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Guided graded exercise self-help plus specialist medical care versus specialist medical care alone for chronic fatigue syndrome (GETSET): RCT

Discussion in 'PsychoSocial ME/CFS Research' started by Tom Kindlon, Jan 9, 2018.

  1. Tom Kindlon

    Tom Kindlon Senior Member (Voting Rights)

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    http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32589-2/fulltext

    Lancet. 2017 Jul 22;390(10092):363-373. doi: 10.1016/S0140-6736(16)32589-2. Epub 2017 Jun 22.

    Guided graded exercise self-help plus specialist medical care versus specialist medical care alone for chronic fatigue syndrome (GETSET): a pragmatic randomised controlled trial.

    Clark LV1, Pesola F2, Thomas JM3, Vergara-Williamson M4, Beynon M5, White PD5.
    Author information

    Abstract
    BACKGROUND:
    Graded exercise therapy is an effective and safe treatment for chronic fatigue syndrome, but it is therapist intensive and availability is limited. We aimed to test the efficacy and safety of graded exercise delivered as guided self-help.

    METHODS:
    In this pragmatic randomised controlled trial, we recruited adult patients (18 years and older) who met the UK National Institute for Health and Care Excellence criteria for chronic fatigue syndrome from two secondary-care clinics in the UK. Patients were randomly assigned to receive specialist medical care (SMC) alone (control group) or SMC with additional guided graded exercise self-help (GES). Block randomisation (randomly varying block sizes) was done at the level of the individual with a computer-generated sequence and was stratified by centre, depression score, and severity of physical disability. Patients and physiotherapists were necessarily unmasked from intervention assignment; the statistician was masked from intervention assignment. SMC was delivered by specialist doctors but was not standardised; GES consisted of a self-help booklet describing a six-step graded exercise programme that would take roughly 12 weeks to complete, and up to four guidance sessions with a physiotherapist over 8 weeks (maximum 90 min in total). Primary outcomes were fatigue (measured by the Chalder Fatigue Questionnaire) and physical function (assessed by the Short Form-36 physical function subscale); both were self-rated by patients at 12 weeks after randomisation and analysed in all randomised patients with outcome data at follow-up (ie, by modified intention to treat). We recorded adverse events, including serious adverse reactions to trial interventions. We used multiple linear regression analysis to compare SMC with GES, adjusting for baseline and stratification factors. This trial is registered at ISRCTN, number ISRCTN22975026.

    FINDINGS:
    Between May 15, 2012, and Dec 24, 2014, we recruited 211 eligible patients, of whom 107 were assigned to the GES group and 104 to the control group. At 12 weeks, compared with the control group, mean fatigue score was 19·1 (SD 7·6) in the GES group and 22·9 (6·9) in the control group (adjusted difference -4·2 points, 95% CI -6·1 to -2·3, p<0·0001; effect size 0·53) and mean physical function score was 55·7 (23·3) in the GES group and 50·8 (25·3) in the control group (adjusted difference 6·3 points, 1·8 to 10·8, p=0·006; 0·20). No serious adverse reactions were recorded and other safety measures did not differ between the groups, after allowing for missing data.

    INTERPRETATION:
    GES is a safe intervention that might reduce fatigue and, to a lesser extent, physical disability for patients with chronic fatigue syndrome. These findings need confirmation and extension to other health-care settings.

    FUNDING:
    UK National Institute for Health Research Research for Patient Benefit Programme and the Sue Estermann Fund.
     
  2. Tom Kindlon

    Tom Kindlon Senior Member (Voting Rights)

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    My letter was not accepted.
    I decided to focus on a specific point that I did not see others raising in discussions. Most of my other letters use more references:

    Response to: Guided graded exercise self-help plus specialist medical care versus specialist medical care alone for chronic fatigue syndrome (GETSET): a pragmatic randomised controlled trial

    The SF-36 physical functioning (PF) outcomes for those in the guided graded exercise selfhelp (GES) group who had a baseline SF-36 PF score ≥45 (call them group B) must have been particularly poor in the GETSET trial.1 We are told that those with a baseline score ≤40 (group A) made up approximately 40% of the sample and ended with average score of 56.9. This means the average outcome for group B, the higher functioning group at baseline, was actually lower, at around 54.9. Also, by definition, group A increased by an average of at least 16.9 (56.9-40). However the whole sample only increased by an average of 8.4. This means that an upper bound on the average increase for group B would be only approximately 2.7, in comparison to the increase of 16.9 for group A. This is an extreme scenario and the difference in improvements was most likely higher than 14.2. It would be interesting if Clark and colleagues could give the exact figure so everyone would be aware of the magnitude of the difference in the response.

