It’s tough, watching this play out slowly, step by painful step. As I’ve blogged before, ME/CFS consumer advocates have been hammering away to get this Cochrane systematic review on exercise and CFS fundamentally changed since 2015. I think they’re right. And now, they have achieved something pretty remarkable…

Kudos to Robert Courtney (now deceased), who got this ball rolling, and those who picked up the baton, especially Tom Kindlon and George Faulkner. But why do I think it’s only a start?

Firstly, I need to disclose that I’ve been directly involved in recent negotiations around the fate of this review, although I didn’t see this version till after it was published. The organization released a statement along with the amended review, making it clear that this is only a first step. Karla Soares-Weiser, the new editor-in-chief, said:

“We have decided, therefore, that a new approach to the publication of evidence in this area is needed; and, today we are committing to the production of a full update of this Cochrane Review, beginning with a comprehensive review of the protocol, which will be developed in consultation with an independent advisory group that we intend to convene. This group will involve partners from patient-advocacy groups from different parts of the world who will help us to embed a patient-focused, contemporary perspective on the review question, methods and findings.”

That is such good news.

In the meantime, what has changed with this amendment, and what hasn’t?

First up, why it merits the “changed conclusions” tag. (Here’s the new version, and here’s the previous one.)

The key bit of the old conclusion:

Patients with CFS may generally benefit and feel less fatigued following exercise therapy, and no evidence suggests that exercise therapy may worsen outcomes.

The key bits of the new conclusion:

Exercise therapy probably has a positive effect on fatigue in adults with CFS compared to usual care or passive therapies. The evidence regarding adverse effects is uncertain… All studies were conducted with outpatients diagnosed with 1994 criteria of the Centers for Disease Control and Prevention or the Oxford criteria, or both. Patients diagnosed using other criteria may experience different effects.

What’s good about this is opening the door at least to the possibility that exercise therapy can do harm. And it opens the door to the question of just who the research reviewed applies to. Let’s go to what the other major systematic review on the question concluded, in 2014, the same year as the Cochrane review being amended now. It’s from the U.S. Agency for Healthcare Research and Quality:

None of the current diagnostic methods have been adequately tested to identify patients with ME/CFS when diagnostic uncertainty exists.

Then, in 2016, after an NIH meeting agreed with them:

[U]sing the Oxford case definition results in a high risk of including patients who may have an alternate fatiguing illness or whose illness resolves spontaneously with time… The National Institute of Health (NIH) panel assembled to review evidence presented at the NIH Pathways to Prevention Workshop agreed with our recommendation, stating that the continued use of the Oxford (Sharpe, 1991) case definition “may impair progress and cause harm.” Blatantly missing from this body of literature are trials evaluating effectiveness of interventions in the treatment of individuals meeting case definitions for ME or ME/CFS.

So we’re talking about a body of evidence that may apply to some degree to people who don’t really have ME/CFS or CFS.

Before we move on, the existence of such important voices as AHRQ and the NIH contradicting the Cochrane review is a Very Big Deal. This is what the amended Cochrane review still says on that score, though:

[T]he results reported here correspond well with those of other systematic reviews (Bagnall 2002; Larun 2011; Prins 2006) and with existing guidelines (NICE 2007). One meta‐analysis of CBT and graded exercise therapy (Castell 2011), suggests that the two treatments are equally efficacious, especially for people with co‐morbid anxiety or depressive symptoms… The conclusions presented in our review correspond well with those of other relevant studies and reviews.

I argued strongly that this shouldn’t be allowed to stand. Yet, there it remains. And now it’s definitely cherry-picking.

Cherry-picking sounds kind of innocuous, doesn’t it? Phrased as it is in that last sentence, though, it’s anything but. (To go full Aussie for a moment: Not happy, Jan!)

Back to what has changed, though – and all of the changes are, I think, changes for the better. From Cochrane’s statement:

It now places more emphasis on the limited applicability of the evidence to definitions of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) used in the included studies, the long-term effects of exercise on symptoms of fatigue, and acknowledges the limitations of the evidence about harms that may occur.

We’ve looked at the first and last of these. Here’s what happened about the long-term effects on symptoms of fatigue. Firstly, the absence of long-term effects is now liberally sprinkled through the abstract, where there was no such mention before.

Secondly, the closest the summary of findings table used to get to this was saying there was moderate certainty from 3 studies that exercise therapy lowered fatigue at the end of treatment. Now, the results of 4 studies with longterm results are included, for fatigue and some other outcomes, with “very low” certainty, for example:

The effect of exercise therapy on fatigue after 52-70 weeks is uncertain.

