ adherence to IBs were also evaluated.

Method

A descriptive, observational, cross-sectional study was performed in four tertiary hospitals in Spain. The main outcome measure was the number of patients prescribed off-label IBs. Prescriptions were checked against the European Medicines Agency-approved indications. The level of evidence supporting off-label prescription of IBs (according to MICROMEDEX 2.0) was also analysed. Patients were interviewed to test differences (off-label vs on-label) in adherence and knowledge about their inhaled therapy.

Results

217 patients were prescribed IBs, 92 of whom were givend off-label IBs (54.7% men, mean age 73.9±12.9 years). The most common off-label prescriptions for IBs were: unspecified dyspnoea (not related to COPD or asthma) (27.2%), respiratory infections (23.9%) and heart failure (22.8%). 76.8% of patients did not have evidence supporting them. Beta₂-agonist+corticosteroids and anticholinergics were most commonly prescribed off-label. Internal Medicine was the main medical specialty involved. There were no differences between off-label and on-label users in terms of patients’ knowledge about treatment and adherence.

Conclusion

Off-label indications for IBs are common in hospitalised patients and are generally indicated without scientific support. Dyspnoea not related to COPD or asthma, respiratory infections and heart failure were the main off-label indications, most frequently treated with anticholinergics and beta₂-agonists+corticosteroids, for which their efficacy and safety has not been proved. Our results show that prescribing needs to be improved to follow the evidence that exists. Moreover, further research focused on off-label indications is needed to clarify whether they are effective, safe and cost-effective.

Introduction

The use of drugs for indications not approved by regulatory agencies (off-label) is common. Available data indicate that they exceed 20% of prescribing.^{1 2} The drug approval process for an indication requires clinical trials that demonstrate efficacy and safety prior to marketing. Once the approval is received, the regulatory agencies do not follow the off-label prescriptions. Using such drugs for unapproved indications does not mean that they are not useful; real-world clinical practice shows that in some cases they are, although there is substantial variation in the evidence supporting such uses. Nevertheless, it is also known that, when medications are prescribed for off-label indications, there are greater risks of adverse effects than when they are prescribed for approved indications.^3–6 Despite the fact that unapproved drug use may jeopardise patient safety when the benefit to risk ratio has yet to be proven,⁷ no systematic research of these uses has been carried out. In the specific field of pulmonology, there are no data to our knowledge regarding off-label indications for inhaled therapies. We consider this an important issue in this medical specialty, given the complexity of patients with chronic respiratory diseases. On the other hand, the high rate of non-respiratory patients with respiratory dysfunction increases the probability of off-label prescriptions involving bronchodilators.

Off-label prescriptions for inhaled bronchodilators (IBs) can provide new data and innovation in clinical practice. However, when they are ineffective for an unapproved indication, their use raises inevitable costs to the healthcare system. It is important to consider this aspect because of their high economic impact.⁸ Thus, in Spain, according to the latest report of the National Health System,⁹ prescription IB costs are remarkably high. The use of IBs for obstructive airway diseases is the second highest cost of drug spending in Spain (476.2 million €/year), 4% of the spending for retail prescription drugs. In terms of economic impact, there are three IBs among the top 10 medications (salmeterol+fluticasone, formoterol+budesonide and tiotropium).

Being aware of the gap in research for the use of off-label drugs, the following study was undertaken. We hypothesised that there is a high rate of IB prescriptions for unapproved indications without evidence supporting them. An understanding of how IBs are used can highlight treatment areas needing more investigation since, to the best of our knowledge, there are no published studies investigating the frequency of off-label use of IBs.

Methods

Aim of the study

The primary outcome was the number of hospitalised patients under off-label IB treatment according to the European Medicines Agency (EMA) product characteristics document and the level of evidence supporting off-label use. Medical specialties prescribing IBs off-label and whether they had been initiated at admission or before admission in primary care were also evaluated. In addition, patients were asked for informed consent to be interviewed in order to check differences between off-label and on-label users in terms of adherence to their inhaled therapies.

Ethics approval

All the participants interviewed were informed in detail of the characteristics of the study, and written informed consent was obtained in accordance with the requirements of the CREC of La Paz University Hospital for approval of the study.

Design

A descriptive, observational, cross-sectional study was performed in four tertiary hospitals in Madrid (Spain) in November 2018. In these hospitals, physicians prescribe therapies to inpatients using a computerised physician order entry (CPOE) programme where they also record the diagnosis. A community-based clinical information programme available in Spain (Horus) linked to these CPOE programmes is used for hospitalised patients. This programme allows physicians and pharmacists in hospitals to access patients’ information of pathologies and drug indications prior to admission, creating a longitudinal electronic health record of clinical and pharmacotheraputic data.

