- Email: [email protected]
The INFANT trial
Correspondence
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Hayen A, Bell K, Glasziou P, Neal B, Irwig L. Monitoring adherence to medication by measuring change in blood pressure. Hypertension 2010; 56: 612–16. Dickerson JE, Hingorani AD, Ashby MJ, Palmer CR, Brown MJ. Optimisation of antihypertensive treatment by crossover rotation of four major classes. Lancet 1999; 353: 2008–13. SPRINT Research Group, Wright RT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015; 373: 2103–16. Jaffe MG, Lee GA, Young JD, Sidney S, Go AS. Improved blood pressure control associated with a large-scale hypertension program. JAMA 2013; 310: 699–705. Chow CK, Teo KK, Rangarajan S, et al. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and lowincome countries. JAMA 2013; 310: 959–68.
The INFANT trial
Published Online May 26, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)31456-3
28
Robert Keith1 (April 28, p 1697) suggests that the INFANT trial 2 is flawed by design. Previous reports3,4 suggested that a key element in substandard intrapartum care is the failure of clinicians to recognise an abnormal fetal heart-rate pattern, so the trial was set up to investigate whether decision support that detects and highlights abnormality of the fetal heart rate could improve outcomes. We compared decision support with no decision support. All other aspects of care were kept constant, including the use of the Guardian platform, which is the electronic data collection system in which the decision-support software operates. The comparison of the decision support software plus Guardian versus continuous cardiotocography alone (ie, without decision support or Guardian system) is a different trial question. We designed the trial that the UK National Institute for Health Research commissioned, our proposal was successfully peer reviewed and funded, and 24 centres throughout the UK successfully completed recruitment. We recognised the possibility that there might be learning in the control group in an individually randomised trial, and the trial team spent many hours discussing this point. However, a key part of our hypothesis was that some individuals cannot recognise
changing heart rate patterns (which would not be improved by training). The alternative of a cluster randomised trial was unfeasible given the very large numbers required. The observation of a significantly higher incidence of fetal blood sampling and lower rate of yellow alerts in the decision-support group indicates a measurable difference in clinician behaviour. This difference was not, however, associated with improved clinical outcome. Keith is also concerned that the mortality component of the primary outcome was lower than estimated in our sample size calculation. However, the primary event rate was higher than anticipated (0·7% vs an estimated 0·3%). The lower than anticipated number of deaths might have been influenced by the Guardian system, but it is more likely to be a lack of relevant routine data on which to base the estimate. Using routine data we were also unable to estimate the relative contribution of events such as abruption, cord prolapse, or severely abnormal cardiotocographs on admission to labour, to mortality, which would exclude some women from the opportunity to participate in the trial. With respect to the comments by Michael Belfort and Steven Clark,5 we are not convinced that specifying actions arising from the system alerts would have made a difference to outcome; moreover, the correct action to take in response to different fetal heartrate patterns is disputed. We set out to assess whether decision support would improve the recognition of abnormal cardiotocographs and thereby improve outcomes. We have shown clearly that the system tested does not achieve this. Improvements in cardiotocograph interpretation, including the use of artificial intelligence to incorporate variables that interact with abnormal cardiotocography patterns (such as fetal growth restriction, meconium staining of the amniotic fluid, maternal pyrexia, and the duration of labour), might improve outcomes, but it could also be the case that fetal heart-
rate monitoring is not a good test of fetal wellbeing. We declare no competing interests.
