Correspondence
4
5
Boussageon R, Supper I, Bejan-Angoulvant T, et al. Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med 2012; 9: e1001204. ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011; 364: 818–28.
Authors’ reply We are delighted to see John Yudkin and colleagues sharing our vision1 of future trials using comprehensive electronic health records. Such systems will allow head-to-head comparisons of glucose-lowering drugs with longer follow-up periods at reduced costs. Some ongoing outcome trials have already used pragmatic designs, aiming to investigate the effectiveness of interventions in routine practice settings, with the intent of providing more generalisable results. However, approaches using electronic health record systems would enable clinical trials to be fully embedded within usual diabetes care. Several major UK and US initiatives (NIH Collaboratory, PCORnet) are developing powerful methods for this purpose.2 We agree with Yudkin and colleagues that balanced patient information is essential to support individualised treatment decision making. Their analysis of utilities is interesting but treatment utilities can vary substantially between individuals and over time, as can complication utilities, limiting the applicability of their examples for individual diabetes care. Additionally, other studies have shown lower complication utilities for macrovascular and microvascular complications than those used by Yudkin and colleagues, which could potentially change the outcome of their analysis.3 Although blood pressure and lipid control have a greater effect than glucose lowering on macrovascular complications, new, improved, and more durable glucose-lowering drugs are still needed to minimise microvascular complications. Such drugs need to have minimum adverse effects and, ideally, reduce cardiovascular events and improve microvascular outcomes. www.thelancet.com Vol 384 September 20, 2014
Olga Vaccaro and colleagues emphasise the indisputable importance of independent funding for large interventional trials. We would welcome such arrangements, but these trials are expensive and the climate of government support provides no solace for those hoping for government funding to cover the costs incurred. In view of the way that most outcome trials are done at present, future research is unlikely to remain feasible without industry support. Besides the TOSCA.IT trial, four additional ongoing cardiovascular outcome trials (NCT00790205, NCT01144338, NCT01730534, ISRCTN91899513) of glucose-lowering drugs are being done as collaborations between an industry sponsor and academic trial centres. If the academic centre has the trial oversight and leads on design, data management, statistical analysis, interpretation, and drafting of the manuscript, we believe that such collaborations are the next best option after independent, public funding. Additionally, we agree with Remy Boussageon that assessment of clinically important outcomes for glucose-lowering drugs is important and that research should not be limited to safety studies, as our report emphasised.1 As rightly mentioned by Boussageon, no double-blind randomised controlled outcome trials has shown cardiovascular benefits for glucose-lowering drugs. However, the open-label UK Prospective Study (UKPDS), which achieved 0·9% lower mean HbA1c concentrations during a 10 year period in the intensive treatment group, showed a 25% reduction (p=0·0099) in so-called hard microvascular disease (photocoagulation, vitreous haemorrhage, renal failure, or renal death), which has affected treatment guidelines worldwide. Epidemiological data suggest that the effect of HbA1c lowering on cardiovascular disease is much less, with UKPDS data suggesting a 14% decrease in fatal and non-fatal myocardial infarction for a 1% decrement in HbA1c.4 This effect size
mirrored the borderline significant 16% reduction in myocardial infarction in the UKPDS intensive treatment group (p=0·52), that became a significant 15% reduction (p=0·014) during the 10 year post-trial monitoring period.5 Self-evidently, use of drugs directly targeting cardiovascular disease, such as statins and antihypertensive drugs, will have larger effect sizes recorded over shorter time periods. The metformin data are from a subgroup of the UKPDS that as a whole trial met our definition of an outcome trial. Despite the relatively few patients, there was a pronounced 36% relative risk reduction in myocardial infarction (p=0·01),6 which persisted during the post-trial monitoring period. As a result of this, most guidelines endorse metformin as first-line treatment for type 2 diabetes. We await the results of the GLINT trial examining the effect of double-blind prolonged-release metformin or placebo on cardiovascular disease in about 12 900 people at risk of diabetes (ISRCTN34875079). The increased mortality risk suggested by a post-hoc analysis of UKPDS participants randomised secondarily to early addition of metformin to sulfonylurea6 has long been debated, but a subsequent analysis including data from the 10 year post-trial monitoring period showed no significant difference between diabetesrelated deaths and all-cause mortality.7 The UKPDS 10 year post-trial monitoring period added 66 000 person-years of follow-up and showed a legacy effect from earlier allocation to glucoselowering therapy. 5 The ACCORD post-trial monitoring, by contrast, which only extended follow-up from mean 3·7 years to 5 years, did not show any new substantive findings.8 Nonetheless, the balance of risk and benefit of aiming for glycaemic targets is a topic worthy of additional research in view of the unexplained increased mortality signal from ACCORD. RRH received grants from Bristol-Myers Squibb, grants and personal fees from Bayer and Merck, and personal fees from Novartis and Jansen, all outside the submitted work. RMC received grants from Amylin, Novartis, Schering-Plough Research Institute, Scios, Eli
1097
Correspondence
Lilly, Johnsons & Johnson/Scios, Aterovax, Bayer, the NIH, and the Patient-Centered Outcomes Research Institute; grants and personal fees from Bristol-Myers Squibb, Janssen Research & Development, Merck, and Roche; personal fees from Genentech, GlaxoSmithKline, Heart.org/Daiichi Sankyo, Kowa, Servier, Medscape, Regeneron, TMC, Pfizer, Gambro, Gilead, DSI-Lilly, CV Sight, Heart.org/Bayer, Bayer Pharma AG, Bayer Healthcare, Parkview, Pozen, Orexigen, Nile, and WebMD; and other financial support from N30 Pharma, Portola, and Nitrox LLC, all outside the submitted work. HS declares no competing interests.
