Moving the Goal Posts to Catch the Ball and Other Hazards of A Chronic Fatigue Syndrome Treatment Trial

When it comes to offering patients high-quality care for a poorly understood disease, solid, well-funded research, medical education, and respect go a long way. In a masterful report today in STAT, Julie Rehmeyer sets the record straight on chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME). She specifically covers the many pitfalls in the landmark UK PACE trial. Rehmeyer is far from the only critic of this research.

The trial serves as a model for how not to conduct a clinical trial and criticism of it has been abundant, as Rehmeyer explains. Worse still, its conclusions that exercise and cognitive behavior therapy are effective have underpinned clinical practice guidelines around the world. That’s a bad thing because the conduct of the trial was questionable, making its recommendations moot and harmful to patients. Read her story. It’s a longread, but well worth the effort.

But I’d like you to take away from this post key problems with the PACE trial. People with ME and their caregivers need all the help and understanding that they can get. Also, many people won’t read Rehmeyer’s piece. Therefore, the more outlets that understand the neglect and misunderstanding about it, the better. Also, this blog is quite interested in the patient point of view on how to be cared for, a topic that remains undercovered and unappreciated. Note well: Rehmeyer and other ME patients add a lot to the discussion and many research scientists agree with her concerns.

 Patient Experience Departs from the Trial

Julie Portrait

As Rehmeyer explains, when she first got wind of the trial, its sheer breadth made it seem potentially valuable. “It seemed like a great study – big controlled, peer-reviewed…,” she wrote. But she delved deeper because the findings did not jibe with her experience and others living with CFS/ME.  She continues: “The hallmark of ME/CFS is that even mild exertion can increase all the other symptoms of the disease, including not just profound fatigue, but also cognitive deficits, difficulties with blood pressure regulation, unrestorative sleep, and neurological and immune dysfunction, among others.”

The trial concluded that graded exercise works – the exact opposite of how patients with CFS/ME describe their endurance. “Staying within my ever changing limits” seemed the safest course for Rehmeyer and others to stop them from spinning down into phenomenal debilitating illness.

The other cornerstone conclusion,  that cognitive behavioral therapy, or training oneself to think positive, become more active, and ignore their symptoms, felt enormously insulting to Rehmeyer and other patients, especially when other science pointed to other clues to what underpins the disease.

What’s become abundantly clear is that besides patients like Rehmeyer, immunologists have identified important patterns in the immune system and physiologists have found “highly unusual physiological changes in ME/CFS patients after exercise,” Rehmeyer points out.

There’s certainly been a long history in medicine of viewing some patients as malingerers, i.e. that they don’t want to get well. Although I haven’t seen Rehmeyer and others discuss this quite this way, I wonder whether the investigators were predisposed to viewing the patients as malingerers. I’ll be honest: I am all for making the best of a situation and trying to look on the bright side, but I am closer to Barbara Ehrenreich here, who wrote the recent book Brightsided: How Positive Thinking is Undermining America. I’ll leave it to others to explore whether the PACE investigators were unfairly biased from the get-go to think cognitive behavioral therapy must work. I am sure that many similar and some different incentives motivate health researchers pinning their hopes on it, but that’s just a hunch.

But when trials like PACE become the quintessential trial for teaching clinical practice guidelines, explanations grounded in science are tossed to the wind or not pursued.

Wouldn’t it be wonderful if research funds were allocated into the pathophysiology of ME/CFS and effective treatments were developed? Slowly, this is starting, and with more attention to the disease, more is bound to come.

PACE Hazards

What’s worse is the highly unorthodox way the trial was conducted. Above, I mentioned moving the goal posts to catch the ball. In midstream, investigators lowered the bar for self-reported recovery. Rehmeyer writes:

“Their revised definition of “recovery” was so loose that patients could get worse over the course of the trial on both fatigue and physical function and still be considered “recovered.” The threshold for physical function was so low that an average 80-year-old would exceed it.”

Rehmeyer also raises questions about the interaction between the researchers and the patients. Specifically, the way patients were asked about their self-reported symptoms also seemed questionable in leading to unfounded conclusions of marked improvement.

It Takes A Movement

To bring you up to date, PACE has been a moving target. Since the trial findings were published in 2011,  patients, scientists, and critics have fought over the merits of the trial in newspapers, peer-reviewed journals, and blogs. The times they are a changing, albeit slowly.

A Freedom of Information Request for the trial investigators to release all the data to patients succeeded in the UK. Alem Matthees, a patient from Perth, Australia, who obtained the data and led the analysis, said that the differences between groups were within the range of chance variation, and indicated no benefit of the therapies.

