Effectiveness and safety of medicines used in COPD patients Wang, Yuanyuan
DOI:
10.33612/diss.123921981
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Wang, Y. (2020). Effectiveness and safety of medicines used in COPD patients: pharmacoepidemiological studies. University of Groningen. https://doi.org/10.33612/diss.123921981
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Effectiveness and safety of
medicines used in COPD patients
Pharmacoepidemiological studies
Effectiveness and safety of medicines used in COPD patients Pharmacoepidemiological studies
ISBN: 978-94-034-2555-9 (printed version) ISBN: 978-94-034-2554-2 (electric version)
Author: Yuanyuan Wang
Cover-design: IRINA SHI (photo) & Off Page (content) Printing: Off Page (www.offpage.nl)
The studies presented in this thesis were funded by University of Groningen and the China Scholarship Council (CSC) Scholarship. This thesis was conducted within the Groningen University Institute for Drug Exploration (GUIDE). Printing of this thesis was financially supported by the University of Groningen and the Graduate School of Science and Engineering (GSSE).
Copyright ©Yuanyuan Wang, 2020, Groningen, The Netherlands.
All rights reserved. No part of this book may be reproduced or transmitted in any form by any means, electronically or mechanically by photocopying, recording, or otherwise, without the written permission of the author. The copy right of previously published chapters of this thesis remains with the publisher or journal.
Effectiveness and safety of
medicines used in COPD patients
Pharmacoepidemiological studies
PhD thesis
to obtain the degree of PhD at the University of Groningen
on the authority of the
Rector Magnificus Prof. C. Wijmenga and in accordance with
the decision by the College of Deans. This thesis will be defended in public on
Friday 8 May 2020 at 14.30 hours
by
Yuanyuan Wang
born on 15 February 1988 in Henan, China
Prof. H.M. oe en
Assessment Committee
Prof. T. .M. erheijProf. . van der Palen Prof. . tienstra
TABLE OF CONTENTS
Chapter 1 General Introduction 7
Part I Effects of antibiotic use for COPD exacerbations and
potential DDIs during COPD exacerbation management
Chapter 2 Effects of Prophylactic Antibiotics on Patients with Stable COPD: 21
A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Chapter 3 The influence of age on real-life effects of doxycycline for 43
acute exacerbations among COPD outpatients: a population-based cohort study
Chapter 4 Real-world short- and long-term effects of antibiotic therapy on 61
acute exacerbations of COPD in outpatients: a cohort study under the PharmLines Initiative
Chapter 5 Improving antibacterial prescribing safety in 81
the management of COPD exacerbations:
systematic review of observational and clinical studies on
potential drug interactions associated with frequently prescribed antibacterials among COPD Patients
Part II Neuropsychiatric safety of varenicline use for smoking cessation
and the application of prescription sequence symmetry analysis in drug safety evaluation
Chapter 6 Neuropsychiatric safety of varenicline in the general and 119
COPD population with and without psychiatric disorders: a retrospective inception cohort study in a real-world setting
Chapter 7 Risk of neuropsychiatric adverse events associated with 145
varenicline treatment for smoking cessation: a prescription sequence symmetry analysis
Chapter 8 Effect estimate comparison between the prescription 165
sequence symmetry analysis and parallel group study designs: a systematic review
Chapter 9 General discussion 183
Chapter 10 Summary 197
Samenvatting 201
Acknowledgement 204
List of publications 208
About the author 211
Supervisors
Prof. . Ha Prof. H.M. oe enAssessment Committee
Prof. T. .M. erheijProf. . van der Palen Prof. . tienstra
General Introduction
1
GENERAL INTRODUCTION
Chronic obstructive pulmonary disease
According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) report 2020, Chronic Obstructive Pulmonary Disease (COPD) is a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation. Such symptoms are caused by airway and/or alveolar abnormalities usually triggered by significant exposure to noxious particles or gases.1 Cigarette smoking is
the main independent causal risk factor for COPD with indoor and outdoor air pollution and occupational exposure to dust and noxious particles also being the risk factors for COPD.2 Moreover, host factors that may contribute to the development of COPD include
age, genetics, airway hyper responsiveness and abnormal lung development.3-5
The prevalence of COPD varies across countries as well as regions within countries. According to the findings of a global meta-analysis, the number of COPD cases increased to 384 million in 2010, with a global prevalence of 12% (ranging between 8% and 15%).6 COPD is commonly diagnosed in individuals aged 40 years or older
based on the presence of associated symptoms and risk factors. However, a definitive COPD diagnosis requires the performance of spirometry. The presence of a post-bronchodilator FEV1/FVC < 0.7 confirms the presence of airflow limitation and results in a COPD diagnosis. COPD patients are currently categorized into four GOLD stages of severity of airflow limitations based on the predicted value of FEV1: mild (stage I, FEV1 ≥ 80% predicted), moderate (stage II, 50% ≤ FEV1 < 80% predicted), severe (stage III, 30% ≤ FEV1 < 80% predicted) and very severe (stage IV, FEV1 < 30% predicted).1 A large
prevalence study estimated that the rate of COPD for GOLD stage II and higher is around 10% in the general population, and a little higher in men than women (11.8% and 8.5%, respectively).7
COPD is one of the leading causes of morbidity and mortality worldwide.8 Its burden is
predicted to increase in the coming decades as a result of continuous exposure to risk factors in developing countries and aging of the population worldwide, particularly in high-income countries.9 Smoking cessation interventions, increased physical activity,
and early diagnosis and treatment of related comorbidities are considered key measures for reducing the health-economic burden of COPD. 10
Up to now, the key goals of COPD treatment have been to improve patients’ prognosis and prevent the disease from worsening. The main treatment used in the daily management of mild and moderate COPD is pharmacotherapy. Bronchodilators, including short- and long-acting β2-agonists (SABA and LABA) and short- and long-acting anticholinergics (SAMA and LAMA) are essential for managing and preventing symptoms, and combined treatment (SABA/SAMA, LABA/LAMA or LABA/ICS) may be used as appropriate.
Non-pharmacological treatment comprises pulmonary rehabilitation (e.g., exercise training, education, and behavioral change).11 Oxygen therapy is necessary for patients with very
severe COPD and lung surgery may also be necessary.
