Exercise therapy beneficial for some ME/CFS patients new Cochrane report says

[Dolphin]

Exercise therapy is often included as part of a treatment programme for individuals with CFS. ’Exercise’ is defined as “planned structured and repetitive bodily movement done to improve or maintain one or more components of physical fitness” (ACSM 2001); ’therapy’ is defined as “treatment intended to relieve or heal a disorder” (Oxford English Dictionary).

So why not report fitness data?

 

[Dolphin]

How the intervention might work

Physical activity can improve health and quality of life for patients with chronic disease (Blair 2009). The causal pathway for CFS is unknown; however several hypotheses have been proposed as to why exercise therapy might be a viable treatment. The ’deconditioning model’ assumes that the syndrome is perpetuated by reversible physiological changes of deconditioning and avoidance of activity; therefore exercise should improve deconditioning and thus the condition of patients with CFS (Clark 2005; White 2011). However, mediation studies suggest that improved conditioning is not associated with better outcomes (Fulcher 1997; Moss-Morris 2005). Some graded exercise therapy (GET) programmes are designed to gradually reintroduce the patient to the avoided stimulus of physical activity or exercise, which may involve a conditioned response leading to fatigue (Clark 2005; Fulcher 2000; White 2011). Mediation studies suggest that reduced symptom focus may mediate outcomes with GET, consistent with this model (Clark 2005; Moss-Morris 2005). Evidence has also been found for central sensitisation contributing to hyperresponsiveness of the central nervous system to a variety of visceral inputs (Nijs 2011). The most replicated finding in patients with CFS is an increased sense of effort during exercise, which is consistent with this model (Fulcher 2000; Paul 2001). Graded exercise therapy may reduce this extra sense of effort, perhaps by reducing central sensitisation (Fulcher 1997).

Further research is needed to verify these hypotheses, but effective treatments may be discovered without knowledge of the effective pathway or underlying cause.

All very speculative. As an outsider, I would like to have some objective data to help me ascertain what could be happening.

No mention of the possibility of response biases (in responses to questionnaires) of course.

 

[Dolphin]

As a point of reference, we used the following empirical definitions, as derived from descriptions of the interventions.
• Graded exercise therapy (GET): exercise in which the incremental increase in exercise was mutually set.
• Exercise with pacing: exercise in which the incremental increase in exercise was personally set.

I don't find these descriptions that good. In Wallman et al. which tested exercise with pacing, patients could skip sessions (or do reduced amounts) if they had increased symptoms. Incremental increase refers to when one will increase and doesn't get this across.

 

[Dolphin]

Types of outcome measures

Primary outcomes

1. Fatigue: measured using any validated scale (e.g. Fatigue Scale (FS) (Chalder 1993), Fatigue Severity Scale (FSS) (Krupp 1989)).

2. Adverse outcomes: measured using any reporting system (e.g. serious adverse reactions (SARs) (European Union Clinical Trials Directive 2001)).

Secondary outcomes

3. Pain: measured using any validated scale (e.g. Brief Pain Inventory (Cleeland 1994)).

4. Physical functioning: measured using any validated scale (e.g. Short Form (SF)-36, physical functioning subscale (Ware 1992)).

5. Quality of life (QOL): measured using any validated scale (e.g. Quality of Life Scale (Burckhardt 2003)).

6. Mood disorders: measured using validated instruments (e.g. Hospital Anxiety and Depression Scale (Zigmond 1983)).

7. Sleep duration and quality: measured by self-report on a validated scale, or objectively by polysomnography (e.g. Pittsburgh Sleep Quality Index (Buysse 1989)).

8. Self-perceived changes in overall health: measured by self-report on a validated scale (e.g. Global Impression Scale (Guy 1976)).

9. Health service resource use (e.g. primary care consultation rate, secondary care referral rate, use of alternative practitioners).

10. Drop-outs (any reason).

So as I mentioned, no results of exercising tests (VO2 max, 6 minute walking test, step test/fitness testing, etc.). No data on employment.

