This is from SOLK.NL De kritiek op de PACE-trial naar effectieve behandelingen bij CVS 24 oktober 2016 4 reacties Auteur: Lineke Tak. Vanuit verschillende hoeken werden we gevraagd commentaar te geven op de discussie rondom de PACE-trial bij het chronischevermoeidheidssyndroom (CVS). In 2011 werd door de onderzoekers gesteld dat de PACE-trial, de grootste behandelstudie bij CVS ooit, een succes was. Patiënten met CVS zouden kunnen herstellen door cognitieve gedragstherapie of graded exercise therapie. Patiënten en patiëntenverenigingen voor CVS uitten echter direct al kritiek. De afgelopen maanden hebben ook sommige wetenschappers zich verzet tegen de in the Lancet gepresenteerde resultaten van de PACE-trial. http://www.solk.nl/2016/10/de-kritiek-op-de-pace-trial-naar-effectieve-behandelingen-bij-cvs/ English translation. Can anyone @Valentijn perhaps be able to translate this better? The criticism of the PACE trial to effective treatments for CFS October 24, 2016 From different angles, we were asked to comment on the debate surrounding the PACE trial in chronic fatigue syndrome (CFS). In 2011, asked by investigators that the PACE trial, the largest treatment study in CFS ever, was a success. Patients with CFS may recover by cognitive behavioral therapy or graded exercise therapy. Patients and patients' organizations for CVS however voiced direct criticism already. In recent months, some scientists have also opposed the results of the PACE trial presented in the Lancet. The PACE trialLet's start with a brief overview of the PACE trial. The rationale for this study by the researchers was described as follows: " Trial findings show cognitive behavior therapy (CBT) and graded exercise therapy (GET) can be effective treatments for chronic fatigue syndrome, but patients' organisaties have Reported That thesis treatments can be harmful and favor pacing and specialist healthcare. We Aimed to Assess effectiveness and safety of all four treatments . " In total, 641 patients with chronic fatigue who were recruited met the Oxford criteria for CFS of six second-line clinics. Four treatments were compared, for which participating patients were randomized: (1) specialist medical care by a physician (SMC); (2) graded exercise therapy (GET) + SMC; (3) cognitive behavioral therapy (CBT) + SMC; (4) adaptive pacing therapy (APT) + SMC.Primary outcomes were fatigue, measured with the Chalder Fatigue Questionnaire, and physical function, measured with an SF-36 subscale. Secondary outcome measures include physical fitness measured by a stress test, return to work and care costs. It was found that after one year the treatment with CGT + + GET SMC and SMC were more effective than either alone or SMC APT + SMC. These treatments also seemed safe, since only 1-2% of all groups occurred severe symptoms (such as critical illness, hospitalization, increased severe physical disability longer than four weeks, self-harm). In addition, it was not known whether these symptoms were severe adverse effects of the treatment effects of CFS or that they acted independently of them (White et al 2011). Later, a follow-up study was published which examined how the results were at least two years to participate. It concluded that the effects of CBT and GET were maintained. Interestingly, the patients from the condition had improved SMC alone or APT + SMC to the same level.Researchers signs that these latter two groups often had followed additional therapies in the meantime (Sharpe et al 2015). Criticism of the PACE trial, there could be written a thick book about all the criticism that has appeared in the PACE trial.Detailed criticism of researchers came ao David Tuller ( link ), Rebecca Goldin ( link ) and James Coyne ( link ). The principal investigators of the PACE trial have also repeatedly responded to the criticism in this link is a representation of the response to criticism of David Tuller. I limit myself to a few most notable criticisms: - 1. Not valid diagnostic criteria . The Oxford criteria were used to establish CFS. This definition focuses on fatigue, and less on exercise intolerance and other associated symptoms. It is feared that possibly patients were enrolled with fatigue and depression. It was also mentioned that patients with CFS according to other possible definitions would not benefit from this treatment, while GET and CBT it would come in the guidelines as effective for every patient with CFS. There is a controversy about the difference between CFS and myalgic encephalitis (ME). Some consider this to be different names for the same phenomenon, others consider ME as a serious form of CFS which also immunological and neurological abnormalities were found. The criticism that the patients with the most severe symptoms (eg completely bedridden patients) could not participate is true. Authors respond that they do not pretend to GET or CBT would help this group; This is also mentioned as early as at the limitations of their paper. - 2. Questionable primary outcome measures. Outcome measures fatigue and physical functioning are entirely based on subjective self-reporting. Actigraphy (measuring physical activity) has been deleted during the investigation and physical fitness were no statistically significant differences between the groups. The researchers defend them self-reporting correctly regarded as an added value, because it is about whether patients consider themselves better.However, patients mention that they are not a scale of fatigue is important, but whether they can do great things again and feel restored. - 3. No blinding possible. Patients obviously knew what kind of therapy they received. Critics of the study suggest that the participants of GET and CBT were more enthusiastic approached with the promise that they would be better and there has occurred a placebo response. However, it should be noted that the degree of placebo response rate in patients with CFS turns out to be correct quite low, especially when they take part in psychologically oriented therapies such CGT (Cho et al 2005). In addition, the researchers mention that in advance of GET and CBT precisely the lowest expectations were among the participants. - 4. Lack efficacy secondary endpoints . There was no statistically significant difference of GET and CBT compared with the other