Exacerbations of COPD and antibiotic use
An exacerbation of COPD is defined as an acute worsening of respiratory symptoms that necessitates additional therapy.1 COPD patients can periodically experience acute
exacerbations that may accelerate the decline in lung function, reduce the quality of life, and increase mortality and health-care costs.12,13 14 Infections, especially bacterial
infections, and inflammation are thought to be an important trigger for exacerbations of COPD. Previous studies have found that bacteria are responsible for around 40% to 50% of exacerbations.15,16 S. pneumoniae, H. influenza, P. aeruginosa, M. catarrhalis,
A. baumannii, and S. aureus were the most frequently reported bacteria that cause exacerbations of COPD.16-18 According to the GOLD guideline, the main goals in
treatment of COPD exacerbations are minimizing the negative impact of the current exacerbation and preventing subsequent exacerbations.1 Because almost 40% of
exacerbations are bacteria-caused respiratory tract infections,16 the use of antibiotics
has become a common component in the management of acute exacerbations among COPD patients, both in terms of treatment and prevention.1,19
Notably, recommendations in prophylactic use of antibiotics in the management of COPD exacerbations are conditional and unspecific. Only long-term macrolides are currently mentioned as first-line therapy.1,19 Moreover, in terms of current evidence, an optimal
regimen of prophylactic antibiotics for exacerbations has not been well established, and related recommendations regarding an appropriate schedule (continuous vs. intermittent) and the duration of a specific antibiotic intervention (below or equal to 6 months vs. above 6 months) are still lacking. Besides, the effects of even the most extensively researched antibiotics macrolides—let alone other potentially suitable antibiotics—on the time to the first exacerbation, changes in lung function, the bacterial load, and airway inflammation have not been adequately evaluated.20 Knowledge of
these outcomes is also vital for elucidating possible mechanisms behind the reduction of exacerbations through the prophylactic use of antibiotics, and for weighing benefits and risks.21
The beneficial effects of oral corticosteroids as an effective treatment for acute exacerbations of COPD (AECOPD) in improving COPD symptoms and lung function are well established.22 However, although antibiotics have been recommended for
the treatment of AECOPOD when signs of bacterial infection are present,1 there
is still uncertainty regarding the beneficial effects of antibiotic treatment used in the combination with oral glucocorticoids for AECOPD, particularly in the case of outpatients in real-world settings. In 2012, a Cochrane review that pooled the results
General Introduction
1
of five RCTs conducted among outpatients did not reveal a significantly reduced risk of treatment failure associated with antibiotics currently prescribed for outpatients.23
However, an updated version of this Cochrane review conducted in 2018 presented statistically significant beneficial effects of current antibiotics prescribed for outpatients.24 Two new RCTs were included in this later study in relation to the earlier
review conducted in 2012.25,26 Notably, one of the two RCTs did not support the beneficial
effects of antibiotics treatment on AECOPD, although it did contribute to almost 25% of the sample size of the updated pooled results.25
Hence, most of the available scientific evidence on the effects of antibiotics for AECOPD is basically derived from RCTs. It is widely accepted that RCTs provide solid evidence with high internal validity, however, their generalizability in the real world, especially in outpatient settings is low. COPD is a chronic disease and is mostly managed on an outpatient basis within a population that is more heterogeneous compared with populations from RCTs. Moreover, the use of antibiotics for AECOPD treatment is not always appropriate and in line with related guidelines.27,28 Therefore, the effect of
antibiotic treatment for AECOPD in real-world settings may differ from those obtained in clinical trials and require further investigation.
Comorbidities of COPD and potential drug-drug interactions
COPD is a chronic disease and its prevalence increases with age; around 15% of the general population over 65 years is affected by COPD.29 Hence, age-related comorbidities
frequently co-exist with COPD.30 The most common concomitant chronic conditions
associated with COPD include cardiovascular disease (e.g., heart failure, ischemic heart disease, and arrhythmias), metabolic disease (e.g., diabetes), osteoporosis, depression and anxiety, lung cancer and gastroesophageal reflux (GERD).1,30
COPD itself is a complex disease that entails the need for a variety of medications to improve lung function and treat exacerbations.1 Multiple comorbidities further
complicate the medical management of COPD, resulting in polypharmacy among a large section of COPD patients. Polypharmacy poses a potential risk of drug-drug interactions (DDIs) that may induce adverse events and treatment failures. Moreover, COPD is an age-related disease that generally manifests at an older age. Therefore, these older patients are more susceptible to DDIs due to gradual physiologic negative changes that may influence their pharmacokinetics and the pharmacodynamics of the drugs used.31
As most evidence about drug effects is from clinical trials, more attention should be paid to issues related to polypharmacy and to potential DDIs in the management of COPD in real-world settings.32 This is especially the case for antibiotic therapy as it
includes different drug classes that vary in their mechanisms relating to absorption and metabolism, making their interaction with other medications more likely. Comprehensive information for clinicians to avoid potential DDIs, however, is lacking.
Smoking cessation drug therapy and neuropsychiatric safety
Tobacco smoking is the main risk factor for COPD and other physical and mental disorders.33-35 This preventable behavior poses huge threats to global public health.36,37
Although in recent years, strict tobacco control policies have prompted a global decline in smoking,36 the actual numbers of smokers and smoking-related disease burden
continues to increase because of the growing population worldwide.38 More than eight
million people continue to die annually as a result of tobacco consumption.39
Therefore, smoking cessation strategies to prevent smoking-related diseases are imperative.40 Varenicline, which was the first non-nicotine, pharmacotherapeutic,
smoking cessation product, has been found to be more efficacious than other therapies, such as single-dose bupropion and nicotine replacement therapy (NRT).41
However, following varenicline’s approval by the FDA in 2006, safety concerns were raised relating to its neuropsychiatric adverse events, which include suicidal thoughts, aggressive behavior, depression, anxiety, and sleep disorders.42 Numerous RCTs were
subsequently conducted with varenicline to generate evidence on its safety.43 In light of
their findings, the FDA warning was removed in 2016. However, concerns remain, given the strict inclusion and exclusion criteria applied in RCTs that result in the participation of relatively healthy individuals and the lack of consistent real-world evidence. Notably, special risk populations demonstrating increased smoking prevalence, such as COPD patients, have generally been excluded from RCTs.44
As previously noted, most COPD patients are elderly and have multi-morbidities, making them more susceptible to adverse drug events (ADEs). Similarly, there is evidence that individuals with psychiatric disorders experience relapses of psychiatric symptoms more frequently than those without these disorders.45,46 The safety of varenicline use for these
specific populations has not been established. Although a few studies were conducted among patients with COPD or psychiatric disorders,47,48 the results were inconsistent.