Data source

Investigators collected data on all prescription events of hospitalised patients being treated with IB including indications for use. Observed drug uses were classified by clinical indications and determined to be off-label when prescribed in a way that is not described in the Summary of Product Characteristics of the EMA.¹⁰ This is a document describing the properties and the approved conditions of use of a medicine. Summaries of Product Characteristics form the basis of information for healthcare professionals on how to use a medicine safely and effectively.

Any indication that could not be matched to these labelled indications was considered off-label, and the level of evidence supporting efficacy was categorised using the MICROMEDEX 2.0 (Truven Health Analytics, Ann Arbour, Michigan, USA) Drug Points System (Thomson Reuters). According to this system, off-label uses were divided into two categories: off-label use with strong scientific evidence and off-label use without strong scientific evidence.

Differences in adherence according to the type of use (off-label vs on-label) were assessed using the Test of Adherence to Inhalers (TAI) questionnaire.¹¹ This is a validated questionnaire to assess adherence to IB in patients with COPD or asthma.

Study population

Adult patients being treated with any IB admitted to any of the following adult wards were included: medical specialties (Oncology, Internal Medicine, Pulmonology, Neurology, Cardiology and Gastroenterology) and surgical specialties (Digestive Surgery, Maxillofacial Surgery, Urology, Vascular Surgery and Neurosurgery). Patients admitted to critical care units and maternity units were excluded.

Statistical analysis

Data management

A database was designed to reflect the case report content form, in which a data entry matrix with possible ranges or values was established, along with the various consistency rules between variables. The quality of information received through exploratory analysis was aimed at detecting discrepancies in the values, out-of-range values, or missing values. An exploratory analysis also provided information on the distribution of the main variables to be studied and provided guidance on possible transformations.

General considerations

The mean, SD, median, maximum, minimum, and 25% and 75% quartiles were included. For the categorical data, the frequency distributions (absolute and relative) were presented. In addition, 95% CIs were calculated when appropriate. The statistical analysis was performed using SAS9.3 (SAS Institute, Cary, North Carolina, USA).

Results

The pharmacotherapy of 217 hospitalised patients in four tertiary hospitals treated with IBs was analysed. The patients were elderly (mean age 78.6±12.9 years) and predominantly male (60.5%). On average they had been on IB treatment for 2.9±1.3 years. We found that 92 of them were prescribed IB for off-label uses (mean age 73.9±12.9 years). Of these, 54.7% were men.

Unapproved indications were: dyspnoea (not related to asthma or COPD) (27.2%), respiratory infection (23.9%), heart failure (22.8%), obstructive sleep apnoea (11.9%), pulmonary hypertension (3.3%), other (10.9%). When analysing scientific support for unapproved indications, we observed that the vast majority of IBs used off-label were prescribed without sufficient scientific support (figure 1).

Figure 1.

Assessment of off-label use and scientific support. EMA, European Medicines Agency.

With regard to the drug classes involved, we found that a combination of beta₂-agonist+cortiocosteroid and anticholinergics were more frequently prescribed for off-label indications (figure 2). When analysed by off-label indications, anticholinergics were found to be the main drug class involved (figure 3).

Figure 2.

Drug classes involved in off-label and on-label prescriptions.

Figure 3.

Type of inhalers according to their off-label use.

With regard to the drugs, formoterol+budesonide was the type of IB most frequently involved (table 1). Only albuterol, ipratropium and budesonide were prescribed with a strong level of evidence. The level of evidence for off-label indications is shown in table 2.

Table 1.

Proportion of off-label uses of different drugs

Inhalers prescribed		n=309	Off-label, n=112
Beta 2 -agonist		n=55	n=16/55 (29.1%)
LABA	Salmeterol	5	4
	Indacaterol	2	0
	Terbutaline	5	1
	Formoterol	15	6
SABA	Albuterol	28	5
Anticholinergic		n=132	n=53/132 (40.1%)
LAMA	Glycopyrronium	3	0
	Aclidinium	22	10
	Tiotropium	65	24
SAMA	Ipratropium	42	19
Corticosteroid		18	n=2/18 (11.1%)
	Budesonide	16	2
	Fluticasone	2	0
Beta 2 -agonist+anticholinergic		5	n=1/5 (20%)
LAMA+LABA	Glycopyrronium+indacaterol	2	1
	Umeclidinium+vilanterol	3	0
Beta 2 -agonist+corticosteroid		99	n=40/99 (40.4%)
LABA+corticoid	Formoterol+budesonide	29	12
	Formoterol+beclomethasone	16	7
	Formoterol+fluticasone	5	3
	Vilanterol+fluticasone	2	0
	Salmeterol+fluticasone	47	18

LABA, long-acting beta-agonist; LAMA, long-acting muscarinic antagonist; SABA, short-acting beta-agonist; SAMA, short-acting muscarinic antagonist.

Table 2.

