What the Zetia controversy means to most of us
PharmaGossip: More on ENHANCE - the case of the shifting endpoint
The controversy has arisen from Merck/Schering-Plough’s failure to date to publish or present in full data from a trial that started in 2002 and was completed in April 2006. While the joint venture put the delay down to technical difficulties – notably, the need to examine more than 40,000 scans of the arterial intima-media thickness (IMT) of patients’ carotid and femoral arteries collected from 18 multinational study sites – some observers inevitably concluded that the companies had something to hide.
As PharmaGossip indicates the New York Times is fueling a controversy over Zetia that now has spilled over into Congress. Initially, the story simply concerned delay in publishing results from ENHANCE, a Phase 3 study of 700 subjects with a genetic form of hypercholesterolemia, which was completed in April 2006. Merck and Schering-Plough chalked up the delay to complicated logisitics analyzing 40,000 IMT scans. Now, the Times is implying that the Merck/Schering-Plough alliance might have purposely delayed publication of studies, including ENHANCE, that might contain information indicating a liver toxicity problem with Zetia.
By way of full disclosure, I have no personal financial relationships with either Merck or Schering-Plough, but my employer might. I’ll also state that I have been medicated with statins for many years and began using Zetia shortly after its U.S. launch. I’ve personally had no problems with the drug and continue using it at its maximal recommended dose daily in combination with a statin at its maximal recommended dose. It has effectively reduced my LDL-cholesterol by around 20% over statins alone.
Published data on Zetia is plentiful, although more is always welcome. The reports of a complete lack of public results from the ENHANCE study, however, are correct. There are no data, published or simply posted in the PhRMA’s clinical study results registry, from ENHANCE (search ZETIA with and without the registered trademark symbol if you look for it on the PhRMA results website). Should Merck/S-P eventually be proven to have purposely delayed publication of this study or to have attempted to rig publication in favor of Zetia by changing the pre-specified primary endpoint, then shame on them. Those responsible will deserve punishment and public embarassment. If, though, the logisitical nightmare of coordinating the reading and interpretations of the tens of thousands of IMT scans are to blame for a conclusive efficacy read-out, then it’s reasonable to expect Merck/S-P to delay both a peer-reviewed publication and any public release of safety and secondary endpoint results as well, so as not to provide a false impression of the benefit to risk ratio in this study population.
I think I can speak for most people who use and prescribe Zetia when I say that we would love for Merck and Schering-Plough to study hard outcomes (MI, death, stroke) with the combination of Zetia and maximal doses of statins versus statins alone in high-risk patients. In the meantime, we rely on reductions in LDL-cholesterol as an unproven surrogate marker for the particular mechanism of action of Zetia (reduced intestinal cholesterol absorption), hoping that reduction in LDL-C with Zetia will offer benefits similar to those of statins alone. The ENHANCE study will offer little additional evidence of efficacy, or lack thereof, to the majority of Zetia users who more closely resemble me than the subjects studied in ENHANCE. Whether Zetia reduces or leaves unchanged carotid IMT compared with statins alone will not change my decision to use the drug in the hope that it is reducing my risk of MI. Likewise, the drug has not adversely affected my liver, so I will not stop using it if ENHANCE shows that some patients with heterozygous familial hypercholesterolemia experience liver damage while using it. Only if ZETIA increases IMT significantly in this population would I think consider stopping it.
I, like many people at high risk for heart disease, need help keeping my LDL-C in a safe range, and Zetia plus statins is the only reasonable choice for me at the moment. Clearly, people in my position need more choices. We could benefit from more information on the long-term effects of Zetia too. But the results from ENHANCE and other “hidden” Zetia data (that have been reviewed by regulators) are unlikely to be of any consequence for all but a small percentage of Zetia users.
January 15th, 2008 at 10:36 am
[...] See my prior post on the implications of ENHANCE for most current Zetia users. As I indicated previously, these results will likely have very little impact on prescribing of Vytorin or Zetia, despite pronouncements to the contrary yesterday, primarily from Steve Nissen of the Cleveland Clinic. Dr. Nissen apparently gave lots of interviews yesterday, saying things like: This wraps it up…That’s all there is. There just isn’t any evidence that adding ezetimibe to simvastatin produces any advantage. [...]
March 5th, 2008 at 2:49 pm
[...] The other chosen example, Vytorin, is another poor one to use against the choice of a surrogate to claim eficacy. As I’ve explained in an earlier post, the ENHANCE study did not establish the lack of efficacy of Vytorin or Zetia, as Sen. Grassley implies. It merely demonstrated that in a highly selected population of patients with atypical hypercholesterolemia, the use of Zetia with statin failed to reduce progression of carotid intimal thickness, itself an unproven surrogate measure for the outcome of cardiovascular death or disability. Genuine cardiovascular outcomes studies with this class of drug are underway. [...]