Treatment of ME-CFS: A Systematic Review for a NIH Pathways to Prevention Workshop

[Dolphin]

This is really weird to look at i.e. you remove the most successful result and it now becomes statistically significant:

A meta-analysis of 4 trials of CBT reporting changes in SF-36 physical function scores indicated no statistically significant difference between intervention and control groups (weighted mean difference, 10.42 [95% CI,3.86 to 24.69];I 2 = 79.6%, 4 trials) (Figure 2) (39, 42, 47, 56). However, physical function scores were higher for the intervention group when an outlier study (59) was removed in a sensitivity analysis (weighted mean difference, 6.02 [CI, 1.05 to 10.88];I 2 = 0.0%; 3 trials) (47, 56, 57).

I didn't get the same figures (actually a bigger difference) when I tried some basic calculations.

However, it is interesting to note that the O'Dowd control group is bigger than the O'Dowd CBT sample.
The lowest scores in both groups were in the O'Dowd study. This has the effect of bringing down the overall average for the control group i.e. artificially increasing apparent benefit for CBT. If one were to use a smaller control group (say 52, the same size as the CBT group), the overall average difference with CBT decreases quite a bit: it may or may not then be statistically significant (my average difference figures are different to start off with as I said so am not going to try to do it properly). Maybe not that important anyway.

 

[Dolphin]

Characteristics of Responders and Nonresponders Four trials suggested that younger patients with less impairment, who are less focused on symptoms, adherent to cognitive therapy programs, and avoid over- and underexertion (that is, they stay within their energy envelope) are more likely to improve in some measures of fatigue and function (36, 40, 52, 60, 63)

The energy envelope measure was used in a Jason study which is reported in references 40 and 60.

 

[Dolphin]

Although adverse effects were rarely reported in most trials, counseling and behavior therapies were associated with fewer harms (low strength of evidence) than medications and GET (insufficient evidence).

This was from the PACE Trial study. I have to wonder is there reporting bias going on in the CBT group that they would report fewer adverse events than the no therapy and APT groups.

These results are consistent with those of previous systematic reviews (66 –70). A recent systematic review of trials of exercise for patients with CFS found no evidence suggesting that exercise worsens symptoms (70). However, no trials reported harms for participants meeting case definitions for ME or ME/CSF (48), and it remains unclear how more severely disabled patients respond to exercise therapy. One trial considered participants meeting the London criteria for ME (n= 357 of 640 total) and found similar results for outcomes of fatigue and physical function but did not evaluate harms in this subgroup (48). It is possible that adverse effects of exercise therapy could be avoided by careful selection of patients, and additional research is needed to determine which patients would achieve maximal benefits without incurring harm. Although trials of counseling and behavioral therapies reported mixed results, improvements in multiple outcomes are consistent with outcomes seen with similar therapies for other chronic illnesses (68 –72).

 

[Dolphin]

This systematic review was limited by deficiencies of the trials. Most trials enrolled participants on the basis of case definitions for CFS only. 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 (16, 71). The Institute of Medicine recently released new diagnostic criteria for CFS that require the presence of postexertional malaise, unrefreshing sleep, and either cognitive impairment or orthostatic intolerance (7, 72). Participants in previous trials did not meet these requirements.

 

[Dolphin]

Although several fatigue and function outcomes were based on validated scales and measures, others were not, and the clinical significance of changes in scores over time is not clear for most of them.

 

[Dolphin]

Whereas this review focused on outcomes that are universal to all case definitions of patients, such as fatigue and function, a review of other types of outcomes, such as postexertional malaise, would also be useful.

 

[Dolphin]

Future research would benefit from using consistent clinical criteria and comparing outcomes according to clinical presentation, such as postexertional malaise, neurocognitive status, and autonomic dysfunction. This approach would identify patient subgroups that may respond differently to specific treatments and could provide greater insight into the underlying causes of ME/CFS. Studies should report adverse effects more consistently and completely to improve identification of patients who may be negatively affected. Similarly, stratification of results by patient characteristics, such as age, sex, race, baseline functional status, and intermediate outcomes, would help determine the applicability of different treatments for specific patients and situations.

