- Email: [email protected]
Carbocisteine for acute exacerbations of COPD
Correspondence
1 2 3 4
5
McCurry J. Japan to rethink suicide-prevention policies. Lancet 2008; 371: 2071. Young J. Morals, suicide, and psychiatry: a view from Japan. Bioethics 2002; 16: 412–24. Vijayakumar L. Suicide and mental disorders in Asia. Int Rev Psychiatry 2005; 17: 109–14. Liu KY, Beautrais A, Caine E, et al. Charcoal burning suicides in Hong Kong and urban Taiwan: an illustration of the impact of a novel suicide method on overall regional rates. J Epidemiol Community Health 2007; 61: 248–53. Shiho Y, Tohru T, Shinji S, et al. Suicide in Japan: present condition and prevention measures. Crisis 2005; 26: 12–19.
Justin McCurry’s World Report1 identifies several concerns about Japan’s suicide prevention policies. In 2007, Japan belatedly outlined a nationwide master plan, the Comprehensive Suicide Prevention Initiative.2 What Japan currently needs, even more than an urgent rethinking of its policies, is the further reinforcement of action plans based on the current master plan. Accordingly, the necessary “rethinking” in Japan underscored by McCurry has already begun. The goal of the initiative is to reduce the rate of suicide by at least 20% by 2016. This is a significant goal and far from constitutes empty words. Indeed, this goal has functioned as a marketing promotion—almost as a slogan—and thus has served to encourage the implementation of various actions. In Japan, as elsewhere, known major risk factors for suicide are mental health problems and a history of suicide attempts. Another significant factor in Japan, as noted in the World Report, is the ageing of its society. The initiative addresses these factors. In fact, the government has allocated new funds for the treatment of depression, including early detection by primarycare physicians and reinforcement of psychiatric consultation at emergency facilities. Additionally, several randomised controlled trials and a regional intervention study are being carried out to generate evidence for further policy making. Suicide prevention is a complex challenge for every nation. Further 1630
discussion and rethinking is necessary to allocate resources effectively within the larger context of social security. We declare that we have no conflict of interest.
*Masatoshi Inagaki, Toshihiko Matsumoto, Kenji Kawano, Mitsuhiko Yamada, Tadashi Takeshima [email protected] Center for Suicide Prevention (MI, TM, KK, TT) and Department of Psychogeriatrics (MY), National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8553, Japan 1 2
McCurry J. Japan to rethink suicide-prevention policies. Lancet 2008; 371: 2071. Government of Japan. The comprehensive suicide prevention initiative. Tokyo: Government of Japan, 2007.
Carbocisteine for acute exacerbations of COPD Neither authors Jin-Ping Zheng and colleagues (June 14, p 2013)1 nor commentators Paul Albert and Peter Calverley2 discuss the KaplanMeier plot provided as figure 2 in the PEACE Study report. This plot seems to indicate that there is no important difference between the carbocisteine and placebo groups in the chance of being exacerbation-free at any point in time during the 12-month study period. This finding contrasts with that of the main analysis, which showed around 25% reduction in the mean number of exacerbations per patient with carbocisteine compared with placebo. The implication seems to be that carbocisteine does not affect the time to the first exacerbation but reduces the number of subsequent exacerbations by around 50%, and that is rather curious. Another surprising finding is that “no deaths were reported”. If 700 people with a mean age of 65 years were observed for a year in a western general population, about 1·5% (ie, 10) would be expected to die.3 In 700 patients with chronic obstructive pulmonary disease (COPD), similar in age and with
similar forced expiratory volumes in 1 s (FEV1) to the TORCH trial patients,4 we would expect about 28 deaths in the year (ie, 4%), with mortality unlikely to be much lower in China. The probability of observing zero deaths in 700 patients when 28 are expected is about 10–13. Presumably the “missing” deaths occurred in the 91 patients who did not complete the trial. Zheng and colleagues should provide further information on their vital status. Inability to account for deaths occurring in a trial of drug efficacy and safety in a population with significant expected mortality would be an important limitation. SS has served on advisory boards and received research grants from the following makers of drugs for COPD: AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, and Sepracor. PW has no conflict of interest.
*Patrick Waller, Samy Suissa [email protected] 15 Tamella Road, Botley, Southampton SO30 2NY, UK (PW); and McGill Pharmacoepidemiology Research Unit, Sir Mortimer B Davis Jewish General Hospital, McGill University, Montreal, QC, Canada (SS) 1
2
3
4
Zheng JP, Kang J, Huang SG. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet 2008; 371: 2013–18. Albert P, Calverley P. A PEACE-ful solution to COPD exacerbations? Lancet 2008; 371: 1975–76. Centers for Disease Control and Prevention. United States life tables, 2003. http://www. cdc.gov/nchs/data/statab/lewk3_2003.pdf (accessed Oct 6, 2008). Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356: 775–89.
