Cochrane has temporarily removed a review from its database that claims exercise therapy is effective for chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME). Cochrane is a database of medical reviews and meta-analyses, which medical providers around the world rely on for diagnosing and treating disease.
Their review, Exercise Therapy for Chronic Fatigue Syndrome, covers eight studies that look at the effects of exercise in ME and CFS, the largest being the PACE trial.
Cochrane editors have asked for the review’s authors, including lead author Lillebeth Larun, to respond to the substantive and concerning questions regarding the methodology of the review and its studies, posed by researchers, scientists, clinicians and patients.
Cochrane editors state that they will decide on the status of the review by the end of November.
“Some of the specific responses by Lillebeth Larun were unsatisfactory,” writes Tom Kindlon, who had spent a good deal of time researching and responding to the review, along with patient Robert Courtney. Kindlon has published 23 articles in peer-reviewed journals, and has lived with ME for 21 years. “And while she claimed that objective outcome measures were not part of the protocol, it is very disappointing that such results are not reported when they are available. Instead, the sole focus was on subjective outcome measures, which can be subject to various biases in open-label trials like those reviewed.”
“I hope that this signifies that Cochrane will now be more rigourous in the reviews it publishes of the ME and CFS literature.”
This past week, 40 academics and clinicians signed a letter in support of Cochrane’s decision to temporarily pull the review until the authors respond to the comments.
“The reviewers need to provide substantive and satisfactory answers to Cochrane’s legitimate methodological and scientific questions. If they are unable or unwilling to do so, the review should be permanently withdrawn,” states the letter.
A re-analysis of the Cochrane review was also published this month that concludes that graded exercise therapy is unsafe and ineffective for ME and CFS. The re-analysis outlines methodological problems with the review and the studies, including questions about relying on subjective self-reporting instead of on objective outcomes, and using flawed diagnostic criteria (the studies relied on the Oxford and Fukuda criteria) that may have meant the studies included participants who did not have ME or CFS.
The letter signed by 40 academics and clinicians outlines the following five critiques of the review and exercise studies:
1) The PACE trial, the largest of the eight studies included in the Cochrane review, has been internationally discredited because of outcome-switching and many other flaws. Yet the review rated the trial as being at “low risk” of reporting bias. In a recent open letter to The Lancet, more than 100 experts, including many of us, expressed concern about PACE’s “unacceptable methodological lapses.”
2) Like PACE, the other studies in the Cochrane review are open label trials relying on subjective outcomes. Trials with this design are fraught with bias, which is why they are no longer considered as reliable evidence for making decisions and developing recommendations for biomedical treatment. The review ignored objective outcomes from exercise interventions, which have generally failed to confirm subjective reports of benefits.
3) Five of the studies included in the Cochrane review used the Oxford criteria, a case definition that only requires six months of unexplained fatigue to render a diagnosis. This case definition generates heterogeneous samples that likely include many people suffering from undiagnosed depression, anxiety disorders and other fatiguing conditions rather than the devastating illness in question. When the US Agency for Healthcare Research and Quality removed Oxford criteria studies from its own analysis, the agency found no evidence to support recommendations for graded exercise therapy. This re-analysis also reported more harms among those assigned to such treatment than among those in the comparison groups.
4) Six of the studies included in the Cochrane review tested graded exercise therapy as a treatment for the illness. This intervention has been predicated on the theory that the ongoing symptoms are not caused by underlying pathophysiological processes but by a fear of activity, which in turn leads to sedentary behavior and severe deconditioning. Yet there is no legitimate scientific evidence to support this theory. A 2015 report from the US Institute of Medicine (now the National Academy of Medicine) concluded that ME/CFS is not driven by psychological factors; biomedical research from major medical centers in the US, UK, Australia and elsewhere supports that conclusion.
5) Given the many methodological and scientific problems with the Cochrane review, its conclusion that exercise therapy is effective cannot be taken at face value. This is of particular concern because it is widely accepted that the cardinal symptom of the illness is post-exertional malaise, or what the Institute of Medicine report called “exertion intolerance.” In other words, patients can suffer prolonged relapses even after engaging in minor physical activities, suggesting that graded exercise therapy is contraindicated and could cause harm.