REVIEW

Preventing COPD exacerbations with

macrolides: A review and budget impact
analysis
Steven Simoens
a,
*, Gert Laekeman
a
, Marc Decramer
b
a
Research Centre for Pharmaceutical Care and Pharmacoeconomics, KU Leuven,
Onderwijs en Navorsing 2, P.O. Box 521, Herestraat 49, 3000 Leuven, Belgium
b
Respiratory Division, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium
Received 22 June 2012; accepted 24 December 2012
Available online 23 January 2013
KEYWORDS
COPD exacerbations;
Macrolides;
Prevention;
Effectiveness;
Safety;
Budget impact
Summary
Long-termtreatment with macrolides has recently been shown to reduce COPD exacerbations in
doses lower than bactericidal doses. This article aims to critically reviewthe international litera-
ture relating to the long-termeffectiveness and safety of macrolides and to estimate the budget
impact of preventing exacerbations with azithromycin in Belgium. Controlled clinical studies fo-
cusing on the prevention of COPD exacerbations with long-termmacrolide treatment were iden-
tied in PubMed, EMBASE, Controlled Trials Registry of the Cochrane Library, and Social Science
and Citation Index. The budget impact of preventing exacerbations with azithromycin in Belgium
over a one-year period was calculated as the difference between the additional expenditure of
annual treatment with azithromycin and the savings in hospital expenditure arising from fewer
COPD exacerbations in patients with GOLD stages IIeIV. Prevalence and resource use data were
derived from the literature and unit cost data from Belgian sources. The literature review sug-
gests that long-term treatment of COPD patients with azithromycin, erythromycin or clarithro-
mycin is effective and safe, and reduces exacerbations and related hospitalizations. However,
uncertainty remains about the specic patient population that is most likely to benet from
long-term macrolide treatment, the optimal dose and duration of macrolide treatment, and
the potential impact of long-term macrolide treatment on resistance. The budget impact anal-
ysis demonstrated that annual hospital savings of V950 million resulting from fewer exacerba-
tions outweighed additional expenditure on azithromycin of V595 million, implying that the
prevention of COPD exacerbations with azithromycin is a cost saving strategy in Belgium.
2013 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: 32 0 16 323465; fax: 32 0 16 323468.
E-mail address: steven.simoens@pharm.kuleuven.be (S. Simoens).
0954-6111/$ - see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.rmed.2012.12.019
Available online at www.sciencedirect.com
j ournal homepage: www. el sevi er. com/ l ocat e/ rmed
Respiratory Medicine (2013) 107, 637e648
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638
Literature review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638
Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638
Inclusion/exclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639
Assessment of methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639
Data analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639
Budget impact analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639
Literature review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639
Effectiveness and safety of azithromycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639
Effectiveness and safety of erythromycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 640
Effectiveness and safety of clarithromycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 640
Budget impact analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 644
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
Introduction
Chronic obstructive pulmonary disease (COPD) is a debilitat-
ing disease that affects 5%e10% of the adult population.
1
It is
currently the fourth leading cause of death and the World
Health Organisation expects it to become the third leading
cause of death by 2030.
2
While in the past three decades,
mortality due to heart disease and stroke clearly decreased,
mortality due to COPD almost doubled.
3
The disease is
characterized by exacerbations, periods of increased symp-
toms often following viral infections that may trigger hospi-
talization, respiratory failureanddeath.
4,5
Inaddition, these
episodes are associated with enhanced progression of the
disease.
4,6
Prevention of exacerbations is one of the prime treatment
goals in COPD.
7
Several medications have been shown to
reduce exacerbations including long-acting b2-agonists,
8
inhaled corticosteroids,
8
xed combinations of these medi-
cations,
8
long-acting anticholinergic agents,
9,10
phosphodies-
terase-4 inhibitors
11,12
and N-acetylcystein.
