- Email: [email protected]
The PACE trial in chronic fatigue syndrome
Correspondence
Published Online May 17, 2011 DOI:10.1016/S01406736(11)60681-8 See Editorial page 1808
health condition (unfortunately, only means were published): “No disease/ current health problem”: 11·2; “Past or current disease”: 12·1; “Current health problem”: 12·5, and “Disease and current health problem”: 14·2. Furthermore, 17·6% of chronic fatigue syndrome patients diagnosed at the Chronic Fatigue Unit (South London and Maudsley NHS Trust) had a score of 18 or less before they were treated.4 This suggests either that the Chronic Fatigue Unit diagnoses and treats fatigue problems in patients with normal levels of fatigue or, alternatively, that the threshold of 18 to represent normal fatigue is not suitable. Given this information, and the fact that those with a Chalder fatigue questionnaire Likert score of 18 could still meet the trial’s entry criteria (bimodal score of 6 or more),1,3 it would be good if White and colleagues would now recalculate the data using the original definition of “fatigue caseness”.2,3 I declare that I have no conflicts of interest.
Sarah M Feehan, on behalf of the Liverpool ME Support Group [email protected] Liverpool ME Support Group, Bootle, Liverpool L20 9LD, UK 1
Published Online May 17, 2011 DOI:10.1016/S01406736(11)60685-5
2
See Editorial page 1808
3
4
5
1832
White PD, Goldsmith KA, Johnson AL, et al, on behalf of the PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011; 377: 823–36. Chalder T, Berelowitz G, Pawlikowska T, et al. Development of a fatigue scale. J Psychosom Res 1993; 37: 147–53. 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. BMC Neurol 2007; 7: 6. Cella M, Chalder T. Measuring fatigue in clinical and community settings. J Psychosom Res 2010; 69: 17–22. Loge JH, Ekeberg O, Kaasa S. Fatigue in the general Norwegian population: normative data and associations. J Psychosom Res 1998; 45: 53–65.
I am concerned by the change in assessment method between the published results of the PACE trial1 and the trial protocol.2 Seven secondary outcomes were not reported and there were changes in several of the measures that were reported.1,2 In particular, the protocol stated that those with short-form 36 physical function subscale scores of 65 or less would be deemed ill enough to participate, and that those with scores of 85 or more would be regarded as “recovered”.2 However, the authors have questionably defined “normal” as a score of 60 or more,1 based on general population scores which did not exclude those reporting chronic illnesses. In the cited study of workingage adults,3 the mean physical function score for respondents without longterm health problems was 92·7 (SD 13·1). The mean physical function scores for those aged 75–84 years, including those with long-term health problems, was 57·9.3 The lack of objective data, such as hours employed or actometer results, is problematic, since Wiborg and colleagues4 showed that improvements on questionnaires are not reflected in an increase in activity, as would be expected if the patients had more energy.4 The only significant difference between treatments for the 6-min walking test was for graded exercise therapy. But the increase in walking distance is small when compared to the distance walked by healthy elderly people (mean age 65 years), which was shown to be 631 m (SD 93).5 Unfortunately, the overall results of the PACE treatments were un-
impressive, and with only 41% of patients reporting “positive” change after cognitive behavioural therapy or graded exercise therapy, further biomedical research is imperative. I declare that I have no conflicts of interest.
Andrew James Kewley kewl0001@flinders.edu.au Faculty of Science and Engineering, Flinders University, SA 5042, Australia 1
2
3
4
5
White PD, Goldsmith KA, Johnson AL, et al, on behalf of the PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011; 377: 611–90. White PD, Sharpe MC, Chalder T, et al. 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. BMC Neurol 2007; 7: 6. Bowling A, Bond M, Jenkinson C, Lamping DL. Short form 36 (SF-36) health survey questionnaire: which normative data should be used? Comparisons between the norms provided by the Omnibus Survey in Britain, the Health Survey for England and the Oxford Healthy Life Survey. J Public Health Med 1999; 21: 255–70. 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; 40: 1281–87. Troosters T, Gosselink R, Decramer M. Six minute walking distance in healthy elderly subjects. Eur Respir J 1999; 14: 270–74.