 

[Dolphin]

I found most of this, the penultimate paragraph, a little interesting so will quote it all:

Definitive treatment trials require larger numbers of participants based on appropriate power calculations for clinically relevant outcomes to determine efficacy, along with more rigorous adherence to methodologic standards, such as blinding of outcome assessors, intention-to-treat analysis, and strategies to minimize patient loss to follow-up. Future trials should enroll more men and racial and ethnic minorities; broader age ranges; and participants with greater disability, such as homebound patients. Given the fluctuating nature of ME/CFS, follow-up periods longer than 1 year would help determine effectiveness and harms over time. The development of a set of core outcome measures, including patient-centered outcomes (such as quality of life, employment, and time spent in activity), would help guide research and facilitate future analyses. Trial registries and collaborations would help consolidate and standardize data. Reporting more information about concomitant treatments and adherence to treatment would improve the applicability of study findings. Given the devastating effect of this condition on patients and families, researchers should consider involving the patient and advocate voice in trial planning and development so that future research is relevant and meaningful to those affected by ME/CFS.

 

[Sidereal]

This is really weird to look at i.e. you remove the most successful result and it now becomes statistically significant:

View attachment 11699

@Dolphin, it's because the outlying study makes the confidence interval for the pooled analysis huge, resulting in its crossing 0. When you remove the extreme outlier, you get a much tighter confidence interval and no heterogeneity.

 

[medfeb]

Peter White submitted a comment to the Annals on this article:

PD White, MD,1 DJ Clauw, MD,2 JWM van der Meer, MD,3 R Moss-Morris, PhD,4 RR Taylor, PhD,5

In their systematic review, Smith and colleagues concluded that “trials of … counseling therapies, and graded exercise therapy suggest benefit for some patients meeting case definitions for CFS, whereas evidence for …. harms is insufficient.”(1)

While we support the general conclusion of benefit with these treatments, we suggest that some aspects of this review may be misinterpreted. Firstly, the most frequently tested behavioural intervention has been cognitive behaviour therapy (CBT), which aims to reduce symptoms and improve functioning, and it would be unusual to consider this as “counseling”, which has different objectives and content. One would not combine different types of medicines in a review; why do this with therapies? A review that combines counselling and CBT simply dilutes the efficacy of CBT, which has been amply demonstrated in several previous meta-analyses (2).

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.” (3) Suggesting evidence of harm by stating that “one trial reported significantly more serious adverse events ….and more nonserious adverse events … in the GET versus comparison groups,…” without mentioning that serious adverse events were independently judged to be unrelated to the intervention, and that the differences between non-serious adverse events was not statistically significant, is a potentially misleading representation of the evidence. Adding that “..in a trial of GET, 20% of patients declined to repeat exercise testing because of perceived harm of testing” encourages further misunderstanding by failing to mention that the exercise testing was not part of the therapy and that the proportion of patients in the control intervention who also declined exercise testing was 50% (4). (Incidentally the proportion declining testing in the GET arm was 44%, not 20%.4) There is a world of difference between the effects of maximum exercise testing and graded exercise therapy. It is important not to overemphasise the harms associated with an effective treatment when there are so few others available.

Finally, the authors concluded that we need trials with analyses of patients meeting different case definitions; we agree and this has already happened. White and colleagues found no statistically significant differences in the efficacy of CBT and GET in sub-groups of those patients meeting Oxford criteria for CFS who also met either CDC defined CFS or myalgic encephalomyelitis (ME)(5).

Note: Seven other CFS clinical scientists supported and approved this letter

 

[Valentijn]

Peter White submitted a comment to the Annals on this article:

He must've written that lovely bit of prose before the current news came out regarding the latest Rituximab research publication. I expect he's feeling rather ridiculous now, and might be envying Wessely's earlier retreat from the field.

 

[Bob]

Firstly, the most frequently tested behavioural intervention has been cognitive behaviour therapy (CBT), which aims to reduce symptoms and improve functioning...

They forgot to mention that CBT fails to meet its aim of improving functioning.

 

[medfeb]

He must've written that lovely bit of prose before the current news came out regarding the latest Rituximab research publication. I expect he's feeling rather ridiculous now, and might be envying Wessely's earlier retreat from the field.

I don't know. As Countess of Mar said in her March presentation at the Royal Society of Medicine, some people are so stuck in their core beliefs that they can't see the evidence to the contrary.

About CBT - their claim that they tested CDC CFS and ME is nonsense. The took little used definitions and then modified them further in ways that would call into question the diagnosis.

 

[Valentijn]

About CBT - their claim that they tested CDC CFS and ME is nonsense. The took little used definitions and then modified them further in ways that would call into question the diagnosis.

Additionally, those patients were only in the trial because they had Oxford fatigue. And that requires that fatigue be the primary symptom, which effectively excludes actual ME patients where PEM, OI, pain, etc, will be much more prominent.

So they pretty much excluded ME patients from the trial, then watered down an ME definition to try to pretend their methodologically flawed and highly spun results could be applied to actual ME patients.

