Correspondence
Underinvestment of both enterprises and banks, and reduction in financing from international funds led to excessive reliance on the government for China’s climate financial system. Excessive reliance on government investment is unsustainable. As highlighted in the Lancet Commission Report,1 the key to increased financial resources is promotion of wellfunctioning markets by establishment of a framework of strong and predictable carbon price signals. These signals will ensure that there is a robust business case to invest and innovate in low-carbon industries.5 By the end of 2014, the local carbon emissions trading pilot programme, a meaningful step in promoting lowcarbon development through market mechanisms, was implemented in 7 cities in China. This institutional framework promoted market-based carbon pricing and boosted the private investment of relevant industries. With the development of carbon markets and prices, China is working towards a sustainable climate financial system. China should engage actively with the opportunity to protect the health and wellbeing of citizens of China and the whole world. We declare no competing interests.
For the COMPare project see www.COMPare-Trials.org
The Global Commission on the Economy and Climate. Better growth, better climate: the new climate economy report. Sept 16, 2014. http://2014.newclimateeconomy.report/ (accessed Sept 16, 2014).
Prophylactic antibiotics to reduce pneumonia after acute stroke The STROKE-INF trial (Nov 7, p1835)1 reported outcomes that were different from those initially included in the ISRCTN registry (number ISRCTN37118456). There were two prespecified primary outcomes, of which one was reported in the Article, and the other (“total hospital costs”) was not reported anywhere in the paper. In addition, the Article reported a new coprimary outcome (“physician diagnosed post-stroke pneumonia”) that was not pre-specified, without declaring it as such. Of the 14 pre-specified secondary outcomes, six were reported in the paper, and eight were unreported anywhere in the paper. Additionally, the Article reported five new secondary outcomes that were not pre-specified, without declaring them as such. We declare no competing interests.
Jing Dai, Chuanhua Xu, Lianming Liao, *Hanxiang An
*Ioan Milosevic, Aaron Dale, Henry Drysdale, Kamal Mahtani, on behalf of the COMPare project team
[email protected]
[email protected]
School of Finance, Hubei University of Economics, Wuhan, China (JD, CX); Central Laboratory, The Union Hospital of Fujian Medical University, Fuzhou, 350001, China (LL); and Department of Oncology, First Affiliated Hospital of Xiamen University, Xiamen, China (HA)
Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Services, Oxford OX2 6GG, UK
1
2
3
4
432
5
Watts N, Adger WN, Agnolucci P, et al, Health and climate change: policy responses to protect public health. Lancet 2015; 386: 1861–914. National Development and Reform Commission of China. The twelfth five-year plan of China. March 16, 2011. http://www. gov.cn/2011lh/content_1825838.htm (accessed March 16, 2011). The Climate Group. Shaping China’s climate finance policy. March 29, 2013. http://www. theclimategroup.org.cn/arc/201304/4129. shtml (accessed March 29, 2013). National Development and Reform Commission of China. China’s policies and actions on climate change. Nov 26,2014. http://www.sdpc.gov.cn/ gzdt/201411/t20141126_649615.html (accessed Nov 26, 2014).
1
Kalra L, Irshad S, Hodsoll J, et al. Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, cluster-randomised, open-label, masked endpoint, controlled clinical trial. Lancet 2015; 386: 1835–44.
We read the Article by Lalit Kalra and colleagues1 with great interest but are concerned about some issues. In our opinion, STROKE-INF was a negative trial because of insufficient dysphagia management before randomisation to antibiotic treatment that was not able to prevent aspiration pneumonia.
The study protocol mentions that nursing staff assessed swallowing function with standard bedside swallowing tests within 48 h of symptom onset, without using any instrument-based tests—eg, fibreendoscopic evaluation of swallowing. First, time is crucial in dysphagia caused by acute stroke, since aspiration can occur immediately after onset. A time period of 48 h might thus be too long to diagnose dysphagia. It was also unclear whether patients were kept nil per os in the meantime to prevent aspiration and subsequently aspiration pneumonia. Second, the sensitivity and specificity of clinical bedside swallowing tests were insufficient to identify stroke patients with dysphagia at risk for aspiration. 2 Therefore, German guidelines recommend standardised swallowing assessment consisting of an instrument-based test of swallowing function to guide dietetic and logopaedic treatment.3 Our hypothesis is underlined by the high rates of pneumonia in both treatment groups of the STROKE-INF trial compared with that in Germany (10–16% vs 5·1%).4 Rates of pneumonia are even lower in our institution (3·0% in 2013, and 3·26% in 2014), most probably because of an abundant use of fibre-endoscopic evaluation of swallowing. Against this background, it would be of major interest if Kalra and colleagues could present data concerning time interval of swallowing assessment and use of instrumental reference tests in the STROKE-INF trial. We declare no competing interests.
