There have not been a lot of topics of late that warrant extensive analysis and discussion. But there are a number of little topics of interest, each worthy of a few paragraphs of discussion, archetypes of issues in medicine, science based and otherwise.
Xigirs. No, it is not whale vomit, but close.
Last month Xigris was pulled from the market by Lilly. Yes, I understand the shock. Xigris, we hardly knew ye. Xigris is the brand name for drotrecogin alfa, or activated protein C. It is an enzyme in the clotting cascade that is/was given for the treatment of sepsis.
Sepsis is the syndrome the occurs when bacteria, or parts of the bacteria, get into the blood stream. A large number of mind bogglingly complex physiologic derangements occur, often with refractory multi-organ system failure and death. At a minimum sepsis kills one in three, about 200,000 deaths a year in the US. During my career the best and brightest have looked for interventions that modify the underlying pathophysiology and alter the course of the disease. Besides antibiotics and support of failing organ systems, there had been no breakthroughs in the treatments of sepsis until the PROWESS trial in 2002, published in the NEJM, that demonstrated survival benefit in patients with severe sepsis: 24.7% of patients taking Xigris surviving and 30.8% in the placebo group died.
Although the drug was approved, the vote was split and there was debate about the results from the beginning. Besides the study protocol changing in mid-trial, the survival benefit was only found in post hoc subgroup analysis aka data dredging.
Was it a statistical fluke or the real deal? Well, at up to $20,000 a therapeutic course, Lilly was of the opinion it was of benefit:
Xigris is a proven lifesaving advance for the treatment of adult patients with life-threatening severe sepsis. To imply otherwise in the pages of one of the world’s most prestigious medical journals — 10 months after the FDA approved this therapy based on the strength of our clinical data — attempts to turn back the clock on the treatment of severe sepsis. The opinion article’s assertions serve only to confuse physicians who are attempting to make the best treatment decisions for their patients with severe sepsis, ” says August M. Watanabe, MD, executive vice president of science and technology for Lilly. “We disagree with the authors’ suggestion that we should contemplate denying severe sepsis patients fighting for their lives access to an FDA-approved therapy in order to replicate the proven findings from the largest trial of its kind ever conducted. In our viewpoint, that would be unethical.”
Severe sepsis shows no mercy, so I want to offer my patients every advantage in their struggle to survive,” Greg A. Schmidt, MD, from the University of Chicago in Illinois, says in Lilly’s news release. “There is no doubt in my mind that Xigris, when used appropriately, is an unprecedented, lifesaving advance for this vulnerable patient population.
So, do you want to give our drug despite real concerns about efficacy and safety, or do you just want people to needlessly die? I will defer that question to Ron Paul. Quite the message for clinicians, who, of course, will always err on the side of patient survival. There are times I truly sympathize with the anti-Pharma conspiracy proponents, I really do. So often Pharma companies behave just as one would expect if they were driven by greed with no concerns for patients. So I repeat the aphorism, “Never ascribe to conspiracy that which is adequately explained by incompetence.”
When the drug was released hospitals developed guidelines to ensure that the agent was only used in severe sepsis, those in whom the drug was allegedly effective and where the risk was less than the benefit, since there was an increased risk of bleeding with the drug. My hospitals used less Xigris than other institutions in the Portland metropolitan area, and I heard through the grapevine that it was being suggested we were not providing optimal care since were relatively parsimonious in using the drug. As the years past, more studies were done, none definitive, that suggested Xigris had no efficacy but did have serious complications. As of 2011 the Cochrane review concluded
This updated review found no evidence suggesting that APC (activated protein C) should be used for treating patients with severe sepsis or septic shock. Additionally, APC is associated with a higher risk of bleeding. Unless additional RCTs provide evidence of a treatment effect, policy-makers, clinicians and academics should not promote the use of APC.
Like acupuncture, despite mounting data that Xigris was neither safe nor effective, it’s use continued, although at volumes far less than Lilly would have liked. When the drug was approved, Lilly was mandated to do another study to prove that Xigris was indeed effective and safe. Up to this year about a billion dollars had been spent on Xigris, but no longer, because a new trial demonstrated that yes indeed, PROWESS was a statistical fluke, and that Xigris as no better than placebo for the treatment of severe sepsis. Unlike acupuncture, or any number of SCAM’s, definite trials demonstrating lack of efficacy and safety are, eventually, heeded and Xigris was pulled from the market.
If Dr. Watanabe has any comment now, I can’t find it on the internet; he is evidently retired and Dr. Schmidt has also been silent in the topic.
There are multiple lessons to be learned from this very expensive exercise in medical futility.
1) Don’t trust the results of a single study, especially a study as flawed as PROWESS.
