Patient characteristics Intervention Comparison Length of followup

Transcription

1 ORAL MUCOLYTICS Ref ID: 2511 Bachh AA, Shah NN, Bhargava R et al. Effect oral N- in COPD - A randomised controlled trial. JK Practitioner. 2007; 14(1): Ref ID: 2511 RCT Single blind; unclear allocation concealment; unclear method randomisation; unclear if ITT; loss to follow-up: not stated 1 centre- India N = 100 Patient characteristics Intervention Comparison Length Inclusion: people > 50 years old with smoking-related COPD who had 2 s COPD/year during previous 24 months; smokers and nonsmokers included; FEV 1 reversibility < 12% predicted value; an FEV 1 /FVC ratio < 0.70 and post FEV 1 between 30%-80% predicted value. Exclusion: history asthma; intolerance to ; who had taken for > 3 months previously; CHF class > 2; treatment with oral corticosteroids; Baseline characteristics: similar between groups N-acetyl cysteine (600 mg/once daily) for 4 months N= 50 for 4 months N=50 Procedure:. randomised to or placebo. Both arms permitted standard treatment for COPD according to GOLD guidelines; ICS allowed at a fixed dose throughout study Outcome measures 1 year Primary outcome: rate over 1 year ( defined increased dyspnoea and/or increased sputum purulence, volume, which leads the patient to seek medical attention and lasting 3 days) Secondary outcomes: Post FEV 1 % predicted Hospitalisations Not stated placebo Mean age (y) Mean post % predicted FEV monitored every 2 months. medications during study placebo medication: % SABA 48 40

2 Comparison group is placebo LABA inhaled anticholinergics ICS outcome N=50 N= 50 people with At least 1 (n) P<0.01 Hospitalisations (n)* P <0.05 Change from baseline in post FEV 1 % predicted (SE) 4.6 (1.8) 3.9 (1.6) P <0.05 *unable to include this in the Poole meta analysis as unable to calculate rate ratio. Ref ID: 2493 Poole P, Black PN. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Systematic Reviews Systematic Review / meta analysis Searched the Cochrane Airways Group Specialised Register trials, derived from systematic searches CENTRAL, MEDLINE, EMBASE and CINAHL, and hand searching respiratory journals and meeting abstracts N= RCTs Patient characteristics Inclusion criteria: adults > 20 years age with chronic bronchitis as defined by ATS, GOLD, ERS, WHO or the British Medical Research Council (cough and sputum on most days during at least three consecutive months for more than two successive years). Included 4 studies Intervention Comparison Length Oral mucolytics: Carbosysteine or Erdosteine or N- () [Have ignored all other mucolytic studies that are included in the Cochrane] 6 months 3 years Outcome measures number acute s. number pts with no in the study period, hospitalisation, lung function (FEV 1 ) and adverse events Cochrane Collaboration

3 mucolytics in COPD. Exclusion: with asthma or cystic fibrosis Frequency No in study period Hospitalisation in study period FEV1 or % predicted FEV1 or PEFR at end study Death during study period Adverse effects Mucolytic vs. placebo N- vs. placebo Carbocysteine vs. placebo Erdosteine vs. placebo WMD: (95% CI: to - WMD: (95% CI: to -0.04) WMD: (95% CI: to - WMD: (95% CI: -0.1 to ) 10 studies, N= ) 0.00) 13 studies, N= studies, N= study, N= 124 RR: 1.46 (95% CI: ) 11 studies, N=2101 RR: 0.76 (95% CI: ) 2 studies, N=678 SMD: 0.18 (95% CI: ) 8 studies, N=1664 Overall: RR: 0.95 (95% CI: ) 3 studies, N=801 More than one year follow up: RR: 1.04 (95% CI: ) 1 study, N=523 6 months follow up: RR: 0.61 (95% CI: ) 2 studies, N=278 RR: 0.82 (95% CI: ) 8 studies, N=2340 RR: 1.51 (95% CI: ) 8 studies, N=1516 RR: 1.30 (95% CI: ) 2 studies, N= SMD: 0.04 (95% CI: ) 6 studies, N=1431 SMD: 0.17 (95% CI: ) 1 study, N= RR: 0.86 (95% CI: ) 5 studies, N=1666 RR: 0.72 (95% CI: ) 2 studies, N=550 RR: 1.94 (95% CI: ) 1 study, N=124 SMD: 1.09 (95% CI: ) 1 study studies, N=124 RR: 0.71 (95% CI: ) 1 study, N=124 Included studies in meta-analysis Included trials Borgia 1981 Grassi 1976 Grillage 1985 Comparison Follow up N FEV1 Country Inclusion Criteria Drop outs Patient Characteristics 200mg vs placebo 6 months 21 >40 Italy 600mg vs. placebo 6 months 80 - Italy Carbosysteine 750mg vs. 6 months UK Chronic bronchitis defined by MRC and an in the period before the study 2 (10%) Mean age 45.3 years, FEV1 3.82L Chronic bronchitis defined by British and American criteria 11 (14%) Mean age 60.9, 80% male Chronic bronchitis defined by MRC. Reversibility <20% 11 (10%) Pts all over 40 years

