Friday, January 18, 2008

Have the Peddlers of Antidepressants (Big Pharma) been Successful in Suppressing Negative Trial Results?

Yes, according to this article in yesterday's NEJM:

Talk about publication bias. According to Erick H. Turner, M.D. and coauthors, the selective publication of only "positive" trials, in addition to publishing in a positive light studies that the FDA considered "negative" leads to a 32% increase in the apparent efficacy of antidepressant drugs, on average (range 11-69%). Once again, profit trumps science, safety, and patient and public health.

What can we do about it? First, reduce by one third the effect size of any antidepressant results you see in an industry-sponsored clinical trial. Next, carefully consider whether whatever [probably modest] effect remains is worth the side effects (e.g., increase in suicide), cost, and nuisance of the drug. Third, prescribe generic agents. Fourth, don't allow pharmaceutical reps to speak with you about new products. Fifth, consider alternative treatments.

I am reminded of a curious occurrence relating to a drug that I think is definately worth the cost, side effects, and nuisance associated with it: Chantix (varenicline) - Pfizer's smoking cessation drug. In JAMA in July 2006,
two nearly identical articles described two nearly identical studies, which shared many of the same authors. What was the intent of this? Why not conduct one larger study? Was the intent to diversify the risk of failure and allow for selective publication of positive results? I'm very interested in any information anyone can provide about this curious arrangement, which appears to be without precedent. Please leave your comments below.

Wednesday, January 16, 2008

Is the American College of Cardiology (ACC) Complicit with Big Pharma (Merck and Shering-Plough)?

I am reminded of the surgical attending at Johns Hopkins who (perhaps apocryphally) would scream at the intern in the morning when a patient had done poorly overnight:
"Whose side are you on, the patient or the disease?!"

And I ask the ACC, "Whose side are you on? Patients' or Big Pharma's"?!

Their main web page now links to this statement:
which states:
"The American College of Cardiology recommends that major clinical decisions not be made on the basis of the ENHANCE study alone."

Is it really a "major clinical decision" to stop Zetia/Vytorin and take a statin or niacin until the very efficacy of Vytorin and Zetia is sorted out?

I'd say that the ACC and its members need to reconsider the rather major decision they made to support the use of this drug based on surrogate end-points. As with torcetrapib, they're going to have to learn the hard way to take their lashings.

The statement goes on to say:
"The ACC recommends that Zetia remain a reasonable option for patients who are currently on a high dose statin but have not reached their goal. The ACC also notes that Zetia is a reasonable option for patients who cannot tolerate statins or can only tolerate a low dose statin."

Well, that sounds reasonable, but do you really thing that the majority of patients on Zetia or Vytorin are on it because they failed a reasonable attempt to use a high-dose statin? We all know that after it hits the market, a drug is generally prescribed willy-nilly rather than carefully and rationally in selected patient groups. The ACC should know this. Hence my suspicion of complicity.

It bothers me how entrenched the use of these drugs becomes and how hard it is to remove patients from them. This is a serious status quo bias that I have commented upon before. Few physicians would start a patient on Avandia now, but the ones who are already on it get left on it. The same is true, it appears, with Vytorin, and the ACC is contributing to the status quo bias!

The mandate for physicians and the FDA is to prescribe only SAFE and EFFECTIVE therapies. The burden of scientific proof is on the drug companies who are driven by profit to promote these drugs. It is up to physicians to stand between patients' health and the companies' profits and prescribe only drugs that have met the burden of proof. And Vytorin and Zetia have not. Boycott them until the proof is in. Use alternative agents in the meantime.

Monday, January 14, 2008

Vytorin Vanquished: ENHANCE comes out from hiding and the call for a BOYCOTT gathers steam

Merck (MRK) and Shering-Plough (SGP) have finally released the ENHANCE data and they do not look good, neither for MRK and SGP stock prices (both of which were significantly down in pre-market trading!) nor for patients who have been taking ezetimibe as either Vytorin or Zetia - all the trends were in the WRONG DIRECTION (i.e., they favored simvastatin alone) IN SPITE OF robust additional LDL lowering with ezitimibe:
This further evidence that this drug does not influence important clinical outcomes should renew interest in BOYCOTTING ezitimibe in all forms until/unless improved clinically meaningful outcomes can be shown with this agent in properly designed and conducted trials with sufficient transparency.
(Of course, I recognize that Vytorin is Vanquished only in this battle, that others will follow, and that MRK and SGP will say that these "real trials" are still being conducted, as if they funded ENHANCE for no good reason, and as if, had it been a postive study, they would have downplayed its significance and emphasized cautious interpretation of the results, pending completion of the "real trials".)