They allude to some missing measures later:

Included studies reported several outcomes in addition to those reported in this review, such as work capacity by oxygen consumption (VO2), the six-minute walking test and illness beliefs.

 

[Dolphin]

We considered two arms (exercise + drug placebo vs exercise placebo + drug placebo) in Wearden 1998 as relevant for this review.

Another possibility would have been to also use the data from exercise + drug vs exercise placebo + drug. This would have meant more weight to the findings of Wearden et al. (1998). As I recall, results for exercise weren't good in it. There are pros and cons in doing it but it would have been interesting if the data had been presented.

 

[Dolphin]

Blinding

As the intervention did not allow for blinding of participants or personnel delivering the exercise-based interventions, and as all measures were performed by self-report, blinding was impossible. This inevitably puts the review at some risk of bias, and all of the included studies were rated as having high risk of bias.

In such a scenario, objective measures might be good.

 

[Dolphin]

For what it's worth (some might not agree with about the PACE Trial for example but they don't cover the recovery criteria which is where the biggest problem was I think it's fair to say):

Selective reporting
Two studies (Wearden 2010; White 2011) referenced published protocols, and when we checked these against the published results, we found that reporting was adequate. In one study (Wearden 1998), trial investigators reported numerical data for only one subscale (health perception) of the Medical Outcomes Survey (MOS) scale (Ware 1992), for which data favour the intervention group; no numerical data were given for the five other subscales, nor for another scale (anxiety), as data were “similar in trial completers.” It was not possible to check the other studies for selective reporting bias; therefore their risk of bias is considered unclear.

 

[Kati]

Peter White, DJ Clauw, MD, JWM van der Meer MD R Moss-Morris PhD, RR Taylor PhD spun the Cochrane results a different way in a comment to the journal, Annals of Internal Medicine


There was not good reporting of harms in the eight trials PD White et al. refer to (at best one could say there was good reporting in one, the PACE trial) so it's misleading to talk about eight trials. Average scores don't tell one whether some people disimproved or not.

And they don't factor in drop out rates.

 

[jimells]

So once again we have self-serving psychobabblers reviewing "chronic fatigue" and then claiming their review has anything to do with our illness.

I used to have a pretty good opinion of the Cochrane reviews, but now it looks like it is as corrupt as any other process. The selective exclusion of evidence is the same tactic we saw in the IOM evidence review, the P2P evidence review, and in previous reviews in UK. I'm thinking of the 2002 Chief Medical Officers Report here, but I can't find a reference.

Fixing the intelligence around the policy is now so commonplace that no one even notices any more.

 

[Bob]

I used to have a pretty good opinion of the Cochrane reviews, but now it looks like it is as corrupt as any other process.

I think Cochrane reviews are supposed to avoid bias such as having interested parties carry out reviews, but their processes don't seem to be very rigorous. Their reviews clearly aren't rigorous either. A couple of us were going to submit a document to Cochrane about their CFS reviews, highlighting potential bias, but we were too ill to complete the project. It's something I'd really like to do when/if my health picks up. I think they might have a CBT review in the works as well, carried out by interested parties, but I'm not certain if I'm remembering that correctly.

 

[Bob]

Peter White, DJ Clauw, MD, JWM van der Meer MD R Moss-Morris PhD, RR Taylor PhD spun the Cochrane results a different way in a comment to the journal, Annals of Internal Medicine

Secondly, there is little evidence of harm caused by graded exercise therapy (GET); a Cochrane systematic review of eight trials of exercise therapy for chronic fatigue syndrome (CFS), published this year, concluded that “..no evidence suggests that exercise therapy may worsen outcomes.”

Re the quote: "no evidence suggests that exercise therapy may worsen outcomes"; that is a correct quote from the Cochrane review but, as you said, to quote that line without any context is spinning the facts. i.e. to omit this detail: "sparse data made it impossible for review authors to draw conclusions"

 

[Bob]

This has probably been posted before, but I just noticed it...

Seven studies used variations of aerobic exercise therapy such as walking, swimming, cycling or dancing provided at mixed levels in terms of intensity of the aerobic exercise from very low to quite rigorous, whilst one study used anaerobic exercise.

