The therapeutic efficacy of erdosteine in the treatment of chronic obstructive bronchitis: a meta-analysis of individual patient data
Introduction
Chronic bronchitis (CB) is very often associated with airflow obstruction and is especially frequent in smokers, is considered to contribute to the airway mucus hypersecretory component of Chronic Obstructive Pulmonary Disease (COPD) [1], and is associated with considerable morbidity and high health-care costs [2]. Patients with chronic bronchitis and COPD suffer from recurrent exacerbations, with an increase in volume and/or purulence of sputum, cough and dyspnoea which contribute to progressive clinical deterioration and account for a significant proportion of the cost of caring for such patients [3], [4], [5].
There is evidence for inflammatory and morphological changes in the airways associated with loss of ciliary function and mucus gland hyperplasia, and the importance of mucus in contributing to airflow limitation and disease progression are underscored by recent studies [6], [7].
The use of mucolytics as adjunctive treatment of both stable and exacerbated CB/COPD has been proposed to improve disease outcome, although the value of the use of such drugs is still considered uncertain [8].
Erdosteine is a a drug approved for the treatment of acute and chronic pulmonary diseases for more than 10 years which has been shown to improve sputum rheology in patients with mucus hypersecretion through an active metabolite (Met-I) having free thiol groups [9]. Although a few studies have been published showing that CB/COPD patients may benefit from erdosteine, marked differences in the perception of its usefulness still remain.
The aim of the present systematic review is therefore to test the available evidence that erdosteine treatment in patients with CB/COPD may be effective and accompanied by clinically relevant improvements.
Section snippets
Methods
This systematic review was performed in accordance with the Quality of Reporting of meta-analyses (QUORUM) guidelines [10].
Types of studies
Randomized controlled trials (RCTs) focusing on the comparison between erdosteine and placebo or mucolytics which reported data on efficacy and safety after 7–10 days of treatment, were used for this meta-analysis.
Types of patients
Adults patients having a medical history of chronic bronchitis (CB), generally defined as the presence of cough and sputum production for at least three months a year over two consecutive years were included in the studies used in this meta-analysis. The three largest studies also included evidence for airway obstruction, defined as an FEV1/FVC ratio at least 10% below the normal theoretical value [11], [12], [13].
Patients were enrolled either at occurrence of an acute exacerbation or during
Type of intervention
Erdosteine (300 mg capsule) was administered two or three times daily on top of background therapy, generally antibiotics and bronchodilators (β2-agonists and aminophyllines) in patients with acute exacerbations, and bronchodilators in those with stable disease.
Placebo or mucolytics (ambroxol, N-acetylcysteine, carbocysteine, sobrerol) were administered with the same dosing schedules as erdosteine (i.e. two or three times daily) on top of background treatments.
Type of outcome measures
The following outcomes were investigated: i) cumulative global efficacy index (cGEI), the sum of all assessed respiratory symptom scores, ii) respiratory individual symptom scores (cough frequency and intensity, sputum viscosity and purulence, difficulty to expectorate, catarrh rhonchi at auscultation, dyspnoea), iii) overall assessment of efficacy (OA) by the Investigator, and frequency of adverse events. In the original studies, similar scoring systems were used for patient self-assessment of
Study search
Literature was search systematically for relevant clinical trials with no language restrictions (Pub Med, Google Scholar and Scirus with search terms “chronic bronchitis”, “COPD” and “acute exacerbations” combined with “erdosteine”). Furthermore, the manufacturer of erdosteine (Edmond Pharma s.r.l., Italy) was contacted and asked for any additional non-indexed publications and relevant unpublished studies. Individual patient data from the published and unpublished studies in patients with CB
Data extraction
For each of the selected trials, the following information was retrieved: first author, publication year, details of study design, studied treatments (type of drug, schedule, duration), patient characteristics (total number, age and sex distribution, number randomized and number included in the analysis), study endpoints, occurrence and type of adverse events.
The quality of the selected trials was assessed according to a five-point validated scale [19] measuring a range of factors that impact
Statistical analysis
Trials were grouped according to the type of erdosteine comparator (active or placebo), study quality (Jadad scale score 1–2 vs 3–4–5) and whether the study was published or not.
The summary measure for the respiratory individual symptom scores, as well as for the c-GEI, was the difference between changes from baseline and the end of treatment mean values calculated in the two treatment arms.
For comparison of OA of the efficacy of erdosteine vs active or placebo group, events of interest were
Study selection
Thirty-one potentially relevant studies conducted in patients with CB/COPD were retrieved. The study selection process is presented in Fig. 1. Of these, 16 were excluded for the following reasons: 3 because they only evaluated mucus rheology [22], [23], [24], 2 because they were dose-range finding studies [25], [26], 5 because of inadequate design [27], [28], [29], [30], [31], 3 because of lack of symptom assessment up to 10 days [32], [33], [34], 1 because of a different formulation of
Discussion
The present systematic review on erdosteine efficacy has been conducted on individual patient data obtained in 15 both published and unpublished studies, selected from a dossier used for recent European registration by the manufacturing company and consistent with the clinical indication object of this meta-analysis, with the evaluation of a total of 1046 patients. Although a company-driven bias in the retrieval of the studies cannot be definitively ruled out and the overall number of patients
Acknowledgements
The Authors would like to acknowledge Edmond Pharma for providing information on unpublished studies and allowing direct access to original patients' data.
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