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| Journal of the New Zealand Medical Association,
22-August-2003, Vol 116 No 1180
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Differential prescribing of inhaled corticosteroids in New
Zealand general practice
Jason Hall, Alister Penrose, Andrew Tomlin and James
Reid
Previous work by the authors has shown that inhaled
budesonide appears to be prescribed in higher daily doses than does inhaled
beclomethasone in New Zealand general
practice.1,2 This is contrary to international
guidelines for the treatment of asthma, which regard inhaled budesonide and
beclomethasone as equipotent,3 and studies
indicating the in vivo equipotency of budesonide and
beclomethasone.4–7 While it is generally
accepted that beclomethasone and budesonide are of equal potency, it is a matter
of some controversy. Fluticasone, not generally available in New Zealand before
1 December 1996, is now an internationally recognised treatment for the
prevention of asthma symptoms. Fluticasone is generally accepted to be twice as
potent as both beclomethasone and
budesonide.8,9
The aim of this study was to determine how general
practitioners (GPs) in New Zealand prescribe inhaled fluticasone, budesonide and
beclomethasone. This topic is of substantial interest in that it helps general
practitioners with anticipated inhaled-corticosteroid equivalent doses and
advances debate about the appropriate prescribing of inhaled
corticosteroids.
MethodsWe accessed the database of the
Dunedin Royal New Zealand College of General Practitioners Research Unit
(Dunedin RNZCGP Research Unit),10,11 which
contains patient identifier codes (all data are anonymised), consultation dates
and free-text notes, prescribing dates, and prescription details.
Forty two general practices with a consulting
population of 174 929 patients provided computerised consultation and
prescription records for the study period 1 July 1997 to 30 June 1998. The Otago
Ethics Committee approved the study protocol in February 1999. All patients
prescribed inhaled fluticasone (FlixotideTM 25,
50, 100, 125, 250 and 500
μg), budesonide
(PulmicortTM
100, 200 and
400 μg) and beclomethasone
(AtomideTM
50, 100 and 250 μg;
BecloforteTM
250 μg;
BecodiskTM
100, 200 and 400 μg;
BecotideTM
50 and 100 μg; RespocortTM
50, 100 and 250
μg) were identified and prescribed daily doses determined.
Prescribed daily doses of corticosteroids were calculated from the number of
micrograms per inhalation for each drug and the number of inhalations indicated
per day. Minimum daily doses were calculated for prescriptions indicating a
range of prescribed daily doses.
A scatter plot of the daily dose by age for patients
prescribed inhaled beclomethasone, budesonide and fluticasone alone showed
higher daily doses and greater variation in average daily dose with increasing
age. These characteristics suggested a log transformation of the data might be
appropriate for subsequent analyses of the average daily dose of inhaled
corticosteroids. Linear regression was therefore used to analyse the log data,
incorporating extra sum-of-squares techniques to determine whether the addition
of a set of explanatory variables significantly improved the regression
model.
Analysis was undertaken of the number of courses of
oral corticosteroids prescribed, the proportion of patients co-prescribed beta
agonists and the volume (mg) prescribed, the volume of inhaled corticosteroids
(mg) prescribed, the number of asthma consultations and overall consultation
rate. Beta-agonist volumes were calculated from prescribed quantities and dose
strength. To compensate for differing relative potencies of different beta
agonists, salbutamol-equivalent doses were calculated. The dose relationship
used to calculate relative terbutaline to salbutamol potency was
250:100.12–14 Prescription data for
prednisone and betnesol were pooled for analysis. A consultation was defined as
asthma related if a prescription for asthma medication, an inquiry about asthma,
or a peak flow reading was recorded in the case notes.
ResultsDuring the study period 10 513
patients were prescribed an inhaled corticosteroid; full dosing instructions
were available for 9878 (94.0%) patients and 30 848 prescriptions and these
patients were the focus of the subsequent analysis. Figure 1 shows the breakdown
of patients by inhaled corticosteroid and inhaler device.
