PACE Trial: letters and reply | Journal of Psychological Medicine | August 2013

From the Journal of Psychological Medicine, August 2013.

CORRESPONDENCE

Editorial note

Unusually for Psychological Medicine, we publish below six letters concerning the paper by White et al (2013) on the PACE Trial. The UK Office of the Journal received 15 letters criticising aspects of this paper, but it seemed unlikely that all of these letters originated entirely independently since a number arrived on consecutive days and reiterated the same points. Nevertheless, in the spirit of scientific openness, we have published six of the letters which cover the main criticisms, and invited Professor White to reply to them.

References
White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M; PACE Trial Management Group (2013). Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Medicine. Published online: 31 January 2013. doi:10.1017/S0033291713000020

ROBIN MURRAY
Joint Editor – Psychological Medicine


In their paper on recovery rates in the PACE trial, White et al. (2013) acknowledge that `objective measures of physical activity have been found previously to correlate poorly with self-reported out- comes. Yet, there is no attempt to utilize the Six Minute Walking Test results. The best results were a mean of 379 metres walked in the graded exercise therapy condition, a gain of 67 metres in 52 weeks, 35 metres more than the specialist medical care (SMC)-only group (White et al. 2011). The cognitive behaviour therapy group showed no improvement compared with the SMC group. The distance of 379 metres is exceeded by patients listed for lung transplantation (Kadikar et al. 1997) and by older patients with chronic heart failure (Lipkin at al. I986). Given the recognized problem with self-reported outcomes, reliance solely on such measures leaves open the question of the validity of the recovery criteria of PACE.

Declaration of Interest
None.

References
Kadikar A, Maurer J, Kesten S (1997). The Six-Minute Walk Test: a guide to assessment for lung transplantation. Journal of Heart and Lung Transplantation 16. 313-319.

Lipkin DP, Scriven A], Crake T, Poole-Wilson PA (I986). Six minute walking test for assessing exercise capacity in chronic heart failure. British Medical Journal 292. 653-655.

White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M; PACE Trial Management Group (2013). Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Medicine – Published online. 31 January 2013. doi:10.1017/S003329173000020

White PD, Goldsmith KA. Johnson AL. Potts 1.. Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus B], Murphy G, Murphy M, O’Dowd H, Wilks D, MrCrone P, Chalder T, Sharpe M; PACE Trial Management Group (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.

SUSANNA AGARDY c/o PO Box 6156, Hawthorn West PO 3122 (Email: susannaa@…)


White and colleagues conclude from the results of the PACE trial that ‘recovery from CFS (chronic fatigue syndrome) is possible, and that CBT (cognitive behavioural therapy) and GET (graded exercise therapy) are the therapies most likely to lead to recovery’ (White et al. 2013).

However, in the body of the text, they qualify their use of the term ‘recovery’. Citing Nisenbaum at al. (2003) they write, `recovery may be taken to imply that the patient has made a transition from ill health to remission and also is at little risk of recurrence’ but then acknowledge that, in the absence of longitudi- nal data, it is not possible to discriminate between remission and recovery in CFS.

Thus, in the current paper, ‘recovery’ does not mean recovery as understood by Nisenbaum but `recovery from the current episode of the illness’, a state described by Nisenbaum as `remission’.

This difference is important because CFS is known to pursue ‘a fluctuating course with periods of relative remission and relapse’ (CFS/ME Working Group. 2002) and Cochrane reviews of CBT (Price et al. 2008) and GET (Edmonds et al. 2004) have reported inconsistent findings at long-term follow-up, with some studies showing that initial gains can diminish with time. Writing about the PACE trial, Edmonds et al. concluded `Even when the results of that study are available, it is possible that uncertainty will remain. Further randomized studies are needed, with longer follow-up, to determine whether patients who respond to exercise stay well or relapse.`

Declaration of Interest
None.

References
CFS/ME Working Group (2002). A Report of the CFS/ME Working Group: Report to the Chief Medical Officer of an Independent working group. Department of Health London. (http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/documents/digitalasset/ dh_4064945.pdf).
Accessed 3 March 2013.

Edmonds M, McGuire H. Price JR (2004). Exercise therapy for chronic fatigue syndrome. Cochrane Database of Systematic Reviews. Issue 3. Art.No.CD003200. Nisenbaum R. Jones JF, Unger ER. Reyes M, Reeves WC (2003). A population-based study of the clinical course of chronic fatigue syndrome. Health and Quality of Life Outcomes 1, 49.