*Peter Brocklehurst, David J Field, Ed Juszczak, Sara Kenyon, Louise Linsell, Mary Newburn, Rachel Plachcinski, Maria Quigley, Liz Schroeder, Philip Steer [email protected] Birmingham Clinical Trials Unit (PB) and Institute of Applied Health Research (SK), College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; Department of Health Sciences, University of Leicester, Leicester, UK (DJF); National Perinatal Epidemiology Unit Clinical Trials Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK (EJ, LL, MQ); CLAHRC South London, Kings College London, London, UK (MN); National Childbirth Trust, London, UK (RP); Centre for Health Economy, Australian Hearing Hub, Macquire University, Sydney, NSW, Australia (LS); and Imperial College London, London, UK (PS). 1 2
3
4
5
Keith R. The INFANT study—a flawed design foreseen. Lancet 2017; 389: 1697–98. The INFANT Collaborative Group. Computerised interpretation of fetal heart rate during labour (INFANT): a randomised controlled trial. Lancet 2017; 389: 1719–29. Gaffney G, Sellers S, Flavell V, Squier M, Johnson A. Case-control study of intrapartum care, cerebral palsy, and perinatal death. BMJ 1994; 308: 743–50. CEMACH. Perinatal mortality surveillance, 2004. England, Wales and Northern Ireland. London: Confidential Enquiry into Maternal and Child Health, 2006. Belfort MA, Clark SL. Computerised cardiotocography—study design hampers findings. Lancet 2017; 389: 1674–76.
Department of Error Heier JS, Kherani S, Desai S, et al. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial. Lancet 2017; 390: 50–61—In figure 1 of this Article, the one patient in cohort 3 that withdrew consent did so after 1 year. Table 1 reports median BCVA data over two rows (ETDRS letter score and Snellen equivalent) with range in parentheses. An error has been corrected in paragraph 6 of the results and should read “…but five of ten patients in cohorts 4 and 5 who received an injection of 2x1010 vg…”. The y-axis of figure 2 has been corrected to read “sFLT01 (ng/mL)”. The legends of parts D and E of figures 3 and 5 have been corrected since the patient numbering was incorrect. A footnote has been added to the caption of figure 5: “*BCVA was reduced from baseline by 28 letters by week 52.” These corrections have been made to the online version as of May 26, 2017, and the printed Article is correct.
www.thelancet.com Vol 390 July 1, 2017
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5
6
7
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Hayen A, Bell K, Glasziou P, Neal B, Irwig L. Monitoring adherence to medication by measuring change in blood pressure. Hypertension 2010; 56: 612–16. Dickerson JE, Hingorani AD, Ashby MJ, Palmer CR, Brown MJ. Optimisation of antihypertensive treatment by crossover rotation of four major classes. Lancet 1999; 353: 2008–13. SPRINT Research Group, Wright RT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015; 373: 2103–16. Jaffe MG, Lee GA, Young JD, Sidney S, Go AS. Improved blood pressure control associated with a large-scale hypertension program. JAMA 2013; 310: 699–705. Chow CK, Teo KK, Rangarajan S, et al. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and lowincome countries. JAMA 2013; 310: 959–68.
The INFANT trial
Published Online May 26, 2017 http://dx.doi.org/10.1016/ S0140-6736(17)31456-3
28
Robert Keith1 (April 28, p 1697) suggests that the INFANT trial 2 is flawed by design. Previous reports3,4 suggested that a key element in substandard intrapartum care is the failure of clinicians to recognise an abnormal fetal heart-rate pattern, so the trial was set up to investigate whether decision support that detects and highlights abnormality of the fetal heart rate could improve outcomes. We compared decision support with no decision support. All other aspects of care were kept constant, including the use of the Guardian platform, which is the electronic data collection system in which the decision-support software operates. The comparison of the decision support software plus Guardian versus continuous cardiotocography alone (ie, without decision support or Guardian system) is a different trial question. We designed the trial that the UK National Institute for Health Research commissioned, our proposal was successfully peer reviewed and funded, and 24 centres throughout the UK successfully completed recruitment. We recognised the possibility that there might be learning in the control group in an individually randomised trial, and the trial team spent many hours discussing this point. However, a key part of our hypothesis was that some individuals cannot recognise
