Correspondence
www.thelancet.com Vol 383 January 4, 2014
to private hospitals grew from $0·4 billion to $4 billion—a ten-fold increase. 55% of health expenditure in Turkey went to the private sector in 2009,5 which represents the growing trend towards privatisation in the Turkish health sector. The Ministry of Health has clearly orientated the system towards privatised health care. Although this is acknowledged by Atun and colleagues, it is not discussed in depth, perhaps because some authors work for the Ministry of Health itself. I declare that I have no conflicts of interest.
any effect on prevention of AAD or CDD they need to be started ideally before prescription of antibiotics or, at the very least, on the same day. Allen and his colleagues should compare patients who began probiotics on the same day that antibiotics were started with those who received antibiotics 5–7 days later. We might note a substantial difference between these two groups. I declare that I have no conflicts of interest.
Mikhail Kogan [email protected]
Bulent Kilic
George Washington University, Washington, DC 20037, USA
[email protected]
1
Department of Public Health Dokuz Eylul University, Izmir, 35340, Turkey 1
2
3
4
5
Atun R, Aydın S, Chakraborty S, et al. Universal health coverage in Turkey: enhancement of equity. Lancet 2013; 382: 65–99. Kilic B. Health finance in Turkey (in Turkish). http://halksagligiokulu.org/anasayfa/ components/com_booklibrary/ebooks/ Turkiye_Saglik_Raporu_2012.pdf (accessed Aug 30, 2013). Ministry of Health. Health Statistics Yearbook 2010. http://www.saglik.gov.tr/TR/dosya/172577/h/saglikistatistikleriyilligi2010.pdf (accessed Aug 30, 2013). Yardim M, Cilingiroglu N, Yardim N. Financial protection in health in Turkey: the effects of the Health Transformation Programme. Health Policy Plan 2013; published online Feb 14. DOI:10.1093/heapol/czt002. Sonmez M. Health is as your own money (in Turkish). Istanbul: Yordam Publications, 2011.
Probiotics and antibioticassociated diarrhoea Stephen Allen and colleagues report findings of the PLACIDE randomised trial (Oct 12, p 1249),1 in which a multistrain probiotic preparation of lactobacilli and bifido bacteria was compared with an identical placebo for prevention of antibioticassociated diarrhoea (AAD) and Clostridium difficile diarrhoea (CDD). The report is timely and important; however, a methodo logical issue needs to be addressed. Patients were allowed to receive antibiotics for up to 7 days before randomisation. For probiotics to have
AFP/Getty Images
in Turkey in the past 10 years, but fail to discuss in depth the problems of the Health Transformation Program (HTP). It is not correct to say that Turkey has achieved universal health coverage or that the HTP in the past 10 years has fulfilled that goal. The Social Health Insurance (SHI) system is not adapted to individuals’ incomes and fails to protect the poor. SHI only provides free health care for people who have a monthly income of US$150 or less. SHI is insufficiently funded, some prescriptions are not covered (eg, vitamins, dermatological products, and diabetic sweeteners), and others only partially (eg, eyeglasses prescriptions and dental treatment). Gender inequality is an important social issue in Turkey. Violence towards women is increasing and women’s participation in the workforce is decreasing. Surprisingly, Atun’s report contained no criticism of absence of substantial action by the government for gender equity in the past 10 years. The three children per women philosophy (supported by the government), the weakening of family planning services, and the abandonment of breastfeeding banks are threatening maternal and child health. The HTP was accompanied by substantial increases in health expenditures. Health expenditure tripled between 2003 and 2009, from $16·2 billion to $51·5 billion, driven by the growth of the private sector, a rise in medical technology expenses, and a performance-based payment system for medical staff.2 Outpatient visits increased from three per year to 7·7 between 2003 and 2011. The number of surgical operations also increased by 4·2 times.3 Another important issue is out-of-pocket health expenditures, which increased from $3 billion to $11 billion between 2003 and 2009, and their proportion of the total health expenditure increased from 16% to 26%.4 Meanwhile, SHI payments
Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2013; 382: 1249–57.