*Hermann Neugebauer, Beate Lindner-Pfleghar, Eric Jüttler, Albert C Ludolph, Axel Riecker [email protected] Department of Neurology, University of Ulm, 89081 Ulm, Germany (HN, BL-P, EJ, ACL, AR); Department of Neurology, Ostalb-Klinikum Aalen, Aalen, Germany (EJ); and Department of Neurology and Rehabilitation, RehaNova, Cologne, Germany (AR) 1
Kalra L, Irshad S, Hodsoll J, et al. Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, clusterrandomised, open-label, masked endpoint, controlled clinical trial. Lancet 2015; 386: 1835–
www.thelancet.com Vol 387 January 30, 2016
Correspondence
3
4
44. Daniels SK, Anderson JA, Willson PC. Valid items for screening dysphagia risk in patients with stroke: a systematic review. Stroke 2012; 43: 892–97. Prosiegel M, Riecker A, Weinert M, et al. [Management of dysphagic patients with acute stroke]. Nervenarzt 2012; 83: 1590–99 (in German). Nimptsch U, Mansky T. Trends in acute inpatient stroke care in Germany—an observational study using administrative hospital data from 2005–2010. Dtsch Arztebl Int 2012; 109: 885–92.
Author’s reply Ioan Milosevic and colleagues pointed out that the outcomes presented in our Article1 were different from those in the ISRCTN registry (number ISRCTN37118456). They stated that one pre-specified primary outcome (“hospital costs”) was not reported, and a new co-primary outcome (“physician diagnosed post-stroke pneumonia”) added. We have clarified in the Methods section that physician diagnosed pneumonia was not a primary outcome but was presented as an alternative to algorithmbased diagnosis to harmonise with diagnostic criteria used in previous studies.2 Our innovative approach to post-stroke pneumonia (PSP) diagnosis helped to minimise detection bias in physician diagnosis arising from overdependence on fever and stroke severity as principal determinants.3 With regards to cost outcomes, both the primary and four of the eight so-called missing secondary outcomes (therapy costs, quality of life, institutionalisation, and cost-effectiveness ratios) will be presented in a later publication as stated in the headline paper, because cost-effectiveness in the absence of clinical effectiveness has little value. The five so-called new endpoints include four of eight “unreported” pre-specified endpoints (National Institutes of Health Stroke Scale [NIHSS] score, change in NIHSS score at 14 days, mortality at 14 days, and modified Rankin Scale 0–2 at 90 days). Length of stay in survivors and days to death (the fifth so-called new endpoint) are components of www.thelancet.com Vol 387 January 30, 2016
length of hospital stay, but they were presented separately to prevent bias from higher mortality in either group that resulted in a difference in length of stay between groups. We commend the vigilance shown by Milosevic and colleagues, but also believe that diligence needs to be exercised in analysing published data for the COMPare project to be credible. In Hermann Neugebauer and colleagues’ letter, the PSP incidence rates quoted are for all stroke patients and include non-dysphagic patients, in whom the risk of PSP is 2%—compared with 16% in dysphagic patients,4 the patient population for the STROKE-INF study. Routine use of fibre-endoscopic evaluation of swallowing is not recommended by UK guidelines, and PSP incidence in dysphagic patients is likely to be determined by dysphagia management rather than the method used for screening. For clarification, dysphagia screening and management were initiated at admission for all patients; 48 h was the maximum interval between stroke to randomisation and trial intervention. Finally, any bias caused by screening methods or management of dysphagia between the control and intervention groups would have been controlled for by randomisation in this study. I declare no competing interests.