4 placebo Rasmussen 1988 Moretti 2004 Pela 1999 Allegra 1996 Meister 1986 Boman 1983 Nowak 1999 Decramer 2005 Parr mg vs. placebo 6 months Sweden Erdosteine 300mg vs. placebo 8 months 155 <70 Italy 600mg vs. placebo 6 months 169 <70 Italy Carbocysteine 2.7g vs. placebo 6 months Italy 300mg vs. placebo 6 months Germany 200mg vs placebo 6 months 259 <50 Sweden Chronic bronchitis defined by MRC. 56 (22%) 600mg vs. placebo 8 months (mean) mg vs. placebo 3 years Europe 200mg vs. placebo 6 months UK Chronic bronchitis defined by MRC and at least one in previous winter 25 (22%) Mean age 58.9yrs, 57% male, 100% had smoked Mean age 67 yrs, 80% male, 33% smokers, FEV1 after salbutamol 1.68L (SD 0.31) in COPD defined by ERS age with one erdosteine grp and 1.59L in or more in previous winter 31 (20%) placebo grp Mean age 66, 76% male, 28% COPD defined by ATS and ERS aged current smokers, mean FEV1 reversibility <12% 6 (4%) 1.49L, 58% predicted 75% smoking history, mean 2.7 COPD (ATS defined) and chronic bronchitis. (SD 1.3) s in At least one in previous 12 previous year, FEV L (SD months. Age (16%) 0.6) ICS not permitted Chronic bronchitis defined by WHO with at Mean age 57.2 yrs, 59% male, least one in the last winter 71 (28%) 88% had smoked 100% smokers mean age 51.9 FEV1 80% predicted 60 (mean) Europe COPD 18 (6%) Mean age 57 yrs, 60% male COPD, reversibility <12% and 200ml, Mean age 62 (SD 8), 79% FEV1/FVC 88% for men and 89% women 70 (27%) in male, FEV1 1.65L (SD 0.38), and history at least 2 s in last group and 99 46% current smokers, 70% on 2 yrs (37%) in placebo ICS Chronic bronchitis defined by MRC with at least one in last 12 mths 204 (39%) Mean age 63, 66% male, 86% had smoked Babolini mg vs placebo 6 months Italy Chronic bronchitis defined by MRC. 249 (33%) 64.3% smokers, 73.5% male, mean FEV L Ref ID: 35 Schermer T, Chavannes N, Dekhuijzen R et al. RCT Randomised; double blind; N = 192 Patient characteristics Intervention Comparison Length Inclusion: people years old; current/former smoker; chronic dyspnoea, sputum production and cough for at N- (600 mg/once daily) N=96 Procedure: 3 Outcome measures 3 years Primary outcome: rate over 1 year ( Dutch Council for Health Insurances;