changing heart rate patterns (which would not be improved by training). The alternative of a cluster randomised trial was unfeasible given the very large numbers required. The observation of a significantly higher incidence of fetal blood sampling and lower rate of yellow alerts in the decision-support group indicates a measurable difference in clinician behaviour. This difference was not, however, associated with improved clinical outcome. Keith is also concerned that the mortality component of the primary outcome was lower than estimated in our sample size calculation. However, the primary event rate was higher than anticipated (0·7% vs an estimated 0·3%). The lower than anticipated number of deaths might have been influenced by the Guardian system, but it is more likely to be a lack of relevant routine data on which to base the estimate. Using routine data we were also unable to estimate the relative contribution of events such as abruption, cord prolapse, or severely abnormal cardiotocographs on admission to labour, to mortality, which would exclude some women from the opportunity to participate in the trial. With respect to the comments by Michael Belfort and Steven Clark,5 we are not convinced that specifying actions arising from the system alerts would have made a difference to outcome; moreover, the correct action to take in response to different fetal heartrate patterns is disputed. We set out to assess whether decision support would improve the recognition of abnormal cardiotocographs and thereby improve outcomes. We have shown clearly that the system tested does not achieve this. Improvements in cardiotocograph interpretation, including the use of artificial intelligence to incorporate variables that interact with abnormal cardiotocography patterns (such as fetal growth restriction, meconium staining of the amniotic fluid, maternal pyrexia, and the duration of labour), might improve outcomes, but it could also be the case that fetal heart-
rate monitoring is not a good test of fetal wellbeing. We declare no competing interests.
*Peter Brocklehurst, David J Field, Ed Juszczak, Sara Kenyon, Louise Linsell, Mary Newburn, Rachel Plachcinski, Maria Quigley, Liz Schroeder, Philip Steer [email protected] Birmingham Clinical Trials Unit (PB) and Institute of Applied Health Research (SK), College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; Department of Health Sciences, University of Leicester, Leicester, UK (DJF); National Perinatal Epidemiology Unit Clinical Trials Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK (EJ, LL, MQ); CLAHRC South London, Kings College London, London, UK (MN); National Childbirth Trust, London, UK (RP); Centre for Health Economy, Australian Hearing Hub, Macquire University, Sydney, NSW, Australia (LS); and Imperial College London, London, UK (PS). 1 2
3
4
5
Keith R. The INFANT study—a flawed design foreseen. Lancet 2017; 389: 1697–98. The INFANT Collaborative Group. Computerised interpretation of fetal heart rate during labour (INFANT): a randomised controlled trial. Lancet 2017; 389: 1719–29. Gaffney G, Sellers S, Flavell V, Squier M, Johnson A. Case-control study of intrapartum care, cerebral palsy, and perinatal death. BMJ 1994; 308: 743–50. CEMACH. Perinatal mortality surveillance, 2004. England, Wales and Northern Ireland. London: Confidential Enquiry into Maternal and Child Health, 2006. Belfort MA, Clark SL. Computerised cardiotocography—study design hampers findings. Lancet 2017; 389: 1674–76.
Department of Error Heier JS, Kherani S, Desai S, et al. Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial. Lancet 2017; 390: 50–61—In figure 1 of this Article, the one patient in cohort 3 that withdrew consent did so after 1 year. Table 1 reports median BCVA data over two rows (ETDRS letter score and Snellen equivalent) with range in parentheses. An error has been corrected in paragraph 6 of the results and should read “…but five of ten patients in cohorts 4 and 5 who received an injection of 2x1010 vg…”. The y-axis of figure 2 has been corrected to read “sFLT01 (ng/mL)”. The legends of parts D and E of figures 3 and 5 have been corrected since the patient numbering was incorrect. A footnote has been added to the caption of figure 5: “*BCVA was reduced from baseline by 28 letters by week 52.” These corrections have been made to the online version as of May 26, 2017, and the printed Article is correct.
www.thelancet.com Vol 390 July 1, 2017