Comment
Scott Camazine/Science Photo Library
N-acetylcysteine in COPD may be beneficial, but for whom?
Published Online January 30, 2014 http://dx.doi.org/10.1016/ S2213-2600(13)70294-7 See Articles page 187
166
Widespread use of N-acetylcysteine, the acetylated variant of the aminoacid L-cysteine, has been reported in reallife analyses of patients with all GOLD stages of chronic obstructive pulmonary disease (COPD).1 Such use is not surprising because N-acetylcysteine has been reported to significantly reduce the risk of acute exacerbations of COPD. However, this effect is possibly attenuated by concomitant use of inhaled corticosteroids (but not smoking).2 Nevertheless, available evidence is insufficient to generate a recommendation about the effects of N-acetylcysteine in COPD patients who are not treated with inhaled corticosteroids. At the recommended dose of 600 mg per day, N-acetylcysteine is not included in most guidelines of therapeutic regimens for stable COPD.3,4 However, the effects of N-acetylcysteine seem to be dose-dependent.5 Specifically, some reports suggest that high-dose N-acetylcysteine (1200 mg per day) is able to reduce the risk of acute exacerbations of COPD6 and even induce changes in airway geometry, inflammation, and oxidative stress.7 Consequently, the PANTHEON study8 was designed to test the hypothesis that high-dose (1200 mg per day) long-term (1 year) N-acetylcysteine treatment can reduce the rate of exacerbations in COPD. Reporting in The Lancet Respiratory Medicine, Jin-Ping Zheng and colleagues8 showed that after 1 year of treatment in about 1000 patients with moderate-tosevere COPD, a significant reduction in the number of exacerbations was noted with N-acetylcysteine compared with placebo (1·16 exacerbations per patient year for 482 individuals given N-acetylcysteine and 1·49 exacerbations per patient-year in 482 patients given placebo; risk ratio 0·78, 95% CI 0·67–0·90; p=0·0011). Furthermore, the investigators noted evidence of an absence of interaction between treatment effects and use of inhaled corticosteroids. Notably, a greater reduction in exacerbations was noted in patients with moderate COPD than in patients with severe disease. These findings lead to the question of whether guidelines should change to include the use of N-acetylcysteine. Although we are fascinated by Zheng and colleagues’ results, we believe that the evidence that emerged from the PANTHEON study is not adequate to make N-acetylcysteine an integral component of COPD treatment. Because a clear tendency now exists to personalise therapy of patients with COPD, it is
disappointing that this trial does not provide information on specific phenotypes that could benefit from treatment with N-acetylcysteine, but rather states that the drug is especially effective in patients with moderate COPD. Miravitlles and colleagues9 have proposed that four different phenotypes exist of prognostic and therapeutic relevance, characterised by the combination of the classical types of emphysema, chronic bronchitis, exacerbators, and patients with overlap COPD–asthma. N-acetylcysteine can seemingly play a part in the management of patients with chronic bronchitis phenotype of COPD.10 However, when this treatment is extended to the whole spectrum of COPD, the results are less useful.10 The large number of patients enrolled in the PANTHEON study could allow confirmation that N-acetylcysteine is not effective in all COPD phenotypes and we hope that a retrospective analysis of data will be done with this aim. Moreover, results of this study do not allow us to understand in what manner N-acetylcysteine is capable of preventing acute exacerbations of COPD. At present, little is known about whether N-acetylcysteine acts as an antioxidant, an antiinflammatory, or a mucolytic drug, or all three, when it prevents COPD exacerbations in humans. Understanding of this concept will be fundamental to the development of successful future treatment regimens. The contrasting results obtained so far and especially the finding of the BRONCUS study11 make replication of the PANTHEON study imperative in white patients with COPD. In particular, we note that previous small trials that showed an effect of N-acetylcysteine on acute exacerbations of COPD were at higher risk of selection or publication bias, whereas the only two well designed trials that have documented an effect of N-acetylcysteine on this outcome6,8 have both been done in China. We cannot exclude that there might be a population effect (ie, one linked to genetic, environmental, and dietary factors) that explains the apparently specific effectiveness of N-acetylcysteine in Chinese patients. Zheng and colleagues stress that N-acetylcysteine would be able to reduce acute exacerbations of COPD through an antioxidant effect.8 However, the PANTHEON study provides no evidence to support this claim. Although a long time has passed since Burgunder and colleagues12 reported that the area under the curve of total plasma cysteine and total plasma glutathione did www.thelancet.com/respiratory Vol 2 March 2014
Comment