Consequently, more observational studies are still needed to generate the real-world evidence relating to the safety of varenicline use.
PSSA and observational study designs in drug safety evaluation
Most evidence regarding the effects of drugs is derived from strictly regulated clinical trials. However, the results from RCTs may not reflect the real-world situations, given that the participants are relatively healthy and because of the limited scope for detecting rare events with clinical trials. Therefore, real-world evidence derived from traditional, non-randomized, observational study designs is valuable for exploring such drug effects or toxicities within the field of pharmacoepidemiology. However, the evidence from observational studies is often inconsistent, and such designs have been criticized for their potential of bias (e.g., selection or information bias) and confounding (e.g. unmeasured confounding).49
General Introduction
1
Prescription sequence symmetry analysis (PSSA) is increasingly being used to detect adverse effects or events associated with medications. PSSA is a self-controlled study design in which genetic and other time-invariant confounding can be well controlled, it does not entail the abovementioned bias.50,51 It compares the symmetry in the sequence
of exposure medication and marker (outcome) medications as proxy for ADRs within a specific time window based on prescriptions or claims databases.52 The sequence
ratio (SR) reflects the association between exposure and outcome. However, PSSA is still sensitive to time-varying variables, notably if the follow-up time is long. The overall validity of PSSA study designs has not been fully evaluated by comparing its result with those from conventional observational parallel group study designs, and such comparisons are urgently required.
AIM OF THIS THESIS
In this thesis, we aim to develop a comprehensive profile on the effectiveness of antibiotic use for acute exacerbations of COPD both prescribed prophylactically and therapeutically, and to provide real-world data on neuropsychiatric safety of varenicline use for smoking cessation, particularly among high risk populations with COPD or psychiatric diseases.
OUTLINE OF THIS THESIS
In part I of this thesis, we present several studies on the role of antibiotics in acute exacerbations of COPD (AECOPD).
In Chapter 2, we report the results from a meta-analysis of RCTs focusing on the beneficial effects and side effects of prophylactic antibiotic therapy in COPD patients.
In Chapter 3, we demonstrate the real-world effects of doxycycline treatment on acute exacerbations among COPD outpatients based on data extracted from the University of Groningen’s prescription database (IADB.nl) and explored the possible influence of age on the clinical outcomes.
In Chapter 4, we further explored the real-world effects of several antibiotic drugs used for acute exacerbations of COPD patients based on a linked database between the Lifelines Cohort biobank with extensive clinical information and the University of Groningen’s prescription database (IADB.nl).
In Chapter 5, we present a systematic review of drug-drug interactions associated with frequently prescribed antibiotics among COPD patients based on causal evidence obtained from observational cohort studies, case-control studies and clinical studies, aimed at improving the safety of antibacterial prescriptions.
In part II of this thesis, we present studies on the role of varenicline for smoking cessation using different designs.
In Chapter 6, we present the results of a retrospective inception cohort study aimed at assessing the risk of neuropsychiatric adverse events (NPAEs) in starters with varenicline versus starters with nicotine replacement therapy (NRT) among both the general and COPD populations, with and without psychiatric disorders. This study was conducted using data extracted from the University of Groningen’s prescription database (IADB.nl). In Chapter 7, we further examine the association between varenicline use and the onset of NPAEs in a real-world setting using a prescription sequence symmetry analysis (PSSA) study design.
Furthermore, in Chapter 8 we systematically compared effect estimates derived from the PSSA study with effect estimates from conventional observational parallel group study designs, to assess the validity and constraints of the PSSA study design within epidemiological research.
Last, in Chapter 9, we summarized the main findings of this thesis, discussed these findings in detail and provided suggestions for future research.
General Introduction
1
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P, de Borgie CA, Prins JM. Antibiotics and steroids for exacerbations of COPD in primary care: compliance with Dutch guidelines. Br J Gen Pract. 2006;56(530):662-665.
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33. Banks E, Joshy G, Korda RJ, et al. Tobacco smoking and risk of 36 cardiovascular disease subtypes: fatal and non-fatal outcomes in a large prospective Australian study. BMC Med. 2019;17(1):128.
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41. Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of
General Introduction
1
varenicline, bupropion, and nicotine patchin smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial. Lancet. 2016;387(10037):2507-2520. 42. Moore TJ, Furberg CD, Glenmullen J,
Maltsberger JT, Singh S. Suicidal behavior and depression in smoking cessation treatments. Plos One. 2011;6(11):e27016. 43. Thomas KH, Martin RM, Knipe DW, Higgins
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48. Evins AE, Benowitz NL, West R, et al. Neuropsychiatric Safety and Efficacy of Varenicline, Bupropion, and Nicotine Patch in Smokers With Psychotic, Anxiety, and Mood Disorders in the EAGLES Trial. J Clin Psychopharmacol. 2019;39(2):108-116. 49. Boyko EJ. Observational
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Effects of antibiotic use for COPD
exacerbations and potential DDIs during COPD
exacerbation management
Yuanyuan Wang
Tanja R. Zijp
Muh. Akbar Bahar
Janwillem W.H. Kocks
Bob Wilffert
Eelko Hak
Effects of Prophylactic Antibiotics on Patients
with Stable COPD: A Systematic Review and
Meta-Analysis of Randomized Controlled Trials
Published as: Wang Y, Zijp TR, Bahar MA, Kocks JWH, Wilffert B, Hak E. Effects of prophylactic antibiotics on patients with stable COPD: a systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2018;73(12):3231–3243.
ABSTRACT
Background
As bacterial infections provoke exacerbations, COPD patients may benefit from prophylactic antibiotics. However, evidence regarding their overall benefit-risk is conflicting.
