PubMed Commons comments on Exercise for CFS review

9142 25674924 14/02/2015 16:49 Ellen M Goudsmit I had contact with the main author to alert her to certain misconceptions published earlier.   Sadly, I found I had wasted my time. For example, we can not tell how many, if any, patients in the PACE trial met the London criteria. Having read that the researchers planned to select individuals with ME and had listed the criteria in the protocol, I checked that Prof. White would use  the original version which had not been published.  I had been the Chair of the Research Working Group at AFME when they were being tested and still had a copy. They came with a questionnaire as well as a physician to establish their reliability. Prof. White was unwilling to confirm that he would use the original so in light of the  uncertainty, I requested that he did not cite me as a co-author.  I did not work on the lay version published in the Westcare report which I felt was deeply flawed. I was right to be cautious. The trial manual indicates that the researchers adapted the lay version and I could tell from the results that the London criteria were not used as they exclude individuals with psychological disorders so the percentage for that variable should have been nil.  It wasn’t. A second point.  The review does not pay the required attention to the lack of actigraphy, an objective measure to confirm fidelity to the protocol. This has been included in most studies conducted in the USA and the Netherlands.  The results from actigraphy indicate that, except for 7 individuals, there were no significant increases in activity after GET and similar therapies. According to Friedberg who assessed the phenomenon, patients on exercise trials tend to reprioritise their activities, choosing those that result in less stress etc. In short, they learn to pace themselves (Goudsmit et al 2012). That is why they feel better and less fatigued, but it’s not possible to attribute improvement to an increase in activity (or fitness). Pacing was not defined and adaptive pacing therapy (APT) refers to a programme consisting of several components including stress management, advice on sleeping etc.  There are no data for pacing alone in the PACE trial, so to conclude that GET is superior to pacing therapies is premature. There is only one pacing therapy. Pacing is not a therapy.  It’s a simple strategy. Research by Jason suggests that people who pace themselves feel better, irrespective of the protocol they are on. Finally, we know that many patients have adverse reactions to activity. It’s a criterion for diagnosis. To dismiss them  (“no evidence  that exercise therapy worsens outcomes”) is hard to comprehend. Every survey in every country to date has revealed that GET does have marked adverse reactions and can result in relapse. See also Sisto et al and Black and McCully, cited in Goudsmit et al 2012.  To summarise: lack of a definition of pacing resulting in confusion, repetition of incorrect information, failure to consider the findings from objective measures suggesting patients did not adhere to the protocol and ignoring consistent reports from surveys that undermine one’s conclusions. I expect more objectivity and attention to detail from the Cochrane Library.  Goudsmit, EM., Jason, LA, Nijs, J and Wallman, KE. Pacing as a strategy to improve energy management in myalgic encephalomyelitis/chronic fatigue syndrome: A consensus document. Disability and Rehabilitation, 2012, 34, 13, 1140-1147.  Online 19th December.  doi: 10.3109/09638288.2011.635746.
9193 25674924 19/02/2015 07:58 Joan Crawford This review states:  “Chronic fatigue syndrome (CFS) is characterised by persistent, medically unexplained fatigue, as well as symptoms such as musculoskeletal pain, sleep disturbance, headaches and impaired concentration and short-term memory.” This is important because the above description of CFS and the addition of trials in the review only requiring chronic fatigue as an inclusionary requirement (Sharpe et al, 1991) makes generalisation of the findings problematic as many patients with major depressive disorder (MDD) would also meet the above description of CFS and Sharpe et al.’s (1991) criteria if their condition was fatiguing – a common feature – along with muscular aches and pains, sleep disturbance, cognitive difficulties and so on.  The high percentage of patients included in these trials suffering from depression (Table 1. Study demographics) indicates this may be their primary condition – confounding the results.  Exercise, through behavioural activation programs, has a moderately positive impact on patients with depression (Cooney et al., 2013).  It is unclear whether the modest improvement seen in some of these trials can be accounted for by an improvement in low mood caused by depression.  