Stephen Allen and colleagues concluded in the PLACIDE randomised trial 1 that patients allocated to probiotic treatment with lactobacilli and bifido bac t eria were no more protected against antibioticassociated diarrhoea (AAD) or Clostridium difficile diarrhoea (CDD) than were those given placebo. A meta-analysis in the same report showed a significant 4% absolute risk reduction in AAD using similar probiotics, based on a fixed-effect analysis. Allen and colleagues stated “the difference was small and unlikely to be of clinical significance”. The fixed-effect model is not the most appropriate choice for analysis because it assumes that the true effect size is exactly the same for all studies. Visual inspection of the forest plot in the report and the very high I² of 90% show clearly that the fixed-effect analysis assumption was violated. A random-effects analysis should have been used. With this approach, the data indicate a risk difference of –0·12 (95% CI –0·21 to –0·02; p=0·018), which translates into a number needed to treat of eight to prevent one additional episode of AAD. This finding is certainly of clinical significance. 29
Correspondence
Charled Bach/Science Photo Library
Furthermore, the power of the PLACIDE study was designed to be 80%, based on a 50% reduction in CDD, assuming a 5% placebo effect. However, the trial ended with a much lower placebo effect (1·2%), which brought the study power down to 40%. Hence, a false-negative finding cannot be ruled out. The final verdict on this multistrain probiotic to prevent AAD or CDD remains unsettled. TCS has received research funding from ViroPharma and Cubist. ACK declares that he has no conflicts of interest.
*Andre C Kalil, Trevor C Schooneveld [email protected] University of Nebraska Medical Center, Omaha, NE 68198, USA 1
Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2013; 382: 1249–57.
Authors’ reply
Published Online October 25, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)62027-9
30
Mikhail Kogan says that probiotics are more effective for prevention of diarrhoea if given before or at the start of antibiotic treatment, rather than after. We are not aware of clinical trials that have addressed this issue. In PLACIDE, only patients exposed to antibiotics were eligible1,2 and, after being provided with trial information, many people wanted to discuss participation with their relatives. The exact start date for antibiotic treatment was known in 2926 patients; the median period of exposure to antibiotics before starting either probiotics or placebo was 3·0 days (IQR 2·0–6·0). Of 64 patients who began probiotic treatment or placebo on the same day they started taking antibiotics, AAD occurred in four (11%) of 35 assigned probiotics and in four (14%) of 29 allocated placebo (relative risk 0·83; 95% CI 0·23–3·03; p=0·78). Of those beginning probiotics or placebo after starting antibiotics, AAD occurred in 154 (11%) of 1428 assigned probiotics and in 149 (10%)
of 1434 allocated placebo (1·04, 0·84–1·28; p=0·73). The treatment effect did not differ by timing of the start of probiotics or placebo (interaction test, p=0·74). No cases of CDD occurred among patients starting probiotics or placebo on the same day as antibiotics. On the basis of the hypothesis that probiotics restore antidiarrhoeal mechanisms that have been lost through antibiotic depletion of gut flora,3 their effectiveness would be expected if administered after antibiotic treatment but before diarrhoea onset. Although we agree with Andre Kalil and Trevor Schooneveld that randomeffects analysis is appropriate in meta-analyses with significant statistical heterogeneity, the striking heterogeneity in our analysis indicates that any pooled estimate of efficacy should be interpreted with caution. Furthermore, in our limited meta-analysis of five trials, different microbial preparations were studied. Therefore, evidence for efficacy of any one preparation remains scant and data are insufficient as a basis for clinical guidelines. Kalil and Schooneveld consider that our study was underpowered because of the lower-than-expected frequency of CDD in the placebo group. However, retro spective power calculation is inappropriate.4 Although the noted frequency of CDD was lower than expected, it is within the range simulated in our sample size calculation. The uncertainty in the efficacy estimate spans a range of protective and harmful values. In combination with the low and declining frequency of CDD, any possible benefit of probiotics must be weighed very carefully against potential risks and costs. SJA has received research funding from Cultech and Yakult. All other authors declare that they have no conflicts of interest.
