Questions about the HELIX trial
Authors: Deepika Kainth, Akash Sharma, Mari Jeeva Sankar
Journal: The Lancet Global Health (2021)

In the HELIX trial, Sudhin Thayyil and colleagues1Thayyil S Pant S Montaldo P et al.Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh.Lancet Glob Health. 2021; 9: e1273-e1285Summary Full Text Full Text PDF PubMed Scopus (35) Google Scholar found no benefit in risk of mortality or severe disability following therapeutic hypothermia in neonates with asphyxia in low-income and middle-income countries (LMICs). The authors made firm conclusions on the use of therapeutic hypothermia in LMICs that warrant careful consideration. First, the risk of mortality was higher in the therapeutic hypothermia group than the group receiving usual care (risk ratio [RR] 1·35 [95% CI 1·04–1·76]).1Thayyil S Pant S Montaldo P et al.Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh.Lancet Glob Health. 2021; 9: e1273-e1285Summary Full Text Full Text PDF PubMed Scopus (35) Google Scholar Conversely, the other component of the composite primary outcome (ie, severe disability among survivors) was lower, albeit not significantly (0·61 [0·34–1·11]). The non-significant result was likely due to the low event rate of the severe disability among the survivors and the resultant low power. The lower risk of cerebral palsy in the therapeutic hypothermia group further corroborates this theory. Therefore, the authors' conclusion that therapeutic hypothermia should not be offered as treatment in LMICs, which was based on one of the components of the composite outcome and not the composite outcome itself, is against the conventional wisdom of interpreting any trial with composite primary outcome.2Freemantle N Calvert M Wood J Eastaugh J Griffin C Composite outcomes in randomized trials: greater precision but with greater uncertainty?.JAMA. 2003; 289: 2554-2559Crossref PubMed Scopus (499) Google Scholar Second, the Fragility Index3Walsh M Srinathan SK McAuley DF et al.The statistical significance of randomized controlled trial results is frequently fragile: a case for a Fragility Index.J Clin Epidemiol. 2014; 67: 622-628Summary Full Text Full Text PDF PubMed Scopus (291) Google Scholar for mortality outcome was 3, which means that the results could become non-significant by changing the outcome of only three neonates in the control group. The number of neonates lost to follow-up in that group (n=5) was higher than the Fragility Index value, which underscores the need to carefully interpret the higher mortality risk in the therapeutic hypothermia group. Third, a higher proportion of neonates in the therapeutic hypothermia group were exposed to pregnancy complications or were born by emergency caesarean section. They were also admitted earlier (126 min vs 160 min) and had a lower temperature at admission (35·7°C vs 36·4°C). The neonates in the therapeutic hypothermia group were possibly more unwell at the time of enrolment, leading to higher mortality. The discordant effect sizes in mortality at the point of discharge between inborn (RR 1·24) and outborn (1·66) neonates possibly reflect this difference. A multivariable analysis adjusting for these factors could have showed the intervention's true effect on mortality. Lastly, previous studies show a clear benefit of therapeutic hypothermia on mortality and neurodevelopmental outcomes.4Abate BB Bimerew M Gebremichael B et al.Effects of therapeutic hypothermia on death among asphyxiated neonates with hypoxic-ischemic encephalopathy: a systematic review and meta-analysis of randomized control trials.PLoS One. 2021; 16e0247229Crossref PubMed Scopus (16) Google Scholar We pooled the results of 12 previous studies and Thayyil and colleagues' study using a random-effects model. The pooled risk did not show any significant increase in mortality (RR 0·74 [95% CI 0·52–1·06]). The certainty of the evidence was graded as low. In summary, we believe that the authors should have made a more nuanced conclusion highlighting therapeutic hypothermia's unexpected lack of effect on the primary outcome, rather than recommending a blanket ban on its use in LMICs. We declare no competing interests. Questions about the HELIX trialWe congratulate Sudhin Thayyil and colleagues1 on publishing the HELIX trial in The Lancet Global Health. Based on their results, which showed increased mortality in the hypothermia group compared with the standard care group, they recommended that cooling for neonatal encephalopathy should not be offered in low-income and middle-income countries (LMICs).However, we feel that their results cannot be generalised. Full-Text PDF Open AccessQuestions about the HELIX trial – Authors' replyWe appreciate the clinician's dilemma when existing practice is challenged by evidence, and have provided a combined response.1 Full-Text PDF Open AccessQuestions about the HELIX trialDespite more than half a decade since the launch of the Every Newborn Action Plan, perinatal asphyxia remains one of the most important causes of perinatal mortality and morbidity in neonates in developing countries.1 Hence, the HELIX trial holds paramount importance. The study reports that therapeutic hypothermia was associated with increased mortality and therefore should not be offered in low-income and middle-income countries. 2 However, we have several critical observations. Full-Text PDF Open AccessHypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and BangladeshTherapeutic hypothermia did not reduce the combined outcome of death or disability at 18 months after neonatal encephalopathy in low-income and middle-income countries, but significantly increased death alone. Therapeutic hypothermia should not be offered as treatment for neonatal encephalopathy in low-income and middle-income countries, even when tertiary neonatal intensive care facilities are available. Full-Text PDF Open AccessQuestions about the HELIX trialIn the HELIX study,1 Sudhin Thayyil and colleagues suggested that all low-income and middle-income countries (LMICs) should immediately suspend use of cooling in neonates.1 The reported absence of benefit and increased mortality in neonates who were cooled are in contrast to our experience and the findings in meta-analyses in LMICs.2,3 Full-Text PDF Open Access