Moreover, where there is data there is a high usage of antidepressants in patients included in the reviewed trials (Table 1. Study demographics).Of the eight exercise trials included in this review, five used broad inclusion criteria (Sharpe et al, 1991) (N=1287) – 85% of all participants.  Two of these studies also used a version of the London criteria, which did not exclude patients with depression and other psychiatric conditions as originally specified by the authors making it hard to assess how these criteria were operationalised.  Three further trials used the CDC Fukuda (1994) CFS criteria (N=231). While these purport to be more selective, they do not necessary include patients whose primary difficulties include post exertional weakness and debility and flu-like symptoms and so on beyond broadly defined fatigue and other general symptoms which could be attributed to CFS or MDD. There is also an issue with lack of evidence of patients’ fidelity to exercise programs using objective measures.  We do not know if patients increased their activity as suggested to them by their clinicians. Without using devises such as actimeters or pedometers to track daily activity levels we have no accurate way of assessing whether an increase in activity occurred and whether this helps.  Black & McCully’s (2005) study demonstrates objectively the difficulties patients face when trying to increase activity and concluded that they were exercise intolerant, unable to sustain activity targets.The report is bold in stating “no evidence suggests that exercise therapy may worsen outcomes“. Many patient surveys from across the world report numerous instances of harm and worsening of symptoms from taking part in exercise programs.  For a summary of the difficulties and limitations of the reporting of harms, in and outside of clinical trials, and why these might be underestimated please see Kindlon (2011).ReferencesCooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE (2013). Exercise for depression. The Cochrane Library.  http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004366.pub6/abstractFukuda, K., Straus, S.E., Hickie, I., Sharpe, M.C., Dobbins, J.G., & Komaroff, A. (1994). The chronic fatigue syndrome: A comprehensive approach to its definition and study. International chronic fatigue syndrome study group. Annals of Internal Medicine, 121(12), 953-959.Kindlon T. (2011). Reporting of harms associated with graded exercise therapy and cognitive behavioural therapy in Myalgic Encephalomyelitis/chronic fatigue syndrome. Bulletin of the IACFS/ME. 19(2): 59-111.M, Archard L, Banatvala J, Borysiewicz LK, Clare AW, David A, et al. (1991). Chronic fatigue syndrome: guidelines for research. Journal of the Royal Society of Medicine, 84(2):118–21.
9229 25674924 24/02/2015 11:58 Laurie Thomas Clinical studies of chronic fatigue syndrome are plagued by serious problems in the inclusion/exclusion criteria. These problems stem from the fact that the syndrome consists of nonspecific symptoms that are “medically unexplained.” However, there is a major difference between medically **unexplained** and medically **inexplicable**. The symptoms of chronic fatigue syndrome can result from a serious circulatory problem that is easily overlooked. In 2003, Peckerman and coworkers showed that low cardiac output, as measured by impedance cardiography, predicts the severity of symptoms in CFS patients.[1] Miwa and Fujita found a small left ventricular size leading to low cardiac output in CFS patients with orthostatic intolerance.[2] Porter and coworkers reported that a case of femoral arteriovenous fistula causing high-output cardiac failure was originally misdiagnosed as chronic fatigue syndrome.[3] The studies of graded exercise for management of CFS are based on the presumption that CFS is the result of laziness and deconditioning and that the solution to the problem is to persuade the patient to exercise. Yet in many reported cases, the real problem was unrecognized cardiac decompensation. This state of cardiac decompensation could account for the push-crash phenomenon (serious, prolonged adverse events from overexertion) among people with CFS. Thus, a graded exercise program that might be beneficial for the large number of people who are tired and achy because of major depressive disorder could be catastrophic for the relatively small number of people whose problem is due to cardiac decompensation. Unfortunately, the existing studies of exercise for management of CFS do not shed light on this problem. The patients whose exercise intolerance is too severe to allow them to participate in the exercise program might refuse to enroll or might be dismissed as noncompliant if they try but fail to exercise. Yet as a result of the positive results of graded exercise for subjects whose real problem is major depressive disorder, patients with unrecognized cardiac decompensation are being scolded for failing to exercise.For ethical and scientific