Figures
- FIGURE 1
Preferred reporting items for systematic reviews and meta-analyses flow diagram for the identification of studies included in the meta-analysis concerning the influence of N-acetylcysteine on chronic bronchitis or chronic obstructive pulmonary disease exacerbations.
- FIGURE 2
Overall forest plot from meta-analysis carried out in all 13 selected studies a) assessing the relative risk of chronic obstructive pulmonary disease (COPD) exacerbations and b) subgroup analysis performed on seven randomised clinical trials in which inclusion criteria required diagnosis of COPD by pulmonary function testing. NAC: N-acetylcysteine.
- FIGURE 3
Forest plot from meta-analysis carried out in 10 studies including low-dose N-acetylcysteine (NAC) treatment a) assessing the relative risk of chronic obstructive pulmonary disease (COPD) exacerbations and b) subgroup analysis performed on five randomised clinical trials in which inclusion criteria required diagnosis of COPD by pulmonary function testing.
- FIGURE 4
Forest plot from meta-analysis carried out on four studies including high-dose N-acetylcysteine (NAC) treatment a) assessing the relative risk of chronic obstructive pulmonary disease (COPD) exacerbations and b) subgroup analysis performed on two randomised clinical trials in which inclusion criteria required diagnosis of COPD by pulmonary function testing.
- FIGURE 5
Overall forest plot from meta-analysis carried out in 11 studies a) assessing the relative risk of adverse events; and subgroup analysis performed on studies including b) low and c) high doses of N-acetylcysteine (NAC).
Tables
- TABLE 1
Definition of exacerbation as reported by studies included in the meta-analysis
Study [ref.], year Definition of exacerbation Zheng et al. [1], 2014 “At least a 2 day persistence of two (type II moderate) or all three (type III, severe) major symptoms (worsening dyspnoea, increase in sputum purulence or volume), or of any one major symptom plus at least one minor symptom (type I, mild) (upper airway infection, unexplained fever, and increased wheezing)” Tse et al. [20], 2013 “Two of the following three symptoms: increase in shortness of breath, volume, or purulence of sputum” Schermer et al. [26], 2009 “An episode with one or more subsequent unscheduled contacts with either a general practitioner or a chest physician due to worsening of respiratory symptoms” Bachh et al. [27], 2007 “Increased dyspnea and/or cough associated with a change in quality and quantity of sputum, which led the patient to seek medical attention and lasting for >3 days” Decramer et al. [3], 2005 “Increase in dyspnoea, cough, or both associated with a change in quality and quantity of sputum, which led the patient to seek medical attention and which lasted for at least 3 days” Gerrits et al. [29], 2003 “Re-hospitalisation for chronic obstructive pulmonary disease” Pela et al. [24], 1999 “The worsening of the clinical profile of the patient with increased cough, dyspnea and expectoration with mucopurulent sputum, with or without fever requiring medical intervention. If the total score of the following questionnaire amounted to >3 points, the occurrence of an exacerbation was confirmed: fever: absent=0, present=1; cough: mild=0, moderate=1, severe=2; mucus: unchanged=0, increased=1, increased and purulent=2; dyspnoea: unchanged=0, increased=1, severely increased=2” Hansen et al. [19], 1994 “A mucopurulent sputum with new or worse cough, plus one or more of the following: new general malaise; new symptoms of cold; fever (38°C or above); increased dyspnoea; increased mucus production; increased viscosity of sputum; new onset of foul-tasting sputum; increased difficulty of expectoration; increase in erythrocyte sedimentation rate in relation to exacerbation; leucocytosis in relation to exacerbation; and/or pneumonia confirmed by X-ray” Rasmussen and Glennow [25], 1988; Boman et al. [23], 1983 “Mucopurulent or purulent sputum and cough (new or aggravated) plus one or more of the following symptoms: general malaise; new symptoms of common cold; fever (>38°C); breathlessness; increased mucus production; increased sputum-thickness; foul tasting sputum; increased difficulty of expectoration; increase in erythrocyte sedimentation rate; leucocytosis or pneumonia” McGavin et al. [22], 1985 “New or deteriorating cough with increased sputum purulence lasting for at least 48 hours plus at least one of the following: general malaise, any recorded fever greater than 38°C, increased breathlessness, increased sputum volume or thickness, increased difficulty in expectoration” Babolini et al. [21], 1980 “A discrete change in the course of the disease marked by rapid increase in coughing and sputum output and purulence, associated with worsening of chest physical signs and possibly dyspnoea but not necessarily with fever” Grassi and Morandini [28], 1976 “Episode or sudden aggravation of the typical signs and symptoms” - TABLE 2