Mean daily dose by age band for 9327 patients prescribed 30
259 prescriptions exclusively with budesonide, beclomethasone or fluticasone are
shown in Table 1. Differences in daily dose by type of inhaler device and for
patients changing medication are shown in Table 2. Over all age groups, the mean
daily dose was significantly lower for fluticasone patients (508
μg) than
budesonide patients (886 μg), a difference of 378 μg (95% CI
344–412μg, p <0.001). It was also lower, although clinically
insignificant, than that for patients prescribed beclomethasone (547 μg), a
difference of 39 μg (95% CI 15–63, p = 0.001),
but not in all
age bands. The mean daily prescribed dose was higher for patients receiving
inhaled budesonide (886 μg) than beclomethasone (547 μg), a difference
of 339 μg (95%CI 311–367, p
<0.001). Analysis of the
log-transformed mean daily doses confirmed the significance of these
differences.
Figure 1. Study population by medication
regimens
 Table 1. Characteristics of prescriptions for inhaled
budesonide, beclomethasone and fluticasone alone over one year in 42 New Zealand
general practices
BD = budesonide; BC = beclomethasone; FL =
fluticasone
Table 2. Comparison of mean daily dose (DD) and
confidence intervals for budesonide, beclomethasone and fluticasone by inhaler
device
BD = budesonide; BC = beclomethasone; FL =
fluticasone
In total, 9169 patients received 29 374 prescriptions
exclusively with beclomethasone, budesonide or fluticasone taken by metered-dose
inhaler or breath-activated devices only. The 158 patients changing from
metered-dose inhalers to breath-activated devices or vice versa were excluded
from this analysis. Mean daily dose by
breath-activated device was lower for fluticasone (545
μg) than for
budesonide (895 μg), a difference of 350 μg (95% CI 257–441, p
<0.001) but there was no difference in comparison with beclomethasone. For
patients using only metered-dose inhalers, mean daily doses were significantly
lower for fluticasone
(500 μg)
than for budesonide (811 μg), a difference of 311 μg (95% CI
252–369, p <0.001). Mean fluticasone dosages were clinically similar to
those prescribed for beclomethasone patients (537 μg), a difference of 37
μg (95% CI 12–61, p = 0.004).
One hundred
and twelve patients
switched from budesonide to fluticasone or vice versa during the year and 279
switched between fluticasone and beclomethasone. The mean daily dose for
patients changing from budesonide to fluticasone was 1176 μg before and 694
μg after
the change, and
for patients changing from fluticasone to budesonide 631 μg before and 1400
μg after. The crossover doses were consistent with the overall data showing
lower prescribed doses for fluticasone. For patients changing from
beclomethasone to
fluticasone the
average dose was 755 μg before and 603 μg after the change, and for
those changing from fluticasone to beclomethasone 602 μg before and 783
μg after.
A total of 2110 patients received 4415 prescriptions for
oral corticosteroids. Table 3 shows a significantly higher proportion of
fluticasone patients were prescribed oral corticosteroids (31.6%) than
budesonide patients (21.5%, p <0.001) or beclomethasone patients (20.9%, p
<0.001). There was no difference in the proportion of budesonide and
beclomethasone patients prescribed oral corticosteroids. To limit confounding
from patients with chronic bronchitis or emphysema, further analysis of a subset
of patients aged less than 35 years of age was undertaken. A similar trend in
oral corticosteroid prescribing to that of all patients was evident. There was
no clinical difference between treatment groups in the number of oral steroids
prescribed.
Table 3. Oral steroid prescribing
To further limit for potential confounding from chronic
respiratory disease, the mean daily dose of a subset of 5220 patients aged less
than 35 years was analysed.
The mean daily dose
was significantly lower for fluticasone patients (397 μg) than budesonide
patients (693 μg), a difference of 296 μg (95% CI 259–333, p
<0.001). Fluticasone was prescribed at a lower, though clinically
insignificant, dose than
beclomethasone
(423 μg), a difference of 26 μg (95% CI 1–50, p = 0.038), but
not in all age bands. The mean daily prescribed dose was higher for patients
receiving inhaled budesonide (693 μg) than beclomethasone (423 μg), a
difference of 270 μg (95% CI 240–302, p
<0.001). Analysis of the
log-transformed mean daily doses confirmed the significance of these
differences.
A significantly lower proportion of fluticasone patients
(69.3%) and budesonide patients (70.8%) were co-prescribed inhaled beta-2
adrenoceptor agonists than beclomethasone patients (77.3%, p <0.001).
