Ezetimibe Coadministered With Atorvastatin in Patients With Primary Hypercholesterolemia - Ezetimibe Coadministered With Atorvastatin in Patients With Primary Hypercholesterolemia

Aug 31, 2003
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Date Published:
01/01/2003
Date Updated:
08/31/2003
Original Posted Date:
08/31/2003
References

Description:

The goal of this trial was to evaluate a novel cholesterol absorption inhibitor given with atorvastatin versus atorvastatin alone for the reduction of low-density lipoprotein cholesterol (LDL-C) in patients with primary hypercholesterolemia.

Hypothesis:

Coadministration of ezetimibe with atorvastatin would result in a significantly greater reduction in LDL-C than atorvastatin alone.

Study Design

Study Design:

Patients Screened: 1,703
Patients Enrolled: 628
Mean Follow Up: 12 weeks
Mean Patient Age: Mean age 58
Female: 59%

Patient Populations:

Patients age ≥18 years with primary hypercholesterolemia, defined as calculated LDL-C7 of 145-250 mg/dl and triglyceride levels ≤350 mg/dl

Exclusions:

Congestive heart failure (CHF) defined as New York Heart Association class III or IV; uncontrolled cardiac arrhythmias; myocardial infarction, CABG surgery, or angioplasty within six months of study entry; history of unstable or severe peripheral artery disease within three months of study entry; unstable angina; uncontrolled or newly diagnosed (within one month of study entry) diabetes mellitus; unstable endocrine or metabolic diseases known to influence serum lipids and lipoproteins; known impairment of renal function; active or chronic hepatic or hepatobiliary disease; and known coagulopathy

Primary Endpoints:

Change from baseline to final assessment in LDL-C

Secondary Endpoints:

Change from baseline to final assessment for calculated LDL-C, total cholesterol, triglyceride, HDL-C, HDL2-C, HDL3-C, non–HDL-C, lipoprotein(a), apo A-I, apo B, and total cholesterol:HDL-C and direct LDL-C:HDL-C ratios

Drug/Procedures Used:

Patients were randomized to 1 of 10 treatments: placebo (n=60), ezetimibe (10 mg), atorvastatin (10 mg), ezetimibe (10 mg) plus atorvastatin (10 mg), atorvastatin (20 mg), ezetimibe (10 mg) plus atorvastatin (20 mg), atorvastatin (40 mg), ezetimibe (10 mg) plus atorvastatin (40 mg), atorvastatin (80 mg), or ezetimibe (10 mg) plus atorvastatin (80 mg).

Principal Findings:

LDL-C was significantly reduced from baseline to final assessment with ezetimibe plus atorvastatin (pooled treatment groups; -54.5%) compared with either atorvastatin alone (-42.4% for pooled treatment groups; p<0.01) or ezetimibe alone (-18.4%; p<0.01).

LDL-C reductions with coadministration (all doses) was generally consistent across all subgroups. Total cholesterol:high-density lipoprotein cholesterol (HDL-C) ratio was also significantly reduced with ezetimibe plus atorvastatin (-44.5%) compared with atorvastatin alone (-34.4%, p<0.01) or ezetimibe alone (-16.8%, p<0.01), as were triglycerides (-32.8% with combination therapy vs. -24.5% with atorvastatin, p<0.01; and vs. -5.1% with ezetimibe alone, p<0.01) and hs-C-reactive protein (-41% vs. -31% with atorvastatin alone, p<0.01).

Combination therapy at the lowest dose of atorvastatin (10 mg) provided similar reductions to results seen with the maximum dose of atorvastatin (80 mg) alone for LDL-C (50% and 51%), total cholesterol:HDL-C ratio (43% and 41%), and triglycerides (both 31%), but significantly greater increase in HDL-C (9% vs. 3%).

Adverse events that were treatment-related occurred in 17% (42/248) of patients receiving atorvastatin monotherapy and 23% (58/255) of patients receiving combination therapy. There were no cases of hepatitis, jaundice, or other clinical signs of liver dysfunction, and no deaths during the study.

Interpretation:

Among patients with primary hypercholesterolemia, treatment with ezetimibe plus atorvastatin was associated with a greater reduction in LDL-C compared with atorvastatin alone or ezetimibe alone. Ezetimibe plus the lowest dose of atorvastatin (10 mg) was associated with reductions in direct LDL-C and triglycerides, and increases in HDL-C that were similar to results seen with the maximum dose of atorvastatin (80 mg) alone. Ezetimibe plus atorvastatin appeared safe, with no excess treatment-related adverse events, and no increase in hepatitis or jaundice indicating liver dysfunction.

The overall duration of the study was relatively short (12 weeks), and additional follow-up is needed to determine if the efficacy is maintained and if the safety profile is similar with longer therapy. Ezetimibe plus atorvastatin may prove to be an alternative for patients in whom maximal dose statin monotherapy is inefficient.

Similar results were also observed in a trial of ezetimibe plus simvastatin (Davidson MH, McGarry T, Bettis R. Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol 2002;40:2125–34).

References:

Ballantyne CM, Houri J, Notarbartolo A, et al. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation 2003;107:2409-15.

Keywords: Follow-Up Studies, Cholesterol, LDL, Hepatitis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Ventricular Fibrillation, Syncope, Heptanoic Acids, Heart Arrest, Hypercholesterolemia, Simvastatin, Pyrroles, Tachycardia, Ventricular, C-Reactive Protein, Azetidines, Jaundice, Cholesterol, HDL, Triglycerides


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