Level of evidence of inhalers for off-label indications

Dyspnoea	Scientific evidence	Respiratory infection	Scientific evidence	Heart failure	Scientific evidence	Obstructive sleep apnoea	Scientific evidence	Pulmonary hypertension	Scientific evidence	Other	Scientific evidence
Formoterol	WO	Salmeterol	WO	Formoterol	WO	Albuterol	WO	Formoterol	WO	Albuterol	W
Aclidinium	WO	Terbutaline	WO	Aclidinium	WO	Aclidinium	WO	Tiotropium	WO	Aclidinium	WO
Ipratropium	W	Formoterol	WO	Ipratropium	WO	Tiotropium	WO			Ipratropium	W
Formoterol+ budesonide	WO	Aclidinium	WO	Tiotropium	WO	Glycopyrronium+ indacaterol	WO			Budesonide	W
Formoterol+ beclomethasone	WO	Ipratropium	WO	Formoterol+ budesonide	WO	Formoterol+ budesonide	WO			Formoterol+ Budesonide	WO
Salmeterol+ fluticasone	WO	Tiotropium	WO	Formoterol+ fluticasone	WO	Formoterol+ beclomethasone	WO			Formoterol+ Beclomethasone	WO
		Budesonide	WO	Salmeterol+ fluticasone	WO

W, with strong scientific evidence; WO, without strong scientific evidence.

Concerning medical specialties prescribing off-label IBs at admission, Internal Medicine was the main medical specialty involved (46/47, 97.9%). With regard to treatment initiation, the first prescription for off-label IBs commonly occurred in hospital settings (49%), either in a current or previous hospitalisation.

Finally, since we detected a lack of scientific evidence of effectiveness for inhalers used off-label, we also wanted to know whether this fact was associated with lower treatment adherence. To evaluate this, 157 patients were assessed using the TAI, a validated questionnaire to assess adherence to IB in patients with COPD or asthma.¹¹ We found similar poor adherence to inhaled therapy without relevant differences between off-label and on-label users (table 3).

Table 3.

Responses to the Test of Adherence to the Inhaler bronchodilator questionnaire (TAI)¹¹

Question	Answer options	Always	More than half	About half	Less than half	None	Score*
Q1. During the last 7 days, how many times did you forget to take your usual IB?	On-label (n=101)	1 (1%)	4 (4%)	5 (4.9%)	75 (74.2%)	16 (15.8%)	4
	Off-label (n=56)	1 (1.8%)	2 (3.6%)	3 (5.3%)	40 (71.4%)	10 (17.8%)	4
Question	Answer options	Always	Sometimes	Almost always	Almost never	Never
Q2. Do you forget to take your IB?	On-label (n=101)	4 (4%)	0	0	60 (59.4%)	37 (36.6%)	4
	Off-label (n=56)	0	0	3 (5.3%)	41 (73.2%)	12 (21.4%)	4
Q3. When you feel good about your illness, do you stop taking your IB?	On-label (n=101)	2 (2%)	0	4 (4%)	72 (71.3%)	23 (22.8%)	4
	Off-label (n=56)	2 (3.6%)	0	3 (5.3%)	38 (68%)	13 (23.2%)	4
Q4. When you are on vacation or on weekends, do you stop taking your IB?	On-label (n=101)	2 (2%)	0	1 (1%)	81 (81%)	17 (16.8%)	4
	Off-label (n=56)	0	0	0	43 (76.8%)	13 (23.2%)	4
Q5. When you are nervous or sad, do you stop taking your IB?	On-label (n=101)	2 (2%)	0	0	83 (82.8%)	16 (15.8%)	4
	Off-label (n=56)	0	2 (3.6%)	0	44 (78.6%)	10 (17.8%)	4
Q6. Do you stop taking your IB because of fear of side effects?	On-label (n=101)	2 (2%)	1 (1%)	0	85 (84.2%)	13 (12.9%)	4
	Off-label (n=56)	2 (3.6%)	0	0	44 (78.6%)	10 (17.9%)	4
Q7. Do you stop taking your IB because you consider it is useless to treat your condition?	On-label (n=101)	3 (3%)	1 (1%)	1 (1%)	73 (72.3%)	23 (22.7%)	4
	Off-label (n=56)	4 (7.1%)	0	0	41 (73.2%)	11 (19.6%)	4
Q8. Do you take fewer inhalations than those prescribed by your doctor?	On-label (n=101)	6 (5.9%)	0	0	85 (84.2%)	10 (9.9%)	4
	Off-label (n=56)	2 (3.6%)	0	0	43 (76.8%)	11 (19.6%)	4
Q9. Do you stop taking your IB because you believe it interferes with your everyday or working life?	On-label (n=101)	4 (4%)	0	3 (3%)	84 (83.2%)	10 (9.9%)	4
	Off-label (n=56)	2 (3.6%)	0	0	48 (85.7%)	6 (10.7%)	4
Q10. Do you stop taking your IB because you have difficulties paying for it?	On-label (n=101)	10 (9.9%)	2 (2%)	2 (2%)	66 (65.3%)	21 (20.8%)	4
	Off-label (n=56)	8 (14.3%)	0	0	37 (66.1%)	11 (19.6%)	4
Total score†	On-label						40
	Off-label						40

*Always, 1 point; More than half/sometimes, 2 points; About half/almost always, 3 points; Less than half/almost never, 4 points; None/never, 5 points.