13,14
Nevertheless,
the reduction in exacerbations obtained in the best of cases,
remains limited to 25e30%, even with combinations of the
aforementioned agents. Hence, an important unmet need
remains.
Macrolides like erythromycin
15
and azithromycin
16
have
recently been proposed as agents that reduce exacerbations
indoses lower thanbactericidal doses. It is at present unclear
what the relevant mechanism of action is to explain the
reduction of exacerbations observed with macrolides. As
these antibiotics exert several immune-modulatory and anti-
inammatory effects, a variety of potential mechanisms of
action can be proposed. Macrolides exert a host of effects
that collectively limit the tissue damage by neutrophils,
including effects on chemo-attractants, inhibition of their
oxidant burst, impairment of granulation, and enhancement
of the rate of neutrophil apoptosis.
17
They also stimulate the
productionof antimicrobial -defensin-1 and-defensin-2 by
epithelial cells.
18
Finally, macrolides stimulate phagocytosis
by macrophages and enhance the expression of Mannose
receptor on these cells, facilitating the elimination of bac-
terial organisms.
19
This may be particularly important in
COPDpatients. Indeed, two observations point to a defective
macrophage function in these patients. First, alveolar mac-
rophages of these patients are defective in phagocytosis of
apoptotic cells.
20
Second, monocyte-derived macrophage
phagocytosis of bacteria is also known to be defective in
thesepatients.
21
Thepotential importanceof theseeffects is
even enhanced by the observation that azithromycin may
reach very high concentrations in alveolar macrophages,
even more so than other macrolides.
22
All of these effects
occur clinically at serum concentrations attainable by low
dose administration.
The aims of this study are to critically review the in-
ternational literature relating to the long-term effective-
ness and safety of macrolides and to estimate the budget
impact of preventing exacerbations with azithromycin in
Belgium over a one-year period.
Methods
Literature review
Search strategy
Studies were identied by searching the following electronic
databases up to April 2012: PubMed, EMBASE, Controlled
Trials Registry of the Cochrane Library, and Social Science
and Citation Index. The search strategy was varied and
adapted as necessary to suit particular databases. In gen-
eral, search terms included chronic obstructive pulmonary
disease, chronic bronchitis, emphysema, acute exac-
erbation, trial, effectiveness, efcacy, clinical out-
comes, quality of life, mortality, safety, side effect,
adverse events, resistance, pharmacotherapy, treat-
ment, long-term, continuous, chronic, macrolide,
638 S. Simoens et al.
azithromycin, erythromycin, clarithromycin, roxi-
thromycin, telithromycin alone and in combination with
each other. Additionally, the bibliography of included stud-
ies was checked for other relevant studies.
Inclusion/exclusion criteria
All controlled studies focusing on the prevention of COPD
exacerbations by means of long-term treatment with mac-
rolides were selected. Preference was given to randomized
controlled trials, but observational studies such as cohort
studies and before-and-after studies were also considered.
Case series were excluded. Studies had to measure the
impact of macrolide treatment on nal clinical outcomes
(e.g. number of exacerbations, time to rst exacerbation,
duration of exacerbation, quality of life). Studies that
examined the impact on intermediate outcomes such as in-
ammatory markers were not included.
Studies needed to focus on long-term treatment (arbi-
trarily set at treatment exceeding three months) of COPD
with macrolides and not on short-term treatment of an
acute exacerbation. Intermittent treatment was not con-
sidered. Long-term treatment was limited to macrolides,
given the well-known anti-inammatory and immunomo-
dulatory properties of macrolides.
23
Inclusion was restricted to articles published in peer-
reviewed journals. Congress abstracts were not considered
becausethey do not provide sufcient details of methodology
and results. The review included studies published between
2000 and 2012. It was considered that any earlier studies
would be of limited relevance due to changes in antibiotics,
bacterial pathogens and their susceptibility over time.
24
Ar-
ticles could be published in English, Dutch or French.
