Long-term macrolide treatment for the prevention of acute exacerbations in COPD: a systematic review and meta-analysis

Figures & data

Figure 1 Flow diagram of studies identified, included, and excluded.

Table 1 Characteristics of included studies

Study	Year	Country	Design	Sample size	Population characteristics (treatment/control)			Treatment arms	Duration of treatment (months)	Primary outcome	Secondary outcomes
					Mean age (years)	Men (%)	Mean FEV % predicted ^Citation1
Albert et al^Citation22	2011	USA	RCT	1,117	65/66	59/59	39/40	Azithromycin 250 mg once daily; placebo	12	The time to the first acute exacerbation of COPD	Quality of life, nasopharyngeal colonization with selected respiratory pathogens, adherence, SGRQ, SF-36, hearing
Banerjee et al^Citation23	2005	UK	RCT	67	65.1/68.1	–	42.5/43.9	Clarithromycin 500 mg once daily; placebo	3	Health status	Sputum bacterial quantitative load, infective exacerbation rate, shuttle walk test, serum C-reactive protein levels
Berkhof et al^Citation24	2013	the Netherlands	RCT	84	67/68	74/76	49.8/47.4	Azithromycin 250 mg once 3 days/week; placebo	3	Mean LCQ total and domain scores	SGRQ, SF-36, FEV1, blood values, microbiology
Blasi et al^Citation25	2010	Italy	RCT	22	72/73	91/82	–	Azithromycin 500 mg 3 days/week; standard care	6	The number of exacerbations and hospitalizations	Time to first exacerbation and hospitalization, steroid and antibiotic use, evaluation of the inflammatory cytokines values in the EBC, mortality, quality of life, safety
Brill et al^Citation26	2015	UK	RCT	99	67.9/68.7	64/75	44/53	Azithromycin 250 mg once 3 days/week; placebo	3	The change in total cultured bacterial load in sputum from baseline	Bacterial numbers by 16S qPCR, sputum inflammatory markers, bacterial resistance, lung function, health status, adherence to therapy, exacerbations, adverse events, comparison of airway load measurements using quantitative culture and 16S qPCR
He et al^Citation27	2010	China	RCT	36	68.8/69.3	83.3/88.9	44.3/42.1	Erythromycin 125 mg 3 times daily; placebo	6	Neutrophil number in sputum; exacerbations	Spirometry, quality of life, inflammatory markers in sputum, sputum bacteriology, adherence, safety
Naderi et al^Citation33	2018	Canada	R	195	67.8/70.8	59.8/47.8	34.8/39.9	Azithromycin 250 mg once at least 3 times per week; placebo	≥6	Exacerbations and health service use	Changes in exacerbations according to patient and disease characteristics and adverse effects
Seemungal et al^Citation28	2008	UK	RCT	109	66.5/67.8	62/64	49.3/50.6	Erythromycin 250 mg twice daily; placebo	12	Exacerbations and airway inflammation	Spirometry, sputum testing for bacteria, adverse events
Shafuddin et al^Citation29	2015	New Zealand	RCT	191	67.6/66.7	85.6/71.3	33.9/35.8	Roxithromycin 300 mg once daily; placebo	3	COPD exacerbations over 48-week posttreatment period	COPD exacerbations over the 12-week treatment period, and the first and last 24-week posttreatment periods, FEV1, FVC, CRQ scores, adverse events
Simpson et al^Citation30	2014	Australia	RCT	30	71.7/69.9	60.0/66.7	56.5/51.1	Azithromycin 250 mg once daily; placebo	3	Airway bacterial load, sputum neutrophil proportion, levels of CXCL8	Exacerbations, symptom score, SGRQ, CCQ, lung function and CT scores, side effect
Suzuki et al^Citation31	2001	Japan	RCT	109	69.1/71.7	85.5/81.5	–	Erythromycin 200–400 mg once daily; riboflavin 10 mg once daily	12	The frequency of the common cold	The frequency of the subsequent exacerbation
Uzun et al^Citation32	2014	the Netherlands	RCT	92	64.7/64.9	47/40	44.2/45.0	Azithromycin 500 mg once 3 days/week; placebo	12	Rate of exacerbations of COPD	Time to first exacerbation, hospital admission for acute exacerbations, change in the treatment of exacerbations, FEV1, FVC, 6 minutes walking test, quality of life, macrolide-resistant microorganisms, adverse events

Abbreviations: CCQ, Clinical COPD questionnaire; CRQ, chronic respiratory disease questionnaire; CXCL8, a neutrophils chemokine; EBC, exhaled breath condensate; LCQ, Leicester Cough Questionnaire; R, retrospective cohort study; RCT, randomized controlled trail; SF-36, the Medical Outcomes Study 36-Item Short-Form Health Survey; SGRQ, St George’s Respiratory Questionnaire; qPCR, quantitative PCR.