Price JR. Mitchell E, Tidy E. Hunot V (2008). Cognitive behaviour therapy for chronic fatigue syndrome in adults. Chochrane Database of Systematic Reviews. Issue 3. Art.No CD001027

White PD, Goldsmith K,]ohnson AL, Chalder T, Sharpe M; PACE Trial Management Group (20l3). Recovery from chronic fatigue syndrome after treatments given in the PACE trial.Psychological Medicine. Published online. 31 January 2013. doi:10.1017/S003329173000020

SAMUEL CARTER, M.A. (Oxon) (Email: sam.carter969@…)


The main trial recovery criteria, described by White et al. (2013), allow participants with SF-36 physical function scores of ≥60 to be classed as recovered if, for example, their `main symptom’ is no longer fatigue.

In terms of clinical interpretation, such a threshold is problematic because it is in conflict with how the condition itself is defined. For example, it indicates worse impairment than the PACE Trial entry criteria threshold of <65 [≤65] (White at al. 2011) and the diagnostic threshold of ≤70 used by Reeves et al. (2005) to indicate `substantial' physical impairment. Further, a score of ≤65 has been used to indicate severely impaired physical function in similar patient groups (Stulemeijer et al. 2004; van't Leven et al. 2009). Declaration of Interest
None.

References
Reeves WC, Wagner D, Nisenbaurn R, Jones JF, Gurbaxani B Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Helm C (2005). Chronic Fatigue Syndrome — a clinically empirical approach to its definition and study. BMC Medicine 3, I9.

Stulemeijer M, de Jong LWAM, Fiselier T]W, Hoogveld SWB, Bleijenberg G (2004). Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial. British Medical Journal 330, 14

van’t Levon M, Zielhuis GA, van der Meer ]W, Verbeek AL, Bleijenberg G (2009). Fatigue and chronic fatigue syndrome-like complaints in the general population. European Journal of Public Health 20, 251-257.

White PD, Goldsmith K,]ohnson AL, Chalder T, Sharpe M; PACE Trial Management Group (20l3). Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Medicine. Published online. 31 January 2013. doi:10.1017/S003329173000020

White PD, Goldsmith KA. Johnson AL. Potts 1.. Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL. Bavinton J, Angus B], Murphy G, Murphy M, O’Dowd H, Wilks D, MrCrone P, Chalder T, Sharpe M; PACE Trial Management Group (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.

ROBERT COURTNEY (Email: information111@…)


White et al. (2013) report various recovery rates from chronic fatigue syndrome (CFS) following the PACE Trial. However, additional information would have been useful.

White et al. use a selection of broad criteria to define recovery, none of which allow one to be confident recovery has been achieved. Firstly, Chalder Fatigue Questionnaire (CFQ) and SF-36 Physical functioning (PF) scores within the normal range are in fact possible at baseline. This means it is possible to have fatigue that is classed as `severe, disabling and affected physical and mental function’ and yet satisfy this particular recovery criterion.

Secondly, not satisfying the Oxford criteria only requires a change on just one measure, and the change may be minimal, across a threshold, e.g. going from an SF-36 PF score of 65 to 70 or a CFQ (bimodal) score of 6 to 5. A sign that this criterion is not that stringent can be seen with the fact that 41% of the specialist medical care (SMC) group, which received no active treatment, no longer met the Oxford criteria at 12 months, much higher than recovery rates seen in previous studies (Cairns & Hotopf, 2005).

Finally, a CGI score of 2, which means a participant rated as `much better’ but not `very much better’ also gives no assurance that somebody had recovered. It seems quite possible that many with CGI scores of 2 have simply improved but not recovered.

Declaration of Interest
None.

References
Cairns R. Hotopf M (2005). A systematic review describing the prognosis of chronic fatigue Syndrome. Occupational Medicine 55, 20-31.

White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M; PACE Trial Management Group (2013). Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Medicine . Published online. 31 January 2013. doi:10.1017/S003329173000020

DUNCAN COX
Warwickshire Network for M.E.
(Email: warksmenet@…)


It is debated whether cognitive behaviour therapy (CBT) or graded exercise therapy (GET) reliably facilitate recovery in chronic fatigue syndrome (CFS). As such, any data on this issue, such as those presented by White et al. (2013), are always of interest.