Assessment of methodological quality
The methodological quality of each study was assessed
according to the criteria outlined by the Cochrane Collab-
oration.
25
For each macrolide product, the available evi-
dence was evaluated using the following items of the
GRADE system: study design, study quality, consistency,
directness and imprecision.
26
Data analysis
A standard inclusion and data extraction form was com-
pleted for each study. This form enquired about the country
of the study, sample, intervention and comparator, study
design, effectiveness and safety results, and methodo-
logical quality (cfr. supra). This form was lled in by two
independent reviewers. Any disagreements were resolved
through discussion. Due to the heterogeneity of the studies,
a descriptive synthesis of the extracted data was made.
Budget impact analysis
In order to calculate the budget impact of preventing exac-
erbations withazithromycininBelgiumover aone-year period,
the additional expenditure of annual treatment with azi-
thromycin was contrasted with the savings in hospital expen-
diture arising from a reduced number of COPD exacerbations.
The target population was COPD patients in GOLD stage
II (who experience many exacerbations under usual care),
patients in GOLD stage III and patients in GOLD stage IV.
7
Data on the mean number of hospitalisations due to COPD
exacerbations per patient per year with azithromycin or
with placebo were derived from Albert et al.
16
: with azi-
thromycin this amounted to 0.5 hospitalisations per patient
per year for GOLD stage II patients, 0.85 hospitalisations for
GOLD stage III patients and 0.74 hospitalisations for GOLD
stage IV patients; with placebo this amounted to 0.65, 0.96
and 1.03 hospitalisations, respectively. As a result, the
reduction in the mean number of exacerbation-related
hospitalisations per patient per year with azithromycin as
compared to placebo was 0.15 for patients in GOLD stage II,
0.11 for patients in GOLD stage III and 0.29 for patients in
GOLD stage IV.
16
To calculate the number of Belgian COPD
patients in each GOLD stage, population-based prevalence
data were taken from the European sites participating in an
international study
27
and from a Dutch study,
28
and applied
to the number of Belgian inhabitants.
29
Belgian sources were used to obtain the unit cost of
a hospitalisation related to COPD exacerbation (inated to
2012 using Health Index gures) (at a unit cost of V6413)
30
and the annual cost of treatment with generic azithromycin
250 mg per day (at a cost of V594 per patient).
31
Unit costs
reected third-party payer reimbursement and patient co-
payment. The price year was 2012.
The net annual budget impact was calculated as the dif-
ference between the annual expenditure of treating Belgian
COPD patients in GOLD stages IIeIV with azithromycin and
savings arising from the reduced number of exacerbation-
related hospitalisations with azithromycin as compared to
placebo. To assess the robustness of our budget impact es-
timate to changes in input parameter values, the following
sensitivity analyses were conducted: a) number of hospital-
isations avoided with azithromycin as compared with pla-
cebo 50%; b) cost of azithromycin 250 mg per day between
V1.63 and V1.68 (in accordance with observed variation in
azithromycin prices in Belgium)
31
; and c) use of azithromycin
in patients with a history of frequent COPD exacerbations
only, i.e. 22% of patients in GOLD stage II, 33% in GOLD stage
III, and 47% in GOLD stage IV.
32
Results
Literature review
The literature search generated 39 articles Fig. 1. Articles
were excluded if they were published prior to 2000 or if they
examined the impact of macrolide treatment on inamma-
tory markers only. Eight studies were included in the review
that focused on the prevention of COPD exacerbations by
means of long-term treatment with a macrolide (i.e. azi-
thromycin, erythromycin and clarithromycin).
15,16,33e38
One
study evaluated treatment with erythromycin and/or clari-
thromycin, but did not document effectiveness and safety
for each antibiotic separately.
38
This study was included in
both the erythromycin and clarithromycin sections (cfr.
infra). No study of the prevention of COPD exacerbations
with other macrolide products was identied.