 

[medfeb]

Additionally, those patients were only in the trial because they had Oxford fatigue. And that requires that fatigue be the primary symptom, which effectively excludes actual ME patients where PEM, OI, pain, etc, will be much more prominent.

So they pretty much excluded ME patients from the trial, then watered down an ME definition to try to pretend their methodologically flawed and highly spun results could be applied to actual ME patients.

Is it possible to post a comment on that article to respond to White?

And if so, could someone more familiar with PACE do it? The other problem is their claim that there's no harm - especially since they are basing that on the Larun paper which used chronic fatigue as the inclusion criteria.

I don't mind doing it if possible but know that others here have much more knowledge about PACE.

 

[Sean]

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.” (3)

IIRC, that review was based mainly on Oxford criteria studies (5/8, I think), which tend to show the most 'safety' and 'benefit'.

Plus, several patient surveys report considerable harm.

 

[medfeb]

IIRC, that review was based mainly on Oxford criteria studies (5/8, I think), which tend to show the most 'safety' and 'benefit'.

Plus, several patient surveys report considerable harm.

exactly!

 

[Dolphin]

Peter White submitted a comment to the Annals on this article:

PD White, MD,1 DJ Clauw, MD,2 JWM van der Meer, MD,3 R Moss-Morris, PhD,4 RR Taylor, PhD,5

In their systematic review, Smith and colleagues concluded that “trials of … counseling therapies, and graded exercise therapy suggest benefit for some patients meeting case definitions for CFS, whereas evidence for …. harms is insufficient.”(1)

While we support the general conclusion of benefit with these treatments, we suggest that some aspects of this review may be misinterpreted. Firstly, the most frequently tested behavioural intervention has been cognitive behaviour therapy (CBT), which aims to reduce symptoms and improve functioning, and it would be unusual to consider this as “counseling”, which has different objectives and content. One would not combine different types of medicines in a review; why do this with therapies? A review that combines counselling and CBT simply dilutes the efficacy of CBT, which has been amply demonstrated in several previous meta-analyses (2).

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.” (3) Suggesting evidence of harm by stating that “one trial reported significantly more serious adverse events ….and more nonserious adverse events … in the GET versus comparison groups,…” without mentioning that serious adverse events were independently judged to be unrelated to the intervention, and that the differences between non-serious adverse events was not statistically significant, is a potentially misleading representation of the evidence. Adding that “..in a trial of GET, 20% of patients declined to repeat exercise testing because of perceived harm of testing” encourages further misunderstanding by failing to mention that the exercise testing was not part of the therapy and that the proportion of patients in the control intervention who also declined exercise testing was 50% (4). (Incidentally the proportion declining testing in the GET arm was 44%, not 20%.4) There is a world of difference between the effects of maximum exercise testing and graded exercise therapy. It is important not to overemphasise the harms associated with an effective treatment when there are so few others available.

Finally, the authors concluded that we need trials with analyses of patients meeting different case definitions; we agree and this has already happened. White and colleagues found no statistically significant differences in the efficacy of CBT and GET in sub-groups of those patients meeting Oxford criteria for CFS who also met either CDC defined CFS or myalgic encephalomyelitis (ME)(5).

Note: Seven other CFS clinical scientists supported and approved this letter

Peter White is the lead author. I imagine he wrote this and circulated.

It is perhaps interesting to see Daniel Clauw and Renee Taylor co-signing this. It would be interesting to know who are the seven other people who would co-sign such a letter with Peter White.

He is/they are aiming to have this published [criteria: 400 words maximum (excludes references) and 5 references]

If one or more people sent in comments it might put the journal off publishing their letter.

The deadline to influence the editors is July 13 or 14. I've quite a few things to do so not sure I'll get something done.

Comments on papers published in Annals. Anyone can submit a comment any time after publication, but only those submitted within 4 weeks of an article’s publication will be considered for print publication. One month after publication, editors review all posted comments and select some for publication in the Letters section of the print version of Annals. [Not peer-reviewed]

 

[worldbackwards]

It is important not to overemphasise the harms associated with an effective treatment when there are so few others available.

An extremely telling line.

 

[Denise]

Peter White is the lead author. I imagine he wrote this and circulated.

It is perhaps interesting to see Daniel Clauw and Renee Taylor co-signing this. It would be interesting to know who are the seven other people who would co-sign such a letter with Peter White.

done.

@Dolphin - is it certain that RR Taylor is Renee Taylor? I ask because Renee Taylor is (as far as I can tell) still at University of Illinois which is not listed among the places of employment of the others.
And I agree that it would be very interesting to know who the other co-signers are.