Tuesday, April 19, 2011

ECMO and logic: Absence of Evidence is not Evidence of Absence

I have been interested in ECMO for adults with cardiorespiratory failure since the late 1990s during the Hantavirus cardiopulmonary syndrome endemic in New Mexico, when I was a house officer at the University of New Mexico. Nobody knows for sure if our use of AV ECMO there saved any lives, but we all certainly suspected that it did. There were simply too many patients too close to death who survived. It made an impression.

I have since practiced in other centers where ECMO was occasionally used, and I had the privilege of writing a book chapter on ECMO for adult respiratory failure in the interim.

But alas, I now live in the Salt Lake Valley where, for reasons as cultural as they are scientific, ECMO is taboo. The main reason for this is, I think, an over-reliance on outdated data, along with too much confidence in and loyalty to, locally generated data.

And this is sad, because this valley was hit with another epidemic two years ago - the H1N1 epidemic, which caused the most severe ARDS I have seen since the Hanta days in New Mexico. To my knowledge, no patients in the Salt Lake Valley received ECMO for refractory hypoxemia in H1N1 disease.

Thus I read with interest the Pro Con debate in Chest a few months back, and revisited in the correspondence of the current issue of Chest, which was led by some of the local thought leaders (and those who believe that, short of incontrovertible evidence, ECMO should remain taboo and outright disparaged) - See: http://chestjournal.chestpubs.org/content/139/4/965.1.citation and associated content.

It was an entertaining and incisive exchange between a gentleman in Singapore with recent ECMO experience in H1N1 disease, and our local thought leaders, themselves led by Dr. Alan Morris. I leave it to interested readers to read the actual exchange, as it is too short to merit a summary here. My only comment is that I am particularly fond of the Popper quote, taken from The Logic of Scientific Discovery: "If you insist on strict proof (or disproof) in the empirical sciences, you will never benefit from experience and never learn from it how wrong you are." Poignant.

I will add my own perhaps Petty insight into the illogical and dare I say hypocritical local taboo on ECMO. ECMO detractors would be well-advised to peruse the first Chapter in Martin Tobin's Principles and Practice of Mechanical Ventilation called "HISTORICAL PERSPECTIVE ON THE DEVELOPMENT OF MECHANICAL VENTILATION". As it turns out, mechanical ventilation for most diseases, and particularly for ARDS, was developed empirically and iteratively during the better part of the last century, and none of that process was guided, until the last 20 years or so, by the kind of evidence that Morris considers both sacrosanct and compulsory. Indeed, Morris, each time he uses mechanical ventilation for ARDS, is using a therapy which is unproved to the standard that he himself requires. And indeed, the decision to initiate mechanical ventilation for a patient with respiratory failure remains one of the most opaque areas in our specialty. There is no standard. Nobody knows who should be intubated and ventilated, and exactly when - it is totally based on gestalt, is difficult to learn or to teach, and is not even addressed in studies of ARDS. Patients must be intubated and mechanically ventilated for entry to an ARDS trial, but there are no criteria which must be met on how, when, and why they were intubated. It's just as big a quagmire as the one Morris describes for ECMO.

And much as he, and all of us, will not stand by idly and allow a spontaneously breathing patient with ARDS to remain hypoxemic with unacceptable gas exchange, those of us with experience with ECMO, an open mind, equipoise, and freedom from rigid dogma will not stand by idly and watch a ventilated patient remain hypoxemic with unacceptable gas exchange for lack of ECMO.

It is the same thing. Exactly the same thing.

Saturday, April 9, 2011

Apixaban: It's been a while since I've read about a new drug that I actually like

In the March 3rd NEJM, Apixaban makes its debut on the scene of stroke prevention in Atrial Fibrillation with the AVERROES trial (see: http://www.nejm.org/doi/full/10.1056/NEJMoa1007432#t=abstract ), and I was favorably impressed. The prophylaxis of stroke in atrial fibrillation is truly an unmet need because of the problematic nature of chronic anticoagulation with coumarin derivatives. So a new player on the team is welcome.

A trusted and perspicacious friend dislikes the AVERROES study for the same reason that I like it - he says that comparing Apixaban to aspirin (placebo, as he called it) is tantamount to a "chump shot". But I think the comparison is justified. There are numerous patients who defer anticoagulation with coumarins because of their pesky monitoring requirements, and this trial assures any such patient that Apixaban is superior to aspirin, beyond any reasonable doubt (P=0.000002). (Incidentally, I applaud the authors for mentioning, in the second sentence of the discussion, that the early termination of the trial might have inflated the results - something that I'm less concerned with than usual because of the highly statistically significant results which all go basically in the same direction.) Indeed, it was recently suggested that "me-too" agents or those tested in a non-inferiority fashion should be tested in the population in which they are purported to have an advantage (see: http://jama.ama-assn.org/content/305/7/711.short?rss=1 ). The AVERROES trial does just that.

Had Apixiban been compared to warfarin in a non-inferiority trial (this trial is called Aristotle and is ongoing) without the AVERROES trial, some[busy]body would have come along and said that non-inferiority to warfarin does not demonstrate superiority over aspirin +/- clopidogrel, nor does it demonstrate safety compared to aspirin, etc. So I respectfully disagree with my friend who thinks it's a useless chump shot - I think the proof of efficacy from AVERROES is reassuring and welcome, especially for patients who wish to avoid coumarins.