reasons, the protocol for a clinical study of subjects with CFS should be based on the best possible model for clinical management of CFS patients. It would begin with a careful assessment of the subject’s circulatory status. This assessment should include a tilt-table test, or at least a measurement of supine, sitting, and standing pulse and blood pressure. Any circulatory problem should be addressed appropriately. (Note that once the patient’s condition is found to be due to a circulatory problem, the patient no longer fits the inclusion criteria of “medically unexplained” symptoms.) As improper diet is the most prevalent cause of chronic ill-health, the cardiology assessment should be followed by a run-in period of at least a week of optimal dietary management. Subjects should be fed a low-fat (<10% of calories), purely plant-based diet that excludes the most common causes of food allergies or intolerance syndromes (i.e., wheat, rye, barley, corn, soy, strawberries, and citrus fruits). To ensure adherence, the diet should be administered in a residential setting. This kind of low-fat, plant-based diet can bring about a significant drop in blood pressure in hypertensive patients within 7 days, even if the patients stop taking blood pressure medication at baseline.[4] This correction of hypertension results from the decrease in systemic resistance. Thus, this diet could lead to a significant improvement in circulation, which would be beneficial to patients whose symptoms are due to poor circulation, even if they are not hypertensive. Note also that the elimination of poorly tolerated foods is the only reliable way to establish that the patient’s problem is due to a food intolerance. Of course, once the subject’s problem has been shown to be dietary in origin, the subject no longer has “medically unexplained” symptoms and thus no longer fits the inclusion criteria for a study of CFS.Many patients with a diagnosis of CFS are inactive, but they may be inactive because they are sick, rather than being sick because they are inactive. Thus, any study of exercise and CFS should be structured to establish the direction of causality. If a study of subjects with a diagnosis of CFS involves exercise, the outcome variables must involve some measurement of the subjects’ overall activity levels, not just to assess compliance with the exercise program but to assess whether the subjects are merely wasting their energy on the exercises and thus become less able to perform activities of daily living. In that situation, the exercise program could actually decrease the subject’s quality of life.   [1] Peckerman A, LaManca JJ, Dahl KA, Chemitiganti R, Qureishi B, Natelson BH. Abnormal impedance cardiography predicts symptom severity in chronic fatigue syndrome. Am J Med Sci. 2003 Aug;326(2):55-60.[2] Miwa K1, Fujita M. Small heart with low cardiac output for orthostatic intolerance in patients with chronic fatigue syndrome.Clin Cardiol. 2011 Dec;34(12):782-6. doi: 10.1002/clc.20962. Epub 2011 Nov 28.[3] Porter J1, Al-Jarrah Q1, Richardson S. A case of femoral arteriovenous fistula causing high-output cardiac failure, originally misdiagnosed as chronic fatigue syndrome. Case Rep Vasc Med. 2014;2014:510429. doi: 10.1155/2014/510429. Epub 2014 May 20.[4] McDougall J1, Thomas LE, McDougall C, Moloney G, Saul B, Finnell JS, Richardson K, Petersen KM.Effects of 7 days on an ad libitum low-fat vegan diet: the McDougall Program cohort. Nutr J. 2014 Oct 14;13:99. doi: 10.1186/1475-2891-13-99.
11779 25674924 14/09/2015 16:54 Tom Kindlon Comment 1 of 2 formally submitted on September 9, 2015 using instructions here: http://www.cochranelibrary.com/help/submitting-comments-on-cochrane-reviews.html—(This is available in one piece at: http://forums.phoenixrising.me/index.php?threads/my-two-detailed-comments-on-the-cochrane-exercise-therapy-for-cfs-review-2015.39801/ )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).”(continues)
11782 25674924 14/09/2015 16:57 Tom Kindlon (contd.)ComplianceThe 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 KindlonConflict of Interest statement:I am a committee member of the Irish ME/CFS Association and do a variety of unpaid work for the Association.(continues)
11785 25674924 14/09/2015 17:00 Tom Kindlon (continues)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.aspx5 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, 203-2159 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, 201510 Critical Illness – A Dreadful Experience with Scottish Provident. http://forums.moneysavingexpert.com/showthread.php?t=2356683 Accessed: September 4, 201511 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, 201515 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 PR Manual ver9 Apr05.pdf Accessed September 7, 201518 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 Encephalomyelitis International Consensus Primer -2012-11-26.pdf Accessed September 5, 201520 Twisk FN. Objective Evidence of Post-exertional “Malaise” in Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. J Sports Med Doping Stud 2015. 5:159. doi: 10.4172/2161-0673.100015921 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/chapter_8/table_8_5_d_criteria_for_judging_risk_of_bias_in_the_risk_of.htm Accessed: September 5, 201522 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