Effectiveness and safety of azithromycin
Three controlled studies investigated the effectiveness and
safety of long-term treatment (6e12 months) with azi-
thromycin in addition to usual care in patients with severe
Preventing COPD exacerbations with macrolides 639
COPD or at high risk of exacerbation. The characteristics and
results of these studies are summarized in Table 1.
The highest quality of evidence was derived from a multi-
centre, double-blindRCTenrolling morethan1100 patients.
16
Patients received azithromycin 250 mg daily for one year or
placebo. The ndings indicated that long-term treatment
with azithromycin decreased time to rst exacerbation,
exacerbation frequency, number of COPD-related hospital-
isations and enhanced quality of life. An acute exacerbation
was dened as an increase in respiratory symptoms lasting for
at least three days, requiring treatment with antibiotics or
systemic steroids. The magnitude of the treatment effect
may have been under-estimated given that patient com-
pliance with azithromycin treatment did not exceed 70%.
Although hearing decrements were more common with azi-
thromycin, this nding canbequestionedas hearingimproved
to baseline levels within one month after study completion in
patients who continued treatment with azithromycin.
A relevant question is whether chronic treatment with
azithromycin may cause the development of resistance to
macrolides. In this study, no difference was found in the
prevalence of resistance to macrolides between the two
groups (azithromycin: 52% versus placebo: 57%, p Z0.64) in
patients who were colonized with respiratory pathogens at
the time of enrollment.
16
However, in patients who became
colonized with respiratory pathogens in the course of the
study, the resistance to macrolides was 81% versus 41% with
placebo (p <0.001). The clinical relevance of this resistance
is not clear, as noevidenceof anincreasedincidenceof acute
exacerbations of COPD or pneumonia was found.
In addition, two observational studies administered
azithromycin 500 mg three times a week in small numbers
of patients (20 patients), thereby raising questions about
the precision of estimates.
34,36
Nevertheless, these studies
consistently showed that azithromycin treatment reduced
the number of exacerbations and the number of related
hospitalizations. This effect was already observed after
three months of treatment in one study. No serious adverse
events were observed with azithromycin in either study.
Effectiveness and safety of erythromycin
Three randomised controlled trials and one cohort study
demonstrated that long-term treatment (6 months) with
erythromycin reduced exacerbation frequency, delayed
time to rst exacerbation and reduced hospitalisations in
COPD patients as compared with no long-term antibiotic
treatment (see Table 2).
15,35,37,38
Furthermore, less severe
exacerbations were observed with erythromycin in one
study
37
and erythromycin treatment was associated with
a shorter duration of exacerbations in another study.
15
The
frequency of adverse events with erythromycin was low in
each study. In the one large study with erythromycin, there
was no difference in detection rate or resistance of micro-
organisms between the two groups.
15
However, these
studies did not explore the impact of erythromycin treat-
ment on quality of life. Also, there is uncertainty sur-
rounding the precision of estimates given the small number
of patients enrolled in these studies. Finally, three out of
four studies had been conducted in one centre only.
Effectiveness and safety of clarithromycin
Table 3 indicates that long-term treatment of COPD pa-
tients with clarithromycin was investigated in one rando-
mised controlled trial and one cohort study, which provided
39 citations identified
Exclusion because of:
- impact of macrolide treatment
on inflammatory markers only;
- short -term treatment with
macrolide or other antibiotic;
- intermittent treatment;
- treatment with antibiotic other
than macrolide;
- publication prior to 2000.
17 abstracts retrieved
12 full articles retrieved
8 studies included
Figure 1 Flow chart of literature search.
640 S. Simoens et al.
Table 1 Effectiveness and safety of long-term treatment with azithromycin in COPD.