Table 2 Risk of bias in the retrospective study

Study	Selection			Comparability		Outcome		Quality score
	Representative exposed group	Representative reference group	Assignment for exposed groupa	Comparable for 1, 2, 3, 4b	Comparable for 5, 6, 7, 8b	Assessment of outcome	Adequate follow-up
Naderi et al^Citation33	Yes	Yes	Yes	2, 4	6, 7	Yes	Yes	⋆⋆⋆⋆⋆⋆⋆

Notes: Comparability variables: 1=age; 2=gender; 3=FEV₁ (%) of predicted; 4=corticosteroids inhalation medication; 5=body mass index; 6=smoking status; 7=any inhalation medication; 8=exacerbation previous year.

a Details of criteria for adequate random assignment of patients to the exposed group were provided.

b If all characteristics were comparable, two stars; if two or three characteristics were comparable, one star; otherwise, no star.

Figure 2 Graph of the bias risk of the enrolled RCTs.

Note: The other bias refers to intention-to-treat analysis.
Abbreviation: RCT, randomized controlled trail.

Figure 3 Forest plot and meta-analysis of the total number of patients with one or more exacerbations treated with macrolides compared with the control.

Abbreviation: M–H, Mantel–Haenszel method.

Figure 4 Forest plot and subgroup analyses of the total number of patients with one or more exacerbations treated with macrolides compared with the control: (A) different types of macrolides and (B) different durations of treatment.

Abbreviation: M–H, Mantel–Haenszel method.

Figure 5 Forest plot and meta-analysis of risk ratios for exacerbations per patient per year treated with macrolides compared with the control.

Figure 6 Forest plot and meta-analysis of the total number of patients requiring hospitalization treated with macrolides compared with the control.

Abbreviation: M–H, Mantel–Haenszel method.

Figure 7 Forest plot and meta-analysis of the mean differences in change in total SGRQ score among patients treated with macrolides compared with the control.

Abbreviation: SGRQ, St George Respiratory Questionnaire.

Figure 8 Forest plot and meta-analysis of the total number of patients who experienced adverse events during follow-up after treatment with macrolides compared with the control.

Abbreviation: M–H, Mantel–Haenszel method.

Figure 9 Forest plot and subgroup analyses of the total number of patients who experienced adverse events during follow-up after treatment with macrolides compared with the control: (A) different types of macrolides and (B) different durations of treatment.

Abbreviation: M–H, Mantel–Haenszel method.

Figure 10 Funnel plots illustrating meta-analysis of the total number of patients with one or more exacerbations after treatment with macrolides compared with the control.

Abbreviation: SE, standard error.

Figure S1 Sensitivity analyses of the total number of patients with one or more exacerbations treated with macrolides compared with the control.

Abbreviation: M–H, Mantel–Haenszel method.

Figure S2 Sensitivity analyses of risk ratios for exacerbations per patient per year treated with macrolides compared with the control.

Figure S3 Sensitivity analyses of the total number of patients requiring hospitalization treated with macrolides compared with the control.

Abbreviation: M–H, Mantel–Haenszel method.

Figure S4 Sensitivity analyses of the mean differences with respect to change in total SGRQ score among patients treated with macrolides compared with the control.

Abbreviation: SGRQ, St George Respiratory Questionnaire.

Figure S5 Sensitivity analyses of the total number of patients who experienced adverse events during follow-up after treatment with macrolides compared with the control.

Abbreviation: M–H, Mantel–Haenszel method.

Table S1 Sensitivity analyses of subgroup based on the number of patients with exacerbations and adverse effects

	Number of patients with exacerbations			Adverse effects
	Studies (n)	OR (95% CI)	P-value	Studies (n)	OR (95% CI)	P-value
Azithromycin	4	0.37 (0.21–0.67)	0.001	4	1.38 (0.69–2.78)	0.36
Erythromycin	3	0.22 (0.09–0.53)	0.0008	3	1.23 (0.57–2.65)	0.6
Clarithromycin	1	3.27 (0.59–18.21)	0.18	1	3.27 (0.59–18.21)	0.18
Roxithromycin	0	NA	NA	1	3.21 (1.56–6.60)	0.002
Three-month treatment	4	0.60 (0.26–1.42)	0.25	5	2.06 (1.27–3.35)	0.004
Six-month treatment	2	0.17 (0.04–0.75)	0.02	2	2.01 (0.51–7.86)	0.32
Twelve-month treatment	3	0.20 (0.08–0.47)	0.0002	3	2.16 (1.03–4.53)	0.04

Abbreviation: NA, data not available.

GOLD Executive Committee [homepage on the Internet]Global strategy for the diagnosis management and prevention of chronic obstructive pulmonary disease2018 Available from: http://goldcopd.comAccessed October 25, 2018

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