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Study Poses New Questions About Cholesterol Drugs

January 23, 2008 at 6:40 PM EDT
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The makers of the cholesterol drug Vytorin pulled its telelvision ads off the air on Tuesday, after a study found the drug was no more effective at reducing the risk of heart attack than one of its generic counterparts. Two doctors offer perspective on the study and the use of cholesterol-lowering drugs.

JIM LEHRER: Health story number two: new questions about drugs to lower cholesterol. Gwen Ifill has that story.

GWEN IFILL: More than 13 million Americans rely on prescription drugs to keep their cholesterol in check. But a new study raises questions about the effectiveness of one of the most heavily marketed of these remedies, Vytorin.

The pill combines two anti-cholesterol drugs, an older one called Zocor and a newer pill, Zetia.

VYTORIN AD NARRATOR: A healthy diet is important. When that’s not enough, adding Vytorin can help.

GWEN IFILL: According to the television ads, Vytorin lowers bad cholesterol. Its manufacturers say it also prevents the buildup of fatty plaque in the arteries of patients with high cholesterol. The more plaque, the greater the risk of heart attack.

The drug’s manufacturers, Merck and Schering-Plough, released the findings of a 2006 report just last week. Their clinical trial, conducted on 720 patients, was meant to show how well the drug worked by lowering so-called bad cholesterol.

But the report also revealed Vytorin worked no better at preventing plaque buildup than a high dose of Zocor alone.

Yesterday, the drug’s manufacturers announced they’d pull their TV ads. They have also taken out full-page ads to reassure patients, reading, “All of us at Merck and Schering-Plough proudly stand behind the established efficacy and safety profiles of Zetia and Vytorin.”

Vytorin and Zetia have combined annual U.S. sales of $5 billion.

Now, for some help in understanding this study and the role of cholesterol, we turn to Dr. Susan Bennett, director of the Women’s Heart Program at George Washington University Hospital; and Dr. Harlan Krumholz, professor of medicine at Yale University School of Medicine. He’s also the director of the Center for Outcomes Research and Evaluation at the Yale New Haven Hospital.

Welcome to you both.

Study exclusive to carotid arteries

GWEN IFILL: Dr. Krumholz, can we start with the basics? What are statins? What is it that we're talking about here?

DR. HARLAN KRUMHOLZ, Yale University School of Medicine: Statins are some of the most commonly prescribed drugs to lower cholesterol. They interfere with an important enzyme, a protein that's used in the manufacture of cholesterol.

So this drug interferes with the manufacture of cholesterol, and is very effective in lowering cholesterol levels, and is also very effective, we know, in reducing the risk of dying, of increasing survival, and reducing the risk of heart attacks.

So these are drugs which interfere with the biochemistry of the body to lower cholesterol levels and seem to have very beneficial effects for people that take them.

GWEN IFILL: And, Dr. Bennett, these new drugs or this new combination of drugs in Vytorin were supposed to do the same thing but a different way?

DR. SUSAN BENNETT, George Washington University Hospital: The Zetia is the other drug in the combination. Vytorin and Zetia essentially blocks the cholesterol that we eat from getting taken up into the intestines and then into the bloodstream.

So it works in a different pathway. And they're very effective as a booster medication when used with statins to really get that LDL to come down nice and low.

GWEN IFILL: So what is the warning that we see in this report?

DR. SUSAN BENNETT: You know, I think this has to be taken into context, in that this is a relatively minor study. It is a small study. It looked as an endpoint at the thickening in the carotid arteries, the big arteries in the neck.

And, of course, what I want for my patients is I want them to have less heart attacks, less need for stent, dying of less cardiovascular disease. And this surrogate endpoint, while an important marker...

GWEN IFILL: What do you mean by "surrogate endpoint"?

DR. SUSAN BENNETT: This endpoint that the carotid artery is getting less thick is nice to know, but to me I really want to know the hard facts: Are my patients having less heart attacks and strokes?

And by looking at the carotid artery, they were looking at essentially a substitute outcome. And it being a relatively small study, I think it raises some questions that are important to look at.

It raises questions of: Should we be using Zetia along with statins? Is it just as effective in helping our patients in the long term? And those studies, those larger clinical trials really have not been done yet.

Drug works in the short term

GWEN IFILL: Dr. Krumholz, are we saying in this report that perhaps these drugs might be reducing the immediate problem, but not reducing the outcomes, that is, whether people actually die or not?

DR. HARLAN KRUMHOLZ: Right, Gwen, there's something really important here, I think, about this study. And I agree with Susan. The study is not definitive in any way.

But it's a mistake to think that the fact that this study is not definitive means that it didn't convey some important information to us. This drug, in combination with statins or by itself, makes your lab report look better. There's no question about it. Your cholesterol will look better on this drug than the drug by the statins by themselves.

But the question is: Does this drug actually improve your life? Does it improve your likelihood of survival? Does it reduce your risk of heart attacks? And this is something we're a lot less certain about.

What this study really did was reinforce the current guidelines, what people are saying now and before this study, is that statins should be the key drug that is used to treat high cholesterol.

It's the drug for which we have the most evidence. It's a drug for which we have the most certainty. It's one of the most remarkable breakthrough drugs of our generation.

Time and time again, it's been shown that this drug used to reduce cholesterol has improved the lives of patients. And we have maybe almost 70,000 or 80,000 patients who have been studied in this way.

Now, this other drug was produced and is probably best used for people who can't tolerate statins or can't be increased in dose of statins without having some problem with them. And in that case, it's reasonable, it seems plausible that if you lower their cholesterol with this other drug...