The trial was not blinded, however, with participants, therapists and research assessors aware of the treatment group for each individual (White et al. 2007). Consequently, there is the possibility of significant response bias. Indeed, while the CBT group performed better than the adaptive pacing therapy (APT) and the specialist medical care only (SMC) groups on the self-rated SF-36 physical functioning (SF-36 PF) scale, there were no significant differences and minimal numerical difference on the more objective six-minute walk distance test (6MWD) (White et al 2011).

This discrepancy between subjective and objective outcome measures is not a novel finding in the CFS literature. Wiborg et al. (2010) analysed three randomized control trials (RCTs) of three CBT interventions, finding that while fatigue was improved in the CBT groups compared to waiting-list controls, there was no difference in actometer readings between the two groups. Moreover, a mediation analysis showed changes in physical activity were not related to changes in fatigue. Similarly, in a GET RCT, Moss-Morris et al. (2005) found that an increase in physical fitness did not mediate the treatment effect of reduced fatigue. In an uncontrolled trial of a graded activity programme, Friedberg & Sohl (2009) reported improvements in SF-36 PF and fatigue while actometers showed overall reduction in total activity levels.

The 6MWD is one objective outcome measure White et al. (20l3) could have incorporated into their recovery criteria (White et al. 2007). Reference ranges for 6MWDs, which adjust for gender and age inter alia, exist for healthy adults (e.g. Chetta et al. 2006; Casanova et al. 2001). Then, after calculating the new recovery percentage with the 6MWDs, analyses could be preformed to compare the means with predicted values.

Declaration of Interest
None.

References
Casanova C, Celli BR, Barria P, Casas A, Cote C, de Torres JP, Jardim J, Lopez MV, Marin JM, Montes de Oca M, Pinto-Plata V, Aguirre-Jaime A; Six Minute Walk Distance Project (ALAT) (2011). The 6-min walk distance in healthy subjects: reference standards from seven countries. European Respiratory Journal 37, 150-6.

Friedberg F, Sohl S (2009). Cognitive-behavior therapy in chronic fatigue syndrome: is improvement related to increased physical activity? Journal of Clinical Psychology 65. 423-442.

Moss-Morris R. Sharon C, Tobin R, Baldi JC (2005). A randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. Journal of Health Psychology 10, 245-259.

White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M; PACE Trial Management Group (2013). Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Medicine. Published online. 31 January 2013. doi:10.1017/S003329173000020

White PD, Goldsmith KA. Johnson AL. Potts 1.. Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL. Bavinton J, Angus B], Murphy G, Murphy M, O’Dowd H, Wilks D, MrCrone P, Chalder T, Sharpe M; PACE Trial Management Group (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.

White PD. Sharpe MC, Chalder T, DeCesare JC. Walwyn R; PACE trial group (2007). 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 Central Neurology 7, 6.

Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G (2010). How does cognitive behaviour therapy reduce fatigue in patients with chronic fatigue syndrome? The role of physical activity. Psychological Medicine 40, 1281-1287.

CARLY MARYHEW
(Email: maryhewc@gmail com)


Important outcome data from the PACE trial (White et al. 2011) appears to be missing from the paper describing recovery in ME/CFS (White et al. 2013) and the participants do not appear to have been asked whether they had recovered as a result of receiving cognitive behaviour therapy (CBT), graded exercise therapy (GET) or Pacing.

The paper would have been improved had three specific markers of recovery been reported. First is the receipt of a state sickness or disability benefit. Claiming such a benefit indicates that the person is still ill and has not recovered. This data was included in the cost analysis study (McCrone et al. 2012) that reported: `Receipt of benefits due to illness or disability increased slightly from baseline
to follow-up.’

Second is employment or education status. The recovery paper argues that ‘Return to work is not, however, an appropriate measure of recovery if the participant was not working before their illness and is influenced by other factors such as the job market.’ However, a sustained return to meaningful paid employment, or education, or the ability to do so, is an objective marker of recovery.

Third is ability to mobilize. Recovery in a condition whose cardinal clinical features relate to mobility – exercise-induced muscle fatigue and weakness – must be matched with an ability to mobilize in a normal and timely manner. The overall results for all the treatments in the PACE trial relating to changes in the six-minute walking test from baseline to 52 weeks do not represent a return to normal levels of activity. It can be seen that the figure for all the treatment groups at 52 weeks are below the 402m reported to be present in patients with class 3 heart failure (Lipkin et al. 1986). So the results for those who had recovered – who should now be achieving a much higher distance – ought to have been included. In addition, the question could be raised as to how it is possible to meet the entry criteria for the PACE trial with a Short Form-36 physical function subscale score of 65 yet leave the trial as recovered with a lower score of 60.

