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Response to: Understanding the null hypothesis (H0) in non-inferiority trials
Critical Care volume 21, Article number: 201 (2017)
- The original article was published in Critical Care 2017 21:101
We thank Dr. Mallat for their interest in our study of stepwise lactate kinetics-oriented hemodynamic therapy and for putting forward a statistical problem . Central venous oxygen saturation (ScvO2)-targeted therapy was recommended by the Surviving Sepsis Campaign (SCC) guidelines in 2012  and we initially envisaged that the stepwise lactate kinetics strategy was, at least, not inferior to the ScvO2 target strategy. Therefore, the design of non-inferiority analysis was adopted at the beginning of the trial.
We rechecked and recalculated the data by non-inferiority and superiority test. The lactate kinetics group mortality rate (P1) was 18.3% and the Scvo2 group mortality rate (P2) was 27.9%. The standard error for the mortality difference between the two groups was 0.0441, and thus the mortality difference was –0.0944 (95% confidence interval –0.1809 to –0.0080). The upper limit of the interval is less than 0, and thus the superiority conclusion is established. At this point, regardless of the non-inferior value (0.15 or 0.10), non-inferior conclusions must be established.
Additionally, the non-inferiority threshold of 10% is indeed more reasonable according to a previous study .Therefore, regardless of whether the non-inferiority threshold is set at 10% or 15%, no effect on the final conclusion was seen in this study.
Last, but not the least, the latest sepsis guidelines released by the SCC in 2016 have weakened early goal-directed therapy (EGDT) and highlighted the importance of normalization of lactate , which also supports the conclusion we draw that stepwise lactate kinetics-oriented hemodynamic therapy can reduce mortality in patients with sepsis-associated hyperlactatemia compared with ScvO2-oriented therapy.
Early goal-directed therapy
Surviving Sepsis Campaign
Central venous oxygen saturation
Mallat J. Understanding the null hypothesis (H0) in non-inferiority trials. Crit Care. 2017;21(1):101.
Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165–228.
Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303(8):739–46.
Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304–77.
We thank Prof. Guangliang Shan and Dr. Biao Zhang from the Department of Epidemiology and Biostatistics, Institute of Basic Medicine Sciences, Chinese Academy of Medical Sciences (CAMS) & School of Basic Medicine, Peking Union Medical College for helping us to check and perform the statistical analysis.
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See related Letter by Mallat, https://ccforum.biomedcentral.com/articles/10.1186/s13054-017-1685-2
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Zhou, X., Liu, D. & Su, L. Response to: Understanding the null hypothesis (H0) in non-inferiority trials. Crit Care 21, 201 (2017). https://doi.org/10.1186/s13054-017-1790-2