|Zetia and Vytorin: Let's Look at the Facts|
WEB MD - JAN 15, 2008
By Michael Richman, MD, FACS
Let's talk about the current media frenzy about the results of a study that seems to conclude that Zetia may not be effective for treating high cholesterol: the ENHANCE study. After the reports were published, I got a bunch of telephone calls from patients and family who are either on Vytorin or on Zetia in combination with another statin and they want to know about what to do now.
My response to them is to relax, and please read this post. I want to make it perfectly clear that I have absolutely no relationship with Merck in any way but I feel it incumbent upon me to state the facts. As a Cardiothoracic Surgeon, my personal goal is to present my patients with the facts in a clear and concise manner and treat them as I would my own family. I went into medicine to save lives, not to be an alarmist and scare the public. The media seems to do that on a daily basis. It is pretty ironic that the same two or three people always seem to make comments in the media about every study, many of whom were "sponsored" by a drug company, and seem to always put their own spin on things and never calmly state the facts.
I think that it is time for the media to come to us, doctors who actually treat patients on a daily basis, for our thoughts.
I. What Was Studied
The ENHANCE Study results were released in part yesterday. This study is a Vytorin 80 mg, which is a combination pill consisting of Zocor and Zetia, versus Simvistatin (Zocor) on the effects of IMT. IMT is the amount of thickening of the layers of the carotid artery and is assessed using a type of duplex ultrasound.
Increased IMT means the person is at a higher risk of Cardiovascular events. It is often used as a marker for either progression or regression of Atherosclerotic Vascular disease. Whether this thickening represents early atherosclerosis or a change that parallels atherosclerosis is a subject of controversy.
II. What Wasn't Studied
IMT is not a measure of the amount of plaque that can cause a blockage in the artery. The ENHANCE study was performed in people with severe familial hypercholesterolemia, (high cholesterol attributed to genetic causes) -- a group notoriously resistant to treatment, and a group that has nothing in common with most of the patients seen in a clinician's office.
In the ENHANCE study, there was no statistically significant difference between the treatment groups for each of the primary endpoints including the carotid artery, nor did key secondary imaging endpoints show any statistical difference between the treatment groups. There were also no safety issues with the Zocor/Zetia whatsoever.
One must remember that reduction in risk for cardiovascular events is directly related to LDL cholesterol lowering. Lower LDL cholesterol is better than higher and has this been shown to reduce the incidence of cardiovascular deaths and complications. While statins are first line management, if one is unable to bring their patients to the NCEP goal of cholesterol reduction, the majority of clinical events will not be reduced.
What Should We Learn?
So are we supposed to give up on an FDA-approved therapy, statins and ezetimibe (Zetia), to get to the goal and listen to these hysterical rants from some physicians or should those of us who actually treat patients continue down the same course? I personally believe we should do the latter.
I perform LDL particle testing on all my patients (Go to my website to find out more about Advanced Cholesterol Testing.) This test allows me to individualize treatment in all my patients and follow their progress with LDL particle testing. I believe this is the reason why heart disease is increasing while even more conventional lipid testing is being done. Simply put, people are not seeing the entire picture clearly.
Like ENHANCE, five recent major clinical studies have failed to meet their primary endpoints. Due to improvements in cardiovascular care the individuals in trials receive, it is becoming increasingly harder for clinical trials to meet their primary endpoint.
III. Why Outcomes Matter More than Predictions
Dr Robert Harrington from the Duke Clinical Research Institute pointed out on Heartwire yesterday that the ENHANCE study should not provoke such a strong reaction.
"Dr. Nissen's suggestion about a moratorium on ezetimibe (Zetia) is rather alarmist, given that this was just an imaging study, an imaging study should not change clinical practice. So for me, whatever way it went. I would not have been blown away by results from this trial".
I could not agree with him more. Dr. Harrington is involved with one of the large clinical-outcome trials under way with Zetia.
"Enhance is just a biomarker study. Whatever the results were, even if they had been positive, I would still have said we have to wait for the clinical-outcome trials before making our minds up about this drug. The imaging guys all say these imaging studies are predictive of clinical events, but they would say that, wouldn't they? To prove a biomarker is a true surrogate is actually very difficult, and I do not believe that IMT or IVUS (Intravascular Ultrasound) meet the criteria for surrogate markers in this setting," he said. He added, "So I would say not much has changed. If you liked Zetia before ENHANCE because it lowers LDL, I would think you would carry on using it but if you were of the opinion that you would rather wait for clinical outcome results before prescribing it, the there is nothing in this trial to change your mind about that...To me, these results just raise my interest even more in the clinical outcome studies. They are now going to be even more important."
As I have stated repeatedly in my talks as well as on my message board, all these studies are great but without clinical outcome studies, it is impossible to draw conclusions. I want to point out that Lipitor became one the best selling drugs of all time before any shred of outcome data was released. Where were these alarmists then? Maybe they worked for Pfizer at that time? Who knows?
There is absolutely no prospective data from clinical trials about how raising HDL levels will lower clinical events. Nobody seems to know this yet everyone seems to think that if there HDL is high that is great and they won't have a heart attack or stoke. They do not know that the CDC says that 50% of people who suffer heart attacks have "normal cholesterol".
I beg to differ and that is why I recommend advanced testing on everyone. Advanced testing misses nobody at risk even when their traditional lipid testing numbers were normal. They forget about the true villains which are LDL particles. All the HDL data is from animal studies or population/epidemiologic studies.
I hope this helps to quell some of the panic in the public. I will continue to prescribe Zetia when my patients are unable to meet their LDL goal on statins alone with no hesitation.