Effect of Losmapimod on Cardiovascular Outcomes in Patients
Hospitalized With Acute Myocardial Infarction A Randomized
Clinical Trial

J 2016

Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction A Randomized Clinical Trial

DONOGHUE, M.L., R. GLASER, M.A. CAVENDER, P.E. AYLWARD, M.P. BONACA et. al.

Basic information

Original name

Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction A Randomized Clinical Trial

Authors

DONOGHUE, M.L. (840 United States of America), R. GLASER (840 United States of America), M.A. CAVENDER (840 United States of America), P.E. AYLWARD (36 Australia), M.P. BONACA (840 United States of America), A. BUDAJ (616 Poland), R.Y. DAVIES (840 United States of America), M. DELLBORG (752 Sweden), K.A.A. FOX (826 United Kingdom of Great Britain and Northern Ireland), J.A.T. GUTIERREZ (840 United States of America), Ch. HAMM (276 Germany), R.G. KISS (348 Hungary), F. KOVAR (703 Slovakia), J.F. KUDER (840 United States of America), K.A. IM (840 United States of America), J.J. LEPORE (840 United States of America), J.L. LOPEZ-SENDON (724 Spain), T.O. OPHUIS (528 Netherlands), A. PARKHOMENKO (804 Ukraine), J.B. SHANNON (840 United States of America), Jindřich ŠPINAR (203 Czech Republic, guarantor, belonging to the institution), J.F. TANGUAY (124 Canada), M. RUDA (643 Russian Federation), P.G. STEG (250 France), P. THEROUX (124 Canada), S.D. WIVIOTT (840 United States of America), I. LAWS (840 United States of America), M.S. SABATINE (840 United States of America) and D.A. MORROW (840 United States of America)

Edition

JAMA-Journal of the American Medical Association, Chicago, USA, American Medical Association, 2016, 0098-7484

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30201 Cardiac and Cardiovascular systems

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 44.405

RIV identification code

RIV/00216224:14110/16:00090655

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1001/jama.2016.3609

UT WoS

000374289300019

Keywords in English

Losmapimod

Abstract

V originále

IMPORTANCE p38 Mitogen-activated protein kinase (MAPK)-stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes inmyocardial infarction (MI). Pilot data in a phase 2 trial in non-ST elevation MI indicated that the p38 MAPK inhibitor losmapimod attenuates inflammation and may improve outcomes. OBJECTIVE To evaluate the efficacy and safety of losmapimod on cardiovascular outcomes in patients hospitalized with an acutemyocardial infarction. DESIGN, SETTING, AND PATIENTS LATITUDE-TIMI 60, a randomized, placebo-controlled, double-blind, parallel-group trial conducted at 322 sites in 34 countries from June 3, 2014, until December 8, 2015. Part A consisted of a leading cohort (n = 3503) to provide an initial assessment of safety and exploratory efficacy before considering progression to part B (approximately 22 000 patients). Patients were considered potentially eligible for enrollment if they had been hospitalized with an acute MI and had at least 1 additional predictor of cardiovascular risk. INTERVENTIONS Patients were randomized to either twice-daily losmapimod (7.5mg; n = 1738) or matching placebo (n = 1765) on a background of guideline-recommended therapy. Patients were treated for 12 weeks and followed up for an additional 12 weeks. MAIN OUTCOMES AND MEASURES The primary end pointwas the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization with the principal analysis specified at week 12. RESULTS In part A, among the 3503 patients randomized (median age, 66 years; 1036 [ 29.6%] were women), 99.1% had complete ascertainment for the primary outcome. The primary end point occurred by 12 weeks in 123 patients treated with placebo (7.0%) and 139 patients treated with losmapimod (8.1%; hazard ratio, 1.16; 95% CI, 0.91-1.47; P =.24). The on-treatment rates of serious adverse events were 16.0% with losmapimod and 14.2% with placebo. CONCLUSIONS AND RELEVANCE Among patients with acute MI, use of losmapimod compared with placebo did not reduce the risk of major ischemic cardiovascular events. The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population.

