L Kristin Newby1, Michael S Marber2, Chiara Melloni3, Lea Sarov-Blat4, Laura H Aberle3, Philip E Aylward5, Gengqian Cai4, Robbert J de Winter6, Christian W Hamm7, John F Heitner8, Raymond Kim9, Amir Lerman10, Manesh R Patel3, Jean-Francois Tanguay11, John J Lepore4, Hussein R Al-Khalidi3, Dennis L Sprecher4, Christopher B Granger3. 1. Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA. Electronic address: kristin.newby@duke.edu. 2. King's College London BHF Centre, Cardiovascular Division, Rayne Institute, St Thomas' Hospital, London, UK. 3. Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA. 4. Heart Failure Discovery Performance Unit, GlaxoSmithKline, Philadelphia, PA, USA. 5. South Australian Health and Medical Research Institute, Flinders University and Medical Centre, Adelaide, SA, Australia. 6. Department of Cardiology, Academic Medical Center-University of Amsterdam, Amsterdam, Netherlands. 7. Kerckhoff Heart and Thoraxcenter, Bad Nauheim, Germany. 8. Division of Cardiology, New York Methodist Hospital, Brooklyn, NY, USA. 9. Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA. 10. Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA. 11. Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.
Abstract
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. 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. 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.
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. 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. 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.
Authors: Joshua G Travers; Fadia A Kamal; Jeffrey Robbins; Katherine E Yutzey; Burns C Blaxall Journal: Circ Res Date: 2016-03-18 Impact factor: 17.367