Monday, January 21, 2008

The ENHANCE study: media hype more than corporate interest trumps EBM!

It’s been a busy week. I haven’t been able to keep up with the dizzying barrage of hyped up soundbites in the wake of ENHANCE. Now that I’ve carved out a little time I’d like to weigh in and try to put the study in perspective. Where to begin? Time constraints don’t allow as thorough an analysis as I’d like to attempt now, so this post may be the first of several on the topic.

I’ll start by mentioning a few of the more thoughtful blog reactions that alerted me to this issue, and with which I partially agree. DB has a series of entries [1], [2], [3], [4] and Retired Doc weighs in with two posts [5], [6].

Despite claims that drug company marketing hijacks evidence based medicine the larger problem, in my view, is the hijacking of EBM by popular media (as happened after the Avandia meta-analysis). If the pharmaceutical industry sat on the ENHANCE results for almost two years as has been reported, it’s cause for concern. In today’s climate you can hardly blame the drug companies, though, for going slow and painstakingly examining the nuances of a controversial study before releasing the information. Once a study like this is out the media salvo (which tends to be adverse to the drug companies) takes over the discussion, stifling reasoned debate, spreading distortion, ignorance and more heat than light. I would submit that in some cases distorted media coverage is worse than no information at all.

So let’s put aside the New York Times for a moment and go to a reliable source. The American Cardiology had this to say in its commentary on the trial: According to the American College of Cardiology (ACC), this study deserves serious thought and follow-up. Yes indeed. But we’ve seen very little of that in the media reaction. The ACC’s summary of the trial contains essential facts for a proper understanding of the issue, largely ignored by the media. It deserves a careful read. I’ll offer a few observations here.

The study patients had familial hypercholesterolemia (FH) with a mean pre-treatment LDLC of 319mg/dl. LDLC was reduced by 41% in the Zocor group (to 188) and by 58% in the Vytorin group (to 134). That’s significant in view of the apparent “shock” that both treatment groups in ENHANCE showed atherosclerosis progression. But it’s not shocking at all. Although there are some conflicting data, previous studies have generally shown that it takes much lower LDLC levels than 134mg/dl to halt atherosclerosis progression. Although an on-treatment LDLC level above which atherosclerosis progression occurs is not precisely known multiple studies (such as this one) suggest it’s around 100mg/dl. Therefore while post treatment LDLC of 134mg/dl in a patient with FH is quite impressive it would not be expected to halt progression.

Although non-progression of atherosclerosis (or, better yet, regression) should predict favorable clinical outcomes and is thus desirable there is no direct evidence that such results are required in order to produce clinical benefit. Multiple lipid trials, in fact, overwhelmingly suggest otherwise. Many trials which achieved more modest LDLC targets than those associated with non-progression (4S, CARE, WOSCOPS, AFCAPS/TEXCAPS to name a few) have been associated with reduction in clinical events.

A New York Times piece egregiously distorted the results of ENHANCE, quoting one cardiologist as saying the results were “shocking” and implying that Vytorin caused atherosclerotic plaque progression to almost double:

The Enhance trial was meant to prove that Vytorin’s combination of Zetia and Zocor would reduce the growth of fatty plaque in the arteries more than Zocor alone. Instead, the plaque actually grew almost twice as fast in patients taking the combination.

There are many distortions and faulty assumptions in the article. First of all, ENHANCE measured carotid intima-media thickness (IMT), a controversial surrogate for atherosclerosis, not atherosclerotic plaques. Secondly, there was no significant difference in the rate of progression between the two treatment groups. At p=0.29, the results of IMT progression difference didn’t even approach statistical significance.

Do the ENHANCE results negate the value of LDLC reduction? Not by a long shot. The evidence that LDLC reduction matters is convincing and includes diet trials, non-statin drug trials and epidemiologic data.

If an ongoing trial fails to show that Vytorin reduces clinical events, that will be shocking. Given what we know now, if I had FH I would do everything I could to reduce my LDLC. If my treatment options were confined to Zocor and Vytorin I would choose Vytorin hands down.


Stem cells bank said...

Very interesting post.

Anonymous said...

xFantastic review. I strongly agree with your following comments:
Indeed the media jumps the gun without regard to fine details such as a trial's design. I agree that the Abstract submitted to the ACC, as well as the ACC summary deserves a careful read. I agree that, as the ACC states, this study deserves serious thought and follow up. No doubt.
I agree with you that it is cause for concern that Merk and S.P. sat on this data for two years.
I also believe that there are some addition causes for even greater concern. Merk and SP attempted to change the endpoints from three arterial measurements to just one of the corotid arteries, after the trial was completed. What was that about? Why did they exclude the leading trial investigator from this decision?
I agree with Dr.Shah of Cedars who said, "This is a good population to study because the patients' condition would get worse in the absence of medicine. So, it should be 'easier' to observe a positive effect by giving them Vytorin." Also, let's not forget that this trial was funded by the Pharm companies that make Vytorin and Zetia. Why would they conduct a study that they even thought for a second would not yield positive results?
If both treatment groups were equal at baseline (IMT of .68mm and .69mm for the Vytorin and Zocor, respectively), then how could the mean change from baseline have been so different from eachother. The Vytorin change was .o111 mm and the Zocor change was .0058 mm. So the change from baseline in IMT did double in the Vytorin group.Statistically significantly different from one another or not, in the real world this difference could matter to our patients. Carotid IMT is a well established measure for assessing the CV risk and extent of atherosclerosis and is a proven independent risk factor for MI and Stroke. The very reason the phrarm companies chose this measurement. MI risk increases 11% for each 1 mm increase in IMT. An IMT above 1 mm equates to a 4 fold greater risk of MI and Stroke. I am anticipating the additional Vytorin trial results due out in 2011, but until then we should yield on the side of caution with further prescribing a drug that is surrounded by uncertainty, especially since there are so many other options for add on therapy. Let's not forget to treat beyond LDL, and for this we have Niacin, and Fenofibrates. In the mean time, for the isolated LDL patient the ACC says that Vytorin is a reasonable option only if a patient hasn't met their LDL goals on a high dose statin. It was never meant for everyone. Additionally, Zetia remains a reasonable option for patients who can't take statins.
In other words, use statins and add-on therapy that has proven results, and as a last resort Vytorin and Zetia are there.

Anonymous said...

Published on

A Failed Attempt to Improve Misperceived Greatness: The ENHANCE Trial

While it seems that pharmaceutical company 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. The trial was named the ENHANCE trial, and possibly this trial was initiated 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 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

Author’s note: What you have read is based upon information and belief. Thank you