11791 25674924 14/09/2015 17:07 Tom Kindlon Comment 2 of 2 formally submitted on September 9, 2015 using instructions here: http://www.cochranelibrary.com/help/submitting-comments-on-cochrane-reviews.html—(This is available in one piece at: http://forums.phoenixrising.me/index.php?threads/my-two-detailed-comments-on-the-cochrane-exercise-therapy-for-cfs-review-2015.39801/ )Second comment:I have decided to split my comment into two as it was getting very long. This is part two.Variation in interventionsIt would have been useful to have some more information on the “exercise with pacing” intervention tested in the Wallman et al. (2004) trial and how it was distinct from some other exercise interventions tested. The authors say (1): “On days when symptoms are worse, patients should either shorten the session to a time they consider manageable or, if feeling particularly unwell, abandon the session altogether” (p. 143). I don’t believe the description given in the review conveys this. In the review, this approach is described as “Exercise with pacing: exercise in which the incremental increase in exercise was personally set.” But Wallman et al.’s approach allows patients to decrease as well as increase how much exercise they do on the day. This approach also contrasts with how White (an investigator in two of the trials) has described graded exercise therapy: “if [after increasing the intensity or duration of exercise] there has been an increase in symptoms, or any other adverse effects, they should stay at their current level of exercise for a further week or two, until the symptoms are back to their previous levels” (2). In the PACE Trial manual White co-wrote (3), the GET intervention was guided by the principle that “planned physical activity and not symptoms are used to determine what the participant does” (p. 21); similarly, “it is their planned physical activity, and not their symptoms, that determine what they are asked to do” (p. 20). Compliance data would help us examine which approach patients are actually using: I suspect many patients are in fact doing exercise with pacing even in trials such as the PACE Trial (i.e. when they have increased symptoms, often reducing levels of exercise and sometimes doing no exercise activities at all on that day).Bimodal versus Likert scoring in Wearden et al. (2010)I find it odd that the fatigue scores for the Wearden et al. (2010) trial (4) are given in the 0-33 format rather than the 0-11 scoring method. The 0-11 scoring system is what is mentioned as a primary outcome measure in the protocol and is what is reported in the main paper reporting the results (4, 5). It is even what your own report says on p. 44 is the scoring method (“Fatigue Scale, FS; 11 items; each item was scored dichotomously on a 4-point scale [0, 0, 1 or 1]”). This is important because using the scoring method for which you don’t report data (0-11), there is no statistically significant difference at the primary outcome point of 70 weeks (5).Diagnostic criteriaOne problem with using these trials as an evidence base, which I don’t believe was mentioned, is that all the trials used the Oxford and Fukuda diagnostic criteria (6, 7). Neither of these criteria require patients to have post-exertional malaise (or something similar). Many consider this to be a core symptom of ME/CFS and it is mandatory in most of the other major criteria (8-11). [Aside: The London criteria were assessed in the PACE Trial (12) but they seem to have been operationalised in an unusual way. Ninety seven per cent of the participants who satisfied the (broad) Oxford criteria who didn’t have a psychiatric disorder satisfied the definition of M.E. used (13). Ellen Goudsmit, one of the authors of the London criteria, has rejected the way they were used in the PACE Trial (14)]. So this lack of requirement for patients to have post-exertional malaise (or a similar description) means we cannot be sure that the evidence can be generalised to such patients. An independent National Institutes of Health committee this year concluded “continuing to use the Oxford definition may impair progress and cause harm. Therefore, for progress to occur, we recommend that this definition be retired” (15). An Agency for Healthcare Research and Quality review of diagnostic methods this year reached a similar conclusion: “Consensus groups and researchers should consider retiring the Oxford case definition because it differs from the other case