Recently, a healthcare journal based in the United States published a prospective, double-blind, randomized controlled trial (RCT) conducted in Canada on the use of hyperbaric oxygen therapy (HBOT) for patients living with diabetes and chronic, nonhealing ulcers of the lower limb. The study claims HBOT does not reduce indications for amputation among these patients. No screening was performed with transcutaneous oximetry (TCOM) as part of the study to determine whether the wounds were hypoxic, as is the norm in clinical practice when HBOT is considered. Additionally, digital photographs were used to determine the primary endpoint of “amputation,” even though photographic assessment has never been validated as a surrogate for actual amputation — particularly after only 12 weeks of care. The percentage of patients requiring major amputation in this study, as determined by photographic assessment, was many times greater than that reported in other studies. Traditionally, studies evaluating the efficacy of HBOT have used the number of amputations actually performed as the definition of “amputated.” The exceptionally high percentage of “amputations” in this study should have raised concern among the reviewers that photographic assessment might be a misleading surrogate for actual amputations. The results of the trial were also largely irrelevant to clinical practice since a high percentage of the wounds in both groups were Wagner Grade II ulcers. The use of HBOT for Wagner Grade II wounds is not supported by current evidence and is not recommended by the clinical practice guidelines produced by the Undersea and Hyperbaric Medical Society — points that are not addressed in the study.
As a result of these and several other issues I could list, the study suffers from enough fatal flaws to have made it unpublishable in a journal such as Undersea and Hyperbaric Medicine (impact factor 0.76), whose reviewers (I occasionally serve as a reviewer) understand the appropriate clinical use of HBOT beyond that of those affiliated with the journal that published the paper, despite its reputation for publishing scholarly work (impact factor 8.4). Several highly respected physicians have shared with me letters they have written to the editor of the journal that published the study expressing their concerns regarding the design of the study and the validity of its conclusions, but the journal has reportedly rejected all correspondence pertaining to the study to date. This is unfortunate because the journal that published the paper is the appropriate place for this discussion so that the authors can publicly respond to questions, concerns, and/or criticisms. Squashing honest discussion about the possible weaknesses of an important clinical trial is not the way to foster confidence in the scientific process.It did not seem possible to me that a study could have been designed in such a questionable way if a reputable hyperbaric medicine or wound care physician had been involved. It is clear from the credentials of the authors listed on the manuscript that five of the seven are not physicians. Also, the manuscript failed to mention the institution in which the HBOT was provided, which seemed to be a curious oversight, so I looked up the trial (www.clinicaltrials.gov). Ron Linden, MD, a well-known hyperbaric medicine physician with considerable experience in the treatment of diabetic foot ulcers (DFUs), is identified as a principal investigator of the trial. Yet, he isn’t listed among the seven authors. I was curious as to why Dr. Linden was not a contributor to the manuscript, so I contacted him for more information. Dr. Linden told me he alone had provided all the wound care to the subjects in both treatment groups (hyperbaric and non-hyperbaric patients), and the hyperbaric treatments were conducted in a facility that’s listed as a sponsor and collaborator of the study. Furthermore, all study data were collected by a research nurse at the same facility, Dr. Linden said, which means he actually examined all the DFU subjects enrolled in the study.
After publication of the study, Dr. Linden told me he also contacted the journal’s staff to assert his rights as a principal investigator and express his concern that changes to the protocol (which he said he subsequently provided to the journal, and provided to me as well) had not undergone approval by the research ethics board that was previously expected to conduct a review. The methods described in the paper differ in substantial ways from the protocol approved by the academic institution with which the research ethics board is affiliated. Specifically:
- The original protocol required enrolled patients to be examined in person by a vascular surgeon to determine the primary outcome measure (amputation versus limb salvage), but that examination reportedly never happened.
- Digital photographs were substituted for a vascular surgeon’s examination to determine the primary outcome measure of amputation, even though photographic assessment was never approved by the ethics committee as the endpoint of the trial.
- TCOM was required as part of the original protocol, but patients reportedly did not undergo screening with TCOM and this change to the protocol also was not approved.
Some further background is also helpful here. In Canada, healthcare decisions are made at the provincial level. The study in question was conducted in Toronto (Province of Ontario), the most populous province in Canada. It is important to note that included in the “detailed description” of the study is the following information: “… the results of the study will be used to make policy decisions regarding the funding and further utilization of HBOT therapy for people with diabetes mellitus with ulcers of the lower limb in the province.” It is clear the purpose of this study was to decide whether HBOT would be funded for patients living with DFUs in the largest province of Canada.
Dr. Linden informed me that, years before the publication of the paper, he had notified the aforementioned research ethics board (and others) of multiple protocol violations, falsified data, sequestering of research data by one of the authors, and refusal of an author to share trial data when confronted with evidence of misconduct. However, according to Dr. Linden, the only individual who has to date experienced any negative ramifications, since he reported the possible misconduct, is Dr. Linden himself. Dr. Linden said his request for an independent review was dismissed and he has reportedly been exposed to a retaliatory complaint against him by one of the paper’s authors. He’s also seen his 26-year teaching position eliminated.