Objectives
To update previous evidence and systematically evaluate the beneficial and side effects of prophylactic antibiotics on stable COPD patients.
Methods
Several databases were searched up to April 26, 2017 for randomized controlled trials (RCTs) on prophylactic antibiotics in stable COPD patients. The Primary outcomes were exacerbations and quality of life. Duration and schedule of antibiotics were considered in sub-group analyses.
Results
Twelve RCTs involving 3,683 patients were included. Prophylactic antibiotics significantly reduced the frequency of exacerbations (risk ratio [RR] 0.74, 95% CI 0.60-0.92) and the number of patients with one or more exacerbations (RR 0.82, 95% CI 0.74-0.90). Erythromycin and azithromycin appeared the most effective with the number needed to treat ranging from four to seven. Quality of life was also significantly improved by prophylactic antibiotics (mean difference -1.55, 95% CI -2.59 to -0.51). Time to first exacerbation was prolonged in six studies with one conflicting result. Neither the rate of hospitalization nor the rate of adverse events was significantly changed. Furthermore, no significant changes were observed in lung function, bacterial load and airway inflammation. However, antibiotic resistant isolates were significantly increased (OR 4.49, 95% CI 2.48-8.12).
Conclusions
Prophylactic antibiotics were effective in preventing COPD exacerbations and improving quality of life among stable patients with moderate to severe COPD. The choice of prophylactic antibiotics should be analysed and considered case by case, especially for long and continuous use.
Effects of prophylactic antibiotics on COPD
2
INTRODUCTION
COPD is an inflammatory disease that is characterized by persistent respiratory symptoms and airflow limitation.1 At present, COPD is one of the leading causes
of chronic morbidity and mortality worldwide, its burden is predicted to increase in the coming decades due to continuous exposure to risk factors and aging of population globally.2 In the course of COPD, exacerbation as an acute worsening of respiratory
symptoms has a profound negative impact on health oucomes.3 A vicious circle of
infection and inflammation is thought as a key to trigger exacerbations of COPD, about 40-50% of exacerbations are caused by bacteria.4
The use of prophylactic antibiotic has been suggested to prevent exacerbations in COPD patients for a long time. However, a Cochrane review in 2003 concluded that antibiotics only contribute to a small 9% reduction of exacerbations and should not be part of routine treatment considering the risk of antibiotic resistance and adverse effects.5 Ten
years later in 2013, the review by Herath et al. concluded a clinically significant benefit in reducing COPD exacerbations from continuous use of prophylactic antibiotics, but not from intermittent way due to only one randomized controlled trial (RCT) included in this subgroup.6 Influence of different duration of antibiotic intervention were not explored
in this study. The most recent review by Ni et al. in 2015 focused on macrolides only and did not evaluate meaningful outcomes including the time to first exacerbation, change of lung function, bacterial load and airway inflammation.7 The latter outcome is
important to support the hypothetical mechanism behind the reduction of exacerbations by antibiotics.8
Current recommendation from guidelines about prophylactic antibiotic use in the management of COPD exacerbations is conditional and unspecific.1,9 At present,
the optimal regimen of prophylactic antibiotics for exacerbations has not been well established, and there are no advices for an appropriate schedule and duration of specific antibiotic intervention. To further enhance information on the public health benefit-risk associated with this intervention, we here aimed to provide a comprehensive overview of the positive and negative effects of prophylactic antibiotics on COPD patients.
METHODS
Search strategy
We performed an update of the previous review by Herath et al. in 20136 according
to the PRISMA guidelines. Cochrane Central Register of Controlled Trials (CENTRAL), Medline, EMBASE, Web of Science, CINAHL, AMED and PsycINFO databases were systematically searched for relevant RCTs published from 29 August 2013 (when the review by Herath et al. ended) until 26 April 2017 using key elements of “COPD”,
“RCT” and “antibiotics” (details are presented in Table S1). References from identified studies and relevant review articles were also checked manually. No language restrictions were applied. For the final analysis, we included both the new studies from this searching strategy and previous studies from the review by Herath et al.
Selection criteria
Studies included in this review met the following criteria: (1) focus on the effects of prophylactic antibiotics in COPD patients; (2) study designs must be RCTs with placebo group; (3) COPD patients should be aged over 18 years and with a well-defined diagnosis of COPD and confirmed evidence of persistent airflow limitation (the presence of a post-bronchodilator FEV1/FVC < 0.7); (4) prophylactic antibiotics must be given for a minimum period of 12 weeks; (5) patients must be clinically stable without exacerbation for at least three weeks before enrolment. Studies that focused on combined antibiotics (≥ 2) and studies of patients with other respiratory disease (e.g. bronchiectasis, asthma) or related genetic diseases such as cystic fibrosis and primary ciliary dyskinesia were excluded.
Outcomes and data analysis
The Primary outcomes were: number of patients with exacerbations; frequency of exacerbation; health-related quality of life assessed by the St Georges Respiratory Questionnaire (SGRQ).10 The Secondary outcomes were: the median time to first
exacerbation; frequency of hospitalization; all-cause mortality; adverse events; antibiotic resistance; change in lung functions, bacteria load and airway inflammation. The influence of different schedules and durations of prophylactic antibiotic use on exacerbations and quality of life in COPD patients were explored. For the missing of standard deviation of SGRQ score change in two studies,11,12 we calculated it according
to Cochrane guideline (see Supplement data). All analyses were done in accordance with the intention-to-treat principle using Review Manager Version 5.3. Risk ratio (RR) or OR was calculated for binary outcomes, while mean difference (MD) was for continuous outcomes. Generic inverse variance (GIV) methods were used for non-standard types of both dichotomous and continuous data. Summary measures were pooled using random-effects models. If data could not be combined, we performed a descriptive analysis. Statistical heterogeneity among studies was assessed using conventional chi-squared (X2, or Chi2) test and I2 statistic of inconsistency. Sensitivity analysis was performed by
removing studies with a high risk for bias or deviation. A funnel plot was used to assess publication bias.
