title: Safety of anacetrapib in patients with or at high risk for coronary heart disease.
abstract: BACKGROUND
  Anacetrapib is a cholesteryl ester transfer protein inhibitor that raises high-density lipoprotein (HDL) cholesterol and reduces low-density lipoprotein (LDL) cholesterol.
  
  
  METHODS
  We conducted a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease or at high risk for coronary heart disease. Eligible patients who were taking a statin and who had an LDL cholesterol level that was consistent with that recommended in guidelines were assigned to receive 100 mg of anacetrapib or placebo daily for 18 months. The primary end points were the percent change from baseline in LDL cholesterol at 24 weeks (HDL cholesterol level was a secondary end point) and the safety and side-effect profile of anacetrapib through 76 weeks. Cardiovascular events and deaths were prospectively adjudicated.
  
  
  RESULTS
  A total of 1623 patients underwent randomization. By 24 weeks, the LDL cholesterol level had been reduced from 81 mg per deciliter (2.1 mmol per liter) to 45 mg per deciliter (1.2 mmol per liter) in the anacetrapib group, as compared with a reduction from 82 mg per deciliter (2.1 mmol per liter) to 77 mg per deciliter (2.0 mmol per liter) in the placebo group (P<0.001)--a 39.8% reduction with anacetrapib beyond that seen with placebo. In addition, the HDL cholesterol level increased from 41 mg per deciliter (1.0 mmol per liter) to 101 mg per deciliter (2.6 mmol per liter) in the anacetrapib group, as compared with an increase from 40 mg per deciliter (1.0 mmol per liter) to 46 mg per deciliter (1.2 mmol per liter) in the placebo group (P<0.001)--a 138.1% increase with anacetrapib beyond that seen with placebo. Through 76 weeks, no changes were noted in blood pressure or electrolyte or aldosterone levels with anacetrapib as compared with placebo. Prespecified adjudicated cardiovascular events occurred in 16 patients treated with anacetrapib (2.0%) and 21 patients receiving placebo (2.6%) (P = 0.40). The prespecified Bayesian analysis indicated that this event distribution provided a predictive probability (confidence) of 94% that anacetrapib would not be associated with a 25% increase in cardiovascular events, as seen with torcetrapib.
  
  
  CONCLUSIONS
  Treatment with anacetrapib had robust effects on LDL and HDL cholesterol, had an acceptable side-effect profile, and, within the limits of the power of this study, did not result in the adverse cardiovascular effects observed with torcetrapib. (Funded by Merck Research Laboratories; ClinicalTrials.gov number, NCT00685776.).
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA. cpcannon@partners.org
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Cannon
authors.forename: Sukrut
authors.initials: S
authors.lastname: Shah
authors.forename: Hayes M
authors.initials: HM
authors.lastname: Dansky
authors.forename: Michael
authors.initials: M
authors.lastname: Davidson
authors.forename: Eliot A
authors.initials: EA
authors.lastname: Brinton
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Gotto
authors.forename: Michael
authors.initials: M
authors.lastname: Stepanavage
authors.forename: Sherry Xueyu
authors.initials: SX
authors.lastname: Liu
authors.forename: Patrice
authors.initials: P
authors.lastname: Gibbons
authors.forename: Tanya B
authors.initials: TB
authors.lastname: Ashraf
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zafarino
authors.forename: Yale
authors.initials: Y
authors.lastname: Mitchel
authors.forename: Philip
authors.initials: P
authors.lastname: Barter
mesh_terms: D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001499:Bayes Theorem; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood*; D003131:Combined Modality Therapy; D003327:Coronary Disease / Q000097:blood / Q000178:diet therapy / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D023303:Oxazolidinones / Q000009:adverse effects / Q000627:therapeutic use*; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D023303:Oxazolidinones; C530884:anacetrapib