not increase after oral administration of N-acetylcysteine (30 mg/kg) in healthy volunteers, some investigators continue to insist that the effect of N-acetylcysteine in COPD is a consequence of its antioxidant activity due to its ability to increase intracellular glutathione, which plays an important role in the control of oxidative–carbonyl stress in this disorder. Theoretically, N-acetylcysteine should have various antioxidant effects; however, several large clinical trials failed to confirm such beneficial effects,13 although a small long-term study documented that N-acetylcysteine reduces exhaled hydrogen peroxide in stable COPD.14 We strongly believe that drugs that can suppress either the generation of reactive oxygen species or can neutralise such species (or do both) have the potential to indirectly influence inflammation in COPD and, consequently, the risk of acute exacerbations of COPD. For this reason, a large long-term study able to document a real antioxidant effect of N-acetylcysteine in COPD would be welcome. However, avaliable evidence suggests to us that the favourable effect of N-acetylcysteine on acute exacerbations of COPD is attributable to its mucolytic action. N-acetylcysteine cleaves disulphide bonds that crosslink glycoproteins in mucus and, consequently, reduces viscosity by producing greater mucosal fluidity, which in turn facilitates clearance of bronchial passages.15 This opinion is strengthened by the documentation that mucolytic drugs, irrespective of whether or not they are able to exert antioxidant effects, are associated with a small reduction in acute exacerbations of COPD.16
We declare that we have no conflicts of interest. 1 2
3
4
5
6
7
8
9
10
11
12
13 14
15
*Mario Cazzola, Maria Gabriella Matera Unit of Respiratory Clinical Pharmacology, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy (MC); and Unit of Pharmacology, Department of Experimental Medicine, Second University of Naples, Naples, Italy (MGM) [email protected]
16
Sutherland ER, Crapo JD, Bowler RP. N-acetylcysteine and exacerbations of chronic obstructive pulmonary disease. COPD 2006; 3: 195–202. Franssen FM, Spruit MA, Wouters EF. Determinants of polypharmacy and compliance with GOLD guidelines in patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2011; 6: 493–501. National Clinical Guideline Centre. Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care. London: National Clinical Guideline Centre. http:// guidance.nice.org.uk/CG101/Guidance/pdf/English (accessed Dec 21, 2013). Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, 2013. http://www.goldcopd.org/guidelines-globalstrategy-for-diagnosis-management.html (accessed Dec 21, 2013). Sadowska AM, Manuel-Y-Keenoy B, De Backer WA. Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo dose-effects: a review. Pulm Pharmacol Ther 2007; 20: 9–22. Tse HN, Raiteri L, Wong KY, et al. High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study. Chest 2013; 144: 106–18. De Backer J, Vos W, Van Holsbeke C, et al. Effect of high-dose N-acetylcysteine on airway geometry, inflammation, and oxidative stress in COPD patients. Int J Chron Obstruct Pulmon Dis 2013; 8: 569–79. Zheng J-P, Wen F-Q, Bai C-X, et al. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir Med 2014; published online Jan 30. http://dx.doi.org/10.1016/S2213-2600(13)70286-8. Miravitlles M, Calle M, Soler-Cataluña JJ. Clinical phenotypes of COPD. Identification, definition and implications for guidelines. Arch Bronconeumol 2012; 48: 86–89. Anderson D, Macnee W. Targeted treatment in COPD: a multi-system approach for a multi-system disease. Int J Chron Obstruct Pulmon Dis 2009; 4: 321–35. Decramer M, Rutten-van Mölken M, Dekhuijzen PN, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet 2005; 365: 1552–60. Burgunder JM, Varriale A, Lauterburg BH. Effect of N-acetylcysteine on plasma cysteine and glutathione following paracetamol administration. Eur J Clin Pharmacol 1989; 36: 127–31. Aitio ML. N-acetylcysteine—passe-partout or much ado about nothing? Br J Clin Pharmacol 2006; 61: 5–15. De Benedetto F, Aceto A, Dragani B, et al. Long-term oral N-acetylcysteine reduces exhaled hydrogen peroxide in stable COPD. Pulm Pharmacol Ther 2005; 18: 41–47. Grandjean EM, Berthet P, Ruffman R, Leuenberger P. Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind placebo-controlled clinical trials. Clin Ther 2000; 22: 209–21. Poole P, Black PN, Cates CJ. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012; 8: CD001287.
Estimation and application of the minimum clinically important difference in COPD The report by Samantha S C Kon and colleagues1 in The Lancet Respiratory Medicine concerning the minimum clinically important difference (MCID) for the COPD Assessment Test (CAT) addresses an important concept. MCIDs have been estimated for several www.thelancet.com/respiratory Vol 2 March 2014
COPD outcomes, but they were first developed for health-related quality-of-life instruments such as the Chronic Respiratory Questionnaire and St George’s Respiratory Questionnaire (SGRQ). MCIDs were needed to provide users with reference points on scales that
Published Online February 25, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70038-4 See Articles page 195
167
Scott Camazine/Science Photo Library
N-acetylcysteine in COPD may be beneficial, but for whom?