definitions and is the least restrictive, probably including individuals with other overlapping conditions” (16). An Agency for Healthcare Research and Quality review of ME/CFS treatments said: “The Oxford CFS case definition is the least restrictive, and its use as entry criteria could have resulted in selection of participants with other fatiguing illnesses or illnesses that resolve spontaneously with time” (17).Exclusion of some data from analyses due to baseline differencesIt seems unfortunate that some data cannot be used due to baseline differences e.g. “Four trials (669 participants) contributed data for evaluation of physical functioning at follow-up (Jason 2007; Powell 2001; Wearden 2010; White 2011). Jason 2007 observed better results among participants in the relaxation group (MD 21.48, 95% CI 5.81 to 37.15). However, results were distorted by large baseline differences in physical functioning between the exercise and relaxation groups (39/100 vs 54/100); therefore we decided not to include these results in the meta-analysis”. It would be good if other methods could be investigated (e.g. using baseline levels as covariates) to analyse such data.Thank you for taking the time to read my comments.Tom KindlonConflict of Interest statement:I am a committee member of the Irish ME/CFS Association and do a variety of unpaid work for the Association.References1 Wallman KE, Morton AR, Goodman C, Grove R. Exercise prescription for individuals with chronic fatigue syndrome. Med J Aust. 2005;183:142-3.2 White P. How exercise can help chronic fatigue syndrome. Pulse: 1998. June 20:86-87.3 Bavinton J, Darbishire L, White PD -on behalf of the PACE trial management group. Graded Exercise Therapy for CFS/ME (Therapist Manual) http://www.pacetrial.org/docs/get-therapist-manual.pdf4 Wearden AJ, Riste L, Dowrick C, Chew-Graham C, Bentall RP, Morriss RK, Peters S, Dunn G, Richardson G, Lovell K, Powell P. Fatigue Intervention by Nurses Evaluation–the FINE Trial. A randomised controlled trial of nurse led self-help treatment for patients in primary care with chronic fatigue syndrome: study protocol. [ISRCTN74156610]. BMC Med. 2006 Apr 7;4:9.5 Wearden AJ, Dowrick C, Chew-Graham C, Bentall RP, Morriss RK, Peters S, Riste L, Richardson G, Lovell K, Dunn G; Fatigue Intervention by Nurses Evaluation (FINE) trial writing group and the FINE trial group. Nurse led, home based self help treatment for patients in primary care with chronic fatigue syndrome: randomised controlled trial. BMJ. 2010 Apr 23;340:c1777. doi: 10.1136/bmj.c1777.6 Sharpe M, Archard L, Banatvala J, Borysiewicz LK, Clare AW, David A, et al. Chronic fatigue syndrome: guidelines for research. Journal of the Royal Society of Medicine 1991;84 (2):118–21.7 Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Ann Intern Med. 1994; 121: 953‑959.8 Carruthers BM, Jain AK, De Meirleir KL, et al. Myalgic Encephalomyelitis/chronic fatigue syndrome: Clinical working case definition, diagnostic and treatments protocols. Journal of Chronic Fatigue Syndrome. 2003; 11: 7-115.9 Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 2011; 270: 327-338.10 IOM (Institute of Medicine). Beyond myalgic encephalomyelitis/chronic fatigue syndrome: Redefining an illness. Washington, DC: The National Academies; 2015.(continues)
11794 25674924 14/09/2015 17:08 Tom Kindlon (contd.)11 National Institute for Health and Clinical Excellence. Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management of CFS/ME in adults and children, 2007. http://www.nice.org.uk/guidance/CG53 Accessed September 6, 2015. London: National Institute for Health and Clinical Excellence.12 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;377:823-36.13 Kindlon T. PACE Trial – 97% of the participants who didn’t have a psychiatric disorder satisfied the definition of M.E. used. https://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind1106A&L=CO-CURE&P=R2764 Accessed: September 6, 201514 Ellen Goudsmit on PubMed Commons: http://www.ncbi.nlm.nih.gov/myncbi/ellen m.goudsmit.1/comments/15 Green CR, Cowan P, Elk R, O’Neil KM, Rasmussen AL. National Institutes of Health Pathways to Prevention Workshop: advancing the research on myalgic encephalomyelitis/chronic fatigue syndrome. Ann Intern Med. 2015; 162:860-5.16 Haney E, Smith MEB, McDonagh M, Pappas M, Daeges M, Wasson N, et al. Diagnostic methods for myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015; 162:834-40.17 Smith MEB, Haney E, McDonagh M, Pappas M, Daeges M, Wasson N, et al. Treatment of myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015; 162:841-50.
15379 25674924 18/04/2016 11:38 Tom Kindlon James C Coyne PhD has blogged here https://jcoynester.wordpress.com/2016/03/20/why-the-cochrane-collaboration-needs-to-clean-up-conflicts-of-interest/  about my comment:”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.and the response I received from one of the authors .