Country Sample Comparators Design Effectiveness Safety Methodological quality Ref
Italy 22 patients > 45 years
with history of severe
COPD and
tracheostomy
Standard care (n Z 11);
standard care plus
azithromycin 500 mg 3 times
a week for 6 months (n Z 11)
Multicentre, open-
label RCT
Azithromycin was
associated with lower
cumulative number of
exacerbations after 3
months of treatment
when compared to
standard care
(p Z 0.001) and with
lower cumulative
number of
hospitalizations
(p Z 0.02). A lower rate
of rst exacerbation
(p < 0.001) and of rst
hospitalization
(p Z0.04) occurred with
azithromycin when
compared to standard
care. Azithromycin
signicantly improved
quality of life when
compared to standard
care. There was no
difference in mortality
rate.
There were no serious
adverse events with
azithromycin.
Small number of
patients; no blinding of
patients, physicians or
researchers; high drop-
out rate, limiting
duration of analysis to 3
months; no evaluation of
liver function in context
of safety assessment.
34
US 1142 patients > 40
years with COPD,
used supplemental
oxygen or systemic
glucosteroid in
previous year, had
gone to emergency
room or been
hospitalized for COPD
exacerbation.
Usual care plus azithromycin
250 mg daily for 1 year
(n Z 570); usual care plus
placebo (n Z 572)
Multicentre,
double-blind RCT
Median time to rst
exacerbation was 266
days with azithromycin
and 174 days with
placebo (p < 0.001).
Frequency of
exacerbations was 1.48
exacerbations per
patient-year with
azithromycin and 1.83
with placebo (p Z0.01).
Hazard ratio for having
an exacerbation per
patient-year was 0.73
with azithromycin (95%
CI, 0.63 to 0.84;
p < 0.001). The mean
number of COPD-related
There were no
differences in frequency
of (serious) adverse
events between
azithromycin and
placebo. Hearing
decrements were more
common with
azithromycin than with
placebo (25% vs 20%,
p Z 0.04).
Hearing decrements can
be questioned as hearing
improved to baseline
levels within 1 month
after study completion in
patients who (dis)
continued azithromycin
or placebo; limited
therapy compliance
(around 67% in both
groups); limited drop-out
rate (around 10% in both
groups).
16
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Table 1 (continued)
Country Sample Comparators Design Effectiveness Safety Methodological quality Ref
hospitalisations per
patient per year was 0.34
with azithromycin and
0.49 with placebo
(p Z 0.14). St. Georges
Respiratory
Questionnaire scores
improved more with
azithromycin than with
placebo (mean decrease
of 2.8 12.8 vs
0.6 11.4, p Z 0.004);
and higher percentage
of patients exceeded
clinically important
difference of 4 units with
azithromycin than with
placebo (43% vs 36%,
p Z 0.03).
Spain 20 patients with
severe COPD and
frequent
exacerbations or
chronically colonized
by P. aeruginosa
Azithromycin 500 mg 3 times
a week for 12 months plus
triple therapy (long acting
anticholinergics, long-term
beta-agonists, inhaled
corticosteroids); triple therapy
Before-and-after
analysis
Azithromycin reduced
number of exacerbations
(2.8 2.5 vs 6.8 2.8,
p < 0.001),
hospitalizations
(1.4 1.5 vs 3.6 1.4,
p < 0.001), and
cumulative annual days
in hospital (25 32.2 vs
43.7 21.4, p Z 0.01).
There were no serious
adverse events with
azithromycin. One
patient stopped
azithromycin due to
dyspepsia.
Small number of
patients; four out of
24 patients did not
complete 12-month
treatment period and
were excluded from
analysis; single centre
study.
36
GRADE assessment:
Study design Study quality Consistency Directness Imprecision
1 RCT, 2 observational
studies
Serious limitations to
quality in 2 observational
studies
Consistency in results across
studies
Direct comparison,
differences in population
between studies
Imprecise estimates in
2 observational studies
Notes: CI Z condence interval; COPD Z chronic obstructive pulmonary disease; RCT Z randomized controlled trial.
6
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Table 2 Effectiveness and safety of long-term treatment with erythromycin in COPD.