 

[Dolphin]

They include some feedback. It looks like it was feedback before the review was published. But it shows feedback might have some prominence.

F E E D B A C K

Feedback

Summary

The two reviews about chronic fatigue syndrome (CFS) (on exercise and CBT) are important documents in a controversial field. However, they seem to be listed on the website as mental health topics, alongside depression, etc. CFS is not a form of mental illness, although of course individual cases may have a psychological component that can be addressed during treatment. May I suggest that you place them elsewhere, as it is misleading and confusing to include them under the mental health umbrella?

Reply

Many thanks for your comment on the two Cochrane CFS reviews. Apologies for the delay in responding, I have been on annual leave. We appreciate your observations about the placement of these reviews in The Cochrane Library. Feedback on reviews is normally dealt with by the relevant review author, but in this case I am responding, as your query relates more to an organisational issue. These reviews are listed as topics under a mental health heading because, as a result of the psychological component to which you refer, both reviews are supported by a mental health Cochrane group. Similar arrangements are in place for reviews of treatments for other disorders involving a variety of component problems and that as a result do not easily fit within the scope of one Cochrane group. These reviews however can be accessed in a number of different ways, for example, by searching for the specific topic (CFS and associated terminology, exercise and associated terminology, CBT and associated terminology); by searching for the study authors; by looking under subject headings, etc. The subject headings are not really intended as a comment on/guide to the aetiology of an illness, but they sometimes reflect the services involved in management of the condition. I have copied this response to the review authors in case they wish to comment further. Many thanks for your feedback.

Contributors Cathy Stillman-Lowe (occupation freelance editor/science writer) cathy.stillman-lowe@care4free.net

Submitter agrees with default conflict of interest statement: I certify that I have no affiliations with or involvement in any organisation or entity with a financial interest in the subject matter of my feedback. Types of evidence included, 3 June 2013

Summary

Unfortunately, this review ignores the large body of patient testimony suggesting that many persons with severe myalgic encephalomyelitis have been harmed by graded exercise therapy. Since it was prepared, the International Consensus Primer and Guidelines for Medical Practitioners have been published. Current thinking is to stay within your energy envelope. People with ME tend to overdo not underdo what they are capable of.... Care must be taken to NOT encourage them to do too much. Further many definitions are used for CFS, and this muddies the waters. I agree with the conflict of interest statement below: I certify that I have no affiliations with or involvement in any organisation or entity with a financial interest in the subject matter of my feedback.

Reply

Thank you for your comments on this Cochrane Review. In conducting this review, our aim was to gather and synthesise a specific type of evidence-that reported by randomised controlled trials. We fully accept that patient testimony, particularly that gathered and synthesised by high-quality qualitative research, is invaluable in any clinical area, particularly in an area as challenging for patients and healthcare professionals as CFS-ME. However, this project was not designed to incorporate such evidence. We do consider the possibility of harm arising from graded exercise therapy by considering reported adverse events. Clearly this is an important issue to consider with any therapeutic intervention. Moreover, in the usual course of any illness, the condition of some patients improves (with or without treatment) and the condition of others worsens (with or without treatment). It is only through the use of randomised controlled trials that the effects (whether beneficial or adverse) of putative treatments can be disentangled reliably from the natural history of illness. You raise the important point that (some) ’people with ME tend to overdo not underdo what they are capable of.’ The critical point is the extent to which patients should be ’encouraged to do more’ and the way in which they should be encouraged to do so. These are important research questions. As you know, new randomised evidence is available from the PACE trial, published in 2011 in Lancet. Whilst this is a controversial trial, it is an important randomised comparison of graded exercise therapy and ’adaptive pacing.’ We look forward to further randomised evidence in due course. 112 Exercise therapy for chronic fatigue syndrome (Review) Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. We also look forward to continuing to work in this clinical area, in the hope that we can advance our understanding of the impact of this treatment approach.

Contributors Submitter: Adrienne. Response prepared by Jonathan Price.