And the effect there is dependent on a single study that drags lots of the meta-analyses towards more apparent benefit, Powell 2001 – in the context of one discussion, they are referred to as “deviating results”. There are more sensitivity analyses now – that’s weighing the impact on results of excluding one or more studies.

The “What’s New” table of the review also points to change in the fatigue analyses, “restructuring the analysis of fatigue to combine data with standardised mean differences”, as opposed to simply mean differences in the original. (My explainer on that here). And that makes a serious difference. For example, Analysis 1.2, fatigue at follow-up, now touches the line – so not statistically significant any more. (My explainer on data in meta-analyses is here.) The result here was affected by dramatic between-study differences (an I2 of 94%, which is pretty much off the charts – see my explainer). That was almost halved by removing the Powell study again, and that also reduced the apparent benefit even more. Don’t forget, though, that this is old data: there are more studies now, so it all feels a bit moot.

The previous editor-in-chief, David Tovey, had originally proposed that the review be withdrawn as it was so out of date, but that wasn’t well received, and it didn’t happen. Looking at it today, with all the statements in there that look current – like saying this version has had trials added – withdrawing it back then seems reasonable, and consistent with Cochrane’s practice, and its policy at the time (section 3.4.7 here). Not withdrawing it then seems political.

In July 2019, though, there was a new policy on withdrawing reviews, making it more clearly a retraction than it used to be, making it much less of an option. An updated review isn’t going to be galloping over the horizon any time soon, though. I think this review now highlights a gap in Cochrane policy: there isn’t currently a mechanism for unambiguously and clearly flagging a review as out of date to readers. There’s just an editorial note where few would see it stating that it’s “substantially out of date”.

This review over-estimated the strength of the evidence and its applicability, and while better, it’s still doing that. That has been having a damaging effect on people to whom the results don’t apply, but on whom the consequences of this review are visited. Yet, until Courtney’s complaint got Tovey involved, consumers had been resolutely locked out of this Cochrane review, and indeed, this amendment process too. That was against Cochrane’s stated ethos. It’s great that Soares-Weiser is going to rectify that. Consumer participation isn’t only for when it’s smooth sailing. When it’s going to rock the boat may be the most important time of all to do it.

Consumer group takes on the amended review have started to appear:

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[Update 4 October 2019] In responding to an enquiry from a consumer group about Cochrane policy on withdrawing reviews, I found that there was a new policy in July 2019. And a new version of the Cochrane Handbook was published this week. That means part of my original post was wrong. The original read:

The previous editor-in-chief, David Tovey, had originally proposed that the review be withdrawn, but that wasn’t well received, and it didn’t happen. An editorial note on the review points out that it is “substantially out of date”. Once that determination has been made, Cochrane reviews are supposed to be either updated or withdrawn. It’s now nearly a year since then, and a replacement review isn’t going to be galloping over the horizon any time soon. Looking at it today, with all the statements in there that look current – like saying this version has had trials added – withdrawing it seems reasonable, and not withdrawing it seems political.

Disclosures: I have had discussions with The Cochrane Library’s Editor-in-Chief, about this review, and participated in a discussion with the Cochrane Editorial Unit and others about it. I did not discuss the contents of this post with anyone before posting.

I was a health consumer advocate (aka patient advocate) from 1983 to 2003, including chairing the Consumers’ Health Forum of Australia (CHF) from 1997 to 2001, and its Taskforce on Consumer Rights from 1991 to 2001. I have not experienced CFS/ME and nor has anyone close to me.

However, at the time I first encountered CFS activists, I had a relevant personal frame of reference. I had to leave my occupation several years prior after a severe bout of repetitive strain injury (RSI) following a stretch of workaholism as a teenager. Then, RSI was regarded by some medical practitioners as malingering or psychological, rather than a physical condition. (You can read about the controversy around Australia’s RSI epidemic here, here, and here [PDF].)

As then editor-in-chief of a consumer health information website based on systematic reviews at the NIH, I was pressured about the inclusion of systematic reviews on GET and CBT and approach to CFS consumer information, but not by CFS activists.

I was the consumer representative from the foundation of the Cochrane Collaboration in 1993, and leader of Cochrane’s Consumer Network from its formal registration in 1995 to 2003. I was the coordinating editor of a Cochrane review group from 1997 to 2001.

One of the authors of the planned Cochrane individual patient data review, the protocol of which was withdrawn, is my PhD supervisor, Paul Glasziou. We have not discussed it, and have not discussed anything related to this post while I was considering, researching, and writing it. We have not discussed the previous post either.

The cartoons are my own (CC BY-NC-ND license). (More cartoons at Statistically Funny and on Tumblr.)