*Stephen J Allen, Michael B Gravenor, Kathie Wareham, Duolao Wang [email protected]
College of Medicine, Swansea University, Swansea SA2 8PP, UK (SJA, MBG); Clinical Research Unit, Morriston Hospital, Swansea, UK (KW); and Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK (DW) 1
2
3
4
Allen SJ, Wareham K, Bradley C, et al. A multicenter, randomised controlled trial evaluating lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea in older people admitted to hospital: the PLACIDE study protocol. BMC Infect Dis 2012; 12: 108. Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2013; 382: 1249–57. Hickson M. Probiotics in the prevention of antibiotic-associated diarrhoea and Clostridium difficile infection. Ther Adv Gastroenterol 2011; 4: 185–97. Hoenig JM, Heisey DM. The abuse of power: the pervasive fallacy of power calculations for data analysis. Am Stat 2001; 55: 19–24.
Department of Error Cahn P, Pozniak AL, Mingrone H, et al, on behalf of the extended SAILING Study Team. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet 2013; 382: 700–08–In table 3 of this Article (Aug 24), the data in the “Adverse events in ≥5% of patients in either group” row should be in a new row, “Drug-related grade 2–4 adverse events”. These corrections have been made to the online version as of Jan 3, 2014. Daugla DM, Gami JP, Gamougam K, et al. Effect of a serogroup A meningococcal conjugate vaccine (PsA–TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study. Lancet 2013; 383: 40–47—The study descriptor of this Article should have been “a community study”. This correction has been made to the online version as of Oct 25, 2013, and to the printed Article. Daugla DM, Gami JP, Gamougam K, et al. Effect of a serogroup A meningococcal conjugate vaccine (PsA–TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study. Lancet 2013; 383: 40–47—The Creative Commons licence for this Article should have been CC BY. The correction has been made to the online version as of Jan 3, 2014, and to the printed Article.
www.thelancet.com Vol 383 January 4, 2014
www.thelancet.com Vol 383 January 4, 2014
to private hospitals grew from $0·4 billion to $4 billion—a ten-fold increase. 55% of health expenditure in Turkey went to the private sector in 2009,5 which represents the growing trend towards privatisation in the Turkish health sector. The Ministry of Health has clearly orientated the system towards privatised health care. Although this is acknowledged by Atun and colleagues, it is not discussed in depth, perhaps because some authors work for the Ministry of Health itself. I declare that I have no conflicts of interest.
any effect on prevention of AAD or CDD they need to be started ideally before prescription of antibiotics or, at the very least, on the same day. Allen and his colleagues should compare patients who began probiotics on the same day that antibiotics were started with those who received antibiotics 5–7 days later. We might note a substantial difference between these two groups. I declare that I have no conflicts of interest.
Mikhail Kogan [email protected]
Bulent Kilic
George Washington University, Washington, DC 20037, USA
[email protected]
1
Department of Public Health Dokuz Eylul University, Izmir, 35340, Turkey 1
2
3
4
5
Atun R, Aydın S, Chakraborty S, et al. Universal health coverage in Turkey: enhancement of equity. Lancet 2013; 382: 65–99. Kilic B. Health finance in Turkey (in Turkish). http://halksagligiokulu.org/anasayfa/ components/com_booklibrary/ebooks/ Turkiye_Saglik_Raporu_2012.pdf (accessed Aug 30, 2013). Ministry of Health. Health Statistics Yearbook 2010. http://www.saglik.gov.tr/TR/dosya/172577/h/saglikistatistikleriyilligi2010.pdf (accessed Aug 30, 2013). Yardim M, Cilingiroglu N, Yardim N. Financial protection in health in Turkey: the effects of the Health Transformation Programme. Health Policy Plan 2013; published online Feb 14. DOI:10.1093/heapol/czt002. Sonmez M. Health is as your own money (in Turkish). Istanbul: Yordam Publications, 2011.
