TY - JOUR
T1 - Inhibition of p38 MAP kinase in patients with ST-elevation myocardial infarction – findings from the LATITUDE–TIMI 60 trial
AU - Cavender, Matthew A.
AU - O'Donoghue, Michelle L.
AU - Abbate, Antonio
AU - Aylward, Philip
AU - Fox, Keith AA
AU - Glaser, Ruchira X.
AU - Park, Jeong-Gun
AU - Lopez-Sendon, Jose
AU - Steg, Ph Gabriele
AU - Sabatine, Marc S.
AU - Morrow, David A.
N1 - Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2022/1
Y1 - 2022/1
N2 - Background: p38 mitogen activated kinase (MAPK) mediates the response to pro-inflammatory cytokines following myocardial infarction (MI) and is inhibited by losmapimod.Methods: LATITUDE-TIMI 60 (ClinicalTrials.gov NCT02145468) randomized patients with MI to losmapimod or placebo for 12 weeks (24 weeks total follow-up). In this pre-specified analysis, we examined outcomes based on MI type [ST-segment elevation MI (STEMI) (865, 25%) and non-STEMI (2624, 75%)].Results: In patients with STEMI, inflammation, measured by hs-CRP, was significantly attenuated with losmapimod at 48 hours (P <0.001) and week 12 (P = 0.01). Losmapimod lowered NT-proBNP in patients with STEMI at 48 hours (P = 0.04) and week 12 (P = 0.02). The effects of losmapimod on CV death (CVD), MI, or severe recurrent ischemia requiring urgent coronary artery revascularization at 24 weeks [MACE] differed in patients with STEMI (7.0% vs 10.8%; HR 0.65, 95%CI 0.41 – 1.03; P= 0.06) and NSTEMI (11.4% vs 8.5%; HR 1.30, 95%CI 1.02 – 1.66; P = 0.04; p[int] = 0.009). CVD or HHF among patients with STEMI were 5.6% (losmapimod) and 8.3% (placebo) (HR 0.66; 95%CI 0.40 – 1.11; P = 0.12) and in NSTEMI were 4.8% (losmapimod) and 4.4% (placebo) (HR 1.09; 95%CI 0.76 – 1.56) in patients with NSTEMI.Conclusions: Patients with STEMI treated with losmapimod had an attenuated inflammatory response. Our collective findings raise the hypothesis that mitigating the inflammatory response may result in different outcomes in patients with STEMI and NSTEMI. While the difference in outcomes is exploratory, these findings do support separate examination of patients with STEMI and NSTEMI and increased emphasis on heart failure in future investigation of modulators of inflammation in MI.
AB - Background: p38 mitogen activated kinase (MAPK) mediates the response to pro-inflammatory cytokines following myocardial infarction (MI) and is inhibited by losmapimod.Methods: LATITUDE-TIMI 60 (ClinicalTrials.gov NCT02145468) randomized patients with MI to losmapimod or placebo for 12 weeks (24 weeks total follow-up). In this pre-specified analysis, we examined outcomes based on MI type [ST-segment elevation MI (STEMI) (865, 25%) and non-STEMI (2624, 75%)].Results: In patients with STEMI, inflammation, measured by hs-CRP, was significantly attenuated with losmapimod at 48 hours (P <0.001) and week 12 (P = 0.01). Losmapimod lowered NT-proBNP in patients with STEMI at 48 hours (P = 0.04) and week 12 (P = 0.02). The effects of losmapimod on CV death (CVD), MI, or severe recurrent ischemia requiring urgent coronary artery revascularization at 24 weeks [MACE] differed in patients with STEMI (7.0% vs 10.8%; HR 0.65, 95%CI 0.41 – 1.03; P= 0.06) and NSTEMI (11.4% vs 8.5%; HR 1.30, 95%CI 1.02 – 1.66; P = 0.04; p[int] = 0.009). CVD or HHF among patients with STEMI were 5.6% (losmapimod) and 8.3% (placebo) (HR 0.66; 95%CI 0.40 – 1.11; P = 0.12) and in NSTEMI were 4.8% (losmapimod) and 4.4% (placebo) (HR 1.09; 95%CI 0.76 – 1.56) in patients with NSTEMI.Conclusions: Patients with STEMI treated with losmapimod had an attenuated inflammatory response. Our collective findings raise the hypothesis that mitigating the inflammatory response may result in different outcomes in patients with STEMI and NSTEMI. While the difference in outcomes is exploratory, these findings do support separate examination of patients with STEMI and NSTEMI and increased emphasis on heart failure in future investigation of modulators of inflammation in MI.
KW - mitogen activated kinase
KW - MAPK
KW - cytokines
KW - myocardial infarction
KW - losmapimod
KW - ST-segment elevation MI
KW - STEMI
KW - inflammatory
UR - http://www.scopus.com/inward/record.url?scp=85122488004&partnerID=8YFLogxK
U2 - 10.1016/j.ahj.2021.08.022
DO - 10.1016/j.ahj.2021.08.022
M3 - Article
C2 - 34508693
AN - SCOPUS:85122488004
SN - 0002-8703
VL - 243
SP - 147
EP - 157
JO - American Heart Journal
JF - American Heart Journal
ER -