Lalit Kalra [email protected] Department of Basic and Clinical Neuroscience, IoPPN, King’s College London, London SE5 8AF, UK 1
2
3
4
Kalra L, Irshad S, Hodsoll J, et al. Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, cluster-randomised, open-label, masked endpoint, controlled clinical trial. Lancet 2015; 386: 1835–44. Smith CJ, Kishore AK, Vail A, et al. Diagnosis of stroke-associated pneumonia: recommendations from the pneumonia in stroke consensus group. Stroke 2015; 46: 2335–40. Harms H, Hoffmann S, Malzahn U, Ohlraun S, Heuschmann P, Meisel A. Decision-making in the diagnosis and treatment of stroke-associated pneumonia. J Neurol Neurosurg Psychiatry 2012; 83: 1225–30. Martino R, Foley N, Bhogal S. Dysphagia after stroke. Incidence, diagnosis and pulmonary complications. Stroke 2005; 36: 2756–63.
The promise of personalised medicine
UK Crown Copyright Courtesy of Fera/Science Photo Library
2
Genomics are anticipated to have an important role in promoting population health by being used to target at-risk individuals. In 2015, Victor Dzau and colleagues1 proposed that identification of genomic variants in major complex diseases would lead to modulation of health-related behaviours, with a 10–50% reduction in disease incidence. Most studies in a Cochrane review,2 however, showed no evidence of incremental behavioural changes by patients after provision of genetic risk information alongside lifestyle interventions. Given that genomics can currently explain only a small fraction of inherited complex disease risks, such testing is also unlikely to lead to behavioural changes. A broad, genomic, health-risk factor modification approach to major complex diseases has not yet proven to be effective. An alternative strategy is needed to deliver on the promise of personalised medicine. Genomic medicine achieved its initial success with its application to serious diseases caused by highly penetrant alleles. Large health benefits have already been shown from the provision of genomic information to individuals at high risk of imminent, serious, preventable, and penetrant disorders, even when the behavioural modification need is arduous. Phenylketonuria is such a disease that genomic medicine can help. For every 4 weeks that dietary treatment is delayed after birth there is an associated decrease of 7–10 intelligence quotient (IQ) points.3 Yet, despite the burden to maintain a phenylalaninerestricted diet being more onerous than the uptake of healthy lifestyle behaviours, the prevalence of the disabling effects of phenylketonuria has been reduced by 92% with introduction of newborn screening and dietary advice.4 Reductions in the prevalence of conditions with high health-care costs, such as fragile 433
Underinvestment of both enterprises and banks, and reduction in financing from international funds led to excessive reliance on the government for China’s climate financial system. Excessive reliance on government investment is unsustainable. As highlighted in the Lancet Commission Report,1 the key to increased financial resources is promotion of wellfunctioning markets by establishment of a framework of strong and predictable carbon price signals. These signals will ensure that there is a robust business case to invest and innovate in low-carbon industries.5 By the end of 2014, the local carbon emissions trading pilot programme, a meaningful step in promoting lowcarbon development through market mechanisms, was implemented in 7 cities in China. This institutional framework promoted market-based carbon pricing and boosted the private investment of relevant industries. With the development of carbon markets and prices, China is working towards a sustainable climate financial system. China should engage actively with the opportunity to protect the health and wellbeing of citizens of China and the whole world. We declare no competing interests.
For the COMPare project see www.COMPare-Trials.org
The Global Commission on the Economy and Climate. Better growth, better climate: the new climate economy report. Sept 16, 2014. http://2014.newclimateeconomy.report/ (accessed Sept 16, 2014).
Prophylactic antibiotics to reduce pneumonia after acute stroke The STROKE-INF trial (Nov 7, p1835)1 reported outcomes that were different from those initially included in the ISRCTN registry (number ISRCTN37118456). There were two prespecified primary outcomes, of which one was reported in the Article, and the other (“total hospital costs”) was not reported anywhere in the paper. In addition, the Article reported a new coprimary outcome (“physician diagnosed post-stroke pneumonia”) that was not pre-specified, without declaring it as such. Of the 14 pre-specified secondary outcomes, six were reported in the paper, and eight were unreported anywhere in the paper. Additionally, the Article reported five new secondary outcomes that were not pre-specified, without declaring them as such. We declare no competing interests.