The findings of the PACE trial1 seem impressive, but the discrepancy between the definitions of improvement in the protocol2 and paper requires an explanation. In the paper “clinically useful differences” were defined as 0·5 SD changes in fatigue or physical functioning compared with baseline. However, the criteria for improvement published in the trial protocol were
Trial protocol
Final publication
Fatigue (bimodal Chalder scale)
50% reduction or score ≤3
7% reduction* or score ≤4†
Physical functioning (SF-36 subscale)
50% increase or score ≥75
21% increase‡ or score ≥60
*Clinically useful difference of 2 points (0·5 SD) and mean baseline Likert score of 28·2. †Likert score of ≤18 used by the authors implies bimodal score of ≤4. ‡Clinically useful difference of 8 points (0·5 SD) and mean baseline short-form 36 (SF-36) physical function subscale score of 38·0.
Table: Definition of positive outcome/improvement in the trial protocol and the final publication
www.thelancet.com Vol 377 May 28, 2011
Correspondence
much more demanding (table).2 Use of a cut-off score of 75 on the short-form 36 physical functioning subscale, as originally proposed, would halve the number of “recovered” patients. Moreover, consulting the normative data for the scale reveals that the mean score of 58 after both cognitive behaviour therapy and graded exercise improved a patient’s physical functioning to the level of someone 40 years older than himself.3 Is this a case of “outcome reporting bias”?4 We declare that we have no conflicts of interest.
*Bart Stouten, Ellen M Goudsmit, Neil Riley [email protected] Einsteindreef 67A, 3562 XT Utrecht, Netherlands (BS); School of Psychology, University of East London, London, UK (EMG); and Byways, Chichester Road, Dorking, UK (NR) 1
2
3
4
White PD, Goldsmith KA, Johnson AL, et al, on behalf of the PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011; 377: 823–36. White PD, Sharpe MC, Chalder T, et al, 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. BMC Neurol 2007; 7: 6. Bowling A, Bond M, Jenkinson C, Lamping DL. Short form 36 (SF-36) health survey questionnaire: which normative data should be used? Comparisons between the norms provided by the Omnibus Survey in Britain, the Health Survey for England and the Oxford Healthy Life Survey. J Public Health Med 1999; 21: 255–70. Smyth RMD, Kirkham JJ, Jacoby A, Altman DG, Gamble C, Williamson PR. Frequency and reasons for outcome reporting bias in clinical trials: interviews with trialists. BMJ 2011; 342: c7153.
Peter White and colleagues1 claim that, if cognitive behaviour therapy and graded exercise therapy are delivered as described, they are “safe” for chronic fatigue syndrome (CFS); the CONSORT statement on harms reporting recommends against such claims.2 If few participants are compliant with the intervention, harms-related www.thelancet.com Vol 377 May 28, 2011
data might not be reliable. Both cognitive behaviour therapy and graded exercise therapy are designed to increase activity; however, actometers were not used, so one cannot be sure how many patients were actually more active.1 Analysis of three trials of cognitive behaviour therapy found that activity levels before and after therapy were similar, despite improvements being reported on fatigue and other subjective measures.3 This finding suggests that patients might simply substitute the activity component of cognitive behaviour therapy for other activities;4 if this situation occurred in White and colleagues’ study, we would not have information on the effects of actually increasing activity levels. On the only objective test, the 6-min walking distance, the cognitive behaviour therapy group only improved by 21 m, suggesting that total daily activity might not have increased.1 The average increase for graded exercise therapy of only 67 m leaves open the possibility that many on that intervention did not achieve or maintain increased exercise or activity levels. If, as seems likely, “real-world” graded exercise therapy practitioners expect higher yearly 6-min walking distance targets than a 379 m crawl (or higher weekly increases than 1·29 m), more adverse reactions could occur. Given many patients’ reports of adverse reactions from such interventions, the biological reasons why they might be problematic (eg, abnormalities in muscle and immunological response to exercise), and the fact that adverse reactions are often only noted outside of trials, the assumption that cognitive behaviour therapy and graded exercise therapy are “safe” is premature.2,4,5 I work in a voluntary capacity for the Irish ME/CFS Association.