The term `recovery’ implies a sustained return to symptom-free health with the ability to repeatedly and reliably participate in all aspects of normal life – employment, education, social activities. etc. Without this information it is difficult to conclude that these patients have in fact recovered.

Declaration of Interest
None.

References
Lipkin DP, Scriven A], Crake T, Poole-Wilson PA (I986). Six minute walking test for assessing exercise capacity in chronic heart failure. British Medical Journal (Clinical Research Edition) 292. 653.

McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, Goldsmith KA, White PD (2012). Adaptive pacing, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome: a cost-effectiveness analysis PLoS One 2012. 7, e408084.

White PD, Goldsmith KA. Johnson AL. Potts 1.. Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL. Bavinton J, Angus B], Murphy G, Murphy M, O’Dowd H, Wilks D, MrCrone P, Chalder T, Sharpe M (2011). Comparison of adaptive pacing therapy. cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised controlled trial. Lancet 377, 823-836.

White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M; PACE Trial Management Group (2013). Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Medicine. Published online. 31 January 2013. doi:10.1017/S003329173000020

CHARLES SHEPHERD
Hon. Medical Adviser, ME Association
(Email: charles.c.shepherd@…)


REPLY

The definition of recovery from any chronic illness is challenging. We therefore agree with Cox (20I3) and Courtney (2013) that no single threshold measurement is sufficient; this is why we measured several domains of improvement and combined them into a composite measure of recovery (White et al. 20l3). Shepherd (2013) suggests asking patients whether they recovered as a result of [our italics] receiving a treatment; we did not ask this since it is not possible for individuals to ascribe change to one particular source in exclusion from all others, such as regression to the mean or external factors.

Maryhew (2013) suggests self-ratings may be biased when participants cannot be masked to treatment allocation; this may be true, but is inconsistent with cognitive behaviour therapy (CBT) being more effective than adaptive pacing therapy (APT) when treatment expectations were significantly lower before treatment (White et al. 2011).

We dispute that in the PACE trial the six-minute walking test offered a better and more `objective’ measure of recovery, as suggested by Agardy (2013), Maryhew (2013), and Shepherd (2013). First, recovery from chronic fatigue syndrome (CFS), which is defined by a patient’s reported symptoms, is arguably best measured by multiple patient-reported outcome measures, rather than a single performance test. Second, and importantly, there were practical limitations to our conduct of the walking test. Due to concerns about patients with CFS coping with physical exertion, no encouragement was given to participants as they performed the test, by contrast to the way this test is usually applied (Guyatt et al. I984; American Thoracic Society, 2002). Rather than encouragement, we told participants, `You should walk continuously if possible, but can slow down or stop if you need to.’ Furthermore we had only 10 metres of walking corridor space available, rather than the 30-50 metres of space used in other studies; this meant that participants had to stop and turn around more frequently (Guyatt et al. I984; Troosters et al. I999; American Thoracic Society, 2002), slowing them down and thereby vitiating comparison with other studies. Finally, we had follow-up data on 72% of participants for this test, which was less than for the self-report measures (White et al. 2011).

Economic data, such as sickness benefits and employment status, have already been published by McCrone et al. (2012). However, recovery from illness is a health status, not an economic one, and plenty of working people are unwell (Oortwijn et al. 2011), while well people do not necessarily work. Some of our participants were either past the age of retirement or were not in paid employment when they fell ill. In addition, follow-up at 6 months after the end of therapy may be too short a period to affect either benefits or employment. We therefore disagree with Shepherd (2013) that such outcomes constitute a usefulcomponent of recovery in the PACE trial.

We agree with Carter (2013) that there is a difference between sustained recovery and temporary remission; this is why we were careful to give a precise definition of recovery and to emphasize that it applied at one particular point only and to the current episode of illness (White et al. 2013).

Despite the complexities of measuring recovery, we believe that our approach of using multiple self-report measures provides a reasonable approach to inform clinicians’ and patients` choice between available treatments.