Jing Dai, Chuanhua Xu, Lianming Liao, *Hanxiang An
*Ioan Milosevic, Aaron Dale, Henry Drysdale, Kamal Mahtani, on behalf of the COMPare project team
[email protected]
[email protected]
School of Finance, Hubei University of Economics, Wuhan, China (JD, CX); Central Laboratory, The Union Hospital of Fujian Medical University, Fuzhou, 350001, China (LL); and Department of Oncology, First Affiliated Hospital of Xiamen University, Xiamen, China (HA)
Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Services, Oxford OX2 6GG, UK
1
2
3
4
432
5
Watts N, Adger WN, Agnolucci P, et al, Health and climate change: policy responses to protect public health. Lancet 2015; 386: 1861–914. National Development and Reform Commission of China. The twelfth five-year plan of China. March 16, 2011. http://www. gov.cn/2011lh/content_1825838.htm (accessed March 16, 2011). The Climate Group. Shaping China’s climate finance policy. March 29, 2013. http://www. theclimategroup.org.cn/arc/201304/4129. shtml (accessed March 29, 2013). National Development and Reform Commission of China. China’s policies and actions on climate change. Nov 26,2014. http://www.sdpc.gov.cn/ gzdt/201411/t20141126_649615.html (accessed Nov 26, 2014).
1
Kalra L, Irshad S, Hodsoll J, et al. Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, cluster-randomised, open-label, masked endpoint, controlled clinical trial. Lancet 2015; 386: 1835–44.
We read the Article by Lalit Kalra and colleagues1 with great interest but are concerned about some issues. In our opinion, STROKE-INF was a negative trial because of insufficient dysphagia management before randomisation to antibiotic treatment that was not able to prevent aspiration pneumonia.
The study protocol mentions that nursing staff assessed swallowing function with standard bedside swallowing tests within 48 h of symptom onset, without using any instrument-based tests—eg, fibreendoscopic evaluation of swallowing. First, time is crucial in dysphagia caused by acute stroke, since aspiration can occur immediately after onset. A time period of 48 h might thus be too long to diagnose dysphagia. It was also unclear whether patients were kept nil per os in the meantime to prevent aspiration and subsequently aspiration pneumonia. Second, the sensitivity and specificity of clinical bedside swallowing tests were insufficient to identify stroke patients with dysphagia at risk for aspiration. 2 Therefore, German guidelines recommend standardised swallowing assessment consisting of an instrument-based test of swallowing function to guide dietetic and logopaedic treatment.3 Our hypothesis is underlined by the high rates of pneumonia in both treatment groups of the STROKE-INF trial compared with that in Germany (10–16% vs 5·1%).4 Rates of pneumonia are even lower in our institution (3·0% in 2013, and 3·26% in 2014), most probably because of an abundant use of fibre-endoscopic evaluation of swallowing. Against this background, it would be of major interest if Kalra and colleagues could present data concerning time interval of swallowing assessment and use of instrumental reference tests in the STROKE-INF trial. We declare no competing interests.
*Hermann Neugebauer, Beate Lindner-Pfleghar, Eric Jüttler, Albert C Ludolph, Axel Riecker [email protected] Department of Neurology, University of Ulm, 89081 Ulm, Germany (HN, BL-P, EJ, ACL, AR); Department of Neurology, Ostalb-Klinikum Aalen, Aalen, Germany (EJ); and Department of Neurology and Rehabilitation, RehaNova, Cologne, Germany (AR) 1
Kalra L, Irshad S, Hodsoll J, et al. Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, clusterrandomised, open-label, masked endpoint, controlled clinical trial. Lancet 2015; 386: 1835–
www.thelancet.com Vol 387 January 30, 2016
Correspondence
3
4
44. Daniels SK, Anderson JA, Willson PC. Valid items for screening dysphagia risk in patients with stroke: a systematic review. Stroke 2012; 43: 892–97. Prosiegel M, Riecker A, Weinert M, et al. [Management of dysphagic patients with acute stroke]. Nervenarzt 2012; 83: 1590–99 (in German). Nimptsch U, Mansky T. Trends in acute inpatient stroke care in Germany—an observational study using administrative hospital data from 2005–2010. Dtsch Arztebl Int 2012; 109: 885–92.
