The effect of inhibition of acyl coenzyme A-cholesterol acyltransferase (ACAT) on exercise performance in patients with peripheral arterial disease.
This study tested the hypothesis that avasimibe, an inhibitor of acyl coenzyme A-cholesterol acyltransferase (ACAT), would improve treadmill exercise performance in patients with claudication secondary to peripheral arterial disease (PAD). Four hundred and forty-two patients with PAD (ankle-brachial index in the index leg of < or =0.90 with a > or =20% reduction post-exercise) were enrolled from 39 centers in the USA. Patients were randomized to receive oral avasimibe 50 mg, 250 mg, 750 mg or placebo for a treatment period of 12 months. Changes from baseline in peak walking time (PWT) using a graded treadmill protocol were compared among groups after 6 and 12 months of treatment. Individual group comparisons were considered statistically significant if p < 0.0245 for the 50 mg and 250 mg groups and p < 0.001 for the 750 mg group. Patients randomized to the 50 mg group experienced a 0.76 min net increase over placebo in PWT, but this did not reach the pre-specified level of statistical significance (Hochberg procedure p = 0.027) using ANCOVA after 12 months of treatment after adjusting for multiple comparisons. This trend in PWT was supported by the changes in treadmill initial claudication time (ICT) (p = 0.026) and Walking Impairment Questionnaire (WIQ) walking distance score (p = 0.058). The 250 mg and 750 mg avasimibe dose groups failed to demonstrate an improvement in PWT over placebo after 6 months of treatment. In conclusion, while the ACAT inhibitor avasimibe did not show clear evidence of benefit on treadmill exercise performance in patients with PAD, the results add to our knowledge of the impact of treatments directed at atherosclerosis on functional endpoints.
Hiatt
William R
WR
Section of Vascular Medicine, University of Colorado Health Sciences Center, 4200 E 9th Ave, Denver, CO 80262, USA. Will.Hiatt@UCHSC.edu
Klepack
Ellen
E
Nehler
Mark
M
Regensteiner
Judith G
JG
Blue
John
J
Imus
James
J
Criqui
Michael H
MH
D000081:Acetamides; D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D015444:Exercise; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007383:Intermittent Claudication / Q000188:drug therapy / Q000503:physiopathology; D035002:Lower Extremity / Q000098:blood supply* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D016491:Peripheral Vascular Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology*; D011597:Psychomotor Performance / Q000187:drug effects*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors; D013449:Sulfonamides; D013451:Sulfonic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology; D000097587:Sterol O-Acyltransferase 2
D000081:Acetamides; D000085:Acetates; D004791:Enzyme Inhibitors; D002785:Sterol O-Acyltransferase; D013449:Sulfonamides; D013451:Sulfonic Acids; D000097587:Sterol O-Acyltransferase 2; C423185:avasimibe; C493492:sterol O-acyltransferase 1