This piece first appeared on MedicalProgressToday.com on January 18, 2008.
The disappointing results of the ENHANCE drug trial (more formally, the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression trial), which failed to show any benefit from Vytorin, a combination pill that lowers "bad" LDL cholesterol, have spurred a medical and media frenzy. Cardiologists are no longer confident in a longstanding paradigm: Does lowering LDL automatically translate into reducing cardiovascular events -- heart attack and stroke?
Patients are confused, which is understandable. Even Congress is getting involved, with charges of cover up and bad faith being hurled at the two major pharmaceutical companies who sponsored the trial, with subpoenas being threatened. Is the hysteria justified?
The issues raised by the apparent failure of Vytorin, the Merck/Schering Plough (MSP) "blockbuster" drug, are complex, involving both medical science and pharmacoeconomics.
The trial's design seems simple enough: 720 patients were divided into two equal groups.
¢ One, the control group of 360 subjects, was given only Zocor, Merck's cholesterol-lowering statin.
¢ The 360 in the other group were given Vytorin, a combination of Zocor and Zetia (ezetimibe). (Zetia also lowers LDL cholesterol but via a different mechanism than the statins, which work in the liver: Zetia blocks cholesterol absorption in the intestine.)
The comparative effects were monitored over two years by doing sophisticated ultrasound scans of the carotid arteries -- the main vessels carrying blood to the brain -- and measuring the change in fatty deposits there. The rationale for this: without those fatty changes -- atheroma -- there can be no vascular events, such as heart attacks and strokes. Levels of LDL cholesterol, and "good" HDL, were also measured.
While the findings were released in an unusual manner -- via company press release, as opposed to the more typical journal publication or medical meeting presentation -- the results were clear enough. The Vytorin group's arteries showed a slightly greater amount of fatty deposits than the control group -- even though they had lower LDL levels than the Zocor only control group. While the increase did not rise to the level of significance, there was clearly no benefit. The one silver lining in this cloudy picture: Vytorin was associated with no increase in adverse effects.
There are several caveats to these data that must be considered to give context to this apparently disappointing result. First, the trial patients all had a genetic trait associated with very high LDL levels -- "familial hypercholesterolemia." Therefore, this was a very high risk group, not at all typical of the usual patient needing cholesterol reducing therapy. Indeed, even on highest dose Zocor, their LDL levels did not come down to the range considered optimal for preventing cardiac events. Further, these patients had been on lipid lowering therapy for years before the trial, reducing the likelihood of finding any benefit from new treatments. Also, this was a very small study, and was never meant to be a "gold standard" evaluation. Lastly, while it is thought that fatty deposits are a marker for vascular events, this was not an outcomes study: large-scale trials of Vytorin, seeking actual outcomes -- that is, heart attacks and strokes -- are now underway.
The whole concept of cause and effect related to LDL, HDL, and vascular disease is now undergoing intense re evaluation. The failure, in December 2006, of Pfizer's HDL raising drug, torcetrapib, first provoked unease among cardiologists about whether merely raising HDL would reduce heart risk. Now, there is early evidence that lowering LDL is not necessarily going to prevent arterial fatty deposits. (Maybe statins reduce heart risk by some mechanism other than their LDL effect -- they have several other potentially beneficial metabolic effects.) The results of the large Vytorin trials will also be crucial in deciding about the robustness of the LDL vascular relationship.
As for the economic issue uproar arising, predictably, from activist "consumer watchdogs" and some Congressmen: the media and governmental concern is focused on whether the drug companies withheld the study from the public and from prescribing doctors (not to mention Wall Street) so as to delay the predictable decline in prescriptions, once the news came out. Vytorin is, after all, a multi billion dollar drug, so the stakes are high for its makers.
In fact, the study design was high risk for both companies from the beginning -- with Vytorin already on the market, they didn't need to prove anything to the FDA, and thus MSP had little to gain and much to lose. The primary end point -- changes in arterial plaques -- was also a roll of the dice, with little prior evidence indicating a therapeutic response might reasonably be anticipated.
In all likelihood, the drug makers hoped that they could use the results as a surrogate marker for treatment effect, perhaps avoiding the time and expense of long-term, large clinical outcomes trials. While the net effect will likely be a bump in sales of simvastatin, generic Zocor, as well as other generics, the companies should be lauded, rather than castigated as they have been, for taking the unnecessary risk of a comparative trial.
Both companies emphatically deny holding back the findings for economic reasons. They assert that while this study appears quite simple to superficial inspection, in fact it is an extremely complex one, requiring all the time that it took for analyzing the raw data. They assert that the complexity of evaluating the tens of thousands of specifically designed intra vascular digital images used to measure the tiny plaques required all the time consumed. They had planned to follow the standard process of presenting the data at cardiology meetings in March -- but given the frenzy, they released it earlier.
It should be emphasized that even large scale clinical trials are not infallible. Remember all the brouhaha when the Women's Health Initiative reported, initially in 2002, that women taking estrogen, with or without progesterone, had increased risks of breast cancer and heart disease? But within only four years, re analysis of different sub groups showed that estrogen users actually had a decreased rate of breast cancer; the following year (2007), researchers published evidence of lower rate of heart disease among estrogen users. Prospective, randomized clinical trials remain the closest we can come to scientific truth about treatments -- but in fact, the best test is the test of time.
As for Vytorin, there is no need for an unseemly rush to judgment. Gratuitous advice by some celebrity cardiologists to abandon Vytorin are clearly premature -- in fact, both the American Heart Association and the American College of Cardiology felt compelled to remind doctors and patients not to abandon their treatment plan. Some activists who never met a pill they liked now call upon the FDA to delay all approvals pending outcomes data for new drugs. This overly cautious approach is also clearly unwise -- after all, it took Pfizer over seven years to accumulate outcome data for its lifesaving cholesterol drug, Lipitor, even though its beneficial effect on LDL was known long before that.
Vytorin and Zetia have no significant toxicity, and have been proven to lower LDL. While we wait for more definitive data to emerge, doctors and patients should decide on their appropriate use -- not the media, activists, or even Congress.