2) Don’t trust the results of a single study whose benefits are only demonstrated in after the fact analysis: post hoc subgroup analysis is not to be believed.
3) This is a good example of the so called decline effect, but is not due to the medications losing effectiveness, but to better designed studies removing potential bias. My rule of thumb, which I discovered in a post hoc analysis, is that in the real world diagnostic tests and therapeutic interventions are only half as good as the published results. Given the minimal effect in the poorly done studies for most CAM efficacy, a 50% decrease in real effectiveness takes even the most robust findings almost to zero.
4) Medical practice changes and ineffective interventions are abandoned. Eventually. That has never happens with CAM.
5) When I was an Intern I carried a NEJM article in my coat on how to interpret Swan-Ganz catheter measurements, and every time I had a patient with a Swan, I would re-read the paper until one day I realized I knew the information in the reference and chucked the paper into the recycler. Swan’s are rarely used today (another change in practice due to evidence), but I would recommend to every resident they carry Why Most Published Research Findings Are False by John P. A. Ioannidis in their lab coat, and read it every time they get excited about a new intervention. To bad Ioannidis was not available when the FDA was approving Xigris.
6) And damn if the whole this doesn’t just piss me the hell off, that so much time and money and potential patient risk was wasted all because of bad science and bio-politics. But of course, if we ignored the bad science and bio-politics and only paid attention to the good science, there would be no Departments of Integrative Medicine.
Dr. Novella, Jann Bellamy, and Orac have discussed the article in Paediatrics on informed consent and CAM. The basic argument is that physicians should give informed consent about those CAMs that allegedly are of increasingly proven value. Not that I can think of one that meets the criteria. The arc of CAM and EBM has consistently been that better designed studies demonstrate decreasing effect until excellent studies show no effect.
The article start with a case designed to tug at the heart strings:
The parents of 6-year-old Jake, a young boy with medulloblastoma, are distressed by the nausea and vomiting he is suffering as a result of chemotherapy. His chemotherapy-induced nausea and vomiting (CINV) occur spontaneously and are also being triggered by sights, sounds, and smells for up to 2 weeks after a course of chemotherapy. His parents believe that this is preventing him from eating properly and that the psychological toll of the adverse effects of treatment are limiting his ability to combat the cancer. They ask Jake’s oncologist about other options to alleviate his nausea. He has tried dimenhydrinate and dexamethasone in addition to ondansetron, but like metoclopromide, they have not provided Jake with sufficient relief. Jake’s oncologist recommended that he continue with nabilone, a synthetic cannabinoid; however, Jake refuses to continue this drug, because it makes him feel dizzy and anxious. Disappointed, his parents resign themselves to the possibility that Jake might not find relief from his CINV.
While communicating online with other families of patients with cancer, Jake’s parents discover that a consensus panel through the US National Institutes of Health (NIH) has recognized the effectiveness of acupuncture for alleviating CINV. They ask their oncologist about it, but his response is noncommittal. Jake’s parents take him out on intermittent passes from the hospital to an acupuncturist in the community. They are delighted to see that his nausea and vomiting are much improved after each acupuncture session. Jake begins to regain his appetite, gains weight, and generally has a better sense of well-being.
Jake’s parents are upset that their physician, whom they believe also had access to information outlining the potential benefits of acupuncture, did not tell them that it was potentially a safe and effective treatment option for CINV. When they describe their son’s improvements after acupuncture, their physician dismisses them as a “placebo effect.” Jake’s parents are concerned that the physician instead offered antiemetic medications that, from their point of view, only created more problems and unnecessary adverse effects.
I would like to offer a more realistic case:
6 year old Jake gets acupuncture, despite the studies that consistently demonstrate that acupuncture is no better than sham acupuncture even for cancer therapy induced nausea and vomiting and that sham acupuncture, such as toothpicks twirled on the skin, has fewer complications.
Because of the suppressed immune system and sloppy acupuncture technique, Jake gets an MRSA necrotizing fasciitis, bacteremia and sepsis that leads to increased vomiting, aspiration, respiratory failure and intubation. Despite aggressive debridement, including limb amputation, he dies of multiorgan system failure, primarily vomiting induced aspiration ARDS.
Oh, says the acupuncturist, it wasn’t my doing.
Due to guilt over inadvertently killing their son by inflicting upon him a dangerous yet worthless intervention, the parents marriage dissolves in a bitter stew of recriminations, infidelity, and alcoholism.
I do agree with one aspect of the authors vignette: acupuncture does have the potential to be safe. It all too often fails to live up to that potential as best I can tell. But effective? Not so much.
There are two studies that compare sham acupuncture with real acupuncture in oncologic nausea and vomiting: one for chemotherapy induced nausea and vomiting and another for radiation induced nausea and vomiting.