Country Sample Comparators Design Effectiveness Safety Methodological quality Ref
Japan 109 patients
with COPD treated
with sustained
release theophylline
and inhaled
anticholinergics
but not
corticosteroids
Erythromycin 200e400
mg per day for 12
months (n Z 55); no
active treatment,
i.e. riboavin 10 mg
per day (n Z 54)
Prospective
open-label
RCT
Relative risk of experiencing exacerbation
in control group as compared with
erythromycin group was 4.71 (95% CI,
1.53 to 14.5; p Z 0.007). Total number
of exacerbations was lower in
erythromycin group than in control
group (p < 0.0001). More severe
exacerbations were observed in
control group than in erythromycin
group (p Z 0.0007). More patients
were hospitalized due to exacerbations
in control group than in erythromycin
group (p Z 0.0007).
One patient
experienced
anorexia and
diarrhea in
erythromycin
group
Small number
of patients;
no blinding of
patients, physicians
or researchers;
single centre study.
37
Japan 123 elderly patients
with COPD
Macrolide therapy
(erythromycin, n Z 23;
clarithromycin, n Z 26)
for mean follow-up of
43 months (12e193
months); no antibiotic
(n Z 78)
Retrospective
multicentre
cohort study
Number of patients with exacerbation
frequency of 1.5 times per year or more
in macrolide group (4.4%) was lower
than in control group (15.4%) (p Z 0.01).
Number of patients with hospitalization
frequency of 0.75 times per year or more
in macrolide group (4.4%) was lower than
in control group (14.1%) (p Z 0.04). Use
of macrolides was related to low
frequency of exacerbations (p Z 0.02)
and hospitalization (p Z 0.04).
e Some differences
in baseline characteristics
between macrolide and
control group (risk for
selection bias); small
number of patients in
macrolide group.
38
UK 109 elderly patients
with moderate-to-
severe COPD,
most of them were
taking inhaled
steroids
Erythromycin 250 mg
twice daily for 1 year
(n Z 53); placebo
(n Z 56)
Double-blind
RCT
Median exacerbation frequency was 2
with placebo and 1 in erythromycin
group (p Z 0.006). Median time to rst
exacerbation was 271 days in
erythromycin group versus 89 days with
placebo (p Z 0.020). Rate ratio for
exacerbations in erythromycin group
as compared with placebo was 0.648 (95%
CI, 0.489 to 0.859; p Z 0.003). Median
duration of exacerbations with placebo
was 13 days, and 9 days in erythromycin
group (p Z 0.036).
No differences in
adverse events
were observed
between
erythromycin and
placebo, and
frequency of
adverse events
was low in both
groups.
Small number of patients
(lower than that required
by sample size calculation);
22% drop-out rate; single
centre study.
15
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inconsistent results.
33,38
On the one hand, based on a ret-
rospective cohort study in which 26 patients were treated
with clarithromycin, long-term treatment reduced exacer-
bation and hospitalisation frequency.
38
Conversely, a dou-
ble-blind randomised controlled trial observed no
differences in clinical outcomes between clarithromycin
and placebo.
33
However, this may be expected due to the
short duration of treatment and the low dose of clari-
thromycin. It should also be noted that baseline de-
mographic and clinical characteristics were not comparable
between clarithromycin and placebo groups. Finally, these
studies provided limited data on the safety of long-term
clarithromycin treatment.
Budget impact analysis
By applying European prevalence data to Belgium, there
were 848,333 COPD patients in GOLD stage II; 132,208 pa-
tients in GOLD stage III and 22,035 patients in GOLD stage IV
in 2012. The additional expenditure of annual treatment
with azithromycin was contrasted with the savings in hos-
pital expenditure arising from a reduced number of COPD
exacerbations. Annual treatment of Belgian COPD patients
in GOLD stages IIeIV with azithromycin generated addi-
tional expenditure of V595 million, but was associated with
hospital savings of V950 million resulting from fewer ex-
acerbations. Therefore, the budgetary savings of prevent-
ing COPD exacerbations with azithromycin in Belgium over
a one-year period was estimated to amount to V355
million.