Author’s reply Ioan Milosevic and colleagues pointed out that the outcomes presented in our Article1 were different from those in the ISRCTN registry (number ISRCTN37118456). They stated that one pre-specified primary outcome (“hospital costs”) was not reported, and a new co-primary outcome (“physician diagnosed post-stroke pneumonia”) added. We have clarified in the Methods section that physician diagnosed pneumonia was not a primary outcome but was presented as an alternative to algorithmbased diagnosis to harmonise with diagnostic criteria used in previous studies.2 Our innovative approach to post-stroke pneumonia (PSP) diagnosis helped to minimise detection bias in physician diagnosis arising from overdependence on fever and stroke severity as principal determinants.3 With regards to cost outcomes, both the primary and four of the eight so-called missing secondary outcomes (therapy costs, quality of life, institutionalisation, and cost-effectiveness ratios) will be presented in a later publication as stated in the headline paper, because cost-effectiveness in the absence of clinical effectiveness has little value. The five so-called new endpoints include four of eight “unreported” pre-specified endpoints (National Institutes of Health Stroke Scale [NIHSS] score, change in NIHSS score at 14 days, mortality at 14 days, and modified Rankin Scale 0–2 at 90 days). Length of stay in survivors and days to death (the fifth so-called new endpoint) are components of www.thelancet.com Vol 387 January 30, 2016
length of hospital stay, but they were presented separately to prevent bias from higher mortality in either group that resulted in a difference in length of stay between groups. We commend the vigilance shown by Milosevic and colleagues, but also believe that diligence needs to be exercised in analysing published data for the COMPare project to be credible. In Hermann Neugebauer and colleagues’ letter, the PSP incidence rates quoted are for all stroke patients and include non-dysphagic patients, in whom the risk of PSP is 2%—compared with 16% in dysphagic patients,4 the patient population for the STROKE-INF study. Routine use of fibre-endoscopic evaluation of swallowing is not recommended by UK guidelines, and PSP incidence in dysphagic patients is likely to be determined by dysphagia management rather than the method used for screening. For clarification, dysphagia screening and management were initiated at admission for all patients; 48 h was the maximum interval between stroke to randomisation and trial intervention. Finally, any bias caused by screening methods or management of dysphagia between the control and intervention groups would have been controlled for by randomisation in this study. I declare no competing interests.
Lalit Kalra [email protected] Department of Basic and Clinical Neuroscience, IoPPN, King’s College London, London SE5 8AF, UK 1
2
3
4
Kalra L, Irshad S, Hodsoll J, et al. Prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (STROKE-INF): a prospective, cluster-randomised, open-label, masked endpoint, controlled clinical trial. Lancet 2015; 386: 1835–44. Smith CJ, Kishore AK, Vail A, et al. Diagnosis of stroke-associated pneumonia: recommendations from the pneumonia in stroke consensus group. Stroke 2015; 46: 2335–40. Harms H, Hoffmann S, Malzahn U, Ohlraun S, Heuschmann P, Meisel A. Decision-making in the diagnosis and treatment of stroke-associated pneumonia. J Neurol Neurosurg Psychiatry 2012; 83: 1225–30. Martino R, Foley N, Bhogal S. Dysphagia after stroke. Incidence, diagnosis and pulmonary complications. Stroke 2005; 36: 2756–63.
The promise of personalised medicine
UK Crown Copyright Courtesy of Fera/Science Photo Library
2
Genomics are anticipated to have an important role in promoting population health by being used to target at-risk individuals. In 2015, Victor Dzau and colleagues1 proposed that identification of genomic variants in major complex diseases would lead to modulation of health-related behaviours, with a 10–50% reduction in disease incidence. Most studies in a Cochrane review,2 however, showed no evidence of incremental behavioural changes by patients after provision of genetic risk information alongside lifestyle interventions. Given that genomics can currently explain only a small fraction of inherited complex disease risks, such testing is also unlikely to lead to behavioural changes. A broad, genomic, health-risk factor modification approach to major complex diseases has not yet proven to be effective. An alternative strategy is needed to deliver on the promise of personalised medicine. Genomic medicine achieved its initial success with its application to serious diseases caused by highly penetrant alleles. Large health benefits have already been shown from the provision of genomic information to individuals at high risk of imminent, serious, preventable, and penetrant disorders, even when the behavioural modification need is arduous. Phenylketonuria is such a disease that genomic medicine can help. For every 4 weeks that dietary treatment is delayed after birth there is an associated decrease of 7–10 intelligence quotient (IQ) points.3 Yet, despite the burden to maintain a phenylalaninerestricted diet being more onerous than the uptake of healthy lifestyle behaviours, the prevalence of the disabling effects of phenylketonuria has been reduced by 92% with introduction of newborn screening and dietary advice.4 Reductions in the prevalence of conditions with high health-care costs, such as fragile 433
