Wednesday, February 27, 2008

More on ENHANCE: Some On and Off Target Comments

The current issue of JAMA (subscription needed to access on-line) features a commentary by Drs. Philip Greenland and Donald Lloyd-Jones of Northwestern U. on the ENHANCE trial (about which see my post,

The result is sort of like Dick Cheney going quail hunting. You fire away with a shotgun, you shoot some things you wanted to, and maybe some things you shouldn't have.

On target: Two major conclusions about ENHANCE. First, the two docs are prepared to mince no words, and to declare flatly that there was no justification for ENHANCE at all except for company marketing. They argue that such studies simply should not be done, and their academic investigator colleagues should refuse to participate. Second, they point out that major organizations that tried to comment on ENHANCE, to help clarify the issues for the public, became tarred with the conflict-of-interest brush, and such organizations should take this seriously and divest themselves of such conflicts to be trustworthy in the future.

Drs. Greenland and Lloyd-Jones do not say if they are adopting their own good advice. The end of the article lists several significant conflicts of interest for each, with regard to statin manufacturers--which may be pertinent to what follows.

Off target: Here I have my own conflict of interest as I am under personal attack as it were. Drs. Greenland and Lloyd-Jones take great umbrage at the media response to ENHANCE, especially with regard to the suggestion that statins may not be all that they are cracked up to be in preventing heart disease. They regard this assertion as ridiculous and irresponsible and argue that physicians quoted in these "erroneous" media articles (like me) should really get out facts straight before shooting off our mouths. One of the two villainous articles they cite is the one by John Carey in Business Week:

As I have tried to explain in this blog previously (, there is very good reason to doubt that statins are all that good especially for the primary prevention of heart disease (as opposed to secondary prevention, preventing future events in people who have already had hearty vattacks or strokes). Many of my colleagues whose work I rely on in reaching that conclusion were also interviewed by John Carey, and in my view he has a blockbuster lineup of experts that were all quoted in that article (not counting myself of course). Carey also did a fantastic job of explaining for the general public the difficult concept of "number needed to treat," which is the only intelligent way to make sense of most clinical trials research on drugs, so he deserves a gold star for great reporting, not the skunk cabbage that Greenland and Lloyd-Jones shove in his direction.

Greenland P, Lloyd-Jones D. Commentary: critical lessons from the ENHANCE trial. JAMA 299:953-55, Feb. 27, 2008.


Anonymous said...

I just want to note that I saw an article quoting Dr. Greenland as saying that statins are overprescribed.

The Business Week article seemed to be saying that the benefits of statins are unrelated to LDL-lowering. Almost no one believes this. Certainly, Dr. Liao doesn't (just read studies he has published and this will be obvious). Rather, the point is that statins have benefits in addition to LDL-lowering, usually referred to as their "pleiotropic effects." This would include such things as improvement of endothelial function. In the last couple of years, there have been studies done on ezetimibe showing that ezetimibe does NOT improve endothelial function. Landmesser et al., Simvastatin Versus Ezetimibe: Pleiotropic and Lipid-Lowering Effects on Endothelial Function in Humans, Circulation 2005;111;2356-2363. Fichtischerer et al., Differential effects of short-term lipid lowering with ezetimibe and statins on endothelial function in patients with CAD: clinical evidence for "pleiotropic" functions of statin therapy, European Heart Journal (2006) 27, 1182-1190.

The discussion in the Business Week article of NNT was useful. However, the NNT depends on baseline risk. I agree that many people are in a category where NNT is very high, but that does not apply to everyone.

Dr. Hayward does not believe LDL levels are irrelevant for all purposes. He believes that LDL (or HDL and TC) should be taken into account in determining cardiovascular risk (along with other risk factors). He does question titrating statin dose to achieve particular LDL targets, which is an altogether different issue.

I am curious about the following quote attributed to you: "I now see it as myth that everyone should have their cholesterol checked." Can you go into a little more detail on your position? Would you check cholesterol in certain groups or under certain circumstances?

I am not a fan of the drug companies or the way they advertise statins. I agree that there were COIs in the panel that developed the NCEP guidelines. I also note that there were guidelines published last year in Circulation for kids with "high-risk lipid abnormalities" such as heterozygous familial hypercholesterolemia (heFH). The chairman of the writing group had ties to several drug companies. These guidelines set LDL targets that many people would view as overly aggressive, especially for girls. Women with heFH, even if untreated, do not generally have heart attacks until after age 50, unless they have diabetes or are smokers.

By the way, Schering-Plough has applied for a new indication for ezetimibe (Zetia): pediatric primary hypercholesterolemia. I would be opposed to that at the current time.

Marilyn Mann

Anonymous said...

Here's a discussion on NNT:

Marilyn Mann

Anonymous said...