*Rury R Holman, Harald Sourij, Robert M Califf [email protected] Diabetes Trials Unit, Churchill Hospital, University of Oxford, Oxford, Headington OX3 7LJ, UK (RRH, HS); Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria (HS); and Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA (RMC) 1
2
3
4
5
Published Online July 11, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60982-X
6
7
8
Holman RR, Sourij H, Califf RM. Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes. Lancet 2014; 383: 2008–17. Selby JV, Lipstein SH. PCORI at 3 years— progress, lessons, and plans. N Engl J Med 2014; 370: 592–95. Huang ES, Brown SE, Ewigman BG, Foley EC, Meltzer DO. Patient perceptions of quality of life with diabetes-related complications and treatments. Diabetes Care 2007; 30: 2478–83. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: 405–12. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 1577–89. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854–65. Holman RR. Post trial monitoring results of the UKPDS sulfonylurea plus metformin substudy. EASD, 2013. http://www.easdvirtualmeeting. org/resources/6795 (accessed July 21, 2014). ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011; 364: 818–28.
Prevention of misconduct in clinical trials in Japan Since the publication of my concerns about the Jikei Heart Study in The Lancet,1 the fabrication and the falsification of data of four valsartan studies (Jikei Heart Study,2 Kyoto Heart Study,3 VART,4 and SMART5) have been 1098
identified by the board of investigators from each of the universities where these trials were done. This misconduct might have caused disadvantages to patients, and has led to unnecessary defrayment of health insurance and an increase in the cost of medical care. In Japan, there are three types of drug-related clinical trials: short-term clinical trials with small-scale assessment of a new drug for approval (a phase 3 trial), which are double-blind trials done according to the ministerial ordinance on Good Clinical Practice; post-marketing phase 4 studies done by pharmaceutical companies, according to the Good Post-Marketing Study Practice; and long-term post-marketing clinical trials of a large scale done by doctors. Long-term post-marketing clinical trials are open trials with a prospective, randomised, open, blinded-endpoint design. Trials were not done under any government regulations and were funded by pharmaceutical companies. Valsartan-related misconduct in Japan occurred in long-term post-marketing clinical trials. Many people believe that employees of pharmaceutical companies should not be involved in clinical trials. However, I believe that this is incorrect. In novel drug trials, the pharmaceutical company funding the study takes responsibility from beginning to end, including of the statistical analysis, and almost no problems have been reported. With the double-blind method, the malicious manipulation of cardiovascular events, especially soft endpoint or blood pressure values advantageous for valsartan, will be prevented. Thus, the Ministry of Health, Labour and Welfare should make the double-blind method an essential requirement in clinical studies done by doctors. Data should be assured by a quality assurance centre and preserved permanently by a national centre; however, too many strict regulations should be avoided. Ideally, similarly to the USA and Europe, the unification of the three types of trial should be considered in the double-blind condition. Even if the number of trials
decreases because of the increased cost, truly scientific clinical trials should still be done for the progress of medical science and the promotion of national health. I declare no competing interests.