Effects of prophylactic antibiotics on COPD
2
Figure 1. Flow diagram of literature search and study selection.
data). All analyses were done in accordance with the intention‐to‐treat principle using Review Manager Version 5.3. Risk ratio (RR) or OR was calculated for binary outcomes, while mean difference (MD) was for continuous outcomes. Generic inverse variance (GIV) methods were used for non‐standard types of both dichotomous and continuous data. Summary measures were pooled using random‐effects models. If data could not be combined, we performed a descriptive analysis. Statistical heterogeneity among studies was assessed using conventional
chi‐squared (X2, or Chi2) test and I2 statistic of inconsistency. Sensitivity analysis was
Figure 1. Flow diagram of literature search and study selection.
RESULTS
Search results
From the 667 records generated by new search strategy, five new RCT studies were eligible and included (Figure 1). Together with the previous seven studies from the review by Herath et al.,6 a total of twelve RCTs were included for this systematic
review. However, of all twelve studies , one was a conference abstract,13 one was not
blinded,14 one did not report effect measures.15 In total, nine studies were qualified for
Table 1. Characteristics of included studies. Studies (1st author, year) Study design Country Patients (T/P) Age (year) (T/P) FEV1/FVC ratio (%) (T/P) Prophylactic Antibiotics (dose) Duration of
treatment & follow up
(months) Maintenance medication
Previous included studies
Albert, 2011 RCT US 570:572 65:66 42:43 Azithromycin, 250 mg daily 12 / 12 ICS, LABA, LAMA
He, 2010 RCT UK 18:18 68.8:69.3 46.9:48.6 Erythromycin, 125 mg, 3 times a day; 6 / 6 ICS,
Mygind, 2010 RCT Denmark 287:288 71 (Median) NA Azithromycin, 500 mg daily, 3 days a month 36 / 36 ICS, Theophylline, inhaled
anticholinergic, inhaled β-adrenergic
Sethi, 2010 RCT US 569:580 66.1:66.6 45.0:46.3 Moxifloxacin, 400 mg daily, 5 days every 8
weeks
12 / 18 LABA, LAMA, SABA, SAMA, ICS, theophylline;
Seemungal, 2008 RCT UK 53:56 66.6:67.8 48.9:50.9 Erythromycin, 250 mg twice daily 12 / 12 LABA, LAMA, theophylline
Banerjee, 2005 RCT UK 31:36 65.1:68.1 43.8:45.5 Clarithromycin, 500 mg once daily 3 / 3 ICS
Suzuki, 2001 RCT Japan 55:54 69.1:71.7 NA Erythromycin, 200-400 mg daily 12 / 12 Inhaled anticholinergic,
theophylline New included studies
*Brill, 2015 RCT UK (25:25:25):24 (70.9:70.4:67.9): 68.7 (51:51:45):51 T
1: Moxifloxacin, 400 mg, 5 times every 4 weeks; T2: Doxycycline, 100 mg daily;
T3: Azithromycin, 250 mg, 3 times a week;
3.25 /3.25 ICS
†Shafuddin, 2015 RCT New Zealand 97:94 67.6:66.7 41.5:43.7 Roxithromycin, 300 mg daily 3 / 12 Not available
Simpson, 2014 RCT Australia 15:15 71.7:69.9 52.3:51.3 Azithromycin, 250 mg daily 3 / 6 ICS
Uzun, 2014 RCT Netherlands 47:45 64.7:64.9 38.0:40.3 Azithromycin, 500 mg, 3 times a week 12 / 12 LABA, LAMA, SABA, ICS,
Prednisolone
Berkhof, 2013 RCT Netherlands 42:42 67:68 42.2:43.2 Azithromycin, 250 mg, 3 times a week 3 / 4.5 LABA, LAMA, ICS
T/P: Treatment group versus Placebo group; ICS: inhaled corticosteroid; LABA: acting beta-2 agonists; LAMA: long-acting muscarinic antagonist; SABA: short-long-acting beta-2 agonists; SAMA: short-long-acting muscarinic antagonist; NA: data were not available; *This study designed
3 different treatment arms with one common placebo arm; †The study included 2 treatment arms, according to preset criteria, we only include the arm about single antibiotic use, the other arm in this study about combined antibiotic treatment is excluded;
Characteristics of included studies
The characteristics of twelve included studies are shown in Table 1, other specific baseline characteristics about COPD severity and exacerbation history were summarized in Table S2. All these studies were conducted over the last seventeen years involving 3,683 stable COPD patients, with 2932 patients involved in the meta-analysis. All included studies focused on one antibiotic arm with one placebo arm except the study by Brill et al.,16 which compared three antibiotics with one
common placebo and we treated this study as three independent RCTs (Trial 1-3: T1, T2, T3). In all, six antibiotics were investigated in this review: azithromycin,11,13,16-19
erythromycin,12,14,20 moxifloxacin,16,21 clarithromycin,15 roxithromycin22 and doxycycline.16
Effects of prophylactic antibiotics on COPD
2
Table 1. Characteristics of included studies.Studies (1st author, year) Study design Country Patients (T/P) Age (year) (T/P) FEV1/FVC ratio (%) (T/P) Prophylactic Antibiotics (dose) Duration of
treatment & follow up
(months) Maintenance medication
Previous included studies
Albert, 2011 RCT US 570:572 65:66 42:43 Azithromycin, 250 mg daily 12 / 12 ICS, LABA, LAMA
He, 2010 RCT UK 18:18 68.8:69.3 46.9:48.6 Erythromycin, 125 mg, 3 times a day; 6 / 6 ICS,
Mygind, 2010 RCT Denmark 287:288 71 (Median) NA Azithromycin, 500 mg daily, 3 days a month 36 / 36 ICS, Theophylline, inhaled
anticholinergic, inhaled β-adrenergic
Sethi, 2010 RCT US 569:580 66.1:66.6 45.0:46.3 Moxifloxacin, 400 mg daily, 5 days every 8
weeks
12 / 18 LABA, LAMA, SABA, SAMA, ICS, theophylline;
Seemungal, 2008 RCT UK 53:56 66.6:67.8 48.9:50.9 Erythromycin, 250 mg twice daily 12 / 12 LABA, LAMA, theophylline
Banerjee, 2005 RCT UK 31:36 65.1:68.1 43.8:45.5 Clarithromycin, 500 mg once daily 3 / 3 ICS
Suzuki, 2001 RCT Japan 55:54 69.1:71.7 NA Erythromycin, 200-400 mg daily 12 / 12 Inhaled anticholinergic,
theophylline New included studies
*Brill, 2015 RCT UK (25:25:25):24 (70.9:70.4:67.9): 68.7 (51:51:45):51 T
1: Moxifloxacin, 400 mg, 5 times every 4 weeks; T2: Doxycycline, 100 mg daily;
T3: Azithromycin, 250 mg, 3 times a week;
3.25 /3.25 ICS
†Shafuddin, 2015 RCT New Zealand 97:94 67.6:66.7 41.5:43.7 Roxithromycin, 300 mg daily 3 / 12 Not available
Simpson, 2014 RCT Australia 15:15 71.7:69.9 52.3:51.3 Azithromycin, 250 mg daily 3 / 6 ICS
Uzun, 2014 RCT Netherlands 47:45 64.7:64.9 38.0:40.3 Azithromycin, 500 mg, 3 times a week 12 / 12 LABA, LAMA, SABA, ICS,