Friday, January 11, 2008

Jumping the Gun with Intensive Insulin Therapy (Leuven Protocol):How ICUs across the nation rushed to adopt a therapy which is probably not beneficial

In this week's NEJM is an anxiously awaited article about intensive insulin therapy in severely septic patients in the ICU:
This business of intensive insulin therapy began with publication in the NEJM in 2001 an article by Van den Berghe et al showing a remarkable reduction in mortality in surgical (mostly post-cardiac surgery) patients in a surgical ICU. Thereafter ensued a veritable rush to adopt this therapy, and ICUs around the country began developing and adopting protocols for "tight glucose control" in spite of concerns about the study and its generalization to non-surgical patients who were not being fed concentrated intravenous dextrose solutions....

I vividly remember one of the ICU attendings at Johns Hopkins Hospital, Dr. Jimmy Sylvester, telling us on the morning after the study was published that "this is either the largest break-through in intensive care therapeutics ever, or these data are faked". In essence what he was saying was that the prior expectation of a result as dramatic as demonstrated by Van den Berghe was very low (see also: ). That lower prior probability should have reduced our confidence in the results, and made us more skeptical of the population studied and the dextrose solutions and the applicability to non-surgical patients. Well then, why didn't it?

My colleague James M. O'Brien, Jr, MD, MSc and I have one possible explanation for the rush to adopt "intensive insulin therapy" which we have dubbed the "normalization heuristic." Physicians, for all of our training, remain quite simple-minded. We like simple, feel-good fixes. Normalizing lab values is one of those things. "Make it normal and all will be fine," goes the mantra. We like to make the potassium normal. We like to make the hematocrit normal. We love it when the magnesium increases after we order 4 grams. It's satisfying. And it feels like we're doing some measurable, that is, easily measurable good in the world. Normalizing blood sugars fits that paradigm and makes us feel like we are doing good. But are we?

We have learned the hard way over the years that many of the things we do to "normalize" some surface value causes an undercurrent of harm for patients. Think suppression of PVCs (the CAST trial: ) or transfusion thresholds (the TRICC study and others: ). Oftentimes, it seems, our efforts to "normalize" some value cause more harm than good. It is quite possible that this is also the case with intensive insulin, and that the "feel-good" appeal of making the blood sugars normal in the short term in acutely ill patients propelled us to early adoption of this probably useless and possibly harmful therapy.

(For an analogous contemporaneous story about biology's complexity and defiance of simple explanations and logic such as the normalization heuristic, see:

The interesting thing regarding the "adoption" of Van den Berghe's "Leuven protocol" is that no ICU I have worked in really adopted that protocol. They softened it up, making the target blood sugar not 80-120, but rather 120-150 or some similar range. So what was adopted was "moderate insulin therapy" rather than intensive insulin therapy. Nobody has any idea whether such an approach is beneficial. It's certainly safer. But it has substantial costs in terms of nursing care that might be better spent on other interventions (think sedation interruption).

(I have been highly critical of Van den Berghe's medical insulin article, and my criticisms were published in the NEJM. I was delighted that she did not even address me/them in "the authors reply" - apparently I left her speechless:

So this wonderful article in the current issue by Brunkhorst et al is music to my ears. Rather than hiding the high rate of severe hypoglycemia in supplementary material, Brunkhorst et al come right out and say that not only was the Leuven protocol NOT associated with reduced mortality, but also that it had a very high incidence of severe side effects and that their DSMB had the wherewithal to stop the study early for safety reasons. Bravo!

We await the results of several other ongoing studies of intensive insulin therapy before we nail shut the coffin on the Leuven protocol. Meanwhile, I hope that someone somewhere will design a protocol to test the "moderate insulin therapy" that we rushed to adopt after the first Van den Berghe article as a half-hearted hedge/compromise between our "normalization heuristic", our tempered enthusiasm for the Leuven protocol, our desire to "do something" for critically ill patients, and our fear of causing side effects that result directly from our interventions (omission bias: ).

Thank you, Brunkhorst et al, for testing the Leuven protocol in an even-handed and scientifically unbiased manner and for reporting your results candidly.

Merck and Schering's "Secret Vytorin Panel"

Matthew Herper continues to lead the pack in investigating the shenanigans perpetrated by Shering-Plough (SGP) and Merck (MRK)in the conduct of the ENHANCE trial of Vytorin. I reiterate that it is my strong but measured and carefully considered opinion that this drug or ezetimibe should NOT be used in ANY patients until definitive evidence of efficacy is available, since alternative, more proven alternatives exist. Patients' health should not be risked on this drug. There is too much uncertainty, and too many proven alternatives.

Matthew's article describes more intriguing aspects of this saga, and I couldn't state it any better than he, so I invite you to read his article:

Type rest of the post here