Yoshiki Yui [email protected] Department of Cardiovascular Medicine, Kyoto University Hospital, Kyoto 6068397, Japan 1 2
3
4
5
Yui Y. Concerns about the Jikei Heart Study. Lancet 2012; 379: e48. Mochizuki S, Dahlof B, Shimizu M, et al, for the Jikei Heart Study group. RETRACTED: Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomized, open-label, blinded endpoint morbidity-mortality study. Lancet 2007; 369: 1431–39. Sawada T, Yamada H, Dahlof B, Matsubara H, for the Kyoto Heart Study Group. RETRACTED: Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: Kyoto Heart Study. Eur Heart J 2009; 30: 2461–69. Narumi H, Takano H, Shindo S, et al, on behalf of the VART Investigators. Effects of valsartan and amlodipine on cardiorenal protection in Japanese hypertensive patients: the Valsartan Amlodipine Randomized Trial. Hypertens Res 2011; 34: 62–69. The Shiga Microalbuminuria Reduction Trial (SMART) Group. RETRACTED: Reduction of microalbuminuria in patients with type 2 diabetes. Diabetes Care 2007; 30: 1581–83.
Department of Error Renfrew MJ, McFadden A, Bastos MH, et al. Midwifery and quality care: findings from a new evidence-informed framework for maternal and newborn care. Lancet 2014; 384: 1129–45—In the table, the outcomes “perinatal, neonatal, or infant mortality reduced” and “fetal loss reduced” should have been placed after “increased contraceptive use”. This change has been made to the online version as of July 11, 2014, and the printed Article is correct. Homer CSE, Friberg IK, Bastos Dias MA, et al. The projected effect of scaling up midwifery. Lancet 2014; 384: 1146–57—In this Series, in the key messages, 78 Countdown countries should have been 78 countries. In the The Lives Saved Tool section, the repetition of morbidity was removed. The Active management of the third stage of labour heading was deleted. In the Construction of the standard populations section, the report should have been The State of the World’s Midwifery 2011 Report. These corrections have been made to the online version as of Sept 19, 2014, and the printed Article is correct. Maartens G, Celum C, Lewin SR. HIV infection: epidemiology, pathogenesis, treatment, and prevention. Lancet 2014; 384: 258–71—In figure 3 of this Seminar, labels for parts B and C should have been reversed. This correction has been made to the online version as of Sept 19, 2014, and the printed Seminar is correct.
www.thelancet.com Vol 384 September 20, 2014
4
5
Boussageon R, Supper I, Bejan-Angoulvant T, et al. Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials. PLoS Med 2012; 9: e1001204. ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011; 364: 818–28.
Authors’ reply We are delighted to see John Yudkin and colleagues sharing our vision1 of future trials using comprehensive electronic health records. Such systems will allow head-to-head comparisons of glucose-lowering drugs with longer follow-up periods at reduced costs. Some ongoing outcome trials have already used pragmatic designs, aiming to investigate the effectiveness of interventions in routine practice settings, with the intent of providing more generalisable results. However, approaches using electronic health record systems would enable clinical trials to be fully embedded within usual diabetes care. Several major UK and US initiatives (NIH Collaboratory, PCORnet) are developing powerful methods for this purpose.2 We agree with Yudkin and colleagues that balanced patient information is essential to support individualised treatment decision making. Their analysis of utilities is interesting but treatment utilities can vary substantially between individuals and over time, as can complication utilities, limiting the applicability of their examples for individual diabetes care. Additionally, other studies have shown lower complication utilities for macrovascular and microvascular complications than those used by Yudkin and colleagues, which could potentially change the outcome of their analysis.3 Although blood pressure and lipid control have a greater effect than glucose lowering on macrovascular complications, new, improved, and more durable glucose-lowering drugs are still needed to minimise microvascular complications. Such drugs need to have minimum adverse effects and, ideally, reduce cardiovascular events and improve microvascular outcomes. www.thelancet.com Vol 384 September 20, 2014