Patient demographics, baseline and study characteristics
Study [ref.], year Study characteristics Duration of study months Patients (completed study visits) NAC (daily dose) mg Disease characteristics Average age years Male % Current smokers % Smoking history pack-years ICS treatment % Post-bronchodilator FEV1 % predicted Jadad score Zheng et al. [1], 2014 Multicentre, prospective, randomised, double-blind, placebo-controlled, parallel groups 12 964 1200 COPD diagnosis using PFT, GOLD II–IV 66.3 81.9 17.8 36.2 44.0 48.9 4 Tse et al. [20], 2013 Double-blind, randomised placebo-controlled 12 108 1200 COPD diagnosis using PFT, GOLD I–IV 70.9 93.3 23.3 NA 79.0 59.6 4 Schermer et al. [26], 2009 Double blind, randomised, double dummy, placebo-controlled 36 108 600 COPD diagnosis using PFT, GOLD I–IV, chronic bronchitis 59.4 72.9 53.6 27.3 49.0 69.8 4 Bachh et al. [27], 2007 Single blind, randomised, placebo-controlled study 4 100 600 COPD diagnosis using PFT, GOLD II and III 61.4 78.0 NA 44.1 18.0 51.7 1 Decramer et al. [3], 2005 Double-blind, randomised, placebo-controlled, parallel groups 36 354 600 COPD diagnosis using PFT, GOLD II and III 62.0 77.0 44.0 NA 70.0 57.0 4 Gerrits et al. [29], 2003 Retrospective cohort investigation 12 1219 From 200 to >600 ICD-9: 491, 492, 496 >55 59.6 NA NA 35.9 NA NA Pela et al. [24], 1999 Open, randomised, controlled 6 167 600 COPD diagnosis using PFT and ATS/ERS criteria, FEV1 <70% pred 66.0 75.7 24.0 NA 39.6 58.1 2 Hansen et al. [19], 1994 Multicentre, double-blind, randomised placebo-controlled, parallel groups 5.5 129 1200 Chronic bronchitis, FEV1 >50% pred 51.4 43.1 92.2 NA NA NA 4 Rasmussen and Glennow [25], 1988 Multicentre, double-blind, randomised placebo-controlled, parallel groups 6 91 600 Chronic bronchitis 58.8 56.9 NA NA NA NA 4 McGavin et al. [22], 1985 Multicentre, double-blind, randomised, placebo-controlled, parallel groups 5 148 600 Chronic bronchitis, FEV1 <50% pred, FEV1/FVC <70% pred NA 85.6 27.1 NA 25.4 30.0# 4 Boman et al. [23], 1983 Multicentre, double-blind, randomised, placebo-controlled, parallel groups 6 203 400 Chronic bronchitis, FEV1 >50% pred 52 NA 81.3 NA NA 80.0# 1 Babolini et al. [21], 1980 Multicentre, double-blind, randomised, placebo-controlled, parallel groups 6 495 400 Chronic bronchitis, FEV1 >40% pred >50 76.6 66.3 NA NA NA 1 Grassi and Morandini [28], 1976 Double-blind, randomised, placebo-controlled 6 69 260 Chronic bronchitis 61 79.7 NA NA NA NA 3 Data are presented as n, unless otherwise stated. NAC: N-acetylcysteine; ICS: inhaled corticosteroid; FEV1: forced expiratory volume in 1 s; COPD: chronic obstructive pulmonary disease; PFT: pulmonary function testing; GOLD: Global Initiative for Chronic Obstructive Lung Disease; NA: not available; ICD: International Classification of Diseases; ATS: American Thoracic Society; ERS: European Respiratory Society; FVC: forced vital capacity. #: post-bronchodilator not defined.
- TABLE 3
Adverse events reported in randomised controlled trials (RCTs) after administration of N-acetylcysteine (NAC) at low and high doses
NAC dose Low High RCTs 8 3 Gastrointestinal disorders Diarrhoea 5 2 Gastrointestinal pain 4 1 Epigastric discomfort 3 1 Nausea 3 0 Vomiting 3 0 Constipation 2 0 Loss of appetite 1 0 Indigestion 1 0 GORD symptoms 0 1 Dry mouth 0 1 Unpleasant taste 1 0 Respiratory disorders Dyspnoea 2 0 Respiratory tract infection 1 1 Cough 1 1 Other disorders Pyrosis 3 0 Joint pain and muscle pain 0 2 Dizziness 0 2 Palpitations 0 1 Headache 1 1 Skin disorders 1 0 CNS disorders 1 0 Weight gain 1 0 Oedema 1 0 Urticaria 1 0 Itching 1 0 Tinnitus 1 0 Pruritus 0 1 Data are presented as n. GORD: Gastro-oesophageal reflux disease; CNS: central nervous system.
Disclosures
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