The PEACE Study1 has shown a new insight into carbocisteine; however, Jin-Ping Zheng and colleagues did not reveal the pharmaceutical form of the drug used in the study (the sodium or lysine salt). The effects of carbocisteine are dependent on the action of two cytosolic enzymes: cysteine dioxygenase and phenylalanine 4-hydroxylase. Patients who are relatively efficient sulphur oxidisers rapidly produce inactive oxygenated metabolites www.thelancet.com Vol 372 November 8, 2008
Correspondence
We declare that we have no conflict of interest.
*Prasanta Raghab Mohapatra, Deepak Aggarwal [email protected] Government Medical College and Hospital, 160030 Chandigarh, India 1
2
3
Zheng JP, Kang J, Huang SG. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet 2008; 371: 2013–18. Goreish AH, Bednar S, Jones H, Mitchell SC, Steventon GB. Phenylalanine 4-monooxygenase and the S-oxidation of S-carboxymethyl-L-cysteine. Drug Metab Drug Interact 2004; 20: 159–74. Allegra L, Cordaro CI, Grassi C. Prevention of acute exacerbations of chronic obstructive bronchitis with carbocysteine lysine salt monohydrate: a multicenter, double-blind, placebo-controlled trial. Respiration 1996; 63: 174–80.
www.thelancet.com Vol 372 November 8, 2008
Authors’ reply We reported a 24·5% lower annualised rate of exacerbation of chronic obstructive pulmonary disease (COPD) with carbocisteine treatment in a 1-year placebo-controlled randomised trial.1 However, the Kaplan-Meier plot did not show any difference between the carbocisteine group and placebo group in the probability of being exacerbation-free during the study. Does the reduced exacerbation rate with carbocisteine conflict with the similar probability of exacerbation in both groups? To answer this question, we compared the number of patients who had an exacerbation between the carbocisteine group (183 [51·8%]) and placebo group (190 [53·7%]) by use of the χ2 test. This calculation showed no significant difference (χ2=0·238, p=0·626), indicating that the reduction of exacerbation rate was not due to fewer patients experiencing exacerbation. Was it related to less frequent exacerbations? We looked at the distribution of exacerbation frequency. The numbers of patients with zero, one, and more than one exacerbation were 170 (48·2%), 99 (28·0%), and 84 (23·8%), respectively, in
the carbocisteine group versus 164 (46·3%), 77 (21·8%), and 113 (31·9%), respectively, in placebo group. The data show that there were significantly fewer patients with more than one exacerbation in the carbocisteine group than in the placebo group (χ2=7·125, p=0·028). To confirm these findings, we did additional analyses on the probability of recurrent exacerbation (more than one exacerbation) with the log-rank test, which showed that recurrent exacerbation was less likely to occur in the carbocisteine group than in the placebo group (χ2=5·772, p=0·016), as shown in the figure. Our study revealed better prevention of exacerbations by carbocisteine in those with frequent events, but the exact mechanism is not known. Because carbocisteine works via its anti-inflammatory and antioxidant effects, improvements in COPD exacerbations will take time, and, as reported in the PEACE study,1 the preventive effects were found only in patients treated with carbocisteine for 6 months or more, indicating that the longer the carbocisteine administration, the better the preventive effects on recurrent exacerbation.
Carbocisteine Placebo
100
Probability of more than one exacerbation (%)
leading to diminished effect of drug. However, patients who are poor sulphur oxidisers are exposed to the active sulphide for longer periods.2 Ethnicity might have a role in altering biotransformation. By contrast with other placebocontrolled studies,3 the PEACE study showed no difference in exacerbation rate between the treatment and placebo group at 3 months; the possible reasons for this are not discussed. With only 16·7% of study participants on inhaled corticosteroids (>50% of patients with Global Initiative for Obstructive Lung Disease [GOLD] stage III and IV), it is likely that the beneficial effects of carbocisteine might indirectly be due to a lack of prevention by inhaled corticosteroids. The study would have been clinically useful if the efficacy of carbocisteine had been compared with that of inhaled corticosteroids and placebo in different groups. Mucolytics such as carbocisteine seem unlikely to replace inhaled steroids in the treatment of COPD, but might be an important alternative where corticosteroid use is contraindicated. The mechanisms by which carbocisteine prevents exacerbation of COPD could provide a clue to the mechanism of the disease itself.
