PACE Trial Comment....

[Guest guest]

For outsiders it must be noted that the

authors use the so-called Oxford

Definition, which do not select patients

with ME nor Chronic Fatigue Syndrome,

but patients with idiopathic fatigue.

Some of them may have a mild form of

chronic fatigue syndrome.

Anyhow the results are clearly

inferior (cost the taxpayer £5 million).

When will there be an independent

investigation into the relationship

between these researchers and the

insurance industry?

~jvr

````

Tom Kindlon

Sun Aug 5, 2012

Comment from me on the data

we have from the PACE Trial

http://bit.ly/NwKUZq

PLOS one

Title:

All the cost-effectiveness

calculations involve self-report

measures (EQ-5D, CFQ, SF-36

PF)

The authors say(1):

" The study has limitations. First, we

relied on self-reported information on

service use and lost employment.

There may be issues of accuracy with

this approach but it was largely

unavoidable given the need for a

comprehensive perspective. Other

studies have shown this to be an

acceptable method [refs]. "

The paper does not mention that all the

cost-effectiveness calculations involve

self-reported information or measures.

That is to say QALYs were calculated

using the EQ-5D questionnaire, while

the other cost-effectiveness

calculations involved the Chalder fatigue

questionnaire (CFQ) and the physical

function (PF) subscale of the

SF-36 questionnaire.

We have reason to believe self-report

measures with interventions that

encourage scheduling increasing

exercise and activity may have

problems.

For example, a review of three studies of

CBT interventions found that changes in

physical activity (as measured by an

objective outcome measure,

actometers) were not related to the

changes in fatigue (2).

Also, although an improvement in fatigue

was reported over the control group,

there was no difference between the

CBT and control groups in terms of

increases in activity levels.

When one looks at the studies that made

up the review, one can also see that

there were other self-reported measures

including SF-36 physical functioning

that had reported improvements.

The actometer data from one of these

three studies wasn't published in the

main paper for the study(3), but was

released in 2002 a long time (4) before

the Wiborg et al. review was published.

As I have highlighted before, Friedberg

and Sohl (5) have published results of a

study on an intervention involving

Cognitive Behavior Therapy (CBT) which

included encouraging patients to go for

longer walks.

It found that on the SF-36 Physical

Functioning (PF) scale, patients

improved from a pre-treatment mean

(SD) of 49.44 (25.19) to 58.18 (26.48)

post-treatment, equivalent to a Cohen's

d value of 0.35.

On the Fatigue Severity Scale (FSS), the

improvement as measured by the

cohen's d value was even great (0.78)

from an initial pre-treatment mean (SD)

of 5.93 (0.93) to a 5.20 (0.95)

post-treatment.

However on actigraphy there was

actually a numerical decrease from a

pre-treatment mean (SD) of 224696.90

(158389.64) to 203916.67 (122585.92)

post-treatment (cohen's d: -0.13).

So just because patients report lower

fatigue and better scores on the SF-36

PF scale, doesn't mean they're doing

more, which is what GET and CBT

based on GET claim to bring about.

These results seem particularly pertinent

for this study given the primary

outcome measures are the SF-36 PF

scale and a fatigue scale.

Friedberg had also earlier released data

showing this effect of a graded activity

program not leading to increased total

activity levels (6).

In a case study paper on a single

patient, Friedberg found " using a

26-session graded activity intervention

involved gradual increases in physical

activity " that " from baseline to

treatment termination, the patient's

self-reported increase in walk time from

0 to 155 min a week contrasted with a

surprising 10.6% decrease in mean

weekly step counts. "

A CFS study published back in 1997

showed the problem of using self-report

data (7). The authors' rationale for the

study was:

" It is not clear whether subjective

accounts of physical activity level

adequately reflect the actual level of

physical activity. Therefore the primary

aims of the present study were to

assess actual activity level in patients

with CFS to validate claims of lower

levels of physical activity and to