    Clark and colleagues say the poor results may be due to a ceiling effect. More than 90% of healthy working-age people score 90 or more.2 Therefore, the mean score of 54.9 for group B and 55.7 overall suggests that if there is a ceiling in the effectiveness of GES, it is a long way below normal functioning. I do not believe this was made clear to readers.

    Tom Kindlon

    Competing interests: I work in a voluntary capacity for the Irish ME/CFS Association.

    References:

    1. Clark LV, Pesola F, Thomas J, 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. The Lancet. June 22, 2017 doi:10.1016/S0140-6736(16)32589-2

    2. Wilshire CE, Kindlon T, Matthees A, McGrath S. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue. 2017;5:1–4.
    ---

    The journal did take a long time to reply (over 6 months): I am left wondering whether they asked the investigators for their opinion. I could imagine the researchers might try to put the journal off the letter.


    Anyway I've posted it on PubMed Commons: https://www.ncbi.nlm.nih.gov/pubmed/28648402#cm28648402_78211
     
  3. Invisible Woman

    Invisible Woman Senior Member (Voting Rights)

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    Now the handy thing about having patients inflict GET on themselves is that when the day comes and we can prove they have actually hurt people with GET, there is no therapist or unit to blame.

    I have no doubt they will try to claim it's the patients own fault for not doing it right somehow.
     
  4. Trish

    Trish Senior Member (voting rights)

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    Thanks for trying, @Tom Kindlon. I expect they were too lazy to look at your calculations.
     
  5. Tom Kindlon

    Tom Kindlon Senior Member (Voting Rights)

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    Matt (@DondochakkaB on Twitter) also submitted a letter that was accepted. He said he got the same refusal letter. He said I could post it with his first name and username.


    The claim that GETSET trial data supports the efficacy of Graded Exercise Therapy when used as a treatment for severe Chronic Fatigue Syndrome patients is unsubstantiated.

    Chronic Fatigue Syndrome (CFS) patients are often described as a heterogeneous group in research[1]. Unexplained, persistent fatigue is a unifying symptom amongst CFS criteria but a variety of aetiological investigations continue. CFS criteria account for the inconsistent number of signs and symptoms patients present with. The level of disability within this group ranges from being unable to speak or feed themselves[2] to the hypothetical 'Julie' featured in the Graded Exercise Self-Help (GES) booklet[3].

    Clauw's claim[4] that a greater response rate amongst participants with lower physical function scores supports the notion that graded exercise is effective for severe patients is unsubstantiated. When Clauw states that the most severe cases could not participate in GETSET, he does not reference a scale of severity, the percentage of patients unable to take part in this trial, or the range of severity levels that exists amongst them.

    The GETSET trial only includes patients with the enthusiasm to take part. A sedentary participant with a lower physical function score can suffer less severe CFS symptoms. The heterogeneity of CFS presentations supports a hypothesis that trial participants comprise a functionally different sub-cohort who are aetiologically or symptomatically distinct from those with significantly higher levels of disability. The use of NICE, Oxford and Reeves (CDC) CFS Criteria in the sensitivity analysis is of limited benefit since they omit a number of documented neurological symptoms[5]. The lack of objective data means that any conclusions about harm are built on a presumption of unimpeachable adherence to GES schedules.

    References:

    [1] Jason LA, Corradi K, Torres-Harding S, Taylor RR, King C. Chronic fatigue syndrome: the need for subtypes. Neuropsychol Rev 2005;15:29–58.