The findings from the PACE trial are clear; however we measured recovery, CBT and graded exercise therapy (GET) were more likely to lead to recovery, when added to specialist medical care (SMC), compared to either adding APT or SMC alone. Recovery after SMC alone, using our composite criteria, was only 7% – the same as that without treatment (Cairns & Hotopf, 2005) – whereas three times as many (22%) recovered after receiving CBT or GET. The PACE trial has shown that both CBT and GET are moderately effective, safe, cost-effective, and are more likely to lead to recovery (White et al. 2011, 2013; McCrone et al. 2012). These treatments should now be routinely offered to all those who may benefit from them (Crawley et al. 2013].

Declaration of Interest
Declaration of interest is as stated in White et al. (2013).

References
Agardy S (2013). Comments on `Recovery from chronic fatigue syndrome after treatments given in the PACE trial’ |letter]Psychological Medicine, doi:10.1017/S003329171300113X

American Thoracic Society (2002). ATS Statement: Guidelines for the six-minute walk test. American Journal of Respiratory and Critical Care Medicine 166, 111-117

Cairns R. Hotopf M (2005). A systematic review describing the prognosis of chronic fatigue Syndrome. Occupational Medicine 55, 20-31.

Carter S (2013). `Recovery from chronic fatigue syndrome after treatments given in the PACE trial’: recovery or remission? [letter] Psychological Medicine, doi:10.1017/ S0033291713001268

Courtney R (2013).`Recovery from chronic fatigue syndrome after treatments given in the PACE trial`: an appropriate threshold for a recovery? [letter]. Psychological Medicine, doi:10.1017/S003329171300127X

Cox D (2013). `Recovery from chronic fatigue syndrome after treatments given in the PACE trial’: data on the recovery groups as a whole would be useful [Letter]. Psychological Medicine. doi:10.1017/S0033291713001281

Crawley E, Collin SM, while PD, Rimes K. Sterne MC, May MT (1113;Treatment outcome in adults with chronic fatigue syndrome: a prospective study in England based on the CFS/ME National Outcomes Database. Quarterly Journal of Medicine. 28 March. doi: 10.1093/qjmed/hct061l.

Guyatt GH, Pugsley SO, Sullivan MJ, Thompson PJ, Berman LB, Jones. NL, Fallen EL, Taylor DW (1984) Effect of encouragement on walking test performance. Thorax 39 818-822

Maryhew C [Z013]. Comments on ‘Recovery from chronic fatigue syndrome after treatments given in the PACE trial’ [Letter] Psychological Medicine doi:10.1017/ S0033291713001293

McCrone P, Sharpe M, Chalder T, Knapp M, Johnson AL, Goldsmith KA, White PD (2012). Adaptive pacing, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome: a cost-effectiveness analysis PLoS One 7,e408084.

Oortwijn W, Nelissen E, Admini S, van den Heuvel S, Geuskens G, Burdof L. Social Determinants state of the art reviews- Health of People of Working Age – Summary Report for Health and Consumers Luxembourg

Shepherd C (2013)Comments on `Recovery from chronic fatigue syndrome after treatments given in the PACE trial’ [Letter]. Psychological Medicine doi:10.1017/ S003329171300113X

Troosters T, Gosselink R, Decramer M (1999) Six minute walking distance in healthy elderly subjects. European Respiratory Journal 14:270-274

White PD, Goldsmith KA. Johnson AL. Potts 1.. Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL. Bavinton J, Angus B], Murphy G, Murphy M, O’Dowd H, Wilks D, MrCrone P, Chalder T, Sharpe M; PACE Trial Management Group (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.

White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M; PACE Trial Management Group (2013). Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Medicine . Published online. 31 January 2013. doi:10.1017/S003329173000020

P.D.WHITE(1), K. GOLDSMITH(2), A. L. JOHNSON (3,4), T. CHALDER (5), M. SHARPE (6)
1 Wolfson Institute of Preventive Medicine, Barts and the London
School of Medicine and Dentistry, Queen Mary University of London, UK
2 Biostatistics Department, Institute of Psychiatry, King’s College
London, UK 3 MRC Biostatistics Unit, Institute of Public Health,
University of Cambridge, UK 4 MRC Clinical Trials Unit, London, UK 5
Academic Department of Psychological Medicine, King’s College London,
UK 6 Department of Psychiatry, University of Oxford, UK
(Email: p.d.white @ qmul.ac.uk)

Follow the ME Association on social media: