The cholesterol drug did absolutely everything it was supposed to do -- except for demonstrably improving the health of the people who took it.
That was the conclusion reached about the popular drug Vytorin in a study published online last week in the New England Journal of Medicine.
The results were a disappointment to the millions of patients who take Vytorin and the thousands of doctors who prescribe it; a blow to its manufacturers, Merck & Co. and Schering-Plough Corp., both of New Jersey; and a surprise to many researchers -- though not all.
The study has raised questions, not only about this particular drug, but about the broader issue of how to treat and prevent heart disease. Here are the answers to some of them.
What is Vytorin?
Vytorin is a combination of two other cholesterol drugs: Zocor, a statin, and Zetia, a non-statin.
Statins work by limiting the amount of cholesterol produced in the liver. They are the only drugs that have been proven to reduce the risk of bad coronary outcomes ( heart attacks, strokes and death).
Zetia works by blocking the absorption of cholesterol from food.
"Vytorin creates a one-two punch," says Dr. Robert Bonow, chief of the cardiology division at Northwestern University and a past president of the American Heart Assn. "It blocks production and absorption."
Why mess with success? Aren't statins good enough?
Statins can have unpleasant, even dangerous side effects, including muscle pain and liver problems. Not everyone can take them. Besides, statins don't always succeed in getting cholesterol levels down to desired levels.
What are the desired cholesterol levels?
They vary from patient to patient. Guidelines issued by the National Cholesterol Education Program are endorsed by the American College of Cardiology, the American Heart Assn. and the National Heart, Lung, and Blood Institute and are widely followed by doctors.
But an editorial in the American Family Physician last year argued that these guidelines are "expensive but not necessarily effective."
The editorial cites a 2006 study in the journal BMJ that compared guidelines in six countries. The cholesterol education program's guidelines lead to treating twice as many patients as New Zealand's guidelines (which were deemed most efficient) without improving mortality rates.
"They have us all on statins," says one of its authors, Dr. Jerome Hoffman, professor of medicine and emergency medicine at UCLA.
What exactly happened in the new study?
The study -- called the Enhance trial -- compared Vytorin to Zocor alone. Vytorin did better at lowering the levels of three undesirables: LDL cholesterol (the so-called "bad cholesterol"), triglycerides and C-reactive proteins.
But researchers found no evidence that it did any better at lowering the big kahuna of undesirables: the risk of bad coronary outcomes.
Enhance didn't actually measure the risk of bad outcomes though. It measured a "surrogate marker" for bad outcomes -- the thickening of artery walls in the neck and leg. Such thickening is caused by atherosclerosis, a disease that can lead to heart attacks, strokes and death.
Researchers expected that patients on Vytorin would have thinner artery walls than patients on Zocor alone. That would have been evidence (though not proof) that Vytorin is better at preventing bad outcomes than Zocor alone.
But artery walls were equally thick for patients on both drugs.
Does that necessarily prove that Vytorin is not better at preventing bad outcomes than Zocor alone?
No. The Enhance study authors, among others, have suggested possible reasons why the trial was not definitive. Here are two:
1. The patients in the study all had extremely high levels of LDL cholesterol due to a genetic condition called familial hypercholesterolemia. It's possible that Vytorin acts differently in patients who have this condition than in patients who don't. Most patients with cholesterol problems do not have this condition.
2. It's possible that thickening of artery walls is not a good surrogate marker for bad outcomes, at least not in patients with familial hypercholesterolemia. (Most of the patients in this study had taken statins previously, and their artery walls were already quite thin. Treating them with Vytorin may have been "like using antibiotics on someone who doesn't have an infection," says Lee Davies, director of global product communications for Schering-Plough.)
"I'm not so strongly on the bandwagon to abandon this drug," says Dr. Stanley Rockson, professor of medicine and chief of consultative cardiology at Stanford University. "There's no evidence yet to say it doesn't work. What we have is no evidence either way."
Should patients who take Vytorin stop taking it?
No. Enhance did not find any safety concerns associated with Vytorin, and experts agree it could be dangerous to suddenly stop taking the drug. Patients who decide to stop taking Vytorin should do so only under their doctor's supervision.
Are there any general rules of thumb for patients to know until they can see their doctors?
Here are a couple from Dr. Ravi Dave, a cardiologist and professor of medicine at UCLA:
1. If you've already tried taking statins, without success, "Don't panic. There's a reason why you're taking Vytorin."
2. "If you took Vytorin from Day 1" -- i.e., if you have never tried any other cholesterol drug -- maybe you should be taking a plain statin instead.
What about patients who take Zetia?
If you've never taken anything else, Dave says, it's possible you should be taking a statin. If you're taking Zetia because you couldn't tolerate statins, it's possible you should be taking a different alternative.
Should doctors continue to prescribe Vytorin?
Here is a general approach advocated by many doctors: Determine the cholesterol level a patient should reach. Try to get there through diet, exercise and statins (if necessary, in combination with other drugs known to be effective when added to statins). Add Zetia only if, after all that, the patient still can't reach the desired cholesterol level.
Is this a change from how doctors prescribed Vytorin before the Enhance results were reported?
"If physicians used Vytorin in the right way to begin with, there should be no change they have to make," Dave says.
Still, judging by Vytorin's popularity, many believe that for some patients, some doctors have been using it as a drug of first choice.
But many experts familiar with this study say doctors shouldn't do that anymore.
How could Vytorin possibly fail to reduce bad outcomes more than Zocor alone when it reduces cholesterol more than Zocor alone? After all, reducing cholesterol reduces the risk of bad outcomes, right?
"There's something called the 'cholesterol hypothesis,' " Hoffman says. "That's the idea that heart disease is caused by cholesterol. But it's not called a hypothesis by everyone. In most of society it's accepted as truth." In fact, he says: "There's no evidence anywhere that fixing your cholesterol helps you as a human being."
But don't statins reduce bad outcomes by fixing your cholesterol?
"Statins do make your cholesterol look 'better,' "Hoffman says. "And in addition, in the right person, they do provide some meaningful benefit in terms of decreasing, by a very little, the chance of a truly bad outcome, such as a heart attack. But these are almost certainly a case of 'true, true and unrelated.' "
Not everyone agrees that improved outcomes are unconnected to improved cholesterol. "To say they're completely unrelated is far-fetched," Rockson says. But he and many others believe statins affect many things, not just cholesterol levels.
Dr. James Liao, director of vascular medicine research at Brigham & Women's Hospital in Boston, has spent the last 12 years studying the non-cholesterol effects of statins, which he called "pleiotropic effects."
One early indication that such effects exist came from stroke studies. All statins reduce the risk of strokes, Liao says. But they don't accomplish that by reducing cholesterol, because cholesterol is not related to strokes.
Some people may be unhappy these days that they've been taking Vytorin. Will there be other studies in which its value might be vindicated?
Another larger study -- called Improve-It -- is underway. The patients in this study are more representative of the general population, Schering-Plough's Davies says. Also, it's a genuine "outcome study" -- i.e., researchers will track actual bad outcomes, not just a surrogate marker for them.
When will this study be completed?
It was originally scheduled to be completed in 2011, but the enrollment of subjects was just recently expanded, and that is expected to delay completion for about a year.
What are the odds that Improve-It will improve on the results of Enhance?
It depends on whom you ask. Schering-Plough's Davies is very optimistic. Liao of Brigham & Women's Hospital is less so.