Tom Kindlon
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Comment on: Exercise therapy for chronic fatigue syndrome. Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Cochrane Database Syst Rev. 2015 Feb 10;2:CD003200.
Author: Tom Kindlon
Comment 1 of 2 submitted on September 9, 2015
I would first like to thank those involved for their work in preparing this document. Even for those of us who have read the individual Chronic Fatigue Syndrome (CFS) papers it is useful to have the results collated, as well as details regarding the interventions. Also it is interesting to see the results of sensitivity analyses, subgroup analyses, standardised mean differences, etc.
I would like to make a few comments. I’m splitting them into two submissions as the piece had become very long. I’ve added some loose headings to hopefully make it more readable.
Objective measures
The review assessed the studies as having a high risk of bias regarding blinding, since neither participants nor assessors were blinded. Evidence suggests that subjective outcomes are more prone to bias than objective outcomes when there is no blinding (1). It is thus unfortunate that the review concentrated almost exclusively on subjective measures, failing to include results from nearly all the objective outcome measures that have been published with trials. (The exception was health resource use for which you presented follow-up data from one trial).
I hope objective outcome data can be included in a future revision or edition of this review.
Examples of objective outcomes include: exercise testing (work capacity by oxygen consumption); fitness test/step test; the six minute walking test; employment status; and disability payments.
Adding in these results would allow a more rigorous assessment of the effectiveness and relevance of the therapies, their causal mechanisms, therapeutic compliance, and safety.
On exercise testing, for example, in the PACE Trial (the largest trial in the review) there was no improvement in fitness levels as measured by a step test (2). The fitness data contrasts sharply with the many positive results from subjective self-report measures in the trial, so one is left wondering how much the subjective measures reflect reality.
On another exercise test used in the PACE Trial, the 6 minute walk test, there was a small (mean) increase from 312 metres at baseline to 379 metres at 12 months: this was 35.3 metres more than the "passive" control group when adjustments were made. However, the final result of 379 metres remains very poor compared to the more than 600 metres one would expect from healthy people of a similar age and gender make-up (3,4). By comparison, a group with Class III heart failure walked an average of 402 metres (5). A score of less than 400 metres has been suggested as the level at which somebody should be put on a lung transplant list (6). Such information from objective measures helps to add important context to the subjective measures and restraint to the conclusions that can be drawn from them.
Objective data is also needed to check compliance with a therapy. If patients diligently exercised for 12 months one would expect much better results on fitness and exercise testing than the aforementioned results in the PACE Trial. This is important when considering adverse events and safety: such trials may not give us good information on the safety of complying with such interventions if patients haven't actually complied.
Employment and receipt of disability payments are practical objective measures of general functional capacity so data on them would help establish whether patients can actually do more overall or whether they may just be doing, for example, a little more exercise but have substituted that for doing less in other areas (7,8). Also, CFS patients are sometimes pressured by insurance companies into doing graded exercise therapy (GET) programs so it would be useful to have data collated on employment outcomes to see whether pressure can in any way be justified (9,10). In the PACE Trial, there was no significant improvement in employment measures and receipt of disability payments in the GET group (11). Outside the realm of clinical trials, the quantitative and qualitative data in a major (UK) ME Association survey also found that GET didn't lead to higher levels of employment and lower levels of receipt of disability payments on average (9). Also, extensive external audits were performed of Belgian CFS rehabilitation clinics that treated using cognitive behavioural therapy (CBT) and GET. The main reports are in French and Dutch (12,13), with an English summary available (14) that says, "Employment status decreased at the end of the therapy, from an average of 18.3% of a 38h working week, to 14.9% [...] The percentage of patients living from a sickness allowance increased slightly from 54 to 57%." This contrasts with the average improvements reported in the audit for some symptoms like fatigue.
While data on (self-reported) symptoms like fatigue (one of your two primary outcomes) is interesting, arguably more important to patients is improving their overall level of functioning (and again, objective measures are needed here). Being able to work, for example, despite experiencing a certain level of fatigue would likely be more important for many than being unable to work but having slightly lower levels of fatigue.
An example of how reductions in the reported levels of fatigue may not lead to improvements in functioning can be seen in an analysis of three graded activity-oriented CBT therapy interventions for CFS (15). The analysis showed, compared to controls, there were no improvements in overall activity levels as measured by actometers despite improvements in self-reported fatigue (15). Activity in these trials was assessed using actometers. Another study that exemplifies the problem of focusing too much on fatigue scores after behavioural interventions is a study of CBT in multiple sclerosis (MS) patients with “MS fatigue”(16). The study found that following the intervention, patients with MS reported significantly lower (i.e. better) scores on the Chalder Fatigue Scale (0-33 scoring) than those in a healthy, nonfatigued comparison group! This significant difference was maintained at 3 and 6 months’ follow-up. It is difficult to believe that patients with MS fatigue (at baseline) truly subsequently had less fatigue than healthy nonfatigued controls: a much more likely scenario is that undertaking the intervention had led to response biases.
You mention that "many patient charities are opposed to exercise therapy for chronic fatigue syndrome (CFS)". One reason for concern about the way in which exercise programmes are promoted to patients is that they are often based upon models which assume that there is no abnormal physiological response to exercise in the condition, and make unsupported claims to patients. For example, in the FINE trial (Wearden et al., 2010) patient booklet (17), it is boldly asserted that: "Activity or exercise cannot harm you" (p. 49). However, a large number of studies have found abnormal responses to exercise, and the possibility of harm being done simply cannot be excluded on the basis of current evidence (discussed in 4, 18-20)."