Olga Vaccaro and colleagues emphasise the indisputable importance of independent funding for large interventional trials. We would welcome such arrangements, but these trials are expensive and the climate of government support provides no solace for those hoping for government funding to cover the costs incurred. In view of the way that most outcome trials are done at present, future research is unlikely to remain feasible without industry support. Besides the TOSCA.IT trial, four additional ongoing cardiovascular outcome trials (NCT00790205, NCT01144338, NCT01730534, ISRCTN91899513) of glucose-lowering drugs are being done as collaborations between an industry sponsor and academic trial centres. If the academic centre has the trial oversight and leads on design, data management, statistical analysis, interpretation, and drafting of the manuscript, we believe that such collaborations are the next best option after independent, public funding. Additionally, we agree with Remy Boussageon that assessment of clinically important outcomes for glucose-lowering drugs is important and that research should not be limited to safety studies, as our report emphasised.1 As rightly mentioned by Boussageon, no double-blind randomised controlled outcome trials has shown cardiovascular benefits for glucose-lowering drugs. However, the open-label UK Prospective Study (UKPDS), which achieved 0·9% lower mean HbA1c concentrations during a 10 year period in the intensive treatment group, showed a 25% reduction (p=0·0099) in so-called hard microvascular disease (photocoagulation, vitreous haemorrhage, renal failure, or renal death), which has affected treatment guidelines worldwide. Epidemiological data suggest that the effect of HbA1c lowering on cardiovascular disease is much less, with UKPDS data suggesting a 14% decrease in fatal and non-fatal myocardial infarction for a 1% decrement in HbA1c.4 This effect size
mirrored the borderline significant 16% reduction in myocardial infarction in the UKPDS intensive treatment group (p=0·52), that became a significant 15% reduction (p=0·014) during the 10 year post-trial monitoring period.5 Self-evidently, use of drugs directly targeting cardiovascular disease, such as statins and antihypertensive drugs, will have larger effect sizes recorded over shorter time periods. The metformin data are from a subgroup of the UKPDS that as a whole trial met our definition of an outcome trial. Despite the relatively few patients, there was a pronounced 36% relative risk reduction in myocardial infarction (p=0·01),6 which persisted during the post-trial monitoring period. As a result of this, most guidelines endorse metformin as first-line treatment for type 2 diabetes. We await the results of the GLINT trial examining the effect of double-blind prolonged-release metformin or placebo on cardiovascular disease in about 12 900 people at risk of diabetes (ISRCTN34875079). The increased mortality risk suggested by a post-hoc analysis of UKPDS participants randomised secondarily to early addition of metformin to sulfonylurea6 has long been debated, but a subsequent analysis including data from the 10 year post-trial monitoring period showed no significant difference between diabetesrelated deaths and all-cause mortality.7 The UKPDS 10 year post-trial monitoring period added 66 000 person-years of follow-up and showed a legacy effect from earlier allocation to glucoselowering therapy. 5 The ACCORD post-trial monitoring, by contrast, which only extended follow-up from mean 3·7 years to 5 years, did not show any new substantive findings.8 Nonetheless, the balance of risk and benefit of aiming for glycaemic targets is a topic worthy of additional research in view of the unexplained increased mortality signal from ACCORD. RRH received grants from Bristol-Myers Squibb, grants and personal fees from Bayer and Merck, and personal fees from Novartis and Jansen, all outside the submitted work. RMC received grants from Amylin, Novartis, Schering-Plough Research Institute, Scios, Eli
1097
Correspondence
Lilly, Johnsons & Johnson/Scios, Aterovax, Bayer, the NIH, and the Patient-Centered Outcomes Research Institute; grants and personal fees from Bristol-Myers Squibb, Janssen Research & Development, Merck, and Roche; personal fees from Genentech, GlaxoSmithKline, Heart.org/Daiichi Sankyo, Kowa, Servier, Medscape, Regeneron, TMC, Pfizer, Gambro, Gilead, DSI-Lilly, CV Sight, Heart.org/Bayer, Bayer Pharma AG, Bayer Healthcare, Parkview, Pozen, Orexigen, Nile, and WebMD; and other financial support from N30 Pharma, Portola, and Nitrox LLC, all outside the submitted work. HS declares no competing interests.
*Rury R Holman, Harald Sourij, Robert M Califf [email protected] Diabetes Trials Unit, Churchill Hospital, University of Oxford, Oxford, Headington OX3 7LJ, UK (RRH, HS); Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria (HS); and Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA (RMC) 1
2
3
4
5
Published Online July 11, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60982-X
6
7
8
Holman RR, Sourij H, Califf RM. Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes. Lancet 2014; 383: 2008–17. Selby JV, Lipstein SH. PCORI at 3 years— progress, lessons, and plans. N Engl J Med 2014; 370: 592–95. Huang ES, Brown SE, Ewigman BG, Foley EC, Meltzer DO. Patient perceptions of quality of life with diabetes-related complications and treatments. Diabetes Care 2007; 30: 2478–83. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: 405–12. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 1577–89. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854–65. Holman RR. Post trial monitoring results of the UKPDS sulfonylurea plus metformin substudy. EASD, 2013. http://www.easdvirtualmeeting. org/resources/6795 (accessed July 21, 2014). ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011; 364: 818–28.
