B Selvan

CR Cernea

KF Schulz

LM Hurtado-Lopez

M Barczyński

Marcin Barczyński

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Intention to Treat Analysis: Are We Really Doing It?: ReplyMarcin Barczyn´skiPublished online: 14 March 2013 The Author(s) 2013. This article is published with open access at Springerlink.comThis reply addresses a response to an article my colleaguesand I wrote on the subject of the principle of intention-to-treat (ITT), which has become widely accepted for theanalysis of controlled clinical trials [1]. Ideally, in order topreserve fully the immense benefit of randomization, allrandomized participants should be included in the analysis,and all should be retained in the group to which they wereallocated. However, a strict ITT analysis is often hard toachieve, for two main reasons: missing outcomes for someparticipants and non-adherence to the trial protocol [2].Indeed, most randomized trials have some missingobservations. A few missing outcomes do not cause aproblem, if the power of the trial is not lost by a reduced totalsample size, and if loss to follow-up is not related to apatient’s response to treatment. There should be concernwhen the frequency or the causes of dropout differ betweenthe intervention groups. Participants with missing outcomescan be included in the analysis only if their outcomes areimputed (estimated from other information that was col-lected). Imputation of the missing data allows the analysis toconform to ITT analysis but requires strong assumptions,which may be hard to justify; otherwise the study should notbe undertaken. Finally, ITT corresponds to analyzing thegroups exactly as randomized, regardless of adherence tothe protocol. One of the noteworthy specific changes in thecurrent CONSORT 2010 Statement was to replace thenotion of ITT analysis, a widely misused term, by a moreexplicit request for information about retaining participantsin their original assigned groups. Thus, in the CONSORTchecklist, the specific request for ITT analysis has beendiscarded in favor of a clear description of exactly who wasincluded in each analysis [2].Mohanty et al. have raised a few questions in their Letterto the Editor about our recently published randomizedcontrolled trial of visualization versus neuromonitoringof the external branch of the superior laryngeal nerve(EBSLN) during thyroidectomy [1]. Those questions merita brief response. In our study, 210 consenting femalepatients considered for total thyroidectomy were randomlyassigned to two groups equal in size (n = 105): visualinspection of the EBSLN and recurrent laryngeal nerve(RLN) versus this visual inspection plus EBSLN and RLNneural monitoring. The primary outcome was the identifi-cation rate of the EBSLN. The secondary outcomesincluded anatomical variability of the EBSLN according tothe Cernea classification, and changes in postoperativevoice performance during a six-month follow-up. Voiceassessment included preoperative and postoperative vid-eostrobolaryngoscopy and an analysis of maximum pho-nation time (MPT), voice level (VL), fundamentalfrequency (Fo), and voice quality rating on the GRBASscale [1]. Males were excluded in order to maintain ahomogeneous study group. Of note, 90 % of thyroid sur-gery is undertaken in women, and many voice parametersevaluated in this study, like MPT, VL, and Fo, differ sig-nificantly between men and women. Similarly, patientswith a large goiter were not included in this study, also toensure the homogeneous population of the study group. Asthe Cernea classification categorizes the nerve in relation tosuperior thyroid vessels and the upper edge of the superiorthyroid pole, the larger the goiter the higher the incidenceof type 2B nerve, which was reported in up to 54 % ofpatients with goiters above 100 ml in volume [3]. Identi-fication of the anatomical variation of the EBSLN in ourM. Barczyn´ski (&)Third Chair and Department of General Surgery, JagiellonianUniversity Medical College, 37 Pra˛dnicka Street,31-202 Krako´w, Polande-mail: marbar@mp.pl123World J Surg (2013) 37:1183–1184DOI 10.1007/s00268-013-1984-ystudy was calculated for nerves at risk and not for patients.Significant differences in distribution of all types of theEBSLN according to the Cernea classification betweenboth study groups were the result of improved identifica-tion rate of all types of the nerve variants with nervemonitoring system. Nerve stimulation technique has asubstantial advantage