†Levels of adherence: high (50 points); intermediate (46–49 points); low (<46 points).

IB, inhaled bronchodilator.

Discussion

This study shows that inhalers are widely prescribed for unapproved indications. We found that about 42% of all indications for these medications were off-label. This percentage is considerably higher than the prevalence of off-label drug use reported in other studies^{1 12–14} and similar to off-label drug use in oncology or paediatrics, two medical specialties that most frequently prescribe off-label medicines. Saiyed et al ⁷ in a systematic review of off-label drug use in cancer treatment found up to 41% of off-label prescriptions were used. In children, Yackey et al ¹⁵ observed that off-label drug use reached 54.2%. To our knowledge, this study is the first to evaluate the degree of IBs prescribed for off-label use as there are no other data with which to compare them. The high percentage detected in our study could be explained by the prevalence of poor respiratory function in hospitalised patients. Compared with other medications, the use of IBs is relatively different because of the high prevalence of these symptoms in patients with respiratory disease and also those in many other specialties.

In agreement with other authors,¹ we found that the vast majority of off-label use lacked scientific evidence of therapeutic efficacy. These results suggest a need for more post-marketing drug monitoring in order to identify the effects of IBs prescribed for off-label use in terms of clinical efficacy as well as their safety and economic impact. In fact, previous studies have found that off-label drug prescriptions have been associated with a higher rate of adverse drug effects^{2 16} and avoidable costs.^17–19

In our study, the main reason reported for IB off-label use was unspecified dyspnoea (not related to COPD or asthma), which could be related to the few medications available to treat this condition. Other authors¹² have also reported that dyspnoea is a significant source of off-label use of medications, however, most of them without evidence. The second reason for off-label use was respiratory infection, and other studies have also found a high percentage of inappropriate use of inhalers for this pathology.^{20 21} Heart failure was the third reason for using off-label prescriptions. In addition, cardiovascular and respiratory diseases often coexist in patients and both need to be treated, but their treatments are not always compatible.^{22 23}

Our research shows that the magnitude of off-label use varied among drug classes, especially for anticholinergics and for the combination of beta₂-agonists and corticosteroids. Other published studies²⁰ have also detected a high proportion of inappropriate uses of beta₂-agonists in combination with corticosteroids.

Finally, we analysed patient’s adherence depending on the type of prescription (on-label vs off-label). Interestingly, no differences were found in treatment compliance between the two types of prescriptions. It is worth asking why therapeutic adherence to these medications is not greater for approved indications for which efficacy and safety have been proven.

The assessment of off-label prescription in a setting not previously described and its multicentre nature gives clinical relevance and strength to this study. However, it is limited by the weaknesses inherent in a cross-sectional study. A further possible limitation is that there could have been patients who met the inclusion criteria but were not assessed because the diagnoses for inhaler prescriptions were omitted in their electronic medical records.

Conclusion

Off-label indications for IBs are common in hospitalised patients. Our results prove that prescribing needs to be improved to follow the evidence that exists and that more research is needed to fill the gap in evidence for these off-label uses.

This study highlights the need for further investigation into the prescription of IBs for dyspnoea not related to COPD or asthma, respiratory infections and heart failure. In addition, our results indicate the need for further research with inhalers containing anticholinergics and beta₂-agonists in combination with corticosteroids, focusing on those off-label indications in order to clarify whether they are actually useful, safe and cost-effective.

What this paper adds.

What is already known on this subject

• There is a high proportion of drug prescriptions for unapproved indications, most of which are initially prescribed in the hospital setting.

• Since there is no scientific evidence for them, these prescriptions can be inefficient. Moreover, the off-label use of drugs is associated with more adverse effects.

• Inhaler prescribing needs to be improved to follow the evidence that exists.

What this study adds

• More than 40% of bronchodilators used in hospitals are prescribed for unapproved conditions; most of them are not supported by adequate scientific evidence.

• An understanding of why these off-label medications are prescribed highlights the areas needing more research to fill the gap in scientific evidence.

Data availability statement

Data are available upon reasonable request. Data are abailable upon reasonable request.

Ethics statements

Patient consent for publication

Not required.

Ethics approval

The study was approved by the Clinical Research Ethics Committee (CREC) of La Paz University Hospital (approval number/ID: HULP-PI2200).