Compliance
The review doesn't include any information on compliance. I'm not sure that there is much published information on this but I know there was a measure based on attendance at therapy sessions (which could be conducted over the phone) given for the PACE Trial (3). Ideally, it would be interesting if you could obtain some unpublished data from activity logs, records from heart-rate monitors, and other records to help build up a picture of what exercise was actually performed and the level of compliance. Information on adherence and what exercise was actually done is important in terms of helping clinicians, and indeed patients, to interpret and use the data. I mention patients because patients' own decisions about their behaviour is likely to be affected by the medical information available to them, both within and outside of a supervised programme of graded exercise; unlike with an intervention like a drug, patients can undertake exercise without professional supervision.
"Selective reporting (outcome bias)" and White et al. (2011)
I don't believe that White et al. (2011) (the PACE Trial) (3) should be classed as having a low risk of bias under "Selective reporting (outcome bias)" (Figure 2, page 15). According to the Cochrane Collaboration's tool for assessing risk of bias (21), the category of low risk of bias is for: "The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way". This is not the case in the PACE Trial. The three primary efficacy outcomes can be seen in the published protocol (22). None have been reported in the pre-specified way. The Cochrane Collaboration's tool for assessing risk of bias states that a “high risk” of bias applies if any one of several criteria are met, including that “not all of the study’s pre-specified primary outcomes have been reported” or “one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified”. In the PACE Trial, the third primary outcome measure (the number of "overall improvers") was never published. Also, the other two primary outcome measures were reported using analysis methods that were not pre-specified (including switching from the bimodal to the Likert scoring method for The Chalder Fatigue Scale, one of the primary outcomes in your review). These facts mean that the “high risk of bias” category should apply.
Thank you for taking the time to read my comments.
Tom Kindlon
Conflict of Interest statement:
I am a committee member of the Irish ME/CFS Association and do a variety of unpaid work for the Association.
References:
1. Turner L, Boutron I, Hróbjartsson A, Altman DG, Moher D: The evolution of assessing bias in Cochrane systematic reviews of interventions: celebrating methodological contributions of the Cochrane Collaboration. Syst Rev 2013, 2:79.
2. Chalder T, Goldsmith KA, White PD, Sharpe M, Pickles AR. Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial. Lancet Psychiatry. 2015;2:141-152.
3. White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, 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. The Lancet 2011;377:823-36.
4. Kindlon T. Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Bull IACFS ME. 2011;19:59-111. http://iacfsme.org/ME-CFS-Primer-Education/Bulletins/BulletinRelatedPages5/Reporting-of-Harms-Associated-with-Graded-Exercise.aspx
5. Lipkin DP, Scriven AJ, Crake T, Poole-Wilson PA (1986). Six minute walking test for assessing exercise capacity in chronic heart failure. British Medical Journal 292, 653-5.
6. Kadikar A, Maurer J, Kesten S. The six-minute walk test: a guide to assessment for lung transplantation. J Heart Lung Transplant. 1997 Mar;16(3):313-9.
7. Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? J Clin Psychol. 2009 Feb 11.
8. Friedberg F. Does graded activity increase activity? A case study of chronic fatigue syndrome. Journal of Behavior Therapy and Experimental Psychiatry, 2002, 33, 3-4, 203-215
9. Results and In-depth Analysis of the 2012 ME Association Patient Survey Examining the Acceptability, Efficacy and Safety of Cognitive Behavioural Therapy, Graded Exercise Therapy and Pacing, as Interventions used as Management Strategies for ME/CFS. Gawcott, England. http://www.meassociation.org.uk/2015/05/23959/ Accessed: September 3, 2015
10. Critical Illness - A Dreadful Experience with Scottish Provident. http://forums.moneysavingexpert.com/showthread.php?t=2356683 Accessed: September 4, 2015
11. McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, Goldsmith KA, White PD. 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.
12. 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://health.belgium.be/internet2Prd/groups/public/@public/@shc/documents/ie2divers/14926531_fr.pdf (Starts on page 223.) Accessed September 4, 2015 (French language edition)
13. 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. http://health.belgium.be/internet2Prd/groups/public/@public/@shc/documents/ie2divers/14926531.pdf (Starts on page 227.) Accessed September 4, 2015 (Dutch language version)
14. 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 September 4, 2015
15. 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. Psychol Med. 2010; 40:1281-1287.
16. Van Kessel K, Moss-Morris R, Willoughby, Chalder T, Johnson MH, Robinson E, A randomized controlled trial of cognitive behavior therapy for multiple sclerosis fatigue, Psychosom. Med. 2008; 70:205–213.
17. Powell P. FINE Trial Patient Booklet http://www.fine-trial.net/downloads/Patient%20PR%20Manual%20ver9%20Apr05.pdf Accessed September 7, 2015
18. Twisk FNM, Maes M. A review on Cognitive Behavorial Therapy (CBT) and Graded Exercise Therapy (GET) in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. Neuro Endocrinol Lett. 2009;30:284-299.
19. Carruthers BM et al. Myalgic Encephalomyelitis – Adult & Paediatric: International Consensus Primer for Medical Practitioners. ISBN 978-0-9739335-3-6 http://www.investinme.org/Documents/Guidelines/Myalgic%20Encephalomyelitis%20International%20Consensus%20Primer%20-2012-11-26.pdf Accessed September 5, 2015
20. Twisk FN. Objective Evidence of Post-exertional “Malaise” in Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. J Sports Med Doping Stud 2015. 5:159. doi: 10.4172/2161-0673.1000159
21. Higgins JPT, Green S: Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. Table 8.5.d. The Cochrane Collaboration; 2011. http://handbook.cochrane.org/chapte...a_for_judging_risk_of_bias_in_the_risk_of.htm Accessed: September 5, 2015
22. White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; on behalf of the PACE trial group. Protocol for the PACE trial: A randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurology 2007, 7:6 http://www.biomedcentral.com/1471-2377/7/6 Accessed: September 5, 2015
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