Wednesday, January 16, 2008

Now That We've Been ENHANCED--What's the Message?

Since I last blogged about the ENHANCE trial:

...the big news of the week, that I'm a couple of days late commenting on, is the mind-numbing flop of the ENHANCE trial. When Merck and Schering-Plough started to do the usual Pharma tapdance, specifically calling in an expert consultant group to change the trial's endpoints before the results were announced (without the supposed principal investigator even being at the meeting), we all started to predict that the study results were not favorable to the companies' drug, and that skullduggery was afoot to re-spin the results to somehow make the sow's ear look like a silk purse. Few of us guessed just HOW totally disastrous the results actually were, as finally revealed this week-- that the drug ezetimibe (Zetia), added to a statin (as in the combination drug Vytorin), not only failed to improve arterial wall plaque in any demonstrable way, but may even have worsened it.

So what can we conclude from this?

First--we have really come a long way since when I first started seriously looking into Pharma issues along about 7-8 years ago. It was not all that long ago when ENHANCE would have fallen in the forest like the proverbial tree that no one ever hears, and the negative data about the drug would never have seen the light of day, period. By contrast, when Merck and Schering-Plough started playing games, the major media were all over them right away. I have no doubt that the unexpectedly sudden and total release of the negative results this week were a calculated decision by the companies, that the truth was bound to come out sooner or later and getting it all over with as soon as possible was their only possible survival tool. So the world is on to the sheninighans of the industry in a way almost unimaginable a few years ago.

Second--I think (as a very definite non-expert in cholesterol metabolism and heart disease) that this also throws a lot of the cholesterol story into doubt. We already know, as per my previous blog post, that statins do not act as we would expect them to, if the most important risk factor for later heart and vessel disease was a high level of serum cholesterol, and that lowering cholesterol (by whatever means) was therefore effective in preventing later disease. Now we have the added evidence that ezetimibe, another drug which is almost guaranteed to lower your cholesterol level by a significant margin if you take it, is either completely unproven as a heart disease preventive, or else in fact is demonstrably useless (if the surrogate markers used in ENHANCE are reliable). Sounds to me like we need to take the entire cholesterol-risk model in for repairs.

Third--and this is related to #2--we need to stand back and appreciate the subtle ways that pharmaceutical marketing (aided and abetted by other sources of irrational thinking in both medicine and in the popular culture) screws over a thoughtful and scientific approach to disease. Only in hindsight can we see how completely physicians in the US were sold a bill of goods about cholesterol. We were convinced, not simply by company reps but also by official guidelines, by tons of CME conferences, and you name it, that the secret of being a Good Doc is to measure everyone's cholesterol level, and then try to get it down within the pre-set target ranges, whether we tried to do that first with life style changes and only reluctantly added drugs later (the Really Good Doc), or went to drugs right off the bat (the Not Quite So Good Doc). We can now see that in all likelihood, this strategy is nearly worthless when it comes to preventing serious bad outcomes in our patients or extending their lives. But we can also see that it sure sold a whole sh*tload of drugs for the industry. In short, the have-your-cholesterol-level-checked model of preventing heart disease functioned much like the serotonin-deficiency model of depression--excellent for selling drugs, even if the final scientific evidence shows that it is a myth. When they come to write the history of medicine in the last decades of the 20th century, how much of our "science" is going to go onto the trash heap for this reason?

Now-- I just said that we cannot blame the industry solely for this debacle, that other sources of irrationality also played a role. Just what did I have in mind? How about American physicians' tendency on the one hand to rail against so-called "cookbook medicine" when ever some expert wants them to follow evidence-based guidelines, and yet secretly in their heart of hearts to yearn above all else for a cookbook that tells them how to practice medicine? (Who could write a better cookbook than the NCEP cholesterol guidelines?) How about the American public's deep yearning for the magic pill that will allow us to have the double cheeseburger with fries and escape the consequences?

Berenson A. Cholesterol drug has no benefit in trial. New York Times, Jan. 14, 2008.

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