Together with patients, statistics professors Bruce Levin of Columbia University and Philip Stark of the University of California Berkeley have recalculated “recovery” statistics. In contrast to the study authors’ claims of recovery rates of 22%,

 the new analyses found that only 4% of patients who received exercise therapy, and 7% who received cognitive behavioral therapy (CBT) recovered, while 3% of a no-therapy comparison group did so.

An evidence review sponsored by the US Agency for Healthcare Research and Quality and finished this year, also reveals that PACE and other research into ME is wanting.  “More definitive studies are needed to fill the many research gaps in diagnosing and treating ME/CFS,” write the authors of the systematic review. On key criteria, the evidence to back widespread adoption of recommendations from previous research remains weak.

ME/CFS  is just the kind of topic that the US Patient Centered Outcomes Research Institute (PCORI)might support, if patients mounted a successful campaign for it as a priority topic.

A movement has grown and patients have every right to be indignant. All along the way, proponents of the trial have raised questions about tactics and anger coming from irate patients. But patients have been largely helpless and disrespected until now, and quibbling about their tactics sounds like a side show.

On September 27, rallies are being organized in 25 cities around the world to press for research funding for ME/CFS. The battle to garner attention to this poorly understood illness is moving forward.





Appendicitis in America: Time for Practice Change?

Chances are good that most readers have had personal experience with appendicitis. Appendectomy is the top inpatient surgery for kids and it far outpaces all other pediatric surgeries. Also, appendicitis is the most frequent reason adults make it to the emergency room. When people worry about their healthcare, appendicitis may seem like small change, mundane compared to big worries like chronic or debilitating conditions, and easily fixable by having your appendix surgically removed. Then it’s over.

However, the sheer volume of the surgery, done routinely and automatically in most of America, against new data that point to equivalent efficacy and a lower complication rate with antibiotic medical management for uncomplicated appendicitis make it an interesting case study of how medical paradigms change.

The tide has shifted in Europe towards using antibiotics as first-line, but probably because national health insurance programs use science much more to guide matters of the public health. In the United States, paradigm shifts towards less use of surgery come slowly and with a great deal of resistance from those threatened by the shift.

An Emblematic Case in Point

I became keenly aware of how uninformed most patients are when a friend over 70 years-old called me from the emergency room on a spring Saturday afternoon, telling me a surgeon wanted to operate on him in an hour for uncomplicated appendicitis. My initial reaction was to tell him to wait a minute because I remembered recent journal articles, notably a Finnish randomized trial suggesting antibiotic therapy had a good shot of curing the appendicitis, without the risks of surgery and an extended recovery. Appendicitis can recur in a minority of patients after antibiotic therapy, but carefully managed, one year out, there is usually no recurrence.

My friend, a skeptical medical writer to boot, had indicated that he wanted more information before he was shooed into surgery. I will say nothing more about his story because he has promised a blog post and will let him tell his story. Suffice it to say that he went the antibiotic therapy route and I am pretty darn sure that it would not have entered the picture if we hadn’t suggested it.

Decision Aid Research: Enter PCORI

This week, I received an announcement from the Patient Centered Outcomes Research Institute that they were funding research into testing a decision aid to help parents figure out what to do when their child has appendicitis. It’s a step in the right direction, but its ultimate value will depend on how widely it is used in the real world.

Decision aids purport to present the options to patients and/or caregivers so that patients can make the decisions that best suit them, based on their personal preferences, the science, and the uncertainties. In the past, they have been introduced when procedures are widely used, costly, when a paradigm shift in medicine is emerging, and when the best strategy seems debatable. Decision aids have been used for things like deciding what to do in the face of a diagnosis of prostate or breast cancer or whether or not to have joint (hip or knee) replacement.

Decision aids have been linked to more satisfactory outcomes, but I hardly think that they will provide the nexus of change in appendix care. I have seen no evidence that they are even used in the institutions that develop them. Nonetheless, they are a start.

A hellufa lot more public education will likely be needed to shift medical practice. I am sure that Rose Kushner and the women’s movement had more impact on reducing unnecessary total mastectomies than decision aids would have, but all is valuable.

The Decline of Surgery: A Moving Target

Robert Colgrove, MD, Division of Infectious Diseases, Mount Auburn Hospital, and Assistant Professor of Medicine, Harvard Medical school, captured the full measure of the shift towards treating appendicitis with antibiotics, rather than surgery.

“Having most of these managed medically means hundreds of thousands of operations averted in the US alone,” he said. “Along with the demise of routine tonsillectomy, it represents a huge reduction in the fraction of otherwise well children who get an operation.”

It’s not just appendectomies that are likely to decline going forward, but other surgeries are also declining as we move ahead, because medical management is showing advantages in lower complication rates, shorter recovery time, and cost.