Both showed that acupuncture and sham acupuncture were equal in decreasing nausea and vomiting. When an intervention is equal to placebo, the procedure is considered to nothing. The conclusion should be that acupuncture does nothing. Oddly with acupuncture the conclusion is often that both real and sham acupuncture are efficacious. No wait. Xigris was equal to a sham intervention. Therefore they both work. Xigirs need not be pulled from the market, just reposition it as an alternative therapy. Lilly, you can keep the Xigris gravy train running.
To quote the abstract
However, as many as 95% of patients in both groups considered the treatment to be effective, and 89% were interested in receiving the treatments in the future. In the light of the apparent conflict between lack of specific effects from verum acupuncture and large subjectively experienced positive effects it seems interesting to evaluate if acupuncture has antiemetic effects related to nonspecific mechanisms.
and the discussion
Our results indicate that nonspecific factors such as the extra care or the high expectations of positive treatment effects, not the specific characteristics of verum acupuncture, reduced emesis.
Acupuncture needles do nothing. Like all SCAM, the benefits are the evolutionary equal of monkeys picking nits and grooming each other. It is calming. So why risk killing a few children with cancer by sticking them with needles? Would it not be better to harness the power of the lie (and we all lie to our kids, just think Santa) by the parents kissing the boo boo to make it better? And maybe get rid of some nits in the process.
Every city has its alternative newspaper, the edgy, often left leaning, and somewhat soft about science, freebie. In Portland it is the Willamette Week, and being left leaning myself (my youngest son says I am edgy in the same way I am cool. In other words not) I pick up a copy every week. In the November 9th edition there was a 3/4 page article in the Headout section entitled Stare Way to Heaven. The topic does lend itself to plays on word.
I tend towards the left leaning, tree hugging approach to the world so I like the Willamette Week, but I could not tell if the tone of the article was meant to be ironic or a legitimate health care recommendation. I emailed the author of the piece asking and he never responded. Although I want to see it as ironic, I can’t tell. I am old enough that my hipster irony meter no longer functions, and perhaps it never has.
They recommend a visit to Braco, the Croatian gaze healer. What does Braco do? He just stands and looks at you, with what appears to be a kind face and a gentle smile. That’s it. He stands and stares for 5 to 7 minutes and miracles happen, from cancers vanishing to preventing Irene induced apartment flooding. His website specifically says his gaze is no substitute for medical care and Braco denies he is a healer, just a conduit for energies. It is the gazed upon who make all the effusive claims of benefit.
My wife points out I tend to stare at people in public, especially if there have medical anomalies, and I know it is not polite to stare. Unless you are Braco. He is a marathon gazer: “Groups of 50 to 1000 people gather for a healing session and Braco now does twenty sessions a day working 10-12 hours each day at locations across Europe. He is booked with appearances four years in advance.” He charges 8 dollars per person for a 5 minute group gaze, preferring volume purchasing, although the web sites say he does take any of the money for these appearances. I would love to see his tax returns.
There is nothing unique in what Braco offers; it is another form of faith healing, albiet it a minimalist form for the practitioner. Low overhead, minimal exertion, the epitome of the ideal of ‘don’t just do something, stand there.” The explanations for the effects he has on others are the usual vague energies and consciousness raising:
Prof. Alex Schneider explains that “Braco is taking the people up to a higher level of consciousness. During those moments when he is gazing at us, he is lifting us up to this higher level where we can feel who we really are – and this is much more than just our physical body. He brings us home to ourselves!
But today, we have some ideas about the structures in the human nervous system that allow some individuals to affect a “non-local reality” just by mere intention. Although Braco doesn’t consider himself to be the saint of any congregation, he often experiences the states of “inner certainty” that things are taking a certain course. He avoids pointing to the individuals in question because that always creates the flow of unneccesary and counterproductive inquieries that are threatening the positive outcome when it’s already at the sight.
The spontaneous and natural flow of energies is an absolute must. The surrender to “what is” is the most favorable starting point to resolve any complex and seemingly hopeless situation.
It is generally believed that there are two possible ways Braco’s „non-active action“ works. First, it’s the activation of a brain structure now known as The God’s Module and second, the creation of a radical change in spiritual anatomy. Of course, both views are opened for discussion, even more, it is desirable to clarify these ideas in the favor of improvement of the statistics connected to Braco’s work.”
Non-active action. Sounds like what occurs when I ask the boys to mow the lawn. I scoffed when Jacques Benveniste suggested that homeopathic information could be transmitted over the phone lines. It turns out Benveniste was ahead of his time. Braco can live stream his stare or you can watch a You Tube video with the same effect as a personal stare down.
I recently was asked what I thought was the oddest CAM and I answered oscillococcinum. But we have a new winner. And it really isn’t polite to stare.