75
50
25
0 0 Carbocisteine Placebo
353 354
3 244 239
6 Time (months) 194 169
9
12
142 146
138 145
Figure: Kaplan-Meier plot of probability of more than one exacerbation over time
1631
1 2 3 4
5
McCurry J. Japan to rethink suicide-prevention policies. Lancet 2008; 371: 2071. Young J. Morals, suicide, and psychiatry: a view from Japan. Bioethics 2002; 16: 412–24. Vijayakumar L. Suicide and mental disorders in Asia. Int Rev Psychiatry 2005; 17: 109–14. Liu KY, Beautrais A, Caine E, et al. Charcoal burning suicides in Hong Kong and urban Taiwan: an illustration of the impact of a novel suicide method on overall regional rates. J Epidemiol Community Health 2007; 61: 248–53. Shiho Y, Tohru T, Shinji S, et al. Suicide in Japan: present condition and prevention measures. Crisis 2005; 26: 12–19.
Justin McCurry’s World Report1 identifies several concerns about Japan’s suicide prevention policies. In 2007, Japan belatedly outlined a nationwide master plan, the Comprehensive Suicide Prevention Initiative.2 What Japan currently needs, even more than an urgent rethinking of its policies, is the further reinforcement of action plans based on the current master plan. Accordingly, the necessary “rethinking” in Japan underscored by McCurry has already begun. The goal of the initiative is to reduce the rate of suicide by at least 20% by 2016. This is a significant goal and far from constitutes empty words. Indeed, this goal has functioned as a marketing promotion—almost as a slogan—and thus has served to encourage the implementation of various actions. In Japan, as elsewhere, known major risk factors for suicide are mental health problems and a history of suicide attempts. Another significant factor in Japan, as noted in the World Report, is the ageing of its society. The initiative addresses these factors. In fact, the government has allocated new funds for the treatment of depression, including early detection by primarycare physicians and reinforcement of psychiatric consultation at emergency facilities. Additionally, several randomised controlled trials and a regional intervention study are being carried out to generate evidence for further policy making. Suicide prevention is a complex challenge for every nation. Further 1630
discussion and rethinking is necessary to allocate resources effectively within the larger context of social security. We declare that we have no conflict of interest.
*Masatoshi Inagaki, Toshihiko Matsumoto, Kenji Kawano, Mitsuhiko Yamada, Tadashi Takeshima [email protected] Center for Suicide Prevention (MI, TM, KK, TT) and Department of Psychogeriatrics (MY), National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8553, Japan 1 2
McCurry J. Japan to rethink suicide-prevention policies. Lancet 2008; 371: 2071. Government of Japan. The comprehensive suicide prevention initiative. Tokyo: Government of Japan, 2007.
Carbocisteine for acute exacerbations of COPD Neither authors Jin-Ping Zheng and colleagues (June 14, p 2013)1 nor commentators Paul Albert and Peter Calverley2 discuss the KaplanMeier plot provided as figure 2 in the PEACE Study report. This plot seems to indicate that there is no important difference between the carbocisteine and placebo groups in the chance of being exacerbation-free at any point in time during the 12-month study period. This finding contrasts with that of the main analysis, which showed around 25% reduction in the mean number of exacerbations per patient with carbocisteine compared with placebo. The implication seems to be that carbocisteine does not affect the time to the first exacerbation but reduces the number of subsequent exacerbations by around 50%, and that is rather curious. Another surprising finding is that “no deaths were reported”. If 700 people with a mean age of 65 years were observed for a year in a western general population, about 1·5% (ie, 10) would be expected to die.3 In 700 patients with chronic obstructive pulmonary disease (COPD), similar in age and with
similar forced expiratory volumes in 1 s (FEV1) to the TORCH trial patients,4 we would expect about 28 deaths in the year (ie, 4%), with mortality unlikely to be much lower in China. The probability of observing zero deaths in 700 patients when 28 are expected is about 10–13. Presumably the “missing” deaths occurred in the 91 patients who did not complete the trial. Zheng and colleagues should provide further information on their vital status. Inability to account for deaths occurring in a trial of drug efficacy and safety in a population with significant expected mortality would be an important limitation. SS has served on advisory boards and received research grants from the following makers of drugs for COPD: AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, and Sepracor. PW has no conflict of interest.
*Patrick Waller, Samy Suissa [email protected] 15 Tamella Road, Botley, Southampton SO30 2NY, UK (PW); and McGill Pharmacoepidemiology Research Unit, Sir Mortimer B Davis Jewish General Hospital, McGill University, Montreal, QC, Canada (SS) 1
2
3
4
Zheng JP, Kang J, Huang SG. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet 2008; 371: 2013–18. Albert P, Calverley P. A PEACE-ful solution to COPD exacerbations? Lancet 2008; 371: 1975–76. Centers for Disease Control and Prevention. United States life tables, 2003. http://www. cdc.gov/nchs/data/statab/lewk3_2003.pdf (accessed Oct 6, 2008). Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356: 775–89.