Prednisolone
Berkhof, 2013 RCT Netherlands 42:42 67:68 42.2:43.2 Azithromycin, 250 mg, 3 times a week 3 / 4.5 LABA, LAMA, ICS
T/P: Treatment group versus Placebo group; ICS: inhaled corticosteroid; LABA: acting beta-2 agonists; LAMA: long-acting muscarinic antagonist; SABA: short-long-acting beta-2 agonists; SAMA: short-long-acting muscarinic antagonist; NA: data were not available; *This study designed
3 different treatment arms with one common placebo arm; †The study included 2 treatment arms, according to preset criteria, we only include the arm about single antibiotic use, the other arm in this study about combined antibiotic treatment is excluded;
Quality assessment
The review authors’ judgment about each risk of bias item in each study can be seen in Figure S1.1. The risk of bias items presented as percentage across all included studies were presented in Figure S1.2. There was no reporting bias in all included studies; only 2 studies14,16 have potential high risk in the blinding process. For the remaining of bias
items, only a small proportion of unclear bias exists. Overall, low risk of bias dominates in all domains of bias.
Primary outcomes
Seven studies involving 2,642 participants11,12,17-21 reported the number of patients
0.74-which requires further confirmation. The risk difference (RD) between antibiotic and placebo
Figure 2. Forest plot of risk ratio (antibiotics versus placebo) for total number of patients with one or more exacerbations stratified by (a) schedule of prophylactic antibiotics and (b)
duration of prophylactic antibiotics. M‐H: Mantel‐Haenszel; *Studies reviewed by Herath et al.
in 2013.
Figure 2. Forest plot of risk ratio (antibiotics versus placebo) for total number of patients with one or more exacerbations stratified by (a) schedule of prophylactic antibiotics and (b) duration of prophylactic antibiotics. M-H: Mantel-Haenszel; *Studies reviewed by Herath et al. in 2013.
and intermittent subgroups. However, the difference between other subgroups with a distinct trend toward significance (p = 0.07) suggested that using antibiotics ≤ 6 months may achieve better treatment effects (RR 0.59, 95% CI 0.40-0.86) than longer time (RR 0.84, 95% CI 0.77-0.93), which requires further confirmation. The risk difference (RD) between antibiotic and placebo groups is presented in Figure 3, for erythromycin, the RD is substantial (RD -0.24, 95% CI -0.39 to -0.08), the corresponding number needed to treat (NNT) was 4; for azithromycin, the RD was moderate (RD -0.14, 95% CI -0.20 to -0.08), the NNT was 7; no statistically significant effect for moxifloxacin intervention.
Effects of prophylactic antibiotics on COPD
2
Figure 3. Forest plot of risk difference (antibiotics versus placebo) for total number of patients with one or more exacerbations stratified by types of antibiotics. M‐H: Mantel‐Haenszel test; *Studies reviewed by Herath et al. in 2013. groups is presented in Figure 3, for erythromycin, the RD is substantial (RD ‐0.24, 95% CI ‐0.39 to ‐0.08), the corresponding number needed to treat (NNT) was 4; for azithromycin, the RD was moderate (RD ‐0.14, 95% CI ‐0.20 to ‐0.08), the NNT was 7; no statistically significant effect for moxifloxacin intervention. Use of prophylactic antibiotic was also associated with a significant reduction in the frequencyof exacerbations (RR 0.74, 95% CI 0.60‐0.92, Figure 4). As the study by Brill et al.16 has a
potential risk of bias in the blinding process, a sensitivity analysis was done with the other 6 studies, which resulted in a 31% RR reduction of exacerbations among patients taking prophylactic antibiotics (RR 0.69, 95% CI 0.58‐0.82). In subgroup analysis showed in Figure 4, macrolides (azithromycin, erythromycin and roxithromycin) showed beneficial effects on frequency reduction of exacerbations, the benefits from both azithromycin and erythromycin were of clinical significance. However, this beneficial effect was not seen in the use of
Figure 3. Forest plot of risk difference (antibiotics versus placebo) for total number of patients with one or more exacerbations stratified by types of antibiotics. M-H: Mantel-Haenszel test; *Studies reviewed by Herath et al. in 2013.
Use of prophylactic antibiotic was also associated with a significant reduction in the frequency of exacerbations (RR 0.74, 95% CI 0.60-0.92, Figure 4). As the study by Brill et al.16 has a potential risk of bias in the blinding process, a sensitivity analysis was done
with the other 6 studies, which resulted in a 31% RR reduction of exacerbations among patients taking prophylactic antibiotics (RR 0.69, 95% CI 0.58-0.82). In subgroup analysis showed in Figure 4, macrolides (azithromycin, erythromycin and roxithromycin) showed beneficial effects on frequency reduction of exacerbations, the benefits from both azithromycin and erythromycin were of clinical significance. However, this beneficial effect was not seen in the use of moxifloxacin and doxycycline. These subgroup differences for frequency of exacerbations were of statistical significance (p = 0.02). Health-related quality of life using SGRQ was measured in seven studies.11,12,16-19,21 When
we performed a sensitivity analysis by removing the study by Berkhof et al.,18 which
was very different from the other data, the heterogeneity reduced sharply (I2 changed
from 92% to 0%). Hence, only the remaining 6 studies were included for the final meta-analysis. The pooled result indicated that prophylactic antibiotics led to a significant improvement in the total SGRQ score (MD -1.55, 95% CI -2.59 to -0.51, Figure 5). In subgroup analysis, the improvement of SGRQ score was not seen in both continuous and intermittent antibiotics. However, another subgroup result indicated that the total
Chapter 2
Health‐related quality of life using SGRQ was measured in seven studies.11,12,16‐19,21 When we
performed a sensitivity analysis by removing the study by Berkhof et al.,18 which was very
different from the other data, the heterogeneity reduced sharply (I2 changed from 92% to 0%).
