title: Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin.
abstract: BACKGROUND
  Despite the efficacy of statins in lowering low-density lipoprotein cholesterol (LDL-C) levels, many patients who are at high risk for heart disease with hypercholesterolemia require additional LDL-C level reduction. The cholesterol absorption inhibitor, ezetimibe, has been shown to provide significant incremental reductions in LDL-C levels when co-administered with statins. This study was performed to compare the efficacy and safety of ezetimibe (10 mg) plus response-based atorvastatin titration versus response-based atorvastatin titration alone in the attainment of LDL-C goals in subjects who are at high risk for coronary heart disease (CHD) and are not at their LDL-C goal on the starting dose of atorvastatin.
  
  
  METHODS
  This was a 14-week, multicenter, randomized, double-blind, active-controlled study conducted in 113 clinical research centers in 21 countries. Participants were adults with heterozygous familial hypercholesterolemia (HeFH), CHD, or multiple (> or =2) cardiovascular risk factors, and a LDL-C level > or =130 mg/dL after a 6- to 10-week dietary stabilization and atorvastatin (10 mg/day) open-label run-in period. Eligible subjects continued to receive atorvastatin (10 mg) and were randomized to receive blinded treatment with ezetimibe (10 mg/day; n = 305) or an additional 10 mg/day of atorvastatin (n = 316). The atorvastatin dose in both groups was doubled after 4 weeks, 9 weeks, or both when the LDL-C level was not at its goal (< or =100 mg/dL), so that patients receiving combined therapy could reach 40 mg/day and patients receiving atorvastatin alone could reach 80 mg/day. The primary end point was the proportion of subjects achieving their LDL-C level goal at week 14. A secondary end point was the change in LDL-C level and other lipid parameters at 4 weeks after ezetimibe co-administration with 10 mg/day of atorvastatin versus 20 mg/day of atorvastatin monotherapy.
  
  
  RESULTS
  The proportion of subjects reaching their target LDL-C level goal of < or =100 mg/dL was significantly higher in the co-administration group than in the atorvastatin monotherapy group (22% vs 7%; P <.01). At 4 weeks, levels of LDL-C, triglycerides, and non-high-density lipoprotein cholesterol were reduced significantly more by combination therapy than by doubling the dose of atorvastatin (LDL-C -22.8% versus -8.6%; P <.01). The combination regimen had a safety and tolerability profile similar to that of atorvastatin alone.
  
  
  CONCLUSIONS
  The addition of ezetimibe to the starting dose of 10 mg/day of atorvastatin followed by response-based atorvastatin dose titration to a maximum of 40 mg/day provides a more effective means for reducing LDL-C levels in patients at high risk for CHD than continued doubling of atorvastatin as high as 80 mg/day alone.
authors.affiliation: Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio 45229, USA. ESteinmrl@aol.com
authors.forename: Evan
authors.initials: E
authors.lastname: Stein
authors.forename: Steen
authors.initials: S
authors.lastname: Stender
authors.forename: Pedro
authors.initials: P
authors.lastname: Mata
authors.forename: Philip
authors.initials: P
authors.lastname: Sager
authors.forename: Damien
authors.initials: D
authors.lastname: Ponsonnet
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Melani
authors.forename: Leslie
authors.initials: L
authors.lastname: Lipka
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Suresh
authors.forename: Darbie
authors.initials: D
authors.lastname: Maccubbin
authors.forename: Enrico
authors.initials: E
authors.lastname: Veltri
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000069059:Atorvastatin; D001384:Azetidines / Q000009:adverse effects / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005260:Female; D006538:Heptanoic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D011758:Pyrroles; D014280:Triglycerides; D002784:Cholesterol; D000069059:Atorvastatin; D000069438:Ezetimibe