Probiotics and antibioticassociated diarrhoea Stephen Allen and colleagues report findings of the PLACIDE randomised trial (Oct 12, p 1249),1 in which a multistrain probiotic preparation of lactobacilli and bifido bacteria was compared with an identical placebo for prevention of antibioticassociated diarrhoea (AAD) and Clostridium difficile diarrhoea (CDD). The report is timely and important; however, a methodo logical issue needs to be addressed. Patients were allowed to receive antibiotics for up to 7 days before randomisation. For probiotics to have
AFP/Getty Images
in Turkey in the past 10 years, but fail to discuss in depth the problems of the Health Transformation Program (HTP). It is not correct to say that Turkey has achieved universal health coverage or that the HTP in the past 10 years has fulfilled that goal. The Social Health Insurance (SHI) system is not adapted to individuals’ incomes and fails to protect the poor. SHI only provides free health care for people who have a monthly income of US$150 or less. SHI is insufficiently funded, some prescriptions are not covered (eg, vitamins, dermatological products, and diabetic sweeteners), and others only partially (eg, eyeglasses prescriptions and dental treatment). Gender inequality is an important social issue in Turkey. Violence towards women is increasing and women’s participation in the workforce is decreasing. Surprisingly, Atun’s report contained no criticism of absence of substantial action by the government for gender equity in the past 10 years. The three children per women philosophy (supported by the government), the weakening of family planning services, and the abandonment of breastfeeding banks are threatening maternal and child health. The HTP was accompanied by substantial increases in health expenditures. Health expenditure tripled between 2003 and 2009, from $16·2 billion to $51·5 billion, driven by the growth of the private sector, a rise in medical technology expenses, and a performance-based payment system for medical staff.2 Outpatient visits increased from three per year to 7·7 between 2003 and 2011. The number of surgical operations also increased by 4·2 times.3 Another important issue is out-of-pocket health expenditures, which increased from $3 billion to $11 billion between 2003 and 2009, and their proportion of the total health expenditure increased from 16% to 26%.4 Meanwhile, SHI payments
Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2013; 382: 1249–57.
Stephen Allen and colleagues concluded in the PLACIDE randomised trial 1 that patients allocated to probiotic treatment with lactobacilli and bifido bac t eria were no more protected against antibioticassociated diarrhoea (AAD) or Clostridium difficile diarrhoea (CDD) than were those given placebo. A meta-analysis in the same report showed a significant 4% absolute risk reduction in AAD using similar probiotics, based on a fixed-effect analysis. Allen and colleagues stated “the difference was small and unlikely to be of clinical significance”. The fixed-effect model is not the most appropriate choice for analysis because it assumes that the true effect size is exactly the same for all studies. Visual inspection of the forest plot in the report and the very high I² of 90% show clearly that the fixed-effect analysis assumption was violated. A random-effects analysis should have been used. With this approach, the data indicate a risk difference of –0·12 (95% CI –0·21 to –0·02; p=0·018), which translates into a number needed to treat of eight to prevent one additional episode of AAD. This finding is certainly of clinical significance. 29
Correspondence
Charled Bach/Science Photo Library
Furthermore, the power of the PLACIDE study was designed to be 80%, based on a 50% reduction in CDD, assuming a 5% placebo effect. However, the trial ended with a much lower placebo effect (1·2%), which brought the study power down to 40%. Hence, a false-negative finding cannot be ruled out. The final verdict on this multistrain probiotic to prevent AAD or CDD remains unsettled. TCS has received research funding from ViroPharma and Cubist. ACK declares that he has no conflicts of interest.
*Andre C Kalil, Trevor C Schooneveld [email protected] University of Nebraska Medical Center, Omaha, NE 68198, USA 1
Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2013; 382: 1249–57.
