TY - JOUR
T1 - Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction
T2 - A randomised phase 2 trial
AU - Newby, L. Kristin
AU - Marber, Michael S.
AU - Melloni, Chiara
AU - Sarov-Blat, Lea
AU - Aberle, Laura H.
AU - Aylward, Philip E.
AU - Cai, Gengqian
AU - De Winter, Robbert J.
AU - Hamm, Christian W.
AU - Heitner, John F.
AU - Kim, Raymond
AU - Lerman, Amir
AU - Patel, Manesh R.
AU - Tanguay, Jean Francois
AU - Lepore, John J.
AU - Al-Khalidi, Hussein R.
AU - Sprecher, Dennis L.
AU - Granger, Christopher B.I.
N1 - Funding Information:
The SOLSTICE trial was funded by GlaxoSmithKline. MSM was supported by the National Institute for Health Research Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. We thank Peter Hoffmann, Communications Group, Duke Clinical Research Institute, Durham, NC, USA, for his assistance with preparation of the paper for submission.
Publisher Copyright:
© 2014 Elsevier Ltd.
PY - 2014/9/27
Y1 - 2014/9/27
N2 - Methods From October, 2009, to November, 2011, NSTEMI patients were assigned oral losmapimod (7·5 mg or 15·0 mg loading dose followed by 7·5 mg twice daily) or matching placebo in a 3:3:2 ratio. Safety outcomes were serious adverse events and alanine aminotransferase (ALT) concentrations over 12 weeks, and cardiac events (death, myocardial infarction, recurrent ischaemia, stroke, and heart failure) at 90 days. Efficacy outcomes were high-sensitivity C-reactive protein (hsCRP) and B-type natriuretic peptide (BNP) concentrations at 72 h and 12 weeks, and troponin I area under the curve (AUC) over 72 h. The losmapimod groups were pooled for analysis. This trial is registered with ClinicalTrials.gov, number NCT00910962.Background p38 MAPK inhibition has potential myocardial protective effects. We assessed losmapimod, a potent oral p38 MAPK inhibitor, in patients with non-ST-segment elevation myocardial infarction (NSTEMI) in a double-blind, randomised, placebo-controlled trial.Findings Of 535 patients enrolled, 526 (98%) received at least one dose of study treatment (losmapimod n=388 and placebo n=138). Safety outcomes did not differ between groups. HsCRP concentrations at 72 h were lower in the losmapimod group than in the placebo group (geometric mean 64·1 nmol/L, 95% CI 53·0-77·6 vs 110·8 nmol/L, 83·1-147·7; p=0·0009) but were similar at 12 weeks. Early geometric mean BNP concentrations were similar at 72 h but significantly lower in the losmapimod group at 12 weeks (37·2 ng/L, 95% CI 32·3-42·9 vs 49·4 ng/L, 38·7-63·0; p=0·04). Mean troponin I AUC values did not differ.Interpretation p38 MAPK inhibition with oral losmapimod was well tolerated in NSTEMI patients and might improve outcomes after acute coronary syndromes.Funding GlaxoSmithKline.
AB - Methods From October, 2009, to November, 2011, NSTEMI patients were assigned oral losmapimod (7·5 mg or 15·0 mg loading dose followed by 7·5 mg twice daily) or matching placebo in a 3:3:2 ratio. Safety outcomes were serious adverse events and alanine aminotransferase (ALT) concentrations over 12 weeks, and cardiac events (death, myocardial infarction, recurrent ischaemia, stroke, and heart failure) at 90 days. Efficacy outcomes were high-sensitivity C-reactive protein (hsCRP) and B-type natriuretic peptide (BNP) concentrations at 72 h and 12 weeks, and troponin I area under the curve (AUC) over 72 h. The losmapimod groups were pooled for analysis. This trial is registered with ClinicalTrials.gov, number NCT00910962.Background p38 MAPK inhibition has potential myocardial protective effects. We assessed losmapimod, a potent oral p38 MAPK inhibitor, in patients with non-ST-segment elevation myocardial infarction (NSTEMI) in a double-blind, randomised, placebo-controlled trial.Findings Of 535 patients enrolled, 526 (98%) received at least one dose of study treatment (losmapimod n=388 and placebo n=138). Safety outcomes did not differ between groups. HsCRP concentrations at 72 h were lower in the losmapimod group than in the placebo group (geometric mean 64·1 nmol/L, 95% CI 53·0-77·6 vs 110·8 nmol/L, 83·1-147·7; p=0·0009) but were similar at 12 weeks. Early geometric mean BNP concentrations were similar at 72 h but significantly lower in the losmapimod group at 12 weeks (37·2 ng/L, 95% CI 32·3-42·9 vs 49·4 ng/L, 38·7-63·0; p=0·04). Mean troponin I AUC values did not differ.Interpretation p38 MAPK inhibition with oral losmapimod was well tolerated in NSTEMI patients and might improve outcomes after acute coronary syndromes.Funding GlaxoSmithKline.
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U2 - 10.1016/S0140-6736(14)60417-7
DO - 10.1016/S0140-6736(14)60417-7
M3 - Article
C2 - 24930728
AN - SCOPUS:84908310935
SN - 0140-6736
VL - 384
SP - 1187
EP - 1195
JO - The Lancet
JF - The Lancet
IS - 9949
ER -