    [2] The Puzzle Solver http://stanmed.stanford.edu/2016spring/the-puzzle-solver.html Tracie White, Stanford Medicine (accessed July 04, 2017)

    [3] Clark LV, ed. Graded exercise therapy: a self-help guide for those with chronic fatigue syndrome/myalgic encephalomyelitis. London: Bart’s and the London NHS Trust, 2011. http://www. wolfson.qmul.ac.uk/images/pdfs/getset/GET%20guide%20booklet%20version%201%2022062010.pdf (accessed June 28, 2017).

    [4] Clauw DJ. Guided graded exercise self-help as a treatment of fatigue in chronic fatigue syndrome. Lancet. 2017 Jun 22.doi: 10.1016/S0140-6736(17)30577-9.

    [5] IOM (Institute of Medicine). Beyond myalgic encephalomyelitis/chronic fatigue syndrome: Redefining an illness. Washington, DC: The National Academies. 2015.
     
  6. Tom Kindlon

    Tom Kindlon Senior Member (Voting Rights)

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  7. Esther12

    Esther12 Senior Member (Voting Rights)

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    Surely that can't just refuse to publish any critical letters?! I'm so looking forward to Horton's smug introduction to any that are published. Lets see if he can top his work with the 2011 letters.
     
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  8. Barry

    Barry Senior Member (Voting Rights)

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    Word for word identical rejection letter to mine.
    I took it as read they would have given the investigators sight of the letters. It will be interesting to see, if they publish any at all, which they are; whether or not they are ones they have come up with answers to?
     
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  9. Tom Kindlon

    Tom Kindlon Senior Member (Voting Rights)

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    There's a reasonable possibility those in the group with an initial score of 45+ on the SF-36 physical functioning subscale actually decreased on average. Unfortunately as this letter wasn't published (unless they publish another letter making the same point), I doubt anyone outside the GETSET team will ever know.
     
    Last edited: Jan 9, 2018
  10. Tom Kindlon

    Tom Kindlon Senior Member (Voting Rights)

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  11. Woolie

    Woolie Moderator

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    It's a very good letter, @Tom Kindlon. Crisp and straight to the point. Nice objective tone. As you say, it addresses one key point, but its a good one.

    To give them the benefit of the doubt, perhaps Lancet were just looking for more comprehensive critiques?
     
  12. Tom Kindlon

    Tom Kindlon Senior Member (Voting Rights)

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    Thanks.

    That is a possibility. But they, for example, published eight letters in reply to the PACE Trial: Andrew Kewley's dealt the main issues and a lot of the others (including mine) dealt with specific points. With only 250 words and 5 (=4) references, any one letter can only make a relatively small number of points well. It is less focused on some core issues than some letters I've submitted before.

    Anyway at least now with PubMed Commons I feel a reasonable number of people reading about the study will see it, but it would have been nice to have got a response from the authors especially if the subgroup they didn't discuss actually deteriorated.
     
    Last edited: Jan 10, 2018
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  13. Tom Kindlon

    Tom Kindlon Senior Member (Voting Rights)

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    As an aside, here is another letter I submitted to another journal before, where the format was quite different to this one. Unfortunately the journal didn't publish it and didn't give any reason (I sent a follow-up email asking why it was refused).

    ---

    Objective outcome data from the chronic fatigue syndrome specialist services would have been interesting

    It is disappointing that Crawley et al.1 presented no objective outcome data from the six chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) specialist services; an audit of Belgian CFS rehabilitation centres that used cognitive behavioural therapy (CBT) and graded exercise therapy (GET) found that, while improvements were reported with various subjective measures, no change was noted with exercise testing.2-4 Moreover, there was actually a decrease in average hours in paid employment, from 18.3% of a 38 hour-working week to 14.9%.