validate the reported relationship

between fatigue and activity level that

was found on self-report

questionnaires.

In addition, we evaluated whether

physical activity level adequately can

be assessed by self-report measures.

An Accelerometer was used as a

reference for actual level of physical

activity. "

The authors reported on the correlations

on 7 outcome measures in relation to

the actometer readings:

" none of the self-report questionnaires

had strong correlations with the

Actometer. Thus, self-report

questionnaires are no perfect parallel

tests for the Actometer. "

The authors of the 1997 study (7)

pointed out that:

" the subjective instruments do not

measure actual behaviour. Responses

on these instruments appear to be an

expression of the patients' views about

activity and may be biased by

cognitions concerning illness and

disability " .

This was re-iterated in another paper

(8):

" In earlier studies of our research group,

actual motor activity has been

recorded with an ankle-worn

motion-sensing device (actometer) in

conjunction with self-report measures

of physical activity. The data of these

studies suggest that self-report

measures of activity reflect the

patients' view about their physical

activity and may have been biased by

cognitions concerning illness and

disability. "

It seems easy to imagine that GET and

particularly CBT might alter such

cognitions.

A systematic review of treatments for

CFS back in 2001 recommended the use

of more objective outcome measures (9)

e.g.

" Outcomes such as " improvement, " in

which participants were asked to rate

themselves as better or worse than

they were before the intervention

began, were frequently reported.

However, the person may feel better

able to cope with daily activities

because they have reduced their

expectations of what they should

achieve, rather than because they have

made any recovery as a result of the

intervention.

A more objective measure of the effect

of any intervention would be whether

participants have increased their

working hours, returned to work or

school, or increased their physical

activities. "

As I mentioned above, the current

authors said the use of self-reported

information on service use and lost

employment was " largely unavoidable " ,

which may be true for those measures

(1). But to get an idea of individuals'

functioning, actigraphy seems a good

way of doing that.

The study investigators appear to agree

as the PACE Trial does use actometers

to measure baseline activity levels (10),

which also means they have this

equipment.

They also said they planned initially to

use actometers as an outcome measure

but then changed their minds (11).

I think this is unfortunate they were

not used as an outcome measure.

I think in this study possibly the nearest

objective surrogate we have of

actigraphy, to help give us an idea of

the levels of activity participants are

regularly maintaining, is the 6 minute

walking test (MWT).

It found that despite various differences

on self-reported measures such as

fatigue and physical functioning

between the CBT and SMC and APT

participants, there were no differences

between the three groups on this

outcome measure (12).

The GET participants did do a little

better, but a result of 379m is still not

good for a group with a mean age of 40

who do not have a range of conditions

(due to the exclusions in the trial) and

who were adjudged well enough to

attend outpatient appointments.

Such individuals in the GET arm of the

trial would generally have had practice

at walking continuously for a few

minutes so might have been better able

to know not to go too fast or slow to

get a better result ? this is a bit like the

training effect which has shown to

increase scores in the 6MWT.

GET participants might also have been

more motivated to push themselves and

impress their therapist than other

therapists - unfortunately the test

doesn't involve sufficient measurements

to know if all groups pushed themselves

equally hard.

The CBT and GET groups had been told

to pay less attention to symptoms

which might have encouraged them to

push themselves harder.

M put the 6MWT results in context

in another comment:

" all of PACE's trial groups at 52 weeks

after baseline were still below those of

patients with various cardiopulmonary

disorders and patients with class III