Published on

A Failed Attempt to Improve Misperceived Greatness: The ENHANCE Trial

While it seems that sponsors of clinical trials usually end up with results that clearly favor their meds studied in their trial, there are rare exceptions, and Merck and Schering proved that with their disappointing ENHANCE Trial, which many have heard about through the media not long ago. The drugs studied were Vytorin, which was compared with Zocor
Vytorin is a combination med for high cholesterol and contains Merck’s Zocor, which is now generic, and Schering’s Zetia, which works differently than Zocor, which is one of many statin drugs. Both Vytorin and Zetia are co-promoted by Merck and Schering. So, several years ago, an outcomes study was initiated to prove superiority of Vytorin over Zocor as monotherapy. The trial was named the ENHANCE trial, possibly because Zocor is generic now, and not a priority from a profit paradigm of its creator.
After several years passed, a disappointment arrived for the sponsors of this trial, which was first brought to the attention of Schering in March of 2007, yet the results existed since the spring of 2006, I believe upon information and belief.
The disappointment is that Vytorin lacked anticipated benefit or superiority over Zocor. Since about 1 million scripts were written for both Vytorin and Zetia every week in 2007, combined with what I believe was about 5 billion in revenue for these two drugs that year, this was a problem for the drug makers, meaning a fear of shareholder reaction. Perhaps for Schering in particular, it was more of a calamity, since over half of their profits and earnings were from these two drugs with Schering, I understand.
Being the responsible corporations both companies are, of course, alterations occurred after such events were discovered that fractured numerous rules and regulations with clinical trials, possibly in illegal and unethical tactics.
The trial sponsors delayed the release of the trial results for secrecy reasons, it has been speculated. Results from the trial existed, yet were not disclosed at the time of their discovery. After several months of possessing these trial results that were only known to the manufacturers, they created or implemented some atrocious tactics to improve the trial’s unimpressive results following the original results of this ENHANCE study. At the end of 2007, the companies changed the primary endpoint of the trial, which is what the results were measured upon during the entire course of the trial. Sort of like sorting cards to make a good hand not dealt to you. Anyway, since their deliberate concealment of these trial results was clearly wrong, to respond to those who asked where the results were actually as they had been anticipated for quite some time, and while such trial manipulation was occurring and results were being kept secret, Schering stated that continued data analysis from the trial results was the etiology for the delay.
With clinical trials, case report forms are used to record data from the trials, and are created in a manner where further analysis is not normally necessary, as such forms are quite clear and often not subject to interpretation as implied by the trial sponsors, one could conclude. So at the end of 2007, both Merck and Schering got the attention of relevant government officials who contacted both companies regarding this ENHANCE trial due to such suspicions on the facts known and presented, and an investigation began into the activities of both companies regarding this trial at that point.
This became a catalyst for the ENHANCE trial results to be finally released at the beginning of 2008, which caught the attention of major media organizations, as expected. In the spring of 2008, a very large cardiology meeting was held, where the audience was told, I understand, to stick with statins due to this trial’s lack of outcomes for Vytorin, when the ENHANCE trial was discussed at this meeting. Furthermore, it has been said that a cardiologist at this meeting also suggested that a moratorium should occur with the utilization of Vytorin by prescribers, since statins are much less expensive, and are highly regarded, as they have been available for a couple of decades, starting with Mevacor in the 1980s. Of course and as expected, Merck and Schering were not pleased, nor were they surprised at the review of Vytorin at this particular meeting. The following month after this cardiology meeting, Schering’s earnings dropped by 48 percent, as I recall. Also during much of this year, Schering in particular blamed the media for amplifying the situation regarding the ENHANCE trial.
Now, these cholesterol drugs promoted by Merck and Schering, Zetia and Vytorin, were aggressively marketed in a number of ways, including investing I believe about 200million dollars in 2007 for DTC ads for these products. To add to this, and soon after both meds were launched, reps from both companies made inferences to doctors about outcomes regarding plaque accumulation and how Vytorin was superior in that area, which, of course, this ENHANCE trial proved it is in fact not the case whatsoever. It did not matter, apparently, to both Merck and Schering that such claims were is entirely void of proof, which is not unique to any pharma rep, in my opinion. No remorse or regret from the makers of these drug makers, either, which did not shock many. Yet what is known now is that these companies, as stated by other researchers, performed junk science with their deliberate manipulation of this ENHANCE trial using such tactics. Also, last year, Zetia and Vytorin had about 20 percent of the cholesterol lowering market. It does not seem that there will be an increase of this percentage because of this scandal. Possibly if they presented the truth, the future of these meds might be better than what is anticipated presently.
Worst of all regarding this ENHANCE trial scandal is the harm caused to both doctors and patients. The ENHANCE trial concerned and confused both of these participants in the health care system. Furthermore, it’s likely they were devastated by being so clearly misled by the marketing of both Merck and Schering regarding the false benefits of Vytorin they were led to believe by the companies that promoted them- the health care providers in particular.
This whole situation is another example of the progressively frequent discovery of corruption of the scientific method by placing profits over the well-being of patients, which harms the well being of patients. In addition, most were shocked by Merck behaving in such a way in particular because of what use to be their excellent reputation as an ethical pharmaceutical company. And this alone shows the progression and infiltration of such damaging ethical atrophy that desperately needs to be stopped and corrected for the sake of others. For the sake of everyone.
Don’t just say something. Have something to say- to the right people, with conviction and with others who share your views.
“Waste no more time arguing what a good man should be. Be one.” --- Marcus Aurelius
Dan Abshear