Moreover, these data bolster the biological plausability of efficacy of oral factor Xa antagonists, and will increase my confidence in the results of any non-inferiority trial, e.g., ARISTOTLE. And that train of thought makes me muse as to whether the prior probability of some outcome from a non-inferiority trial might not depend on the strength of evidence for efficacy of each agent prior to the trial (self-evident, I know, but allow me to finish). That is, if you have an agent that has been used for decades compared to one that is a newcomer, is there really equipoise, and should there be equipoise about the result? Shouldn't the prior be higher that the old dog will win the fight or at least not be beat? These musings might have greater gravity in light of the high rate of recall from the market of new agents with less empirical evidence of safety buttressing them.

One concerning finding, especially in light of the early termination, is illustrated in Figure 1B. The time-to event curves for major bleeding were just beginning to separate between 9 and 14 months, and then, inexplicably, there were no more bleeding events documented after about 14 months. It almost looks as if monitoring for severe bleeding stopped at 14 months. I'm not sure I fully understand this, but one can't help but surmise that, if this agent truly is a suitable replacement for warfarin, it will come with a cost - and that cost will be bleeding. I wager that had the trial continued there would have been a statistically significant increase in major bleeding with apixaban.

It is one interesting that not a single mention is made by name in the article to a competitor oral factor Xa inhibitor, indeed one that is going to make it to market sooner than Apixaban albeit for a different indication: Rivaroxaban. Commercial strategizing is also seen foreshadowed in the last paragraph of the article before the summary: the basic tenets of a cost benefit analysis are laid bare before us with one exception: cost of Apixaban. Surely the sponsor will feel justified in usurping all but just a pittance of the cost savings from obviated INR monitoring and hospitalizations when they price this agent. Only time will tell.

Thursday, April 7, 2011

Conjugated Equine Estrogen (CEE) reduces breast cancer AFTER the trial is completed?

I awoke this morning to a press release from the AMA, and a front page NYT article declaring that, in a post-trial follow-up of the WHI study, CEE reduces breast cancer in the entire cohort of post-hysterectomy patients, and lowers CHD (coronary heart disease) risk in the youngest age stratum studied.

Here's a couple of links: http://well.blogs.nytimes.com/2011/04/05/estrogen-lowers-risk-of-heart-attack-and-breast-cancer-in-some/?src=me&ref=general


Now why would that be?

One need look no further than the data in figures 2 and 5 to see that it's a Type I statistical error (a signigicant result is found by chance when the null hypothesis is true and there is in reality no effect) - that's why.

For the love of Jehovah, did this really make the headlines? The P-value for the breast cancer risk is....well, they don't give a P-value, but the upper bound of the 95% CI is 0.95 so the P-value is about 0.04, BARELY significant. Seriously? This is one of FIFTEEN (15) comparisons in Table 2 alone. Corrected for multiple comparisons, this is NOT a statistically significant effect, NOT EVEN CLOSE. I think I'm having PTSD from flashbacks to the NETT trial.

And table 5? There are TEN outcomes with THREE age strata for each outcome, so, what, 30 comparisons? And look at the width of the 95% CI for the youngest age stratum in the CHD outcome - wide. So there weren't a lot of patients in that group.
And nevermind the lack of an a priori hypothesis, or a legitimate reason to think some difference based on age strata might make biological sense.

Bad old habits die hard. Like a former colleague is fond of pointing out, don't assume that because an investigator does not have drug company ties that s/he is not biased. Government funding and entire careers are at stake if an idea that you've been pursuing for years yields to the truth and dies off. Gotta keep stoking the coals of incinerated ideas long enough to get tenure!

Sunday, April 3, 2011

If at first you don't succeed, try, try again: Anacetrapib picks up where Torcetrapib left off

I previously blogged on Torcetrapib because of my interest in causality and in a similar vein, the cholesterol hypothesis. And I was surprised and delighted when the ILLUMINATE trial showed that Torcetrapib, in spite of doubling HDL, failed miserably. Surprised because like so many others I couldn't really believe that if you double HDL that on balance wonderful things wouldn't happen; and delighted because of the possible insights this might give into the cholesterol hypothesis and causality. (See this post: http://medicalevidence.blogspot.com/2007/11/torcetrapib-torpedoed-sunk-by-surrogate.html )

I must have been too busy skiing when this article on Anacetrapib came out last year: http://www.nejm.org/doi/full/10.1056/NEJMoa1009744 . You may recall that after Torcetrapib was torpedoed, the race was on for apologists to find reasons it didn't work besides the obvious one, that it doesn't work. It raised blood pressure and does things to aldosterone synthesis, etc. Which I find preposterous. Here is an agent with profound effects on HDL and mild effects on other parameters (at least the parameters we can measure) and I am supposed to believe that the minor effects outweigh the major ones when it comes time to measure final outcomes? Heparin also affects aldosterone synthesis, but to my knowledge, when used appropriately to treat patients with clots, its major effects prevail over its minor effects and thus it doesn't kill people.

This is no matter to the true believers. Anacetrapib doesn't have these pesky minor effects, and it too doubles HDL, so the DEFINE investigators conducted a safety study to see if its lack of effects on aldosterone synthesis and the like might finally allow its robust effects on HDL to shine down favorably on cardiovascular outcomes (or at least not kill people.) The results are favorable, and there is no increase in blood pressure or changes in serum electrolytes, so their discussion focuses on all the reasons that this agent might be that Holy Grail of cholesterol lowering agents after all. All the while they continue to ignore the lack of any positive signal on cardiovascular outcomes at 72 weeks with this HDL-raising miracle agent, and what I think may be a secret player in this saga: CRP levels.

Only time and additional studies will tell, but I'd like to be on the record as saying that given the apocalyptic failure of Torcetrapib, the burden of evidence is great to demonstrate that this class will have positive effects on cardiovascular outcomes. I don't think it will. And the implications for the cholesterol hypothesis will perhaps be the CETP inhibitors' greatest contributions to science and medicine.