heart failure as well as scores of 80-89

year olds, a result which doesn't

exactly scream good health. (13-15) " .

The latest study shows neither CBT nor

GET led to an improved rate of days of

lost employment [Means (sds): APT:

148.6 (109.2);

CBT: 151.0 (108.2); GET: 144.5 (109.4);

SMC (alone): 141.7 (107.5)] (Table 2).

Neither CBT nor GET led to

improvements in numbers receiving

welfare benefits or other financial

payments (Table 4). Combine those

two sets of data with the 6MWT tests

and the results for GET and CBT

really aren't good at all.

Incidentally, the authors previously said

(11):

" We have used several objective

outcome measures; the six minute

walking test, a test of physical fitness,

as well as occupational and health

economic outcomes. "

Thus far, the results of the test of

physical fitness have not been released.

References:

1. McCrone P, Sharpe M, Chalder T,

Knapp M, AL, et al. (2012)

Adaptive Pacing, Cognitive Behaviour

Therapy, Graded Exercise, and

Specialist Medical Care for Chronic

Fatigue Syndrome: A Cost-Effectiveness

Analysis.PLoS ONE 7(8):e40808.

doi:10.1371/journal.pone.0040808

2 Wiborg JF, Knoop H, Stulemeijer M,

Prins JB, Bleijenberg G. How does

cognitive behaviour therapy reduce

fatigue in patients with chronic fatigue

syndrome? The role of physical activity.

Psychol Med. 2010 Aug;40(8):1281-7.

Epub 2010 Jan 5.

3 Prins JB, Bleijenberg G, Bazelmans E, et

al. Cognitive behaviour therapy for

chronic fatigue syndrome: a multicentre

randomised controlled trial. Lancet

2001; 357: 841-47.

4. Van Essen, M and de Winter, LJM.

Cognitieve gedragstherapie by het

vermoeidheidssyndroom (cognitive

behaviour therapy for chronic fatigue

syndrome). Report from the College voor

Zorgverzekeringen. Amstelveen:

Holland. June 27th, 2002. Bijlage B.

Table 2.

5 Friedberg F, Sohl S. Cognitive-behavior

therapy in chronic fatigue

syndrome: is improvement related to

increased physical activity? J Clin

Psychol. 2009 Feb 11.

6 Friedberg, F. Does graded activity

increase activity? A case study of

chronic fatigue syndrome. Journal of

Behavior Therapy and Experimental

Psychiatry, 2002, 33, 3-4, 203-215

7 Vercoulen JH, Bazelmans E, Swanink

CM, Fennis JF, Galama JM, Jongen PJ,

Hommes O, Van der Meer JW,

Bleijenberg G. Physical activity in

chronic fatigue syndrome: assessment

and its role in fatigue. J Psychiatr Res.

1997 Nov-Dec;31(6):661-73.

8 van der Werf SP, Prins JB, Vercoulen

JH, van der Meer JW, Bleijenberg G.

Identifying physical activity patterns in

chronic fatigue syndrome using

actigraphic assessment. J Psychosom

Res. 2000 Nov;49(5):373-9.

9 Whiting P, Bagnall AM, Sowden AJ,

Cornell JE, Mulrow CD, Ramírez G.

Interventions for the treatment and

management of chronic fatigue

syndrome: a systematic review. JAMA.

2001 Sep 19;286(11):1360-8.

10 White PD, Sharpe MC, Chalder T,

DeCesare JC, Walwyn R; on behalf of

the PACE trial group. Protocol for the

PACE trial: a randomised controlled trial

of adaptive pacing, cognitive behaviour

therapy, and graded exercise, as

supplements to standardised specialist

medical care versus standardised

specialist medical care alone for

patients with the chronic fatigue

syndrome/myalgic encephalomyelitis or

encephalopathy. BioMed Cent Neurol

2007; 7: 6. - http://bit.ly/NwNtL4

11 White PD, Sharpe MC, Chalder T,

DeCesare JC, Walwyn R, for the PACE

trial management group. Response to

comments on " Protocol for the PACE

trial " . BMC Neurol. 2007,

7:6doi:10.1186/1471-2377-7-6.

http://bit.ly/NwNFKb

12 White PD, Goldsmith KA, AL,

Potts L, Walwyn R, et al.

(2011) Comparison of adaptive pacing

therapy, cognitive behaviour therapy,

graded exercise therapy, and specialist

medical care for chronic fatigue

syndrome (PACE): a randomised trial.

Lancet 377: 823?836.

13 Steffen et al. Age- and

Gender-Related Test Performance in

Community-Dwelling Elderly People:

Six-Minute Walk Test, Berg Balance

Scale, Timed Up & Go Test, and Gait

Speeds Physical Therapy February

2002 vol. 82 no. 2 128-137

http://bit.ly/NwNTkC

14. Lipkin et al. Six minute walking test

for assessing exercise capacity in

chronic heart failure. Br Med J (Clin Res

Ed) 1986; 292 : 653 doi:

10.1136/bmj.292.6521.653

http://bit.ly/NwO3Zp

15. Kadikar A, Maurer J, Kesten S. The

six-minute walk test: a guide to

assessment for lung transplantation. J

Heart Lung Transplant. 1997

Mar;16(3):313-9.