in identifying all nerve types,including Cernea type 1, which is found at a higher posi-tion and sometimes is crowded under the laryngeal head ofthe sternothyroid muscle, as well as descending types 2Aand 2B, which are most vulnerable to surgical manipulationinjury. In the study by Selvan et al. [4], a considerablenumber of false-positive results were seen when visualidentification alone was used prior to electrical stimulationof the nerve. In many cases, non-neural fibers or tendinousfibers of the cricothyroid or inferior constrictor muscleswere wrongly assumed to be the EBSLN, but wereunmasked by the lack of an action potential when stimu-lated. This finding suggests that visual identification of theEBSLN without electromyographic confirmation maylikely be flawed. It is our belief that adding quantitativedata to this technique could make the process of nerveidentification and preservation more definitive and precise.To detect a difference of 5 % in the prevalence of primaryor secondary outcomes in our trial, which is in agreementwith the study of Hurtado-Lopez et al. [5], with a two-sided5 % significance level and a power of 90 %, a sample size of105 patients (210 nerves at risk) per group was necessary,given an anticipated dropout rate of 10 %. All the recruitedpatients received the planned intervention and the identifi-cation rate of the EBSLN (primary outcome) and anatomicalvariability of the EBSLN according to the Cernea classifi-cation (one of the secondary outcomes) were analyzed in all210 patients included in the study, which is clearly reportedin the Results section and summarized in our Table 2.However, 4 (3.8 %) patients operated on without nervemonitoring versus 5 (4.7 %) patients operated on with nervemonitoring were lost to follow-up (non-significant differ-ence; 5 patients opted to withdraw from the trial, 2 patientsmoved away, and 2 patients became unavailable forunknown reasons), whereas the remaining 201 patientscompleted the six-month follow-up [1]. Thus, the actualdropout rate for evaluation of changes in postoperative voiceperformance (the other secondary outcome) was far belowthe anticipated dropout rate of 10 %, and the power of thetrial has not been lost by this reduction in number of theanalyzed participants. Any imputation of the missing post-operative voice performance data was not done, as they wereimpossible to be reliably estimated, and it was also notnecessary from the statistical point of view, because thestudy was not in danger of being underpowered. In addition,the outcomes of this study were analyzed in the subgroupsexactly as randomized. Taking into consideration all theabove points, I must strongly disagree with the suggestionraised by Mohanty et al. in their letter that the analysis ofdata in our trial was per protocol rather than ITT.Open Access This article is distributed under the terms of theCreative Commons Attribution License which permits any use, dis-tribution, and reproduction in any medium, provided the originalauthor(s) and the source are credited.References1. Barczyn´ski M, Konturek A, Stopa M et al (2012) Randomizedcontrolled trial of visualization versus neuromonitoring of the externalbranch of the superior laryngeal nerve during thyroidectomy. World JSurg 36:1340–1347. doi:10.1007/s00268-012-1547-72. Schulz KF, Altman DG, Moher D, CONSORT Group (2010)CONSORT 2010 Statement: updated guidelines for reportingparallel group randomized trials. Ann Intern Med 152:726–7323. Cernea CR, Ferraz AR, Furlani J et al (1992) Identification of theexternal branch of the superior laryngeal nerve during thyroidec-tomy. Am J Surg 164:634–6394. Selvan B, Babu S, Paul MJ et al (2009) Mapping the compoundmuscle action potentials of cricothyroid muscle using electromy-ography in thyroid operations: a novel method to clinically typethe external branch of the superior laryngeal nerve. Ann Surg250:293–3005. Hurtado-Lopez LM, Pacheco-Alvarez MI, Montes-Castillo Mde Let al (2005) Importance of the intraoperative identification of theexternal branch of the superior laryngeal nerve during thyroidec-tomy: electromyographic evaluation. Thyroid 15:449–4541184 World J Surg (2013) 37:1183–1184123

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Intention to Treat Analysis: Are We Really Doing It?: Reply

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Intention to Treat Analysis: Are We Really Doing It?: Reply

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