N-Acetylcysteine and Exacerbations of Chronic Obstructive Pulmonary Disease

Figures & data

Figure 1 Flow diagram depicting the selection of studies for meta-analysis.

Table 1 Age, physiologic and smoking status of study subjects randomized to placebo or N-acetylcysteine

	Age (years)		FEV1		% Smokers
Study	Placebo	NAC	Placebo	NAC	Placebo	NAC
Boman et al. (20)	51.0 ± 10.1	53.2 ± 11.4	80.0 ± 19.4^A	80.7 ± 20.3^A	82.8	79.6
British Thoracic Society ([21])	62.6 ± 7.9	64.3 ± 7.3	31 ± NR^A	29 ± NR^A	26	28
Decramer et al. ([12])	62 ± 8	62 ± 8	57 ± 9^A	57 ± 9^A	41	51
Grassi et al. ([22])	62 [37–80]	60 [40–78]	NR	NR	NR	NR
Hansen et al. ([23])	51.7 ± NR	51.1 ± NR	2.3 ± 0.1^B	2.3 ± 0.1^B	89.7	94.6
Multicenter Study Group ([24])	≤ 50: 35.7%	≤50: 44.2%	2.2 ± NR^B	2.2 ± NR^B	61.1	67.7
	51–70: 54.7%	51–70: 46.1%
	≥71: 9.6%	≥71: 9.7%
Pela et al. ([25])	66 ± 8.4	66 ± 10.1	59.3 ± 18.6^A	56.8 ± 19.7^A	23	34
Rasmussen et al. ([26])	58.9 ± NR	58.8 ± NR	NR	NR	NR	NR

Data reported as mean ± SD, except where noted (*) reported as mean [range].

^A FEV₁ % predicted,^B FEV₁ measured (L).

NAC: N-acetylcysteine, NR: not reported.

Table 2 Number of randomized subjects and treatment allocation by study

	n randomized
Study	Placebo	NAC	N-acetylcysteine dose	Duration
Boman et al. ([20])	132	127	200 mg po bid	6 months
British Thoracic Society ([21])	96	85	200 mg po tid	5 months
Decramer et al. ([12])	267	256	600 mg po qd	3 years
Grassi et al. ([22])	40	40	300 mg po bid, 3 days/week	6 months
Hansen et al. ([23])	78	75	600 mg po bid	5.5 months
Multicenter Study Group ([24])	373	371	200 mg po bid	6 months
Pela et al. ([25])	84	85	600 mg po qd	6 months
Rasmussen et al. ([26])	57	59	300 mg po bid	6 months

NAC: N-acetylcysteine.

* 6-month data extrapolated from annual exacerbation frequency.

Table 3 Definition of exacerbation by study

Study	Definition of exacerbation
Boman et al. ([20])	Obligatory: (1) Purulent or mucopurulent sputum and (2) new or aggravated cough plus
Hansen et al. ([23])
Rasmussen et al. ([26])	One or more: (1) general malaise, (2) symptoms of common cold, (3) fever > 38C, (4) breathlessness, (5) increased mucus production, (6) increased sputum thickness, (7) foul-tasting sputum, (8) increased difficulty of expectoration, (9) elevation of the erythrocyte sedimentation rate, (10) leukocytosis or (11) pneumonia
British Thoracic Society ([21])	Obligatory: (1) New or deteriorating cough with (2) increased sputum purulence lasting for at least 48 hours plus
	One or more: (1) general malaise, (2) any recorded fever great than 38°C, (3) increased breathlessness, (4) increased sputum volume or thickness or 4) increased difficulty in expectoration
Decramer et al. ([12])	“An increase in dyspnea, 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”
Grassi et al. ([22])	“The appearance of an acute infectious episode or sudden aggravation of the typical signs and symptoms”
Multicenter Study Group ([24])	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 dyspnea but not necessarily fever”
Pela et al. ([25])	Point system (≥3 points = exacerbation): 1 point for fever, moderate cough, increased mucus, increased dyspnea 2 points for fever, severe cough, increased and purulent mucus, severely increased dyspnea

Table 4 Outcomes and odds of exacerbation with N-acetylcysteine therapy, by study

Study	Outcome	Placebo	NAC	Odds ratio [95% CI]
Boman et al. ([20])	0 exacerbations (n)	20	39	0.36 [0.19–0.66]
	≥ 1 exacerbation (n)	85	59
British Thoracic Society ([21])	0 exacerbations (n)	8	11	0.65 [0.25–1.73]
	≥1 exacerbation (n)	68	61
Decramer et al. ([12])	0 exacerbations (n)	92	89	0.99 [0.69–1.42]
	≥1 exacerbation (n)	175	167
Grassi et al. ([22])	0 exacerbations (n)	11	18	0.45 [0.17–1.20]
	≥1 exacerbation (n)	23	17
Hansen et al. ([23])	0 exacerbations (n)	34	36	0.60 [0.30–1.22]
	≥1 exacerbation (n)	36	23
Multicenter Study Group ([24])	0 exacerbations (n)	58	134	0.28 [0.20–0.41]
	≥1 exacerbation (n)	183	120
Pela et al. ([25])	0 exacerbations (n)	17	37	0.34 [0.17–0.66]
	≥1 exacerbation (n)	63	46
Rasmussen et al. ([26])	0 exacerbations (n)	23	28	0.57 [0.25–1.35]
	≥ 1 exacerbation (n)	23	16

* Count data extrapolated from reported exacerbation frequency.

Figure 2 Summary effect of N-acetylcysteine on the odds of exacerbation in patients with COPD. The center of diamond indicates the summary effect and its width the 95% confidence interval.

Figure 3 Begg's funnel plot with pseudo-95% confidence limits.

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