The sensitivity analyses indicated that the budget
impact estimates were sensitive to changes in the absolute
number of exacerbation-related hospitalisations per pa-
tient per year avoided with azithromycin as compared to
placebo: when the number of avoided hospitalisations
increased by 50%, the budgetary savings with azithromycin
rose to V830 million, but when the number of avoided
hospitalisations fell by 50%, long-term treatment of COPD
patients with azithromycin would cost an additional V120
million. When the cost of azithromycin 250 mg per day
varied between V1.63 and V1.68, the budgetary savings
with azithromycin ranged from V336 to V355 million.
Finally, when the use of azithromycin was restricted to
patients with a history of frequent COPD exacerbations,
budgetary savings amounted to V87 million.
Discussion
The literature review suggests that long-term treatment of
COPD patients with azithromycin, erythromycin or clari-
thromycin is in general effective and safe. Macrolide
treatment appears to reduce exacerbations and related
hospitalizations. However, a number of issues relating to
long-term macrolide treatment remain unresolved.
First, existing studies have employed different patient
in/exclusion criteria, so that it is not possible to identify
a patient population that is most likely to benet from long-
term macrolide treatment. Intuitively, we would expect
that patients who retain high exacerbation rates, despite
conventional therapy with long-acting bronchodilators and
inhaled steroids, would be the best candidates for such
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644 S. Simoens et al.
Table 3 Effectiveness and safety of long-term treatment with clarithromycin in COPD.
Country Sample Comparators Design Effectiveness Safety Methodological quality Ref
Japan 123 elderly
patients
with COPD
Macrolide therapy
(erythromycin, n Z 23;
clarithromycin, n Z 26)
for mean follow-up of 43
months (12e193 months);
no antibiotic (n Z 78)
Retrospective
multicentre
cohort study
Number of patients with
exacerbation frequency of
1.5 times per year or more in
macrolide group (4.4%) was
lower than in control group
(15.4%) (p Z 0.01). Number
of patients with hospitalization
frequency of 0.75 times per year
or more in macrolide group (4.4%)
was lower than in control group
(14.1%) (p Z 0.04). Use of macrolides
was related to low frequency of
exacerbations (p Z 0.02) and
hospitalization (p Z 0.04).
e Some differences in
baseline characteristics
between macrolide and
control group (risk for
selection bias); small
number of patients in
macrolide group.
38
UK 67 patients with
moderate-to-severe
COPD taking inhaled
corticosteroids
Clarithromycin 500 mg
once daily for 3 months
(n Z 31);
placebo (n Z 36)
Double-blind
RCT
Clarithromycin did not improve
health status, sputum bacterial
numbers or exacerbation rate
as compared to placebo.
In clarithromycin
group, 1 patient
had gastrointestinal
upset.
Small number of patients;
low dose of clarithromycin
and short treatment duration;
some differences in baseline
characteristics between groups
(risk for selection bias); 10%
drop-out rate.
33
GRADE assessment
Study design Study quality Consistency Directness Imprecision
1 RCT, 1
observational
study
Serious limitations
to quality in all
studies
Results not
consistent
across studies
Direct comparison,
differences in
population
between studies
Imprecise
estimates in
all studies
Notes: COPD Z chronic obstructive pulmonary disease; RCT Z randomized controlled trial.
P
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6
4
5
therapy. However, it is at present not clear whether
treatment effects would be larger in these patients.
Second, there is also uncertainty surrounding the opti-
mal dose and duration of macrolide treatment. It would be
particularly interesting to investigate whether doses below
250 mg azithromycin daily or equivalent doses of other
macrolides, would also produce effects. Third, no study has
carried out a direct comparison between long-term treat-
ment with one macrolide product and long-term treatment
with another macrolide. Fourth, the possible adverse
events associated with long-term macrolide treatment
need to be investigated in more detail.
