Ezetimibe plus atorvastatin lowers cholesterol

Journal of Family Practice,  Sept, 2003  by Wendy S. Madigosky,  Kevin Y. Kane

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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; 107:2409-2415.

* PRACTICE RECOMMENDATIONS

Ezetimibe plus atorvastatin lowers low-density lipoprotein (LDL) cholesterol more than either alone. When combined with low-dose atorvastatin (10 mg), ezetimibe achieves reductions similar to those seen with atorvastatin (80 mg) alone in LDL cholesterol, the ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol, and triglycerides.

Despite these modest reductions in cholesterol, this study does not provide evidence that this combination lessens cardiovascular morbidity or mortality. With this caveat, adding ezetimibe to atorvastatin may be a reasonable alternative for patients already on high-dose atorvastatin who either can't reach target cholesterol levels or experience significant side effects.

* BACKGROUND

Ezetimibe is a new medication that prevents intestinal absorption of cholesterol. This trial assessed reductions in LDL cholesterol levels from coadministration of ezetimibe and atorvastatin compared with those of each drug alone.

* POPULATION STUDIED

The researchers conducting this trial enrolled 628 (primarily white) individuals aged [greater than or equal to] 18 years with hypercholesterolemia (calculated LDL 145-250 mg/dL) and triglycerides <350 mg/dL.

Exclusion criteria included but were not limited to congestive heart failure; uncontrolled arrhythmias; recent myocardial infarction, coronary bypass surgery, or angioplasty; unstable or severe peripheral artery disease; unstable angina; uncontrolled or new diabetes; and renal dysfunction.

Across the treatment groups, the mean age was 56.7 to 58.7 years; 52% to 62% were female. Less than 10% had diabetes or coronary heart disease, and approximately 15% were current smokers. More than one third had hypertension and a family history of coronary heart disease.

* STUDY DESIGN AND VALIDITY

This industry-sponsored randomized, double-blind, placebo-controlled trial consisted of 3 phases. Screening included a 2- to 12-week washout of previous lipid-altering drug therapy and instruction in a National Cholesterol Education Program Step I (or stricter) diet.

Pre-randomization included a 4-week, single-blind, placebo-controlled lead-in with assessment of calculated LDL cholesterol samples to assure that no single value was <145 mg/dL or >250 mg/dL. The investigators then randomized patients to 10 treatment groups: placebo; ezetimibe 10 mg; atorvastatin 10, 20, 40, and 80 mg; and ezetimibe 10 mg plus atorvastatin 10, 20, 40, and 80 mg. They measured lipid profiles at baseline and at 2, 4, 8, and 12 weeks.

Strengths of the methodology include the randomized, double-blinded, controlled design and the use of intention-to-treat analysis. It is unclear whether allocation was concealed. The short, 12-week treatment period limits the assessment of rare and potentially serious side effects as well as long-term efficacy. The extensive exclusion criteria limit the generalizability of these results.

* OUTCOMES MEASURED

The investigators measured percent change in direct LDL cholesterol from baseline to final measurement. Secondary outcomes included change from baseline to final measurement of calculated LDL, total cholesterol, triglyceride, HDL cholesterol, and several other lipid-related variables. Patient-oriented outcomes, such as rates of death, stroke, or myocardial infarction were not addressed. Cost-effectiveness of the combination was not evaluated.

* RESULTS

Demographics and baseline characteristics were similar across treatment groups. Ninety-two percent of subjects completed the 12-week study. When the treatment groups were pooled together, the combination of ezetimibe with atorvastatin resulted in a greater mean decrease in direct LDL cholesterol than atorvastatin alone (-54.5% vs -42.4%; P<.01) or ezetimibe alone (-54.5% vs -18.4%; P<.01). This combination also resulted in statistically significant reductions in total cholesterol (-9%), triglycerides (-8%), and an increase in HDL cholesterol (3%) compared with atorvastatin alone.

When analyzed separately by dose, the combination of ezetimibe with atorvastatin 10 mg produced reductions similar to atorvastatin 80 mg alone for LDL (50% vs 51%), total cholesterol to HDL cholesterol ratio (43% vs 41%), and triglycerides (31% each). HDL levels were 6% greater at this combined dose (9% vs 3%).

Approximately 60% of patients in each group (including placebo) reported an adverse event. However, only 17% of patients treated with atorvastatin and 23% of patients receiving the combination therapy reported "treatment-related" adverse events. Events included mild to moderate gastrointestinal and musculoskeletal problems. One to two percent of patients receiving atorvastatin (alone or in combination) had a 3-fold rise in liver enzymes. Five percent of patients in each group discontinued treatment.