Fluticasone patients were prescribed a lower mean annual volume (127 mg) of
inhaled beta-2 adrenoceptor agonists than budesonide patients (165 mg, p
<0.001) and beclomethasone patients (142 mg, p <0.001) despite being more
likely to require oral steroids.
DiscussionThese results reflect our earlier
work in relation to daily dosages of beclomethasone and budesonide, and we
maintain that budesonide is prescribed in higher doses than beclomethasone for
treating asthma in New Zealand general practice, despite their reported
equipotency in the medical literature. The primary focus of this study, however,
is to report the prescribing of inhaled corticosteroids as it happens in general
practice, not to dispute the reported relative potency of different inhaled
corticosteroids.
Fluticasone cannot be assumed to be equipotent to budesonide
or beclomethasone. A bulletin to all New Zealand GPs in 1997 from the National
Preferred Medicines Centre Incorporated (PreMec) suggests fluticasone is at
least twice as potent as either budesonide or
beclomethasone,15 largely based on the work of
Barnes et al.8 PreMec is an agency funded
largely by the Government to provide quantitative and qualitative feedback to
GPs about their prescribing based on case studies and best evidence. This
bulletin is likely to have been widely consulted in general practice.
We believe GPs do not prescribe fluticasone in line with a
2:1 ratio compared with beclomethasone in general practice, while they prescribe
budesonide at a ratio of 1.7:1. Further, they do not prescribe budesonide and
beclomethasone in terms of expected dose equivalencies. Studies asserting a 2:1
efficacy ratio between fluticasone and beclomethasone should be interpreted with
caution.16 One study comparing the 2:1 ratio
clearly had no room for improvement in the subject, hence a 4:1 ratio could just
have easily been proved due the flat dose-response
curve.17,18 The review by Barnes et al used
only those trials in which the fluticasone dose was less than or equal to half
the budesonide or beclomethasone dose, imposing a degree of bias by the nature
of the study design.8 However, a more recent
Cochrane review of the relative potencies of these medications has concluded
that fluticasone prescribed at half the daily dose of budesonide and
beclomethasone leads to small improvements in airway calibre, but appears to
have a higher risk of side effects when given at the same daily
dose.19
A case-study survey of the treatment of a 21-year-old female
with worsening asthma was conducted by
PreMec.20,21 The survey was sent to all 2844
GPs in New Zealand, and 1005 responded. Eighty six per cent of respondents
indicated they would prescribe inhaled corticosteroids, the mean daily doses
being budesonide 808
μg; beclomethasone 518 μg; fluticasone 434 μg. These doses are
similar to those found in this study. PreMec concluded that the higher doses of
fluticasone and budesonide prescribed in New Zealand are unlikely to be solely
due to the preferential prescribing of fluticasone and budesonide to
patients with more severe asthma.
GlaxoWellcome initially marketed fluticasone in New Zealand
as being more suited for the treatment of severe asthmatics than other
corticosteroids. Our evidence suggests that this may have been the case, given
that a higher proportion of the fluticasone group were prescribed oral
corticosteroids, although consultation rates for asthma were similar between
treatment groups.
There was no significant difference in the time between
prescriptions for the budesonide and beclomethasone groups, but the duration
between fluticasone and budesonide was shorter compared with both budesonide
(Mann-Whitney U test z = -5.268, p <0.001) and beclomethasone (Mann-Whitney U
test z = -4.958, p <0.001). There was no evidence of differing patterns of
dose titration between treatment groups as 92% of fluticasone patients, 95.6% of
budesonide patients, and 94.9% beclomethasone patients were prescribed constant
inhaled corticosteroid doses over the study period (no significant difference).
Patients may adjust their own dose but it was not possible to assess the level
of patient compliance or rate of dispensing in this study. Evidence suggests
that 50% or more of asthma patients do not take their medication as
prescribed,22,23 but we could find nothing to
suggest compliance rates should differ between treatment groups.