5 Fluticasone and N- in primary care with COPD or chronic bronchitis. Respiratory Medicine. 2009; 103(4): Ref ID: 35 allocation concealment; ITT; Drop outs: : 44/96 (45.8%) placebo: 40/96 (41.7%) multicentre- Netherlands least 3 consecutive months/year in previous 2 years; FEV 1 /FVC ratio < 88% (men) or < 89% (women) and post FEV 1 <90% Exclusion: post FEV 1 <40% and/or history asthma; allergic rhinitis, or allergic eczema Baseline characteristics: similar between groups placebo Mean age (y) Mean post % predicted FEV1 Mean yearly rate N= 96 month washout from and/or ICS. Two week pretreatment with 30 mg oral prednisolone o.d. randomised to or placebo. monitored every 3 months. defined increased dyspnoea and/or increased sputum purulence, volume, which leads the patient to seek medical attention. Moderate defined as requiring antibiotics or prednisolone. Severe defined as requiring ER visit or hospitalisation. Secondary outcomes: Change in post FEV 1 Netherlands Asthma Foundation medications during study placebo medication: % SABA LABA ICS death

6 Comparison group is placebo outcome N=96 N= 96 Mean number s/year (includes hospitalisation) 1.00 (95% CI 0.77, 0.73 (95% CI 0.57, Rate ratio 1.35; p= ) 0.88) Change from baseline in post BD-FEV1 at 3 years (adjusted for age, gender, - 64 ml (SE 5.4) -60 ml (SE 5.4) P=0.569 smoking, FEV1) Death 1 3 RR 0.33 (95% CI 0.04, 3.15) Ref ID: 2504 Zheng JP, Kang J, Huang SG et al. Effect on acute chronic obstructive pulmonary disease (PEACE Study): a randomised placebocontrolled study. Lancet. 2008; 371(9629): Ref ID: 2504 RCT (PEACE) Double blinded; allocation concealment; ITT; powering the study not possible loss to follow-up: 13% 12% placebo Multicentre- China Patient characteristics Intervention Comparison Length N = 707 Inclusion: people between 40 and 80 years old with COPD who had 2 s COPD within previous 24 months and clinically stable for 4 weeks prior to study; smokers and non-smokers included; an FEV 1 /FVC ratio < 0.70 and post FEV 1 between 25%-79% predicted value. Exclusion: history asthma; non-copd respiratory disorder; previous lung transplantation or lung volume reduction surgery, requirement for LTOT or pulmonary rehab; alcohol/drug misuse; hypersensitivity to study medication; current use oral corticosteroids; onset during run-in period; severe glaucoma, heart, liver, kidney disease, diffuse bilateral bronchiectasis; (2x250 mg/3 times daily) N= 353 (2 tablets/3 times daily) N=354 Procedure:. randomised to or placebo. monitored every 3 months for 1 year. Both arms permitted short or long acting s and ICS if they had been used prior to study and the drugs were sustained Outcome measures 1 year Primary outcome: rate over 1 year ( defined as 2 day persistence at least 2 major symptoms worsening dyspnoea and increased sputum purulence, volume, or both; or any single major symptom plus more than 1 minor symptom such as wheezing, upper airway infection, unexplained fever) Secondary outcomes: Kyorin Pharma, Japan

7 Comparison group is placebo RR adjusted for concomitant use ICS outcome pregnancy or breastfeeding Baseline characteristics: similar between groups carbocystein e placebo Mean age (y) % beta agonists % anticholinergics % ICS Mean post FEV1 (L) Mean % predicted FEV1 Mean SRGQ N=353 N= 354 during the study. Systemic corticosteroids, antibiotics, mucolytics, antitussives not permitted unless used to treat an during the study. Change in SGRQ Change in mean FEV 1 Adverse events Mean s/patient-year (SE) 1.01 (0.06) 1.35 (0.06) Adjusted rate ratio 0.75 (0.62, 0.92), p=0.004 Change in SGRQ (at 1 year) (SD) (16.43) (19.01) P = Change in mean pre FEV1 (at 1 year, litres) Data not shown Data not shown Authors state NS between the groups; but data not shown All-cause mortality at 1 year (n) 0 0 Not reported Adverse events (n) Not reported Note: low use ICS; beta 2 agonists, or anticholinergics in each arm; specific to a Chinese population.