DR. HARLAN KRUMHOLZ: ... that it would be beneficial, but we're a lot less certain about that. That's the key point. And this drug reinforces that uncertainty, because it did not provide any evidence that lowering it with this extra drug is beneficial.

GWEN IFILL: Another question, Dr. Bennett, about this report. The people, the 720 people who were in this report, they all had a higher risk, didn't they?

DR. SUSAN BENNETT: They had very high cholesterol levels. They were really the people with super-high cholesterol levels. And that population is a relatively small population that we treat.

I mean, I think one of the other things that we need to focus on is that, you know, there are over 800,000 people dying of heart disease and stroke every year. And many of those deaths, when we look at controlling blood pressure and controlling cholesterol, among other things, stopping smoking, if we were really good at controlling all those risk factors, we could reduce heart disease and stroke by over 80 percent.

The statins, as Dr. Krumholz said, are a mainstay therapy. We have the most data about statins. And if anything, I think we're probably not giving higher risk patients the benefit of statin, in particular, not getting them to goal, which is a struggle for some patients.

Company slow in releasing report

GWEN IFILL: Dr. Krumholz, we saw those ads that we're all so familiar with for these products. And I wonder how much of the prescription, $5 billion business, of these products has been brought about in doctors' offices because of that kind of marketing, rather than because of evidence that they influence outcomes.

DR. HARLAN KRUMHOLZ: I think that there are two stories here. I mean, one story is about this particular drug. And I think the message for people is that, really, the statins should be the things that they should be on first. And if they can't tolerate them, then these others are beneficial.

I do want to note there's one thing that's important to understand: There was no direct harm that was found from the Vytorin. So there really should be no reason for panic.

But what the message is, is the regimen that includes these new drugs that were marketed so strongly, is it the best regimen? Is it the best strategy for patients? And I think many of us are questioning that, thinking that statins are the most important.

The other story is whether or not doctors and their patients are really paying attention to the evidence or being influenced unduly by marketing. To get to $5 billion a year, it seems likely to me that many people are opting for this combination or for this drug first and that they're being persuaded by very good marketing, but not really focusing on the fact that the evidence is strongest for the statins.

And I agree with Susan. Our big-picture thing is that we need to do better on risk factors, but it may make a difference how you get those risk factors improved. And it may make a difference how you lower your cholesterol.

And the evidence is for statins now. And I would be very pleased if we would have evidence about ezetimibe, so that there's another drug I can be very confident about. But right now...

GWEN IFILL: It's just not there.

DR. HARLAN KRUMHOLZ: ... we're not at that point.

GWEN IFILL: Does it concern you at all, Dr. Bennett, that this report was completed in 2006, done by the company, and not released until last week?

DR. SUSAN BENNETT: Well, what we have been told is that they've really been working very hard on getting the data out, but two years is quite a long time after a study closes in order to publish the data.

So it does raise some red flags as far as, why was that data withheld? And it impresses the point upon us that we need transparency and clarity when we get our scientific data.

Bypass surgery vs. drug stent

GWEN IFILL: I want to ask you both about another story which we saw today, Dr. Krumholz, which is a new report which is out this evening showing that there may be actually some advantage in going with a heart bypass operation over these drug-coated stents we've heard so much about.

What would you advise people, based on what we see in that report?

DR. HARLAN KRUMHOLZ: You know, this is a study that's likely to get a lot of play, that some people will understand as very strongly favoring bypass surgery over angioplasty.

I think if you look closely at this study -- which is not a randomized trial, it's a study where we're just looking at large populations and trying to draw inferences about which treatment may be better -- you'll see that the rates are relatively similar.

I mean, there's a slight advantage towards bypass surgery. But given the design and the way the study is done, I think what we need to do is emphasize that these are difficult decisions.

Should I undergo angioplasty? Should I be treated with medical therapy? Or should I have surgery? And these should be largely driven by the patient's preferences and goals and an understanding for each individual of what the risks and benefits are.

I do not believe this study should change practice. And I think what it should do is focus us more on these decisions in conversations with patients, trying to understand how they weigh those different options in trying to help them come to the best conclusion.

But the differences were not so large, Gwen, that you would say, "My goodness, we really should avoid angioplasty and start sending people to surgery all the time."

They were enough for us to have conversations with our patients that there might be small differences. Whether those are important depend on the patients.

GWEN IFILL: Small differences, Dr. Bennett?

DR. SUSAN BENNETT: Yes, I agree that the study really did show relatively small differences. But I think the other point to keep in mind is that some patients are just not good candidates for bypass surgery.

You buy a lot of your risk upfront with bypass surgery, in just getting through the surgery. And there are some patients that are just too sick, their kidneys aren't working well, their lungs aren't working well, and the stents really pose a very nice alternative than putting them through tough surgery.

GWEN IFILL: You focus a lot on women's health care and women's heart issues. Does this affect at all what choices women ought to make?

DR. SUSAN BENNETT: Well, I think the whole issue of women and heart disease is that sometimes we don't have the clinical trial data.

Women tend to represent about 25 percent of clinical trials in general. African-Americans, Hispanics represent a relatively small proportion of trial participants, in particular in cardiovascular disease.

And that's one of the big questions we face, is that a lot of the data, when we look at how do women do versus men and other groups versus each other, we often don't have that data initially. And it comes out in dribs and drabs later on. So it would be sure nice to have that data upfront.

GWEN IFILL: Dr. Susan Bennett, Dr. Harlan Krumholz, thank you both very much.