Hence, only the remaining 6 studies were included for the final meta‐analysis. The pooled result indicated that prophylactic antibiotics led to a significant improvement in the total SGRQ score (MD ‐1.55, 95% CI ‐2.59 to ‐0.51, Figure 5). In subgroup analysis, the improvement of SGRQ score was not seen in both continuous and intermittent antibiotics. However, another
Figure 4. Forest plot of risk ratio (antibiotics versus placebo) for frequency of exacerbations
stratified by types of antibiotics. SE: standard error; IV: inverse variance; *Studies reviewed by
Herath et al. in 2013; T1‐3: three independent RCTs in study by Brill et al.
Figure 4. Forest plot of risk ratio (antibiotics versus placebo) for frequency of exacerbations stratified by types of antibiotics. SE: standard error; IV: inverse variance; *Studies reviewed by Herath et al. in 2013; T1-3: three independent RCTs in study by Brill et al.
SGRQ score significantly changed by long-term intervention (MD -1.70, 95% CI% -2.81 to -0.60), although it was not changed by short-term (≤ 6) intervention (MD -0.34, 95% CI -3.43 to 2.75).
Four studies12,17,19,21 also reported the component scores of SGRQ (Figure S2). Both
the symptom (MD -3.89, 95% CI -5.48 to -2.31) and impact (MD -1.32, 95% CI -2.61 to -0.03) scores were improved with prophylactic antibiotics. However, the activity score did not show any significant improvement. Of note, none of these improvements mentioned above in SGRQ score reached the hypothesized clinically beneficial level (> 4-unit reduction).10
Effects of prophylactic antibiotics on COPD
2
Secondary outcomes
Seven studies involving 2,803 patients reported the median time to first exacerbation (Table S3). Four studies indicated that using prophylactic antibiotics lengthened the median time to first exacerbation signficantly.12,17,19,20 Two other studies found
a similar trend, but without statistical significance.18,21 Only one study showed
the opposite result in antibiotic and placebo arms.22
Figure 5. Forest plot of mean difference (antibiotics versus placebo) of quality of life by SGRQ stratified by (a) schedule of prophylactic antibiotics and (b) duration of prophylactic antibiotics. SGRQ: St Georges Respiratory Questionnaire; IV: inverse variance; SE: standard error; *Studies reviewed by Herath et al. in 2013; T1-3: three independent RCTs in study by Brill et al.
Figure 5. Forest plot of mean difference (antibiotics versus placebo) of quality of life by SGRQ stratified by (a) schedule of prophylactic antibiotics and (b) duration of prophylactic
antibiotics. SGRQ: St Georges Respiratory Questionnaire; IV: inverse variance; SE: standard
error; *Studies reviewed by Herath et al. in 2013; T
1‐3: three independent RCTs in study by Brill
et al.
subgroup result indicated that the total SGRQ score significantly changed by long‐term intervention (MD ‐1.70, 95% CI% ‐2.81 to ‐0.60), although it was not changed by short‐term ( 6) intervention (MD ‐0.34, 95% CI ‐3.43 to 2.75).
Chapter 2
32
Figure 7. Forest plot of risk ratio (antibiotics versus placebo) for adverse events. M‐H: Mantel‐
Haenszel test; *Studies reviewed by Herath et al. in 2013.
show significant difference between two arms (RR 0.93, 95% CI 0.83‐1.05, I2 = 2%). In
subgroups, gastrointestinal disorders were more frequent in the intervention group than control group (RR 1.87, 95 CI 0.98‐3.59, Figure S4) with a boundary statistical significance (p = 0.06). However, no statistical significant difference for respiratory and cardiovascular disorders were found.
Eight studies had the bacteriological assessments (see Table S4),12,15‐21 however, only three
studies with five RCTs reported the quantitative results for antibiotic resistance.16,17,19 Due to
the different definition about bacterial resistant outcome in study by Uzun et al, only the other homogeneous studies involving four RCTs were included for pooled results (OR 4.49, 95% CI 2.48‐8.12, Figure 8), long‐term (versus short‐term) and continuous (versus intermittent) antibiotic intervention seems to cause more antibiotic resistance, although these subgroup difference did not reach statistical significant level. Antibiotic resistance appeared in all types of antibiotics involved (Figure 9), although the result from moxifloxacin did not reach statistical significance. No subgroup differences about this outcome were seen among azithromycin, moxifloxacin and doxycycline (p = 0.63).
Eight studies11,13,16‐18,20‐22 provided the data on changes of lung function (Table S5). However,
no study found significant increase by antibiotic intervention compared with placebo. Mygind
et al. did not compare the lung function change directly, but measured and compared the lung
function in both groups at enrolment and endpoint separately, they also did not find any
significant difference.13
Figure 6. Forest plot of risk ratio (antibiotics versus placebo) for frequency of hospitalization. M-H: Mantel-Haenszel test; *Studies reviewed by Herath et al. in 2013.
were improved with prophylactic antibiotics. However, the activity score did not show any significant improvement. Of note, none of these improvements mentioned above in SGRQ
score reached the hypothesized clinically beneficial level (> 4‐unit reduction).10 Secondary outcomes Seven studies involving 2,803 patients reported the median time to first exacerbation (Table S3). Four studies indicated that using prophylactic antibiotics lengthened the median time to first exacerbation signficantly.12,17,19,20 Two other studies found a similar trend, but without statistical significance.18,21 Only one study showed the opposite result in antibiotic and placebo arms.22
The frequency of hospitalization related to COPD was pooled from five studies with 2,576
participants,17‐21 no significant difference was observed between antibiotic and placebo
groups (RR 0.94, 95% CI 0.83‐1.06, Figure 6). Also, no difference in the rate of all‐cause mortality were found between the two arms (Figure S3).