The PEACE Study1 has shown a new insight into carbocisteine; however, Jin-Ping Zheng and colleagues did not reveal the pharmaceutical form of the drug used in the study (the sodium or lysine salt). The effects of carbocisteine are dependent on the action of two cytosolic enzymes: cysteine dioxygenase and phenylalanine 4-hydroxylase. Patients who are relatively efficient sulphur oxidisers rapidly produce inactive oxygenated metabolites www.thelancet.com Vol 372 November 8, 2008
Correspondence
We declare that we have no conflict of interest.
*Prasanta Raghab Mohapatra, Deepak Aggarwal [email protected] Government Medical College and Hospital, 160030 Chandigarh, India 1
2
3
Zheng JP, Kang J, Huang SG. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet 2008; 371: 2013–18. Goreish AH, Bednar S, Jones H, Mitchell SC, Steventon GB. Phenylalanine 4-monooxygenase and the S-oxidation of S-carboxymethyl-L-cysteine. Drug Metab Drug Interact 2004; 20: 159–74. Allegra L, Cordaro CI, Grassi C. Prevention of acute exacerbations of chronic obstructive bronchitis with carbocysteine lysine salt monohydrate: a multicenter, double-blind, placebo-controlled trial. Respiration 1996; 63: 174–80.
www.thelancet.com Vol 372 November 8, 2008
Authors’ reply We reported a 24·5% lower annualised rate of exacerbation of chronic obstructive pulmonary disease (COPD) with carbocisteine treatment in a 1-year placebo-controlled randomised trial.1 However, the Kaplan-Meier plot did not show any difference between the carbocisteine group and placebo group in the probability of being exacerbation-free during the study. Does the reduced exacerbation rate with carbocisteine conflict with the similar probability of exacerbation in both groups? To answer this question, we compared the number of patients who had an exacerbation between the carbocisteine group (183 [51·8%]) and placebo group (190 [53·7%]) by use of the χ2 test. This calculation showed no significant difference (χ2=0·238, p=0·626), indicating that the reduction of exacerbation rate was not due to fewer patients experiencing exacerbation. Was it related to less frequent exacerbations? We looked at the distribution of exacerbation frequency. The numbers of patients with zero, one, and more than one exacerbation were 170 (48·2%), 99 (28·0%), and 84 (23·8%), respectively, in
the carbocisteine group versus 164 (46·3%), 77 (21·8%), and 113 (31·9%), respectively, in placebo group. The data show that there were significantly fewer patients with more than one exacerbation in the carbocisteine group than in the placebo group (χ2=7·125, p=0·028). To confirm these findings, we did additional analyses on the probability of recurrent exacerbation (more than one exacerbation) with the log-rank test, which showed that recurrent exacerbation was less likely to occur in the carbocisteine group than in the placebo group (χ2=5·772, p=0·016), as shown in the figure. Our study revealed better prevention of exacerbations by carbocisteine in those with frequent events, but the exact mechanism is not known. Because carbocisteine works via its anti-inflammatory and antioxidant effects, improvements in COPD exacerbations will take time, and, as reported in the PEACE study,1 the preventive effects were found only in patients treated with carbocisteine for 6 months or more, indicating that the longer the carbocisteine administration, the better the preventive effects on recurrent exacerbation.
Carbocisteine Placebo
100
Probability of more than one exacerbation (%)
leading to diminished effect of drug. However, patients who are poor sulphur oxidisers are exposed to the active sulphide for longer periods.2 Ethnicity might have a role in altering biotransformation. By contrast with other placebocontrolled studies,3 the PEACE study showed no difference in exacerbation rate between the treatment and placebo group at 3 months; the possible reasons for this are not discussed. With only 16·7% of study participants on inhaled corticosteroids (>50% of patients with Global Initiative for Obstructive Lung Disease [GOLD] stage III and IV), it is likely that the beneficial effects of carbocisteine might indirectly be due to a lack of prevention by inhaled corticosteroids. The study would have been clinically useful if the efficacy of carbocisteine had been compared with that of inhaled corticosteroids and placebo in different groups. Mucolytics such as carbocisteine seem unlikely to replace inhaled steroids in the treatment of COPD, but might be an important alternative where corticosteroid use is contraindicated. The mechanisms by which carbocisteine prevents exacerbation of COPD could provide a clue to the mechanism of the disease itself.
75
50
25
0 0 Carbocisteine Placebo
353 354
3 244 239
6 Time (months) 194 169
9
12
142 146
138 145
Figure: Kaplan-Meier plot of probability of more than one exacerbation over time
1631