Citation Information :
Choupoo NS, Das SK, Saikia P, Dey S. How Robust are the Evidences that Formulate Surviving Sepsis Guidelines? An Analysis of Fragility and Reverse Fragility of Randomized Controlled Trials that were Referred in these Guidelines. Indian J Crit Care Med 2021; 25 (7):773-779.
Objectives: “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016” provides guidelines in regard to prompt management and resuscitation of sepsis or septic shock. The study is aimed to assess the robustness of randomized controlled trials (RCTs) that formulate these guidelines in terms of fragility index and reverse fragility index.
Method: RCTs that contributed to these guidelines having parallel two-group design, 1:1 allocation ratio, and at least one dichotomous outcome were included in the study. The median fragility index was calculated for RCTs with significant statistical outcomes, whereas the median reverse fragility index was calculated for RCTs with nonsignificant statistical results.
Results: Hundred RCTs that met the inclusion criteria were analyzed. The median fragility index was 5.5 [95% confidence interval (CI) 1–30] and median reverse fragility index was 13 (95% CI 12.07–16.8) at a p value of 0.05. The median reverse fragility index was 16 (95% CI 10–26) at a p value of 0.01. Most of the RCTs included in this analysis were of good quality, having a median Jadad score of 6.
Conclusion: This analysis found that the surviving sepsis guidelines were based on highly robust RCTs with statistically insignificant results and on some moderately robust RCTs with statistically significant results. RCTs with statistically insignificant results were more robust than RCTs with statistically significant results in regard to these guidelines.
Highlights: The study assessed the robustness of randomized controlled trials (RCTs) that were used to formulate surviving sepsis guidelines. Most RCTs showed statistically nonsignificant results. RCTs with statistically significant results were moderately fragile whereas RCTs with nonsignificant results were more robust.
Dahiru T. P-value, a true test of statistical significance? A cautionary note. Ann Ib Postgrad Med 2008;6(1):21–26. DOI: 10.4314/aipm.v6i1.64038.
Nuzzo R. Scientific method: statistical errors. Nature 2014;506(7487):150–152. DOI: 10.1038/506150a.
Bertolaccini L, Viti A, Terzi A. Are the fallacies of the P value finally ended?. J Thorac Dis 2016;8(6):1067–1068. DOI: 10.21037/jtd.2016.04.48.
Wayant C, Scott J, Vassar M. Evaluation of lowering the P value threshold for statistical significance from .05 to .005 in previously published randomized clinical trials in major medical journals. JAMA 2018;320(17):1813–1815. DOI: 10.1001/jama.2018.12288.
Halsey LG. The reign of the p-value is over: what alternative analyses could we employ to fill the power vacuum? Biol Lett 2019;15(5):20190174. DOI: 10.1098/rsbl.2019.0174.
Condon TM, Sexton RW, Wells AJ, To MS. The weakness of fragility index exposed in an analysis of the traumatic brain injury management guidelines: a meta-epidemiological and simulation study. PLoS One 2020;15(8):e0237879. DOI: 10.1371/journal.pone.0237879.
Feinstein AR. The unit fragility index: an additional appraisal of “statistical significance” for a contrast of two proportions. J Clin Epidemiol 1990;43(2):201–209. DOI: 10.1016/0895-4356(90)90186- s.
Khan MS, Fonarow GC, Friede T, Lateef N, Khan SU, Anker SD, et al. Application of the reverse fragility index to statistically nonsignificant randomized clinical trial results. JAMA Netw Open 2020;3(8):e2012469. DOI: 10.1001/jamanetworkopen.2020.12469.
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):304–377. DOI: 10.1007/s00134-017-4683-6.
Oremus M, Wolfson C, Perrault A, Demers L, Momoli F, Moride Y. Interrater reliability of the modified Jadad quality scale for systematic reviews of Alzheimer's disease drug trials. Dement Geriatr Cogn Disord 2001;12:232–236. DOI: 10.1159/000051263.
Walsh M, Srinathan SK, McAuley DF, Mrkobrada M, Levine O, Ribic C, et al. The statistical significance of randomized controlled trial results is frequently fragile: a case for a Fragility Index. J Clin Epidemiol 2014;67(6):622–628. DOI: 10.1016/j.jclinepi.2013.10.019.
Ahmed W, Fowler RA, McCredie VA. Does sample size matter when interpreting the fragility index? Crit Care Med 2016;44(11):e1142–e1143. DOI: 10.1097/CCM.0000000000001976.
Del Paggio JC, Tannock IF. The fragility of phase 3 trials supporting FDA-approved anticancer medicines: a retrospective analysis. Lancet Oncol 2019;20(8):1065–1069. DOI: 10.1016/S1470-2045(19)30338-9.