Impact on U.S. Wound Clinics
Here’s what this means to wound care clinicians and their wound clinic businesses: In the U.S., the current coverage of Wagner Grade III DFUs by the Centers for Medicare & Medicaid Services (CMS) was made largely on the basis of a rather small randomized trial.1,2 Therefore, it is possible CMS could use the negative conclusions in the Canadian study as a reason to withdraw coverage for HBOT of DFUs in the U.S. I was at the meeting with CMS officials in Baltimore when its decision regarding coverage of Wagner Grade III DFUs was made in the spring of 2002. While one additional RCT published since then has demonstrated the efficacy of HBOT in DFUs, a large retrospective study of effectiveness did not. While payers insist on high-level data from randomized trials before they agree to cover treatments, they are willing to withdraw coverage on the basis of lower-level data. Despite the apparent payer bias for accepting negative data, if there really is evidence that HBOT does not improve outcomes in advanced DFUs, then, given our dwindling Medicare budget, those Medicare dollars need to be spent somewhere else. However, if the results of the Canadian study were manipulated by anyone (payer or investigator) to ensure a negative result, not only may many thousands of patients suffer as a result, but the entire fabric of our decision-making process will have been betrayed. Oxygen is not made by a pharmaceutical company, so HBOT has long suffered from a lack of funding for research. Until the publication of the Canadian study, every prospective trial of HBOT in DFUs had shown that HBOT improved outcomes in Wagner Grade III and/or ischemic DFUs. However, all of these trials have been criticized for their small size and short follow-up periods, and for not making a sufficiently compelling case that HBOT is worth the price tag. The recent trial is the first prospective trial of HBOT funded by a national payer specifically for the purpose of making a coverage decision.
As clinicians, we have agreed to use evidence-based medicine as the guiding principle for clinical practice and for payer coverage. If it turns out that a payer can manipulate the results of a trial in order to produce the result they want for payment purposes, and if a respected, peer-reviewed journal (along with its editorial board) is unwilling to shine a light on what happened, then we as an industry will have colluded in one of the greatest betrayals of patient trust since the Tuskegee syphilis study.
This current situation makes me wonder how often medical journals might cover up potential issues of misconduct in relation to a clinical trial. Evidently, this situation is not unique. In his 2006 book The Trouble With Medical Journals, Richard Smith, a British medical doctor and former editor of the British Medical Journal (BMJ), a position in which he served 25 years, provides a shocking behind-the-scenes look at similar situations.3 Dr. Smith believes journals have the responsibility to investigate possible cases of investigator misconduct because, sadly, journals may be the only reason misconduct is ever brought to light. In an article in the Journal of the Royal Society of Medicine, Smith laments the number of times during his tenure as BMJ editor he contacted authorities with concerns of investigator misconduct, only to have his concerns completely ignored by the various academic institutions, funding agencies, and other responsible parties. It appears the kind of character exhibited by Smith at BMJ to doggedly pursue the truth when there are questions of misconduct is unique. One major question requiring resolution in relation to the Canadian study is, “What was the actual outcome of the subjects — was it the same as determined by photographic assessment or something different?” Who can resolve this dispute? Presumably, the patients. I recently participated in a webinar hosted by CMS discussing its “quality measure development plan.” There was a continuous drumbeat for “patient-reported outcome measures” as part of value-based payment reform. There has also been much discussion about the U.S. Food and Drug Administration’s (FDA’s) guidance document on wound healing research that is currently under revision. I mention this because Dr. Linden claims to have irrefutable evidence that many patients in the Canadian study who were allocated to the outcome of “amputated” on the basis of a photograph actually healed. Among HBOT patients, he states 83% of the vascular surgeon’s adjudications were wrong and many wounds healed within weeks of being adjudicated for amputation. In addition, according to Dr. Linden, the paper also did not include the one-year outcome that was part of the approved protocol. When he evaluated subjects at one year, as per the protocol, in the HBOT treatment group 78% of patients were healed and 13% had amputations (mostly minor), and 9% still experienced chronic wounds. In the control group, at 12 weeks there were 40 patients remaining unhealed. As part of the approved protocol, unhealed control subjects could cross over to open-label HBOT and 80% (32 patients) did in fact cross over and received HBOT. More than 60% of those were healed at one year, Dr. Linden said. To view a video clip of an “amputated” patient, visit the online version of this article at www.todayswoundclinic.com/issue. I encourage all readers to watch it and forward the link to colleagues.
Some months ago, during a conference call with an FDA official about the FDA guidance document, I sheepishly asked whether the FDA would like us to just ask patients if they were healed. I felt quite foolish even suggesting this question, but the answer I received was, “Yes, why don’t you just ask patients if they have healed?” What a novel idea! I propose “asking patients what their outcomes are” be included as an endpoint in all prospective RCTs in wound healing. This endpoint needs to be mandatory if our love affair with the RCT as the “highest form of evidence” is going to continue and if payers are going to use the results of these trials to decide whether limb-saving treatments will be available to patients in a province the size of Ontario. Because, apparently, as in the case of the Canadian trial, a picture is not worth a thousand words, and it is certainly not worth a published manuscript in a major U.S. journal.