The mean number of prescriptions and number of inhalers per
patient, as well as the number of inhalers per prescription were clinically
similar between treatment groups, yet the volume of corticosteroid prescribed
over the study year differed markedly between treatment groups. A possible
explanation for this is the different number of inhalations available in the
devices. All budesonide inhalers and 88.9% of beclomethasone inhalers prescribed
contained 200 doses, while 89.7% of fluticasone inhalers contained 120 doses. We
hypothesised that GPs commonly prescribe fluticasone as if the inhaler device
contains 200 doses. To test this we adjusted for the smaller fluticasone pack
size using a factor of 1.67 (200 doses/120 doses). This adjustment factor
applied to the yearly volume ratio of fluticasone/budesonide of 0.345 produces
an adjusted volume ratio of 0.576. This is remarkably close to the prescribed
daily dose ratio of 0.570, and multiplied by 1.67 produces an adjusted volume
ratio of 0.952, also close to the prescribed daily dose ratio of 0.929 (Table
4). This argument requires that most prescribing was by quantity, not
months’ or days’ supply. The data supported this, with 85.1% of
budesonide and beclomethasone prescriptions, and 77.9% of fluticasone
prescriptions, written in quantity rather than time. Therefore, we believe GPs
commonly prescribe fluticasone as if the inhaler device contains 200 doses.
Furthermore, a telephone survey of contributing practices in May 1999 showed 55%
were unaware that most fluticasone inhalers contained 120 doses without
reference to written drug information.
Table 4. Prescribed daily dose and medication volume
ratios
An important consideration when interpreting these results
is the strength of medications available for the different inhaled
corticosteroids. Budesonide is frequently prescribed via the 400 mcg turbuhaler,
while the 400 mcg becodisk diskhaler is infrequently prescribed. This could have
an effect on the difference found in prescribed doses. However, comparisons of
metered-dose inhalers, which are not available in the 400 mcg strength, show
very similar differences to those found with breath-activated devices.
Another question is whether the GPs’ prescribing
practices included in this study are different to other GPs in any systematic
way. The use of computerised practices only was necessary to provide
standardised data for the purposes of this study. Issues such as validity and
bias of data collections are frequent criticisms of such databases. Studies by
the Dunedin RNZCGP Research Unit have revealed that data collected in this way
show morbidity in patients similar to that from practices not contributing to
the network,11 and that data recorded by
contributing practitioners are relatively
complete.24
Due to the lack of morbidity coding by New Zealand GPs and
the reported underdiagnosis of chronic obstructive pulmonary disease
(COPD),25 it is difficult to differentiate
between patients prescribed inhaled corticosteroids for asthma and those who
have chronic respiratory symptoms. However, COPD is uncommon in patients aged
less than 45 years of age.26 Our analysis shows
similar differences in the prescribing of inhaled corticosteroids for a subgroup
of patients aged 35 years and less, where potential for confounding by chronic
respiratory conditions is greatly lessened.
We reiterate that a higher dose of inhaled budesonide seems
to be prescribed in New Zealand than beclomethasone and this is also the case
for budesonide when compared with fluticasone. There is insufficient evidence to
ascertain differing perceptions of the relative potencies of fluticasone and
beclomethasone. One possibility is that GPs may not be aware of the differing
pack sizes for fluticasone and are failing to prescribe sufficient medication to
cover the time intended. If inhaled corticosteroids are being prescribed at
inappropriately high levels in New Zealand, as appears in this study, this has
important health and cost implications.
This study provides important benchmark data of the
prescribing of inhaled corticosteroids in New Zealand general practice. Due to
the changing nature of prescribing for asthma, such as the introduction of
long-acting beta agonists, further research is required using more recent data.
The Dunedin RNZCGP Research Unit intends to repeat this study in one
year’s time to provide comparative data.
Author information:
Jason Hall, Assistant Research Fellow, Royal New Zealand College of General
Practitioners Research Unit, Department of General Practice, Dunedin School of
Medicine, Dunedin; Alister Penrose, Consultant Health Economist, Dunedin; Andrew
Tomlin, Assistant Research Fellow; James Reid, Associate Professor, Head of
Department of General Practice and Associate Dean for Postgraduate Education,
Royal New Zealand College of General Practitioners Research Unit, Department of
General Practice, Dunedin School of Medicine, Dunedin
Acknowledgements: We
thank the participating GPs, practice staff and research officers who managed
the data collection. The Dunedin RNZCGP Research Unit is funded by the New
Zealand Health Information Service.
Correspondence:
Jason Hall, Royal New Zealand College of General Practitioners Research Unit,
Department of General Practice, Dunedin School of Medicine, University of Otago,
P O Box 913, Dunedin. Fax: (03) 477 2056; email: jhall@gp.otago.ac.nz
References:
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