Early findings from the study showed that Vytorin, which combines the unique cholesterol drug Zetia with the older, cheaper statin drug Zocor, was no better than Zocor alone at slowing plaque buildup in high-risk patients.
The full results, released at the American College of Cardiology (ACC) meeting and published online by The New England Journal of Medicine, not only confirmed those findings, but extended them.
"There is absolutely no subgroup [of patients] that either benefited more or had more harm [from Vytorin treatment] than the mean, which is basically zero," says study researcher John Kastelein, MD, of the Academic Medical Center in Amsterdam, Netherlands.
The Vytorin Controversy
Vytorin has been embroiled in controversy since the early findings were revealed in January in a news release issued by drug companies Merck and Schering-Plough, which jointly market Vytorin and Zetia.
Two congressional panels launched investigations into why there was a two-year delay between when the study ended and the release of the results. Critics also accused the companies of attempting to change the endpoints of the study, known as the ENHANCE trial, in an effort to present the results in a more favorable light.
Statins are one of the most widely prescribed drugs used in the U.S. to treat high cholesterol. They include medications such as Zocor, Pravachol, Mevacor, Lipitor, Lescol, and Crestor. They work by actually blocking the body's ability to produce cholesterol.
In contrast, Zetia works only by blocking the absorption of cholesterol in the body.
Vytorin Lowers LDL but Doesn’t Slow Plaque Buildup
It's not that Vytorin doesn't lower bad LDL cholesterol -- it does, by about 50 points in the study. It also reduced blood levels of a marker of inflammation known as C-reactive protein that's been implicated in heart disease.
What Vytorin didn't do is meet the study goal of reducing plaque buildup in the carotid arteries that run through both sides of the neck to the brain. And it hasn't been shown to reduce the risk of heart attack, stroke, or death, although that was not a goal of this study.
In contrast, statins have proven benefit in improving patient outcomes, says past ACC president Steven E. Nissen, chairman of the department of cardiovascular medicine at Cleveland Clinic.
"We know that they reduce risks," he tells WebMD.
‘Turn Back to Statins’
Speaking on behalf of the ACC panel, Harlan Krumholz, MD, a cardiologist at Yale University, says that the publication of the full results leave little room for debate: Vytorin should be used as a last resort.
"There is no new evidence to support use of [Vytorin]. People need to turn back to statins," he told the audience of cardiologists, drawing applause.
"We are all aware that with aggressive marketing, people used Zetia then Vytorin without exhausting the statin option. ... We believe that to get to a $5 billion drug, there was a lot of movement to premature use of [Zetia/Vytorin] before statin use was exhausted," he says.
The ENHANCE trial included 720 patients with a rare genetic condition predisposing them to very high cholesterol.
During the two-year study, patients were treated with high doses of either Zocor or Vytorin.
Vytorin was found to lower LDL cholesterol by 58% vs. a 41% drop for those on Zocor, a significant difference.
But Vytorin users had slightly more plaque buildup in their carotid arteries, although the difference was so small it could have been due to chance.
The ACC panel notes that some other treatments, such as hormone therapy for postmenopausal women, have also been shown to lower cholesterol, but not the risk of heart disease.
Bob Spiegel, MD, chief medical officer of Schering-Plough, tells WebMD that this was just one study.
"We hope doctors will come away from this information saying there was an experiment that failed," he says.
What to Do
So what's a patient to take home from all of this?
First and foremost, don't just stop taking Vytorin, the experts say. Talk to your doctor about any concerns.
If one statin doesn't work, ask your doctor about trying a higher dose or a stronger statin such as Crestor, he says.
If that doesn't work or patients can't tolerate higher doses, it's time to reach for other medications that have proven benefit, says Harvard cardiologist Patrick O'Gara, MD, another member of the ACC panel.
Panel member Joseph Messer, MD, of Rush University Medical Center in Chicago, says he typically starts patients with slow-release niacin. Drugs called fibrates and bile acid resins can also be considered, although the latter can be difficult for some patients to tolerate, he tells WebMD.
Additionally, efforts to improve your diet and exercise more should be redoubled, says American Heart Association (AHA) past president Sidney Smith, MD, of the University of North Carolina at Chapel Hill.
Vytorin Still Has Place in Treatment
If all those efforts fail, it's time to try Vytorin, the panel says.
Also, some patients taking statins, particularly at high doses, develop side effects such as muscle weakness and need alternatives, Smith says.
Study researcher Kastelein says that for the people he studied, all of whom had a genetic disposition to high cholesterol, high-dose statins plus Zetia is the only treatment that works.
"So what can I do? I certainly can't [take them off it]," he tells WebMD.
"I don't think we should take patients off it if they are doing well," agrees AHA past president Robert Bonow, MD, of Northwestern University in Chicago.
Why Did Vytorin Fail?
Kastelein says there are three possible reasons why Vytorin failed. One possibility is flaws in the technique used to measure plaque, but that’s "highly unlikely," he says.
Or it could be that the drug just doesn't work, but he says previous studies have shown that LDL is what counts, and it "doesn't matter how you reduced LDL," Kastelein says.
The most likely explanation, he tells WebMD, is that the participants did not have enough plaque buildup at the start of the study -- in other words, they were at too low of a risk to show benefit in a two-year study period.
Michael Davidson, MD, of the University of Chicago, says, "Lower LDL is better, and it doesn't matter how you get there.
"We don't feel Zetia is the reason ENHANCE didn't work. That is a possibility we have to list, but it is far less likely [than the population being too low-risk]," he says.
Krumholz maintains it's the pill. "It could also be that Zetia is just an expensive placebo and that its principal harm is it drains precious resources from our health care system and may lead people to use less of the drugs that we know are effective and beneficial," he says.
The bottom line, of course, is that no one knows for sure.
For now, all the doctors say they are eagerly awaiting the results of three larger ongoing trials, involving more than 20,000 patients, that are designed to show whether Zetia and Vytorin prevent more adverse events and deaths than statins alone.
Researchers said this week that they are expanding enrollment of the largest of those trials, IMPROVE-IT, to 18,000 patients, to ensure there are enough participants to show clear results. Those findings won't be available until about 2012.