 

[Dolphin]

Quality of the evidence

Risk of bias across studies was relatively low. We were able to identify pre-published protocols for only two studies (Wearden 2010; White 2011) and have identified a risk of unpublished outcomes. One limitation is that formal blinding of participants and clinicians to treatment arm is not inherently possible in trials of exercise therapy. This increases risk of bias, as instructors’ and participants’ knowledge of group assignation might have influenced the true effect. In addition, outcomes were measured subjectively (e.g. questionnaires, visual analogue scales), leading to risk that this might increase the outcome estimate. Against this, many patient charities are opposed to exercise therapy for chronic fatigue syndrome (CFS), and this may in contrast reduce the effect.

Perhaps fair to mention the patient charities' stance. Though if patients were that influenced by patient charities they probably wouldn't have entered the trial or if they had, might have chosen to leave after being allocated to exercise therapy.

They could have spelled out how subjective outcomes might involve response biases more rather than just saying they might be biased.

 

[Dolphin]

We don't get any unpublished data:

For this updated review, we have not collected unpublished data for our outcomes but have used data from the 2004 review (Edmonds 2004) and from published versions of included articles.

 

[Dolphin]

There are a few ongoing studies (the Vos-Vromans et al. one has just been published)

References to ongoing studies

Broadbent 2012 {unpublished data only}

Broadbent S, Coutts R. The protocol for a randomised controlled trial comparing intermittent and graded exercise to usual care for chronic fatigue syndrome patients. BMC Sports Science, Medicine & Rehabilitation 2013;5(1):1–6. Broadbent, S. A pilot study on the effects of intermittent and graded exercise compared to no exercise for optimising health and reducing symptoms in chronic fatigue syndrome (CFS) patients. anzctr.org.au/Trial/Registration/ TrialReview.aspx?ACTRN=12612001241820 (accessed 7 May 2013).

Kos 2012 {unpublished data only}

∗ Kos D, Nijs J. Pacing activity self-management for patients with chronic fatigue syndrome: randomized controlled clinical trial, 2012. clinicaltrials.gov/show/NCT01512342 (accessed 7 May 2013).

Marques 2012 {unpublished data only}

Marques M, De Gucht V, Maes S, Leal I. Protocol for the “four steps to control your fatigue (4-STEPS)” randomised controlled trial: a self-regulation based physical activity intervention for patients with unexplained chronic fatigue. BMC Public Health 2012;12:202. [DOI: 10.1186/ 1471-2458-12-202]

Vos-Vromans 2008 {unpublished data only}

∗ Vos-Vromans D. Is a multidisciplinary rehabilitation treatment more effective than mono disciplinary cognitive behavioural therapy for patients with chronic fatigue syndrome? A multi centre randomised controlled trial [FatiGo, ISRCTN77567702]. http://www.controlledtrials.com/isrctn/pf/77567702 (accessed 7 May 2013). [: ISRCTN77567702 ] Vos-Vromans DCWM, Smeets RJEM, Rijnders LJM, Gorrissen RRM, Pont M, Köke AJA, et al. Cognitive behavioural therapy versus multidisciplinary rehabilitation treatment for patients with chronic fatigue syndrome: study protocol for a randomized controlled trial (FatiGo). Trials [electronic resource] 2012;13:71.

White 2012 {published data only}

White PD. Therapy guided self-help treatment (GETSET) for patients with chronic fatigue syndrome/myalgic encephalomyelitis: a randomised controlled trial in secondary care. ISRCTN22975026, 2012. http:// www.controlled-trials.com/ISRCTN22975026/GETSET (accessed 30 Octrober 2014)

There may of course be other ones they are not aware of.

 

[Dolphin]

In the description of the Wearden et al. (2010) paper (i.e. the FINE Trial), they say (p.44):

• Fatigue (Fatigue Scale, FS; 11 items; each item was scored dichotomously on a 4-point scale (0, 0, 1 or 1); total scores of 4 or more designated significant levels of fatigue. Lower scores indicated better outcomes)

So odd that they don't give the results for this scoring method but for the 0-33 scoring method (that gives better results).

 

[Dolphin]

Characteristics of excluded studies [ordered by study ID]

[..]