treatment arms on outcomes such as return to work and taking care consumption. Critics of the study are those seen as important measures, but this was not effective. Healthcare costs were correct for all groups higher. - 5. Change of outcomes at long-term follow-up . In the follow-up study in which the effect was observed after two years, the cut-off points were those according to researchers 'recovery' defined adjusted. They describe that they found this clinical cut-off points more valuable and that they have submitted these amendments to have a committee and adjusted before they analyzed the data. Critics doubt this argument and believe that this cut-off (artificial) would lead to increased recovery. In addition, it is appointed as remarkable that all four groups are as much improved after two years, but the researchers did not clearly specify and analyze what therapies have followed patients in the meantime. - 6. Investigators will not release data . There have been many requests to release the data so that they can be independently analyzed. Researchers call that was promised in the informed consent process that personal medical data should be monitored and that this is ethically binding. Eventually they became after various procedures required by the court to release the data. Polarization of the debatein my view it is unfortunate that the debate is so polarized. It seems as if opponents only see shortcomings. It is often put forward as an argument that the authors were more in favor of these therapies and so were biased and wanted to get their way. However, it is equally well known that opponents of each study GET or CBT for CFS, and therefore in their criticism could also be biased. It is on the other hand understandable that some CFS patient groups show great resistance, especially if they have seen people they know with therapies like CBT or GET deteriorated: it emerges from survey studies they hold themselves. In addition, in society there is a stigma attached to CVS (it is wrongly thought to affectation or a purely psychological illness). If therapies as GET and CBT then so hailed as the press took place after the publication of the PACE trial, while these treatments are not nearly effective for everyone, it can lead to further stigmatization ( "It's your own fault if you not better). I think it is striking that the researchers of the PACE trial to defend their research tooth and nail, and do not seem to be very susceptible to the effects of sincere suggested criticisms. This may be a result of the fierce criticism which they were made personally suspect, as if it were criminals. Unfortunately, the PACE trial is often used to settle the debate about what CVS. That does not seem constructive. Researchers who investigate CBT as a treatment for CFS do this because it is one of the known active treatments. CBT is also effective in somatic said diseases such as cancer (Strong et al 2011; Larkin et al 2014). It says nothing about the cause of CFS. In the discussions I read that sometimes studies on CBT or GET be considered a denial of CFS, CFS laziness would be whether it is a mental illness. This is obviously onfundeerd; The cause of CFS is unknown fact.Studies on the effectiveness of a treatment of a disease are in fact independent of the cause. Even though there are patients who have just deteriorated by CBT and GET, these examples can not be used to shoot the therapies as a whole (to draw the comparison again: not every patient with cancer is better to chemotherapy, some are even worse, but that does not mean that the therapy is bad for everyone). In my own clinical practice, I see patients with CFS that are better GET and CBT, which is not scientific evidence. The Way ForwardThe PACE trial was indeed the biggest treats rial at CVS, but not the only one. A Cochrane review found that there is evidence that exercise therapy have a small to medium effect (Larun et al, 2015), as well as another meta-analysis (Marques et al 2015). In both of them was, however, included the PACE trial. There is also a Cochrane review which concluded that CBT is effective for CFS (Price et al 2008), not taken into account the PACE trial was. It should be mentioned that authors of all these reviews to compare the results with each other heterogeneous and difficult found, particularly in the area of long-term follow-up. It would be a great step forward if there would be a consensus CFS research protocol that is widely accepted by various independent researchers and patients. It seems to me at this time namely very difficult to make such treats rial for CVS, given the many possible case definitions and outcome measures. CFS knows many criteria, in addition to the Center for Disease Control and Prevention (CDC) criteria (Holmes et al., 1988), there are also the Oxford criteria (1991), the revised CDC criteria (1994), the London-criteria (1994), the Canadian criteria (2003), the Australian criteria (2004), the standardized CDC criteria (2005), the Nightingale definition (2006), the pediatric criteria (2006), the international consensus criteria (2011) and Institute of Medicine criteria (2015) (Brurberg et al 2014). There are also numerous outcome measures (which in some cases can be both more objectively measured by self-report) in the field of fatigue, exercise intolerance, activity, additional symptoms, physical and mental functioning, cut-off for recovery, medical expenses, return to work, et cetera. In each study primary outcome measures should be chosen, probably always will give debate. ConclusionIt seems that the PACE trial not as a definitive study can be considered, in which the most effective therapy for CFS can be based. For this, there seem to be serious flaws in the methodology, which has called the study too much doubt in the broader scientific community.However, outside of this trial, there are also other studies that effectiveness of therapies based on physical exertion or CGT demonstrated in a part of the patients with CFS. Even though the PACE trial is now considered methodologically questionable, that does not mean that this trial shows that CBT and GET are not effective. Hopefully gradually becoming more known about who GET and CBT can and will not be effective (so. Personalized medicine), or there may have found new treatments.