Venice, Italy - Results of a head-to-head study involving the ezetimibe/simvastatin combination tablet (Vytorin^®, Merck and Schering-Plough) and atorvastatin (Lipitor^®, Pfizer) have shown that the combination drug is more effective in lowering LDL cholesterol and raising HDL cholesterol in patients with hypercholesterolemia. In addition to more patients achieving the target goal of LDL cholesterol <100 mg/dL with ezetimibe/simvastatin, more Vytorin-treated patients with CHD or CHD risk equivalents achieved the more stringent optional target of <70 mg/dL.

Dr Christie Ballantyne

"One of the more interesting aspects of this study is the high-risk patient," Dr Christie Ballantyne (Baylor College of Medicine, Houston, TX) told heartwire. "One thing that has come up is the new optional target of less than 70 mg/dL, and one of the reasons it has not been fully adopted is because we need more data. We're waiting on trials such as TNT, SEARCH, and IDEAL, but the other reason it hasn't been fully adopted is because it is really difficult to get to less than 70 mg/dL in these patients. What we showed was that if you try to get to this low target, with the top dose of atorvastatin, you get there about 36% of the time. The top dose of Vytorin, instead, was able to reduce LDL cholesterol to below this target in 64% of patients."

The results of the study—known as the Vytorin versus Atorvastatin (VYVA) trial—were presented this week at the Drugs Affecting Lipid Metabolism 2004 (DALM) meeting.

The VYVA trial was a six-week, active-controlled, double-blind study conducted in approximately 2000 patients with hypercholesterolemia. Patients were included in the study if they were not currently at the NCEP ATP III LDL-cholesterol goal based on their defined risk categories. Close to half the patients enrolled in the study were defined as high risk with either CHD or CHD risk equivalents, including >2 risk factors conferring a 10-year risk for CHD >20% with an LDL cholesterol >130 mg/dL.

Patients were randomized equally to eight treatment groups:

• Ezetimibe/simvastatin: 10/10 mg, 10/20 mg, 10/40 mg, and 10/80 mg.
• Atorvastatin: 10 mg, 20 mg, 40 mg, and 80 mg.

The primary end point of the study was the percent change from baseline to the end of the six-week treatment period in LDL cholesterol, while secondary end points included the percent change from baseline in HDL cholesterol and triglycerides.

Ballantyne and colleagues found that, averaged across the entire dose range and also at equivalent starting doses, patients treated ezetimibe/simvastatin had significantly greater reductions in LDL cholesterol compared with those treated with atorvastatin. Also averaged across the dose range and at the 40- and 80-mg doses, patients treated with the combination tablet had significantly greater increases in HDL cholesterol. The percent change in triglycerides from baseline was equivalent between the two drugs.

"Basically, what we were able to do with this trial was a comparison across the full dose ranges," said Ballantyne. "So we have four doses of atorvastatin and four doses of Vytorin, and it's a pretty straightforward comparison. The key findings are that the LDL reductions were superior across the entire dose range, including the highest dose of Vytorin vs the highest dose of atorvastatin, and HDL raising at the highest doses was also superior with the ezetimibe/simvastatin combination."

We're getting similar reduction in CRP, so this is quite reassuring.

In a post hoc analysis that measured high-sensitivity CRP levels from archived baseline and postbaseline plasma samples in 1800 patients, investigators found that the mean reduction in CRP was similar for ezetimibe/simvastatin and atorvastatin across the entire dose ranges. "We're getting similar reductions in CRP, so this is quite reassuring," said Ballantyne.

Ballantyne pointed out that with regard to raising HDL, Vytorin was "basically flat" across the entire dose range, raising HDL on average approximately 8%. Atorvastatin increased HDL cholesterol at lower doses, but less so as higher doses of the drug were used, something Ballantyne said is unexplainable at the present time. Safety was equivalent in both study arms, although a greater percentage of patients treated with atorvastatin had elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >3 times the upper limit of normal.

"The transaminase elevations were very low in both groups," said Ballantyne. "That's important to note, because any time you're getting increased efficacy, you're always concerned about getting more side effects, and that was not the case in this study."