Mazzinari G, Ball L, Neto AS, Errando CL, Dondorp AM, Bos LD, et al. The fragility of statistically significant findings in randomised controlled anaesthesiology trials: systematic review of the medical literature. Br J Anaesth 2018;120(5):935–941. DOI: 10.1016/j.bja.2018.01.012.
Evaniew N, Files C, Smith C, Bhandari M, Ghert M, Walsh M, et al. The fragility of statistically significant findings from randomized trials in spine surgery: a systematic survey. Spine J 2015;15(10):2188–2197. DOI: 10.1016/j.spinee.2015.06.004.
Docherty KF, Campbell RT, Jhund PS, Petrie MC, McMurray JJ. How robust are clinical trials in heart failure? Eur Heart J 2016;38(5):338–345. DOI: 10.1093/eurheartj/ehw427.
Matics TJ, Khan N, Jani P, Kane JM. The fragility of statistically significant findings in pediatric critical care randomized controlled trials. Pediatr Crit Care Med 2019;20(6):e258–e262. DOI: 10.1097/PCC.0000000000001922.
Shen C, Shamsudeen I, Farrokhyar F, Sabri K. Fragility of results in ophthalmology randomized controlled trials: a systematic review. Ophthalmology 2018;125(5):642–648. DOI: 10.1016/j.ophtha.2017.11.015.
Shen Y, Cheng X, Zhang W. The fragility of randomized controlled trials in intracranial hemorrhage. Neurosurg Rev 2019;42(1):9–14. DOI: 10.1007/s10143-017-0870-8.
Parisien RL, Dashe J, Cronin PK, Bhandari M, Tornetta P III. Statistical significance in trauma research: too unstable to trust? J Orthop Trauma 2019;33(12):e466–e470. DOI: 10.1097/BOT.0000000000001595.
Skinner M, Tritz D, Farahani C, Ross A, Hamilton T, Vassar M. The fragility of statistically significant results in otolaryngology randomized trials. Am J Otolaryngol 2019;40(1):61–66. DOI: 10.1016/j.amjoto.2018.10.011.
Svantesson E, Senorski EH, Danielsson A, Sundemo D, Westin O, Ayeni OR, et al. Strength in numbers? The fragility index of studies from the Scandinavian knee ligament registries. Knee Surg Sports Traumatol Arthrosc 2020;28(2):339–352. DOI: 10.1007/s00167-019-05551-x.
Ruzbarsky JJ, Rauck RC, Manzi J, Khormaee S, Jivanelli B, Warren RF. The fragility of findings of randomized controlled trials in shoulder and elbow surgery. J Shoulder Elb Surg 2019;28(12):2409–2417. DOI: 10.1016/j.jse.2019.04.051.
Ridgeon EE, Young PJ, Bellomo R, Mucchetti M, Lembo R, Landoni G. The fragility index in multicenter randomized controlled critical care trials. Crit Care Med 2016;44(7):1278–1284. DOI: 10.1097/CCM.0000000000001670.
Majeed M, Agrawal R, Attar BM, Kamal S, Patel P, Omar YA, et al. Fragility index: how fragile is the data that support the American College of Gastroenterology guidelines for the management of Crohn's disease? Eur J Gastroenterol Hepatol 2020;32(2):193–198. DOI: 10.1097/MEG.0000000000001635.
Edwards E, Wayant C, Besas J, Chronister J, Vassar M. How fragile are clinical trial outcomes that support the CHEST clinical practice guidelinesfor VTE? Chest. 2018;154(3):512–520. DOI: 10.1016/j.chest.2018.01.031.
Chase Kruse B, Matt Vassar B. Unbreakable? An analysis of the fragility of randomized trials that support diabetes treatment guidelines. Diabetes Res Clin Pract 2017;134:91–105. DOI: 10.1016/j.diabres.2017.10.007.
Lin L. Factors that impact fragility index and their visualizations. J Eval Clin Pract 2021;27(2):356–364. DOI: 10.1111/jep.13428.
Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et al. Surviving Sepsis Campaign Management Guidelines Committee: Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32(3):858–873. DOI: 10.1097/01.ccm.0000117317.18092.e4.
Levy MM, Rhodes A, Phillips GS, Townsend SR, Schorr CA, Beale R, et al. Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study. Crit Care Med 2015;43(1):3– 12. DOI: 10.1097/CCM.0000000000000723.
Desnoyers A, Nadler MB, Wilson BE, Amir E. A critique of the fragility index. Lancet Oncol 2019;20(10):e552. DOI: 10.1016/S1470-2045(19)30583-2.
Leung WC. Balancing statistical and clinical significance in evaluating treatment effects. Postgrad Med J 2001;77(905):201–204. DOI: 10.1136/pmj.77.905.201.