My letter to the editor was turned down because “we feel that the issues raised were discussed sufficiently in the Discussion section of the article and the linked Comment.” (This is clearly not the case.)
I am posting it below in case it might serve in the future. Thanks to
@Lucibee for her suggestions.
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The implausible clinical relevance of the LIFT trial
Bachmair et al’s claim that telephone-delivered cognitive behavioural and personalised exercise interventions (CBA & PEP) “produced and maintained statistically and clinically significant reductions in the severity and impact of fatigue” in their trial LIFT [1] is disputable.
LIFT’s open-label nature, reliance on patient-reported outcome measures (PROM) and lack of an active comparator (e.g. counseling) means that performance and attention biases were not controlled for, leading to expectation and response biases. These were compounded by the interventions’ aims of “[replacing] unhelpful beliefs and behaviours (…) with more adaptive ones” and “[normalising] misperceptions of effort”. As documented for trials of similar interventions, such biases alone can explain modest reported changes on PROMs. [2]
The authors assumed a minimally important difference (MID) of 2 and 0·5 points on the Chalder fatigue scale (CFS) and Fatigue Severity Scale (FSS), respectively. However, a trial of similar interventions led by one member of the study group retained a 3 point MID for the CFS, [3] and previous trials for rheumatoid arthritis, lupus and multiple sclerosis used MIDs of 2·3 to 3·3 and 0·5 to 1·2 for the CFS and the FSS, respectively. [4] This also casts doubt over the clinical significance of LIFT’s primary outcomes, especially given their imprecision (large confidence intervals that include the author-specified MIDs). [1]
Further, the Chalder fatigue scale is unsuitable as an outcome measure as it measures changes in fatigue intensity rather than absolute fatigue. Since it confusingly mentions three timepoints (“as usual”, “in the last month”, “when you last felt well”), it is plausible that at baseline, a participant may understand “as usual” as when they last felt well and indicate their fatigue is “worse than usual”, but at outcome, they may interpret it as the time of enrollment and answer “no more than usual”. They would thus score lower at outcome despite no change in their fatigue, resulting in an artificial improvement. The scale is also prone to recall bias.
While the Bristol Rheumatoid Arthritis Fatigue Multidimensional Questionnaire secondary outcome is statistically significant, the modest reported improvements (mean reductions under 7 points) may not be clinically significant. [1, 5] The lack of improvement in pain, anxiety and physical health-related quality of life further questions the reported improvements in fatigue. [1]
Overall, owing to LIFT’s inherent biases, its true primary outcomes likely approach the lower bounds of their confidence intervals, or may even fall below them, and thus lack clinical significance.
References
1 Bachmair E, Martin K, Aucott L, et al. Remotely delivered cognitive behavioural and personalised exercise interventions for fatigue severity and impact in inflammatory rheumatic diseases (LIFT): a multicentre, randomised, controlled, open-label, parallel-group trial. Lancet Rheumatology 2022;
doi: 10.1016/S2665-9913(22)00156-4.
2 Tack M, Tuller DM, Struthers C. Bias caused by reliance on patient-reported outcome measures in non-blinded randomized trials: an in-depth look at exercise therapy for chronic fatigue syndrome. Fatigue: Biomedicine, Health & Behavior 2020; 8: 181–192.
doi: 10.1080/21641846.2020.1848262.
3 Clark LV, Pesola F, Thomas JM, Vergara-Williamson M, Beynon M, White PD. Guided graded exercise self-help plus specialist medical care versus specialist medical care alone for chronic fatigue syndrome (GETSET): a pragmatic randomised controlled trial. Lancet 2017; 390: 363–373.
doi: 10.1016/S0140-6736(16)32589-2.
4 Nordin Å, Taft C, Lundgren-Nilsson Å, Dencker A. Minimal important differences for fatigue patient reported outcome measures-a systematic review. BMC Med Res Methodol 2016; 16: 62.
doi: 10.1186/s12874-016-0167-6.
5 Dures EK, Hewlett SE, Cramp FA, et al. Reliability and sensitivity to change of the Bristol Rheumatoid Arthritis Fatigue scales. Rheumatology (Oxford). 2013; 52: 1832–1839.
doi: 10.1093/rheumatology/ket218