Authors’ reply
Published Online October 25, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)62027-9
30
Mikhail Kogan says that probiotics are more effective for prevention of diarrhoea if given before or at the start of antibiotic treatment, rather than after. We are not aware of clinical trials that have addressed this issue. In PLACIDE, only patients exposed to antibiotics were eligible1,2 and, after being provided with trial information, many people wanted to discuss participation with their relatives. The exact start date for antibiotic treatment was known in 2926 patients; the median period of exposure to antibiotics before starting either probiotics or placebo was 3·0 days (IQR 2·0–6·0). Of 64 patients who began probiotic treatment or placebo on the same day they started taking antibiotics, AAD occurred in four (11%) of 35 assigned probiotics and in four (14%) of 29 allocated placebo (relative risk 0·83; 95% CI 0·23–3·03; p=0·78). Of those beginning probiotics or placebo after starting antibiotics, AAD occurred in 154 (11%) of 1428 assigned probiotics and in 149 (10%)
of 1434 allocated placebo (1·04, 0·84–1·28; p=0·73). The treatment effect did not differ by timing of the start of probiotics or placebo (interaction test, p=0·74). No cases of CDD occurred among patients starting probiotics or placebo on the same day as antibiotics. On the basis of the hypothesis that probiotics restore antidiarrhoeal mechanisms that have been lost through antibiotic depletion of gut flora,3 their effectiveness would be expected if administered after antibiotic treatment but before diarrhoea onset. Although we agree with Andre Kalil and Trevor Schooneveld that randomeffects analysis is appropriate in meta-analyses with significant statistical heterogeneity, the striking heterogeneity in our analysis indicates that any pooled estimate of efficacy should be interpreted with caution. Furthermore, in our limited meta-analysis of five trials, different microbial preparations were studied. Therefore, evidence for efficacy of any one preparation remains scant and data are insufficient as a basis for clinical guidelines. Kalil and Schooneveld consider that our study was underpowered because of the lower-than-expected frequency of CDD in the placebo group. However, retro spective power calculation is inappropriate.4 Although the noted frequency of CDD was lower than expected, it is within the range simulated in our sample size calculation. The uncertainty in the efficacy estimate spans a range of protective and harmful values. In combination with the low and declining frequency of CDD, any possible benefit of probiotics must be weighed very carefully against potential risks and costs. SJA has received research funding from Cultech and Yakult. All other authors declare that they have no conflicts of interest.
*Stephen J Allen, Michael B Gravenor, Kathie Wareham, Duolao Wang [email protected]
College of Medicine, Swansea University, Swansea SA2 8PP, UK (SJA, MBG); Clinical Research Unit, Morriston Hospital, Swansea, UK (KW); and Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK (DW) 1
2
3
4
Allen SJ, Wareham K, Bradley C, et al. A multicenter, randomised controlled trial evaluating lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea in older people admitted to hospital: the PLACIDE study protocol. BMC Infect Dis 2012; 12: 108. Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifidobacteria in the prevention of antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in older inpatients (PLACIDE): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2013; 382: 1249–57. Hickson M. Probiotics in the prevention of antibiotic-associated diarrhoea and Clostridium difficile infection. Ther Adv Gastroenterol 2011; 4: 185–97. Hoenig JM, Heisey DM. The abuse of power: the pervasive fallacy of power calculations for data analysis. Am Stat 2001; 55: 19–24.
Department of Error Cahn P, Pozniak AL, Mingrone H, et al, on behalf of the extended SAILING Study Team. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet 2013; 382: 700–08–In table 3 of this Article (Aug 24), the data in the “Adverse events in ≥5% of patients in either group” row should be in a new row, “Drug-related grade 2–4 adverse events”. These corrections have been made to the online version as of Jan 3, 2014. Daugla DM, Gami JP, Gamougam K, et al. Effect of a serogroup A meningococcal conjugate vaccine (PsA–TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study. Lancet 2013; 383: 40–47—The study descriptor of this Article should have been “a community study”. This correction has been made to the online version as of Oct 25, 2013, and to the printed Article. Daugla DM, Gami JP, Gamougam K, et al. Effect of a serogroup A meningococcal conjugate vaccine (PsA–TT) on serogroup A meningococcal meningitis and carriage in Chad: a community study. Lancet 2013; 383: 40–47—The Creative Commons licence for this Article should have been CC BY. The correction has been made to the online version as of Jan 3, 2014, and to the printed Article.
www.thelancet.com Vol 383 January 4, 2014