But change will be resisted. Take gall bladders. “The most definitive way to manage cholecystitis (an inflamed gall bladder) is with cholecystectomy (removal of the gall bladder), a well validated procedure with over a century of experience to back it up,” Colgrove told me. “The best way to manage it now is very much an open question and a moving target. Classically, most people with acute cholecystitis would go on  to have recurrent and/or chronic cholecystitis, so the argument has been that you might as well just go ahead and take it out.”

Colgrove begs to differ. “As medical management improves, though, it is not at all clear that that is true any longer. Current data suggest that most people with uncomplicated cholecystitis do well with non-surgical management, but it will take a few more years before we really know the long-term implications. This is a big deal, representing a huge change in the management of one of the most common surgical procedures, so it is natural that the medical culture is taking some time to absorb it.”

From my vantage point as a public observer, it bothers me that my friend in the emergency room was set to be routed directly to surgery. When will patient safety people be available to consult with patients, some of whom might have fewer risks with an antibiotic course of action?

There are numerous other issues worthy of public discussion tied to appendicitis in kids and adults, too large for a blog post here.

My computer went belly-up this morning and I wanted this out before my short vacation. I regret the lack of links on this post, more comprehensive attention to the latest research, and the role of excessive imaging in evaluating appendicitis – topics covered previously here.

Please share your point of view in the comments below. We need a movement to move practice rationally forward.





Join Patient-Centered Outcomes Research Institute (PCORI) Dialogue on National Research Priorities Today

Are you interested in participating in efforts to shape patient-centered outcomes research priorities. Then, don’t miss today’s meeting, webcast starting 9:30 am, or via telephone to 800 number line posted below. Got comments for the PCORI people: see submission guidelines. Disclosure: This blog is independent and not part of this effort.

The Patient-Centered Outcomes Research Institute (PCORI) will hold a National Patient and Stakeholder Dialogue on its first draft National Priorities for Research and Research Agenda on Monday, February 27, 2012, from 9:30 a.m.-5:00 p.m. EST, at the National Press Club in Washington, D.C.


View Webcast

The event will dedicate three and a half hours to receiving public comment, and include presentations by PCORI and a roundtable discussion involving patient advocates, clinicians and others from the health care community.

Individuals can register to attend and provide public comment here. A webcast and teleconference will be provided. A portion of the comment period will be reserved to receive input from individuals participating by phone.

Advanced Registration is now closed, as of February 23, because the event space has reached capacity. The webcast will remain open to the public. You do not need to register in advance to view the webcast.

The event webcast will feature full audio through your computer so there is no need to call in to the teleconference if you are watching online. We strongly encourage individuals with internet access to watch the webcast to keep the phone lines open to those who do not. You can access the Monday’s webcast here.

To listen to the event by telephone call: 800-704-5185.

The National Patient and Stakeholder Dialogue supports PCORI’s public comment period on the national priorities and research agenda and provides individuals an opportunity to speak directly to PCORI in an open, public format.

Guidelines for Public Comments

Clarification: Patient-Centered Outcomes Research Meeting Set for Two Days, One Evening

My earlier post neglected to mention that this meeting will take place on Monday, May 16th and May 17th. Unfortunately, the Discussion Forum was on a separate announcement. It will still take place, but you may want to attend all or part of the rest of the meeting. Draft agenda is listed below.
If you are a patient and plan to attend, consider letting me know at patientpov “at” gmail “dot” com. I’d like to get your take on this meeting. I may be interested in guest posts.

Patient Centered Outcomes Research Institute, May 16-17, 2011, New York City

Board of Governors Meeting
Millennium Broadway Hotel New York
145 West 44th Street, New York, NY 10036-4012

Draft Agenda

Monday, May 16, 2011
1:00-1:10 pm Welcome and Approval of Jan. Board Meeting Meeting Minutes
1:10-1:45 pm Presentation and Discussion of Mission Statement and Logo
1:45-3:15 pm Program Development Committee Report
3:15-3:30 pm Break
3:30 to 4:00 pm Public Comment Period
4:00 to 5:30 pm Methodology Committee Report
5:30 pm Adjournment

Monday evening, May 16, 2011 – RSVP requested

Discussion Forum (see above link)

Tuesday, May 17, 2011
8:00 – 8:45 am Finance and Administration Committee Report
8:45 – 9:15 am Consideration of and Vote on Budget
9:15—9:45 am Public Comment Period
9:45 – 10:15 am Break
10:15-11:30 am Public Affairs and Communications Committee Report
11:30-11:45 am Wrap-Up and Adjournment

All of the above sessions are open to the public. Individuals only need to RSVP to the evening session. If you want to issue a public comment on the day of the event, you can sign up to speak on-site the day of the event or can provide PCORI advance notice of their intent to speak by emailing