Atopaxar and its effects on markers of platelet activation and inflammation: results from the LANCELOT CAD program.
Atopaxar is a reversible protease activated receptor (PAR)-1 thrombin receptor antagonist that interferes with platelet signaling. The effects of PAR-1 antagonists on biomarkers remain unknown. The primary objective was to assess the effects of atopaxar on biomarkers of inflammation and platelet activation. The LANCELOT-CAD trial randomized 720 subjects to atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks. Biomarkers were assessed at serial time points. A linear mixed model to account for repeated measures was used to evaluate the change in biomarker concentration from randomization across time to week 24. Least square means were determined from the linear mixed models. The concentration of sCD40L decreased on average over time by -553 (95 % CI -677, -429) ng/L in the combined atopaxar group versus -30.3 (-249 to 189) ng/L fall in the placebo arm (P < 0.001) and a dose-dependent trend was seen across treatment groups (P < 0.001 for trend). In contrast, Lp-PLA(2) mass rose on average over time by 12.6 (95 % CI 10.0, 15.3) ng/ml in the combined atopaxar group as compared with 2.6 (95 % CI -2.1, 7.3) ng/ml in the placebo arm (P < 0.001). Similarly, the concentration of IL-18 rose by 17.5 (95 % CI 12.4, 22.6) pg/ml in the atopaxar group versus a -1.2 (95 % CI -10.2, 7.8) pg/ml fall in the placebo group (P < 0.001). The effects of atopaxar on Lp-PLA(2) and IL-18 appeared to be dose-dependent (P < 0.001 for trend) and were observed in J-LANCELOT. Atopaxar did not have a significant effect on other inflammatory markers. In conclusion, atopaxar appeared to decrease sCD40L, but did not demonstrate an anti-inflammatory effect in patients with stable CAD. Although atopaxar increased the concentration of Lp-PLA(2) and IL-18, the clinical relevance of these findings remains unknown and warrants further investigation and validation.
Cardiovascular Division and TIMI Study Group, Brigham and Women's Hospital, 350 Longwood Avenue, 1st floor, Boston, MA 02115, USA. modonoghue@partners.org
Michelle L
ML
O'Donoghue
Deepak L
DL
Bhatt
Marcus D
MD
Flather
Shinya
S
Goto
Dominick J
DJ
Angiolillo
Shaun G
SG
Goodman
Uwe
U
Zeymer
Philip E
PE
Aylward
Gilles
G
Montalescot
Rafal
R
Ziecina
Hiroyuki
H
Kobayashi
Fang
F
Ren
Stephen D
SD
Wiviott
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000097:blood*; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D023201:CD40 Ligand / Q000097:blood*; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007097:Imines / Q000008:administration & dosage*; D007249:Inflammation / Q000097:blood / Q000188:drug therapy; D020382:Interleukin-18 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015539:Platelet Activation / Q000187:drug effects*; D011725:Pyridines / Q000008:administration & dosage*; D013997:Time Factors; D010975:Platelet Aggregation Inhibitors
D015415:Biomarkers; C540445:E 5555; D007097:Imines; D020382:Interleukin-18; D011725:Pyridines; D023201:CD40 Ligand; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D010975:Platelet Aggregation Inhibitors