Mark Vink: Assessment of Individual PACE Trial Data: CBT and GET are Ineffective

[Cheshire]

Assessment of Individual PACE Trial Data: in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Cognitive Behavioral and Graded Exercise Therapy are Ineffective, Do Not Lead to Actual Recovery and Negative Outcomes may be Higher than Reported

Journal of Neurology and Neurobiology

Abstract
The PACE trial concluded that Cognitive Behavioral Therapy (CBT) and Graded Exercise Therapy (GET) are moderately effective in managing Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and yielded a 22% recovery rate. Nonetheless, the recently released individual participant data shows that 13.3% of patients had already recovered, on one or both primary outcomes, upon entering the trial.

Moreover, no one classifid as recovered achieved the physical functioning, together with the fatigue scores, of the healthy sedentary controls from another trial by the PACE trial‘s lead principal investigator or achieved Kennedy‘s defiition of recovery, whereby symptoms are eliminated and patients return to
premorbid levels of functioning, due to CBT or GET (alone). Therefore, CBT and GET do not lead to actual recovery.

After CBT and GET therapy, 59% and 61% of participants, respectively were labeled as improvers in the original paper, which was lowered by the PACE trial authors to 20% and 21% in the newly released papers in which they used the original protocol; nevertheless, only 3.7% and 6.3% were objective improvers in the objective 6-minute walk test as defied by the same improvement of 50% or more, as used by the trial itself,
to classify someone as an improver.

If the effect of Specialist Medical Care had been removed from the analysis, then 0% and 1.3% of patients
improved objectively with CBT and GET, respectively. Highlighting the fact that unblinded trials like the PACE trial, should not rely on subjective primary outcomes, but use either objective primary outcomes alone, or combined with subjective primary outcomes, as a methodological safeguard against the erroneous inference of effiacy in its absence. The objective individual participant data shows that in up to 82.2% and
79.8% of ME patients their health might have been negatively affected by CBT and GET, respectively.

The independent PACE trial review had shown that this proportion was between 46% and 96%, and found to be between 63% and 74% by surveys involving more than 3000 patients by the Norwegian, British, and the Dutch ME Associations. These data confim the conclusions of a number of studies that patient health was
negatively affected by CBT and GET, including one that found that in 82% of patients with severe ME their symptoms were made worse by GET.

Analysis of the individual participant PACE trial data has shown that CBT and GET are ineffective and (potentially) harmful, which invalidates the assumption and opinion-based biopsychosocial model. Consequently, we should stop using CBT and GET as (compulsory) treatments for ME/
CFS to prevent further unnecessary suffering inflcted on patients by physicians, which is the worst of all harms, yet totally preventable.

https://www.sciforschenonline.org/journals/neurology/article-data/JNNB-3-136/JNNB-3-136.pdf

 

[A.B.]

 

[TiredSam]

I'm running out of superlatives today, I've already used "brilliant" on the Things are Heating Up in Canada thread, so I'll just have to say

Fabulous

to this.

Hope there isn't any more good news today, having to find too many new words in such a short space of time can be a bit of a challenge.

 

[user9876]

I think it is a shame he didn't do a significance test on his version of improved with the 6mwt. I suspect this would show a lack of significance especially when using an ITT analysis. But I'm not convinced that the improvement measure he has used is a good one.

I like that he has looked at a comparison of improvement for the 6mwt against the subjective measures but I feel looking at correlations here would be more interesting in terms of the improvement on scales rather then those marked as improved. Its not clear to me how many of those marked as improving on the subjective outcomes don't improve on objective outcomes due to a lack of data. To a certain extent is may be irrelevant since those refusing to do the 6mwt at the end may well be refusing because they are not up to it suggesting an improved label would be difficult.

 

[trishrhymes]

Bloody brilliant.

I've only read the abstract so far, haven't enough brain cells left today to tackle the rest, but I can see it's a further demolition of PACE.

Three cheers for Mark Vink.

 

[Jenny TipsforME]

My brain is hurting today. Please can someone explain in brainfog English how he gets to the 'negatively affected ' figures?

 

[CFS_for_19_years]

The same author, Mark Vink, published his first criticism of the PACE trial in March 2016 before the Alem Matthees data re-evaluation was done:

The PACE Trial Invalidates the Use of
Cognitive Behavioral and Graded Exercise
Therapy in Myalgic Encephalomyelitis/
Chronic Fatigue Syndrome: A Review
https://www.sciforschenonline.org/journals/neurology/article-data/JNNB-2-124/JNNB-2-124.pdf

 

[Hajnalka]

Apparently Mark Vink has been bedridden after GET for over 10 years now. He tells his story in this self-case-study (under participant): https://www.sciforschenonline.org/journals/neurology/article-data/JNNB-1-112/JNNB-1-112.pdf

 

[Dolphin]

Well done to him. His analysis makes lots of interesting points. However, some of it is written a bit differently to standard scientific papers which might take away a little credibility for some people reading it.