    Discrepancies between subjective and objective measures have also been found in trials of both CBT5,6 and GET for CFS.7 Indeed, in the PACE Trial (which compared to the specialist services reported similar improvements on the Chalder Fatigue questionnaire (CFQ) but better SF-36 physical functioning (PF) scores), although moderate sized improvements were found with self-report instruments like the CFQ and SF-36 PF, differences with more objective measures were smaller, if they existed at all.8,9 For example, there was no difference between the CBT and specialist medical care only (SMC) groups on the six minute walking test.8 And no difference between SMC and both CBT and GET in terms of employment losses, overall service costs, welfare benefits or other financial payments.9

    Research on patient-reported outcome measures, and measures of improvement that CFS patients consider important, is underdeveloped.10 Given the known considerable impact of CFS/ME on productivity and employment in those attending such services, it is reasonable to speculate that many patients, and indeed other taxpayers, would find employment data of more interest.11

    References:

    1 Crawley E, Collin SM, White PD, Rimes K, Sterne JAC, May MT, et al. Treatment outcome in adults with chronic fatigue syndrome: a prospective study in England based on the CFS/ME National Outcomes Database. QJM first published online March 28, 2013 doi:10.1093/qjmed/hct061

    2 Rapport d’évaluation (2002-2004) portant sur l’exécution des conventions de rééducation entre le Comité de l’assurance soins de santé (INAMI) et les Centres de référence pour le Syndrome de fatigue chronique (SFC). 2006. http://www.inami.fgov.be/care/fr/re...rmation/studies/study-sfc-cvs/pdf/rapport.pdf. Accessed March 30, 2013 (French language edition)

    3 Evaluatierapport (2002-2004) met betrekking tot de uitvoering van de revalidatieovereenkomsten tussen het Comité van de verzekering voor geneeskundige verzorging (ingesteld bij het Rijksinstituut voor Ziekte- en invaliditeitsverzekering) en de Referentiecentra voor het Chronisch vermoeidheidssyndroom (CVS). 2006. Available online: http://www.inami.fgov.be/care/nl/re...rmation/studies/study-sfc-cvs/pdf/rapport.pdf. Accessed March 30, 2013 (Dutch language version)

    4 Stordeur S, Thiry N, Eyssen M. Chronisch Vermoeidheidssyndroom: diagnose, behandeling en zorgorganisatie. Health Services Research (HSR). Brussel: Federaal Kenniscentrum voor de Gezondheidszorg (KCE); 2008. KCE reports 88A (D/2008/10.273/58) https://kce.fgov.be/sites/default/files/page_documents/d20081027358.pdf Accessed March 30, 2013

    5 Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychological Medicine 2010; 40:1281–1287.

    6 Knoop H, Prins JB, Stulemeijer M, van der Meer JW, Bleijenberg G. The effect of cognitive behaviour therapy for chronic fatigue syndrome on self-reported cognitive impairments and neuropsychological test performance. Journal of Neurology, Neurosurgery & Psychiatry 2007; 78:434-446.

    7 Moss-Morris R, Sharon C, Tobin R, Baldi JC. A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. Journal of Health Psychology 2005; 10:245-59.

    8 White P, Goldsmith K, Johnson A, Potts L, Walwyn R, Decesare J, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011; 377:823–36.

    9 McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, Goldsmith KA, et al. Adaptive Pacing, Cognitive Behaviour Therapy, Graded Exercise, and Specialist Medical Care for Chronic Fatigue Syndrome: A Cost-Effectiveness Analysis. PLoS ONE 2012; 7(8):e40808.

    10 Haywood KL, Staniszewska S, Chapman S. Quality and acceptability of patient-reported outcome measures used in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. Quality of Life Research 2012; 21:35-52.

    11 Collin SM, Crawley E, May M, Sterne JA, Hollingworth W, UK CFS/ME National Outcomes Database ME. The impact of CFS/ME on employment and productivity in the UK: a cross-sectional study based on the CFS/ME National Outcomes Database. BMC Health Services Research 2011; 11:217.

    ---

    No letters were published in that case. Hopefully some will be in this case.

    I've uploaded over 100 e-letters and unpublished letters to PubMed Commons:
    https://www.ncbi.nlm.nih.gov/myncbi/tom.kindlon.1/comments/
     
    Last edited: Jan 10, 2018
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  14. Luther Blissett

    Luther Blissett Senior Member (Voting Rights)

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    Could someone explain what this means please?
     
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