Eight studies involving 2,833 participants reported adverse events related to antibiotic use.11,12,17‐22 Overall, there was no significant difference between two comparison arms in the rate of adverse events (RR 1.09, 95% CI 0.84‐1.42, Figure 7). As there was a lack of uniform definition about adverse events, the heterogeneity was substantial (I2 = 73%). Considering that the result by Shafuddin et al.22 was deviant from the other seven studies, a sensitivity analysis was, therefore, performed after removal of this study. The homogeneous result also did not Figure 6. Forest plot of risk ratio (antibiotics versus placebo) for frequency of hospitalization. M‐H: Mantel‐Haenszel test; *Studies reviewed by Herath et al. in 2013.
Figure 7. Forest plot of risk ratio (antibiotics versus placebo) for adverse events. M-H: Mantel-Haenszel test; *Studies reviewed by Herath et al. in 2013.
The frequency of hospitalization related to COPD was pooled from five studies with 2,576 participants,17-21 no significant difference was observed between antibiotic and
placebo groups (RR 0.94, 95% CI 0.83-1.06, Figure 6). Also, no difference in the rate of all-cause mortality were found between the two arms (Figure S3).
Eight studies involving 2,833 participants reported adverse events related to antibiotic use.11,12,17-22 Overall, there was no significant difference between two comparison
arms in the rate of adverse events (RR 1.09, 95% CI 0.84-1.42, Figure 7). As there was a lack of uniform definition about adverse events, the heterogeneity was substantial (I2 = 73%). Considering that the result by Shafuddin et al.22 was deviant from the other
seven studies, a sensitivity analysis was, therefore, performed after removal of this study. The homogeneous result also did not show significant difference between two arms (RR 0.93, 95% CI 0.83-1.05, I2 = 2%). In subgroups, gastrointestinal disorders were
Effects of prophylactic antibiotics on COPD
2
Three studies reported the change of bacterial load.11,15,16 Although both Brill et al. and
Simpson et al. have found the more reduction of bacterial load by prophylactic antibiotic compared with placebo, the results did not reach the level of statistical significance, even both quantitative culture and 16S qPCR methods were used by Brill et al. Benerjee et al. also did not find a significant difference between pre‐and post‐ sputum cfu numbers/bacterial (PPM) isolates in two arms.
Figure 8. Forest plot of odds ratio (antibiotics versus placebo) for antibiotic resistance stratified by (a) schedule of prophylactic antibiotics and (b) duration of prophylactic
antibiotics. IV: inverse variance; *Studies reviewed by Herath et al. in 2013; T
1‐3: three
independent RCTs in study by Brill et al.
Figure 8. Forest plot of odds ratio (antibiotics versus placebo) for antibiotic resistance stratified by (a) schedule of prophylactic antibiotics and (b) duration of prophylactic antibiotics. IV: inverse variance; *Studies reviewed by Herath et al. in 2013; T
1-3: three independent RCTs in study by Brill et al.
Figure S4) with a boundary statistical significance (p = 0.06). However, no statistical significant difference for respiratory and cardiovascular disorders were found.
Eight studies had the bacteriological assessments (see Table S4),12,15-21 however, only three
studies with five RCTs reported the quantitative results for antibiotic resistance.16,17,19 Due
to the different definition about bacterial resistant outcome in study by Uzun et al, only the other homogeneous studies involving four RCTs were included for pooled results (OR 4.49, 95% CI 2.48-8.12, Figure 8), long-term (versus short-term) and continuous (versus intermittent) antibiotic intervention seems to cause more antibiotic resistance, although these subgroup difference did not reach statistical significant level. Antibiotic resistance appeared in all types of antibiotics involved (Figure 9), although the result
Figure 9: Forest plot of odds ratio (antibiotics versus placebo) for antibiotic resistance stratified by types of antibiotics. SE: standard error; IV: inverse variance; *Studies reviewed by Herath et al. in 2013; T1‐3: three independent RCTs in study by Brill et al. The change of airway inflammation was only reported in two studies.11,16 The study by Brill et al. showed that no significant changes were seen in cytokines IL‐6, IL‐8 and IL‐1 in any of three antibiotic arms compared with placebo.16 Similarly, Simpson et al. also did not report a
significant reduction in sputum neutrophil proportion level of IL‐8 in those who received
azithromycin compared to placebo group.11
Figure 9. Forest plot of odds ratio (antibiotics versus placebo) for antibiotic resistance stratified by types of antibiotics. SE: standard error; IV: inverse variance; *Studies reviewed by Herath et al. in 2013; T1-3: three independent RCTs in study by Brill et al.
from moxifloxacin did not reach statistical significance. No subgroup differences about this outcome were seen among azithromycin, moxifloxacin and doxycycline (p = 0.63). Eight studies11,13,16-18,20-22 provided the data on changes of lung function (Table S5).
However, no study found significant increase by antibiotic intervention compared with placebo. Mygind et al. did not compare the lung function change directly, but measured and compared the lung function in both groups at enrolment and endpoint separately, they also did not find any significant difference.13
Three studies reported the change of bacterial load.11,15,16 Although both Brill et al.
and Simpson et al. have found the more reduction of bacterial load by prophylactic antibiotic compared with placebo, the results did not reach the level of statistical significance, even both quantitative culture and 16S qPCR methods were used by Brill et al. Benerjee et al. also did not find a significant difference between pre-and post- sputum cfu numbers/bacterial (PPM) isolates in two arms.
The change of airway inflammation was only reported in two studies.11,16 The study by
Brill et al. showed that no significant changes were seen in cytokines IL-6, IL-8 and IL-1β
in any of three antibiotic arms compared with placebo.16 Similarly, Simpson et al. also
did not report a significant reduction in sputum neutrophil proportion level of IL-8 in those who received azithromycin compared to placebo group.11