Nunez 2011 RCT
Combination treatment of which exercise therapy is a minor part

The Nunez trial is a bit messy in terms of including it. But I don't think saying "exercise therapy is a minor part" is that accurate.

Intervention

The intervention group received multidisciplinary treatment with group CBT, GET, and conventional pharmacological symptomatic treatment. CBT was carried out by one author (GS, T) a clinical psychologist with 7 years experience in CBT [16, 24, 25]. Patients received CBT and GET in groups of 16. The CBT program was composed of nine, twice-weekly, 90-min sessions during a 2.5–3-month period. The main objective was to identify correct behavioural patterns and adaptive thought models and create a therapeutic link [15]. CBT contents included (1) psychoeducational interventions to explain the multi-factorial character of CFS, (2) progressive muscle relaxation procedures (Jacobsen) to identify muscle tension, (3) sleep hygiene patterns to enable entry into and maintenance of phase IV sleep, (4) detection and control of verbal and non-verbal pain-inducing attitudes, (5) cognitive restructuring to modify non-adapted and catastrophic thought patterns, (6) information about the relationship between vegetative and anxiety symptoms, (7) modification of type A behavioural patterns, (8) improvement in assertiveness, (9) patterns to increase attention and memory, (10) sensorial focalization for sexual inhibition, and (11) disease relapse prevention [16].

GET included thrice-weekly 1-h sessions carried out in intermittent periods of 10 min for 3 months, according to established protocols [26, 27]. Patients were informed that exercise was designed to restore their ability to do sustained physical exercise as far as possible. After a 1-week baseline assessment with a 10-min walking session, gradual increases in aerobic exercise at a rate of 5 min per session were introduced. Complementary activities such as flexibility exercise and relaxation therapy were also included. Total exercise load was maintained or increased to a maximum of 40 min per day, according to individual tolerance. All GET sessions were personally supervised by a qualified physiotherapist, who is a registered nurse with a diploma in physiotherapy, and more than 20 years experience in general physiotherapy for neurological disease and 8 years experience in a third-level CFS and fibromyalgia (FM) reference unit. CBT and GET were administered in an integrated manner according to the previously mentioned Catalan protocol [22].

The control group received usual CFS therapy including exercise counselling and conventional pharmacological symptomatic treatment [19, 28]. Exercise counselling was performed by personal interview with the same physiotherapist. The objective was to provide activities that restored the patient's ability to do sustained physical exercise as far as possible. The program included three daily 10-min sessions, performed in separate periods, with adapted aerobic exercise, including walking and home-stretching exercises.

Symptomatic pharmacological treatment was equal in the two groups and included analgesia (paracetamol 1– 3 g/day p.o.), ibuprofen (600–1800mg/dayp.o.)if subjects reported inflammation (fever, myalgia, enlarged cervical nodes), and zolpidem 10 mg/ night p.o. if patients reported significant insomnia [19]. No other treatment was admitted during the study period. Verbal and written information on thegeneral characteristics of CFS was provided to the two groups at baseline. Further verbal information was provided during the study and new written information at the end of study according to the previously mentioned Catalan protocol. [22].

 

[Dolphin]

As I mentioned, I think they could have described the Wallman et al. intervention better.
They say:

Criteria for (non) -increment

Keep Borg within 11 to 14. Adjust every 2 weeks. Average peak HR when exercising comfortably at a typical day represents patient’s target heart rate (± 3 bpm) for future sessions

There is no mention of this:

“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”

which is different from other approaches.

 

[Dolphin]

As you have said it is a different review. This is a review that updates a previous version (from 2004). However it is very sympathetic to those pushing GET since it uses subjective measures as the main outcomes and doesn't look at compliance to treatment (ok I've not read it all yet) or more objective measures.

Basically as a review it blindly accepts flawed methodologies and measures in the original papers and looks at their preferred results.

I've just finished reading it and there's no mention of compliance to treatment. They say this:

Participants were asked to perform self-monitoring by using such tools as heart monitors, the Borg Scale or a diary including an exercise log to measure adherence to treatment (Table 2).

but there's no data in Table 2.