Effects of varespladib methyl on biomarkers and major cardiovascular events in acute coronary syndrome patients.
OBJECTIVE
The purpose of this study was to investigate the effects of varespladib on cardiovascular biomarkers in acute coronary syndrome patients.


BACKGROUND
Secretory phospholipase A(2) (sPLA(2)) represents a family of proatherogenic enzymes that hydrolyze lipoprotein phospholipids, increasing their affinity for intimal proteoglycans; contribute to cholesterol loading of macrophages by nonscavenger receptor mediated pathways; and activate inflammatory pathways. In prospective studies, high sPLA(2)-IIA levels predicted major adverse cardiovascular events in acute coronary syndrome (ACS) and stable coronary heart disease patients.


METHODS
This randomized, double-blind, prospective controlled clinical trial (phase 2B) was designed to investigate the effects of sPLA(2) inhibition with varespladib 500 mg daily versus placebo as adjunctive therapy to atorvastatin 80 mg daily on biomarkers (low-density lipoprotein cholesterol [LDL-C], high-sensitivity C-reactive protein [hsCRP], and sPLA(2)-IIA levels), major adverse cardiovascular events (unstable angina, myocardial infarction, death), and safety. In all, 625 ACS subjects were randomized within 96 h of the index event and treated for a minimum of 6 months.


RESULTS
After 8 weeks (primary efficacy end point), varespladib/atorvastatin reduced mean LDL-C levels from baseline by 49.6% compared with 43.4% with placebo/atorvastatin (p = 0.002). Respective 8-week median reductions in sPLA(2)-IIA levels were 82.4% and 15.6% (p < 0.0001), and hsCRP levels were lowered by 75.0% and 71.0% (p = 0.097). At 24 weeks, respective reductions with varespladib and placebo were as follows: LDL-C 43.5% versus 37.6% (p < 0.05), hsCRP 79.8% versus 77.0% (p = 0.02), and sPLA(2)-IIA 78.5% versus 6.4% (p < 0.0001). Major adverse cardiovascular events were not different from placebo 6 months post-randomization (7.3% varespladib vs. 7.7% placebo). No treatment differences in elevated liver function studies on >1 occasion were observed.


CONCLUSIONS
Varespladib therapy effectively reduced LDL-C and inflammatory biomarkers in ACS patients treated with conventional therapy including atorvastatin 80 mg daily. There were no treatment differences in clinical cardiovascular events. (FRANCIS [Fewer Recurrent Acute Coronary Events With Near-Term Cardiovascular Inflammation Suppression]-ACS Trial: A Study of the Safety and Efficacy of A 002 in Subjects With Acute Coronary Syndromes; NCT00743925).
Rosenson
Robert S
RS
Mount Sinai School of Medicine, New York, New York 10029, USA. robert.rosenson@mssm.edu
Hislop
Colin
C
Elliott
Michael
M
Stasiv
Yuri
Y
Goulder
Michael
M
Waters
David
D
D000085:Acetates / Q000008:administration & dosage*; D054058:Acute Coronary Syndrome / Q000175:diagnosis / Q000188:drug therapy*; D000368:Aged; D000069059:Atorvastatin; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis / Q000187:drug effects*; D008078:Cholesterol, LDL / Q000032:analysis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006538:Heptanoic Acids / Q000008:administration & dosage*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D007651:Keto Acids; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D054497:Phospholipases A2, Secretory / Q000097:blood / Q000187:drug effects*; D011446:Prospective Studies; D011758:Pyrroles / Q000008:administration & dosage*; D012016:Reference Values; D016896:Treatment Outcome
D000085:Acetates; D015415:Biomarkers; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D007211:Indoles; D007651:Keto Acids; D011758:Pyrroles; C117948:varespladib; D002097:C-Reactive Protein; D000069059:Atorvastatin; D054497:Phospholipases A2, Secretory