Tom Kindlon [email protected] Irish ME/CFS Association, PO Box 3075, Dublin 2, Ireland
1
2
3
4
5
White PD, Goldsmith KA, Johnson AL, et al, on behalf of the PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011; 377: 611–90. Ioannidis JP, Evans SJ, Gøtzsche PC, et al, for the CONSORT Group. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med 2004; 141: 781–88. 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; 40: 1281–87. Kindlon T. Harms of cognitive behaviour therapy designed to increase activity levels in chronic fatigue syndrome: questions remain. Psychother Psychosom 2011; 80: 110–11. Twisk FN, Maes M. A review on cognitive behavorial therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. Neuro Endocrinol Lett 2009; 30: 284–99.
A very controversial paper was published on March 5, 2011, about treatments for chronic fatigue syndrome (CFS).1 I have suffered from this disease for more than 20 years and have been nearly bedridden for the past few years. I hope that the study will be beneficial for patients with CFS. Surprisingly, patients who participated in the study were young, and their symptoms were mild to moderate. Furthermore, their disease duration was short, and they were still in the process of adjusting to the fact that they had an illness whose cause is not known. Probably, the participants learned coping skills through self-help strategies.2 Cognitive behaviour therapy and graded exercise therapy can be effective for many chronic diseases other than CFS. As this study showed, it is reasonable that cognitive behaviour therapy and graded exercise therapy are effective for CFS. However, whether these treatments will be effective for patients with severe CFS who need medical support remains unknown. I am concerned that this study might lead to further misunderstanding of this disease.
Published Online May 17, 2011 DOI:10.1016/S01406736(11)60686-7 See Editorial page 1808
Published Online May 17, 2011 DOI:10.1016/S01406736(11)60684-3 See Editorial page 1808
1833
Published Online May 17, 2011 DOI:10.1016/S01406736(11)60681-8 See Editorial page 1808
health condition (unfortunately, only means were published): “No disease/ current health problem”: 11·2; “Past or current disease”: 12·1; “Current health problem”: 12·5, and “Disease and current health problem”: 14·2. Furthermore, 17·6% of chronic fatigue syndrome patients diagnosed at the Chronic Fatigue Unit (South London and Maudsley NHS Trust) had a score of 18 or less before they were treated.4 This suggests either that the Chronic Fatigue Unit diagnoses and treats fatigue problems in patients with normal levels of fatigue or, alternatively, that the threshold of 18 to represent normal fatigue is not suitable. Given this information, and the fact that those with a Chalder fatigue questionnaire Likert score of 18 could still meet the trial’s entry criteria (bimodal score of 6 or more),1,3 it would be good if White and colleagues would now recalculate the data using the original definition of “fatigue caseness”.2,3 I declare that I have no conflicts of interest.
Sarah M Feehan, on behalf of the Liverpool ME Support Group [email protected] Liverpool ME Support Group, Bootle, Liverpool L20 9LD, UK 1
Published Online May 17, 2011 DOI:10.1016/S01406736(11)60685-5
2
See Editorial page 1808
3
4
5
1832
White PD, Goldsmith KA, Johnson AL, et al, on behalf of the PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011; 377: 823–36. Chalder T, Berelowitz G, Pawlikowska T, et al. Development of a fatigue scale. J Psychosom Res 1993; 37: 147–53. 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. BMC Neurol 2007; 7: 6. Cella M, Chalder T. Measuring fatigue in clinical and community settings. J Psychosom Res 2010; 69: 17–22. Loge JH, Ekeberg O, Kaasa S. Fatigue in the general Norwegian population: normative data and associations. J Psychosom Res 1998; 45: 53–65.