 

[Tom Kindlon]

https://twitter.com/i/web/status/821503392749158400

 

[Tom Kindlon]

https://twitter.com/i/web/status/821506117767462913

 

[Dolphin]

I'm going to post a few minor criticisms I have.

I liked an awful lot of this, too much for me to highlight.
But I think it is important that readers know all the facts.

 

[Dolphin]

The PACE trial coded participants as improvers for physical functioning, “if they had either a score of 75 or more (out of 100) at 52 weeks postrandomisation, or a 50% increase from the baseline score at that time point”; improvers for fatigue had “either a score of 3 or less (out of 11) at 52 weeks post-randomization, or a 50% decrease from the baseline score on the bimodal scored Chalder fatigue scale at this time point” [11]. The percentage of overall improvers, those who improved on both physical functioning and fatigue [11], dropped from 59% and 61% as presented in the 2011 paper [1], to 20% and 21% when using the criteria from the original protocol for CBT and GET, respectively [11]. Since patients in all treatment groups were also receiving specialist medical care (SMC), the effect of SMC should be subtracted, resulting in overall improver rates in the CBT and GET groups of 10% and 11%, respectively. The figures published in the original PACE trial paper, which did not take the SMC effect into account, were six times higher [1]. Even if the effect of SMC was not subtracted, the effect of making an extensive number of endpoint changes during an unblinded trial would still increase the number of overall improvers threefold.

I think he should have said that by the improvement rates reported in the Lancet paper, 45% improved in the specialist medical care group. So the improvement rate wasn't really 6 times higher when you subtract the effect for specialist medical care.

 

[Dolphin]

In addition, the objective outcomes showed no significant improvement on any of their self-chosen objective measures, such as how many patients returned to work, or their level of fitness [9].

There was a statistically significant improvement for the 6 minute walking test in the graded exercise therapy group. Though the improvement of 35 m over specialist medical care alone when adjusted for baseline factors is not that big given there was plenty of scope for possible improvement.

 

[trishrhymes]

There was a statistically significant improvement for the 6 minute walking test in the graded exercise therapy group. Though the improvement of 35 m over specialist medical care alone when adjusted for baseline factors is not that big given there was plenty of scope for possible improvement.

Statistically significant, but not clinically significant, which I think is the point he's making, and from memory, I think there was a higher proportion of Get patients who didn't do the second walk, which as far as I'm concerned invalidates that small statistical significance.

 

[Dolphin]

Statistically significant, but not clinically significant, which I think is the point he's making

If he meant clinically significant, I think he should have used different language to this:

In addition, the objective outcomes showed no significant improvement on any of their self-chosen objective measures, such as how many patients returned to work, or their level of fitness [9].

 

[Dolphin]

a bimodal Chalder Fatigue score of 0, which equates to a Likert Chalder Fatigue score of 0 or 1.

was a Bimodal score of 0 [23], which equates to a Likert score of 0 or 1).

A bimodal score of 0 is equivalent to a Likert score of 0 to 11.
However I don't think he uses this in any of his analyses so it is not a big error it seems to me.

 

[Dolphin]

Objective improvers [22]

These are people whose 6 minute walking test distances improved by at least 50%.

Sometimes if somebody had a good baseline score, improving by 50% would be unrealistic. It would have been interesting if he had given data on the numbers of these (I suspect the number is quite small in this sample)

Similarly for this calculation:

Objective improvers when the SMC effect was taken into account

 

[Dolphin]

I think it would have been good if he had explicitly said that "very much better" was an option. People who are ticking "much better" are saying they are not "very much better". You would expect people who recovered to take the top possibility.

Instead of acknowledging this, White continues to write the following about the analysis by Matthees et al. [31] (whose authors also include two Professors of Statistics): “In the latest step in this saga, a blog that hasn’t gone through the rigours of scientific peer-review, or being published in a journal claims that CBT and GET are not as effective as we reported. The authors got their figures by tweaks such as increasing the pass-grade for what counted as recovery, and excluding patients who had reported themselves as “much better”” [33]. Yet as noted by the independent review of the PACE trial (published earlier this year in a peer-reviewed medical journal), if you are “much better” you have improved, but you have not recovered yet [5] as anyone knows who has been ill with a flu like illness, for example. White had also stated in an article in The Times a few days earlier “it is very difficult to define recovery” [26]. Yet, if an ordinary person was asked the meaning of recovery, the answer would be that all problems have gone and that health has returned to how it was before the illness. This was worded by Kennedy in the following manner: recovery “is the elimination of...symptoms and a return to premorbid levels of functioning” [34].

 

[Dolphin]

For this sensitivity analysis, I think he should also have highlighted that the other possibility is that nobody with ME was negatively affected.

Also he should probably have given the figures for the specialist medical care group and possibly also the adaptive pacing group. There can be some random variation: you need to be careful how much you read into the scores of some people deteriorating.