Prevention of misconduct in clinical trials in Japan Since the publication of my concerns about the Jikei Heart Study in The Lancet,1 the fabrication and the falsification of data of four valsartan studies (Jikei Heart Study,2 Kyoto Heart Study,3 VART,4 and SMART5) have been 1098
identified by the board of investigators from each of the universities where these trials were done. This misconduct might have caused disadvantages to patients, and has led to unnecessary defrayment of health insurance and an increase in the cost of medical care. In Japan, there are three types of drug-related clinical trials: short-term clinical trials with small-scale assessment of a new drug for approval (a phase 3 trial), which are double-blind trials done according to the ministerial ordinance on Good Clinical Practice; post-marketing phase 4 studies done by pharmaceutical companies, according to the Good Post-Marketing Study Practice; and long-term post-marketing clinical trials of a large scale done by doctors. Long-term post-marketing clinical trials are open trials with a prospective, randomised, open, blinded-endpoint design. Trials were not done under any government regulations and were funded by pharmaceutical companies. Valsartan-related misconduct in Japan occurred in long-term post-marketing clinical trials. Many people believe that employees of pharmaceutical companies should not be involved in clinical trials. However, I believe that this is incorrect. In novel drug trials, the pharmaceutical company funding the study takes responsibility from beginning to end, including of the statistical analysis, and almost no problems have been reported. With the double-blind method, the malicious manipulation of cardiovascular events, especially soft endpoint or blood pressure values advantageous for valsartan, will be prevented. Thus, the Ministry of Health, Labour and Welfare should make the double-blind method an essential requirement in clinical studies done by doctors. Data should be assured by a quality assurance centre and preserved permanently by a national centre; however, too many strict regulations should be avoided. Ideally, similarly to the USA and Europe, the unification of the three types of trial should be considered in the double-blind condition. Even if the number of trials
decreases because of the increased cost, truly scientific clinical trials should still be done for the progress of medical science and the promotion of national health. I declare no competing interests.
Yoshiki Yui [email protected] Department of Cardiovascular Medicine, Kyoto University Hospital, Kyoto 6068397, Japan 1 2
3
4
5
Yui Y. Concerns about the Jikei Heart Study. Lancet 2012; 379: e48. Mochizuki S, Dahlof B, Shimizu M, et al, for the Jikei Heart Study group. RETRACTED: Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomized, open-label, blinded endpoint morbidity-mortality study. Lancet 2007; 369: 1431–39. Sawada T, Yamada H, Dahlof B, Matsubara H, for the Kyoto Heart Study Group. RETRACTED: Effects of valsartan on morbidity and mortality in uncontrolled hypertensive patients with high cardiovascular risks: Kyoto Heart Study. Eur Heart J 2009; 30: 2461–69. Narumi H, Takano H, Shindo S, et al, on behalf of the VART Investigators. Effects of valsartan and amlodipine on cardiorenal protection in Japanese hypertensive patients: the Valsartan Amlodipine Randomized Trial. Hypertens Res 2011; 34: 62–69. The Shiga Microalbuminuria Reduction Trial (SMART) Group. RETRACTED: Reduction of microalbuminuria in patients with type 2 diabetes. Diabetes Care 2007; 30: 1581–83.
Department of Error Renfrew MJ, McFadden A, Bastos MH, et al. Midwifery and quality care: findings from a new evidence-informed framework for maternal and newborn care. Lancet 2014; 384: 1129–45—In the table, the outcomes “perinatal, neonatal, or infant mortality reduced” and “fetal loss reduced” should have been placed after “increased contraceptive use”. This change has been made to the online version as of July 11, 2014, and the printed Article is correct. Homer CSE, Friberg IK, Bastos Dias MA, et al. The projected effect of scaling up midwifery. Lancet 2014; 384: 1146–57—In this Series, in the key messages, 78 Countdown countries should have been 78 countries. In the The Lives Saved Tool section, the repetition of morbidity was removed. The Active management of the third stage of labour heading was deleted. In the Construction of the standard populations section, the report should have been The State of the World’s Midwifery 2011 Report. These corrections have been made to the online version as of Sept 19, 2014, and the printed Article is correct. Maartens G, Celum C, Lewin SR. HIV infection: epidemiology, pathogenesis, treatment, and prevention. Lancet 2014; 384: 258–71—In figure 3 of this Seminar, labels for parts B and C should have been reversed. This correction has been made to the online version as of Sept 19, 2014, and the printed Seminar is correct.
www.thelancet.com Vol 384 September 20, 2014