I am concerned by the change in assessment method between the published results of the PACE trial1 and the trial protocol.2 Seven secondary outcomes were not reported and there were changes in several of the measures that were reported.1,2 In particular, the protocol stated that those with short-form 36 physical function subscale scores of 65 or less would be deemed ill enough to participate, and that those with scores of 85 or more would be regarded as “recovered”.2 However, the authors have questionably defined “normal” as a score of 60 or more,1 based on general population scores which did not exclude those reporting chronic illnesses. In the cited study of workingage adults,3 the mean physical function score for respondents without longterm health problems was 92·7 (SD 13·1). The mean physical function scores for those aged 75–84 years, including those with long-term health problems, was 57·9.3 The lack of objective data, such as hours employed or actometer results, is problematic, since Wiborg and colleagues4 showed that improvements on questionnaires are not reflected in an increase in activity, as would be expected if the patients had more energy.4 The only significant difference between treatments for the 6-min walking test was for graded exercise therapy. But the increase in walking distance is small when compared to the distance walked by healthy elderly people (mean age 65 years), which was shown to be 631 m (SD 93).5 Unfortunately, the overall results of the PACE treatments were un-
impressive, and with only 41% of patients reporting “positive” change after cognitive behavioural therapy or graded exercise therapy, further biomedical research is imperative. I declare that I have no conflicts of interest.
Andrew James Kewley kewl0001@flinders.edu.au Faculty of Science and Engineering, Flinders University, SA 5042, Australia 1
2
3
4
5
White PD, Goldsmith KA, Johnson AL, et al, on behalf of the PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011; 377: 611–90. White PD, Sharpe MC, Chalder T, et al. 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. BMC Neurol 2007; 7: 6. Bowling A, Bond M, Jenkinson C, Lamping DL. Short form 36 (SF-36) health survey questionnaire: which normative data should be used? Comparisons between the norms provided by the Omnibus Survey in Britain, the Health Survey for England and the Oxford Healthy Life Survey. J Public Health Med 1999; 21: 255–70. 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; 40: 1281–87. Troosters T, Gosselink R, Decramer M. Six minute walking distance in healthy elderly subjects. Eur Respir J 1999; 14: 270–74.
The findings of the PACE trial1 seem impressive, but the discrepancy between the definitions of improvement in the protocol2 and paper requires an explanation. In the paper “clinically useful differences” were defined as 0·5 SD changes in fatigue or physical functioning compared with baseline. However, the criteria for improvement published in the trial protocol were
Trial protocol
Final publication
Fatigue (bimodal Chalder scale)
50% reduction or score ≤3
7% reduction* or score ≤4†
Physical functioning (SF-36 subscale)
50% increase or score ≥75
21% increase‡ or score ≥60
*Clinically useful difference of 2 points (0·5 SD) and mean baseline Likert score of 28·2. †Likert score of ≤18 used by the authors implies bimodal score of ≤4. ‡Clinically useful difference of 8 points (0·5 SD) and mean baseline short-form 36 (SF-36) physical function subscale score of 38·0.
Table: Definition of positive outcome/improvement in the trial protocol and the final publication
www.thelancet.com Vol 377 May 28, 2011
Correspondence
much more demanding (table).2 Use of a cut-off score of 75 on the short-form 36 physical functioning subscale, as originally proposed, would halve the number of “recovered” patients. Moreover, consulting the normative data for the scale reveals that the mean score of 58 after both cognitive behaviour therapy and graded exercise improved a patient’s physical functioning to the level of someone 40 years older than himself.3 Is this a case of “outcome reporting bias”?4 We declare that we have no conflicts of interest.