39
So far, side effects
appear acceptable. Fifth, it is not clear whether long-term
treatment with a macrolide could lead to restricting or
abandoning other medication (e.g. inhaled corticosteroids).
Finally, the question needs to be asked whether long-
term treatment with macrolides may induce resistance to
these antibiotics. At present, the data in the literature
appear conicting.
15,16
More studies on this important topic
are required. A particularly important question is whether
possible changes in resistance pattern may increase the
incidence of infections clinically.
It should be noted that the use of macrolides such as
erythromycin and clarithromycin may raise the risk of
serious ventricular arrhythmias and the risk of car-
diovascular death.
40e43
A recent retrospective cohort study
has suggested that a ve-day course of azithromycin also
increases the risk of cardiovascular death.
44
However, the
authors acknowledged that this observational study was not
able to control for confounding factors that are associated
with azithromycin use and an increased risk of car-
diovascular death. Furthermore, the literature points to
the minimal cardiotoxicity of azithromycin.
45
Although this fell outside the scope of this literature
review, the reader should note that there is also limited
clinical evidence about long-term intermittent therapy of
COPD patients with moxioxacin and about long-term
treatment with inhaled antibiotics (e.g. inhaled tobramy-
cin). Extensive experience with the latter was obtained in
patients with cystic brosis.
46,47
These treatments appear
to reduce exacerbations in COPD patients as well, but these
initial results need to be validated by future research.
24
To date, to the best of the authors knowledge, no
economic evaluation has calculated the cost-effectiveness
of long-term treatment with a macrolide in the prevention
of COPD exacerbations. It is hypothesised that cost-
effectiveness will mainly depend on the additional costs
of long-term macrolide treatment and on savings arising
from fewer exacerbation-related hospitalisations. In this
respect, a 2010 audit of COPD care across Europe included
499 Belgian patients admitted to hospital and described
their demographic characteristics as follows: median age of
68 years (37% of patients were younger than 65 years),
mean height of 166 cm, mean weight of 68 kg, BMI of 24.8,
Charlson index of comorbidity of 1.0, 44% of patients were
smokers, 51% were former smokers and 5% had never
smoked.
48
Our simplistic budget impact analysis demonstrated that
hospital savings from fewer exacerbations outweighed
additional expenditure of annual treatment with azi-
thromycin in COPD patients in stages IIeIV, implying that
the prevention of COPD exacerbations with azithromycin is
a cost saving strategy in Belgium. As is expected, the sen-
sitivity analysis showed that the budget impact estimate
depends on the absolute number of avoided hospitalisations
with azithromycin as compared with placebo. The number
of avoided hospitalisations in our budget impact analysis
was derived from a multi-centre, double-blind RCT, which
possibly under-estimated the treatment effect of azi-
thromycin in light of the limited compliance of the enrolled
patient population with azithromycin.
16
Changes in input
parameters associated with the cost of azithromycin
treatment and the size of the patient population conrmed
that long-term treatment of COPD patients with azi-
thromycin is cost saving, thus supporting the general-
izability of our results. However, the reader should note
that this budget impact analysis did not account for adverse
events or possible changes in resistance patterns associated
with long-term treatment with azithromycin. Also, in the
absence of data, it was not possible to consider the budget
impact of changes in the number of physician visits related
to COPD exacerbations.
Conict of interest
Financial support for this research was received from TEVA.
The study sponsor did not have a role in the study design, in
the collection, analysis and interpretation of data, in the
writing of the manuscript, or in the decision to submit the
manuscript for publication. The authors have no conicts of
interest that are directly relevant to the content of this
manuscript.
Acknowledgements
Financial support for this research was received from TEVA.
The study sponsor did not have a role in the study design, in
the collection, analysis and interpretation of data, in the
writing of the manuscript, or in the decision to submit the
manuscript for publication. The authors have no conicts of
interest that are directly relevant to the content of this
manuscript.
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