Published Online January 30, 2014 http://dx.doi.org/10.1016/ S2213-2600(13)70294-7 See Articles page 187
166
Widespread use of N-acetylcysteine, the acetylated variant of the aminoacid L-cysteine, has been reported in reallife analyses of patients with all GOLD stages of chronic obstructive pulmonary disease (COPD).1 Such use is not surprising because N-acetylcysteine has been reported to significantly reduce the risk of acute exacerbations of COPD. However, this effect is possibly attenuated by concomitant use of inhaled corticosteroids (but not smoking).2 Nevertheless, available evidence is insufficient to generate a recommendation about the effects of N-acetylcysteine in COPD patients who are not treated with inhaled corticosteroids. At the recommended dose of 600 mg per day, N-acetylcysteine is not included in most guidelines of therapeutic regimens for stable COPD.3,4 However, the effects of N-acetylcysteine seem to be dose-dependent.5 Specifically, some reports suggest that high-dose N-acetylcysteine (1200 mg per day) is able to reduce the risk of acute exacerbations of COPD6 and even induce changes in airway geometry, inflammation, and oxidative stress.7 Consequently, the PANTHEON study8 was designed to test the hypothesis that high-dose (1200 mg per day) long-term (1 year) N-acetylcysteine treatment can reduce the rate of exacerbations in COPD. Reporting in The Lancet Respiratory Medicine, Jin-Ping Zheng and colleagues8 showed that after 1 year of treatment in about 1000 patients with moderate-tosevere COPD, a significant reduction in the number of exacerbations was noted with N-acetylcysteine compared with placebo (1·16 exacerbations per patient year for 482 individuals given N-acetylcysteine and 1·49 exacerbations per patient-year in 482 patients given placebo; risk ratio 0·78, 95% CI 0·67–0·90; p=0·0011). Furthermore, the investigators noted evidence of an absence of interaction between treatment effects and use of inhaled corticosteroids. Notably, a greater reduction in exacerbations was noted in patients with moderate COPD than in patients with severe disease. These findings lead to the question of whether guidelines should change to include the use of N-acetylcysteine. Although we are fascinated by Zheng and colleagues’ results, we believe that the evidence that emerged from the PANTHEON study is not adequate to make N-acetylcysteine an integral component of COPD treatment. Because a clear tendency now exists to personalise therapy of patients with COPD, it is
disappointing that this trial does not provide information on specific phenotypes that could benefit from treatment with N-acetylcysteine, but rather states that the drug is especially effective in patients with moderate COPD. Miravitlles and colleagues9 have proposed that four different phenotypes exist of prognostic and therapeutic relevance, characterised by the combination of the classical types of emphysema, chronic bronchitis, exacerbators, and patients with overlap COPD–asthma. N-acetylcysteine can seemingly play a part in the management of patients with chronic bronchitis phenotype of COPD.10 However, when this treatment is extended to the whole spectrum of COPD, the results are less useful.10 The large number of patients enrolled in the PANTHEON study could allow confirmation that N-acetylcysteine is not effective in all COPD phenotypes and we hope that a retrospective analysis of data will be done with this aim. Moreover, results of this study do not allow us to understand in what manner N-acetylcysteine is capable of preventing acute exacerbations of COPD. At present, little is known about whether N-acetylcysteine acts as an antioxidant, an antiinflammatory, or a mucolytic drug, or all three, when it prevents COPD exacerbations in humans. Understanding of this concept will be fundamental to the development of successful future treatment regimens. The contrasting results obtained so far and especially the finding of the BRONCUS study11 make replication of the PANTHEON study imperative in white patients with COPD. In particular, we note that previous small trials that showed an effect of N-acetylcysteine on acute exacerbations of COPD were at higher risk of selection or publication bias, whereas the only two well designed trials that have documented an effect of N-acetylcysteine on this outcome6,8 have both been done in China. We cannot exclude that there might be a population effect (ie, one linked to genetic, environmental, and dietary factors) that explains the apparently specific effectiveness of N-acetylcysteine in Chinese patients. Zheng and colleagues stress that N-acetylcysteine would be able to reduce acute exacerbations of COPD through an antioxidant effect.8 However, the PANTHEON study provides no evidence to support this claim. Although a long time has passed since Burgunder and colleagues12 reported that the area under the curve of total plasma cysteine and total plasma glutathione did www.thelancet.com/respiratory Vol 2 March 2014
Comment
not increase after oral administration of N-acetylcysteine (30 mg/kg) in healthy volunteers, some investigators continue to insist that the effect of N-acetylcysteine in COPD is a consequence of its antioxidant activity due to its ability to increase intracellular glutathione, which plays an important role in the control of oxidative–carbonyl stress in this disorder. Theoretically, N-acetylcysteine should have various antioxidant effects; however, several large clinical trials failed to confirm such beneficial effects,13 although a small long-term study documented that N-acetylcysteine reduces exhaled hydrogen peroxide in stable COPD.14 We strongly believe that drugs that can suppress either the generation of reactive oxygen species or can neutralise such species (or do both) have the potential to indirectly influence inflammation in COPD and, consequently, the risk of acute exacerbations of COPD. For this reason, a large long-term study able to document a real antioxidant effect of N-acetylcysteine in COPD would be welcome. However, avaliable evidence suggests to us that the favourable effect of N-acetylcysteine on acute exacerbations of COPD is attributable to its mucolytic action. N-acetylcysteine cleaves disulphide bonds that crosslink glycoproteins in mucus and, consequently, reduces viscosity by producing greater mucosal fluidity, which in turn facilitates clearance of bronchial passages.15 This opinion is strengthened by the documentation that mucolytic drugs, irrespective of whether or not they are able to exert antioxidant effects, are associated with a small reduction in acute exacerbations of COPD.16
We declare that we have no conflicts of interest. 1 2
3
4
5
6
7
8
9
10
11
12
13 14
15
*Mario Cazzola, Maria Gabriella Matera Unit of Respiratory Clinical Pharmacology, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy (MC); and Unit of Pharmacology, Department of Experimental Medicine, Second University of Naples, Naples, Italy (MGM) [email protected]
16
Sutherland ER, Crapo JD, Bowler RP. N-acetylcysteine and exacerbations of chronic obstructive pulmonary disease. COPD 2006; 3: 195–202. Franssen FM, Spruit MA, Wouters EF. Determinants of polypharmacy and compliance with GOLD guidelines in patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2011; 6: 493–501. National Clinical Guideline Centre. Chronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care. London: National Clinical Guideline Centre. http:// guidance.nice.org.uk/CG101/Guidance/pdf/English (accessed Dec 21, 2013). Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, 2013. http://www.goldcopd.org/guidelines-globalstrategy-for-diagnosis-management.html (accessed Dec 21, 2013). Sadowska AM, Manuel-Y-Keenoy B, De Backer WA. Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: discordant in vitro and in vivo dose-effects: a review. Pulm Pharmacol Ther 2007; 20: 9–22. Tse HN, Raiteri L, Wong KY, et al. High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study. Chest 2013; 144: 106–18. De Backer J, Vos W, Van Holsbeke C, et al. Effect of high-dose N-acetylcysteine on airway geometry, inflammation, and oxidative stress in COPD patients. Int J Chron Obstruct Pulmon Dis 2013; 8: 569–79. Zheng J-P, Wen F-Q, Bai C-X, et al. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir Med 2014; published online Jan 30. http://dx.doi.org/10.1016/S2213-2600(13)70286-8. Miravitlles M, Calle M, Soler-Cataluña JJ. Clinical phenotypes of COPD. Identification, definition and implications for guidelines. Arch Bronconeumol 2012; 48: 86–89. Anderson D, Macnee W. Targeted treatment in COPD: a multi-system approach for a multi-system disease. Int J Chron Obstruct Pulmon Dis 2009; 4: 321–35. Decramer M, Rutten-van Mölken M, Dekhuijzen PN, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet 2005; 365: 1552–60. Burgunder JM, Varriale A, Lauterburg BH. Effect of N-acetylcysteine on plasma cysteine and glutathione following paracetamol administration. Eur J Clin Pharmacol 1989; 36: 127–31. Aitio ML. N-acetylcysteine—passe-partout or much ado about nothing? Br J Clin Pharmacol 2006; 61: 5–15. De Benedetto F, Aceto A, Dragani B, et al. Long-term oral N-acetylcysteine reduces exhaled hydrogen peroxide in stable COPD. Pulm Pharmacol Ther 2005; 18: 41–47. Grandjean EM, Berthet P, Ruffman R, Leuenberger P. Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind placebo-controlled clinical trials. Clin Ther 2000; 22: 209–21. Poole P, Black PN, Cates CJ. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2012; 8: CD001287.
Estimation and application of the minimum clinically important difference in COPD The report by Samantha S C Kon and colleagues1 in The Lancet Respiratory Medicine concerning the minimum clinically important difference (MCID) for the COPD Assessment Test (CAT) addresses an important concept. MCIDs have been estimated for several www.thelancet.com/respiratory Vol 2 March 2014
COPD outcomes, but they were first developed for health-related quality-of-life instruments such as the Chronic Respiratory Questionnaire and St George’s Respiratory Questionnaire (SGRQ). MCIDs were needed to provide users with reference points on scales that
Published Online February 25, 2014 http://dx.doi.org/10.1016/ S2213-2600(14)70038-4 See Articles page 195
167