*Bart Stouten, Ellen M Goudsmit, Neil Riley [email protected] Einsteindreef 67A, 3562 XT Utrecht, Netherlands (BS); School of Psychology, University of East London, London, UK (EMG); and Byways, Chichester Road, Dorking, UK (NR) 1
2
3
4
White PD, Goldsmith KA, Johnson AL, et al, on behalf of the PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011; 377: 823–36. White PD, Sharpe MC, Chalder T, et al, 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. BMC Neurol 2007; 7: 6. Bowling A, Bond M, Jenkinson C, Lamping DL. Short form 36 (SF-36) health survey questionnaire: which normative data should be used? Comparisons between the norms provided by the Omnibus Survey in Britain, the Health Survey for England and the Oxford Healthy Life Survey. J Public Health Med 1999; 21: 255–70. Smyth RMD, Kirkham JJ, Jacoby A, Altman DG, Gamble C, Williamson PR. Frequency and reasons for outcome reporting bias in clinical trials: interviews with trialists. BMJ 2011; 342: c7153.
Peter White and colleagues1 claim that, if cognitive behaviour therapy and graded exercise therapy are delivered as described, they are “safe” for chronic fatigue syndrome (CFS); the CONSORT statement on harms reporting recommends against such claims.2 If few participants are compliant with the intervention, harms-related www.thelancet.com Vol 377 May 28, 2011
data might not be reliable. Both cognitive behaviour therapy and graded exercise therapy are designed to increase activity; however, actometers were not used, so one cannot be sure how many patients were actually more active.1 Analysis of three trials of cognitive behaviour therapy found that activity levels before and after therapy were similar, despite improvements being reported on fatigue and other subjective measures.3 This finding suggests that patients might simply substitute the activity component of cognitive behaviour therapy for other activities;4 if this situation occurred in White and colleagues’ study, we would not have information on the effects of actually increasing activity levels. On the only objective test, the 6-min walking distance, the cognitive behaviour therapy group only improved by 21 m, suggesting that total daily activity might not have increased.1 The average increase for graded exercise therapy of only 67 m leaves open the possibility that many on that intervention did not achieve or maintain increased exercise or activity levels. If, as seems likely, “real-world” graded exercise therapy practitioners expect higher yearly 6-min walking distance targets than a 379 m crawl (or higher weekly increases than 1·29 m), more adverse reactions could occur. Given many patients’ reports of adverse reactions from such interventions, the biological reasons why they might be problematic (eg, abnormalities in muscle and immunological response to exercise), and the fact that adverse reactions are often only noted outside of trials, the assumption that cognitive behaviour therapy and graded exercise therapy are “safe” is premature.2,4,5 I work in a voluntary capacity for the Irish ME/CFS Association.
Tom Kindlon [email protected] Irish ME/CFS Association, PO Box 3075, Dublin 2, Ireland
1
2
3
4
5
White PD, Goldsmith KA, Johnson AL, et al, on behalf of the PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011; 377: 611–90. Ioannidis JP, Evans SJ, Gøtzsche PC, et al, for the CONSORT Group. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med 2004; 141: 781–88. 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; 40: 1281–87. Kindlon T. Harms of cognitive behaviour therapy designed to increase activity levels in chronic fatigue syndrome: questions remain. Psychother Psychosom 2011; 80: 110–11. Twisk FN, Maes M. A review on cognitive behavorial therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients with ME/CFS. Neuro Endocrinol Lett 2009; 30: 284–99.
A very controversial paper was published on March 5, 2011, about treatments for chronic fatigue syndrome (CFS).1 I have suffered from this disease for more than 20 years and have been nearly bedridden for the past few years. I hope that the study will be beneficial for patients with CFS. Surprisingly, patients who participated in the study were young, and their symptoms were mild to moderate. Furthermore, their disease duration was short, and they were still in the process of adjusting to the fact that they had an illness whose cause is not known. Probably, the participants learned coping skills through self-help strategies.2 Cognitive behaviour therapy and graded exercise therapy can be effective for many chronic diseases other than CFS. As this study showed, it is reasonable that cognitive behaviour therapy and graded exercise therapy are effective for CFS. However, whether these treatments will be effective for patients with severe CFS who need medical support remains unknown. I am concerned that this study might lead to further misunderstanding of this disease.
Published Online May 17, 2011 DOI:10.1016/S01406736(11)60686-7 See Editorial page 1808
Published Online May 17, 2011 DOI:10.1016/S01406736(11)60684-3 See Editorial page 1808
1833