Citovat

DONOGHUE, M.L., R. GLASER, M.A. CAVENDER, P.E. AYLWARD, M.P. BONACA, A. BUDAJ, R.Y. DAVIES, M. DELLBORG, K.A.A. FOX, J.A.T. GUTIERREZ, Ch. HAMM, R.G. KISS, F. KOVAR, J.F. KUDER, K.A. IM, J.J. LEPORE, J.L. LOPEZ-SENDON, T.O. OPHUIS, A. PARKHOMENKO, J.B. SHANNON, Jindřich ŠPINAR, J.F. TANGUAY, M. RUDA, P.G. STEG, P. THEROUX, S.D. WIVIOTT, I. LAWS, M.S. SABATINE and D.A. MORROW. Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction A Randomized Clinical Trial. JAMA-Journal of the American Medical Association. Chicago, USA: American Medical Association, 2016, vol. 315, No 15, p. 1591-1599. ISSN 0098-7484. Available from: https://dx.doi.org/10.1001/jama.2016.3609.

@article{1352677,
   author = {Donoghue, M.L. and Glaser, R. and Cavender, M.A. and Aylward, P.E. and Bonaca, M.P. and Budaj, A. and Davies, R.Y. and Dellborg, M. and Fox, K.A.A. and Gutierrez, J.A.T. and Hamm, Ch. and Kiss, R.G. and Kovar, F. and Kuder, J.F. and Im, K.A. and Lepore, J.J. and LopezandSendon, J.L. and Ophuis, T.O. and Parkhomenko, A. and Shannon, J.B. and Špinar, Jindřich and Tanguay, J.F. and Ruda, M. and Steg, P.G. and Theroux, P. and Wiviott, S.D. and Laws, I. and Sabatine, M.S. and Morrow, D.A.},
   article_location = {Chicago, USA},
   article_number = {15},
   doi = {http://dx.doi.org/10.1001/jama.2016.3609},
   keywords = {Losmapimod},
   language = {eng},
   issn = {0098-7484},
   journal = {JAMA-Journal of the American Medical Association},
   title = {Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction A Randomized Clinical Trial},
   volume = {315},
   year = {2016}
}

TY  - JOUR
ID  - 1352677
AU  - Donoghue, M.L. - Glaser, R. - Cavender, M.A. - Aylward, P.E. - Bonaca, M.P. - Budaj, A. - Davies, R.Y. - Dellborg, M. - Fox, K.A.A. - Gutierrez, J.A.T. - Hamm, Ch. - Kiss, R.G. - Kovar, F. - Kuder, J.F. - Im, K.A. - Lepore, J.J. - Lopez-Sendon, J.L. - Ophuis, T.O. - Parkhomenko, A. - Shannon, J.B. - Špinar, Jindřich - Tanguay, J.F. - Ruda, M. - Steg, P.G. - Theroux, P. - Wiviott, S.D. - Laws, I. - Sabatine, M.S. - Morrow, D.A.
PY  - 2016
TI  - Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction A Randomized Clinical Trial
JF  - JAMA-Journal of the American Medical Association
VL  - 315
IS  - 15
SP  - 1591-1599
EP  - 1591-1599
PB  - American Medical Association
SN  - 00987484
KW  - Losmapimod
N2  - IMPORTANCE p38 Mitogen-activated protein kinase (MAPK)-stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes inmyocardial infarction (MI). Pilot data in a phase 2 trial in non-ST elevation MI indicated that the p38 MAPK inhibitor losmapimod attenuates inflammation and may improve outcomes. OBJECTIVE To evaluate the efficacy and safety of losmapimod on cardiovascular outcomes in patients hospitalized with an acutemyocardial infarction. DESIGN, SETTING, AND PATIENTS LATITUDE-TIMI 60, a randomized, placebo-controlled, double-blind, parallel-group trial conducted at 322 sites in 34 countries from June 3, 2014, until December 8, 2015. Part A consisted of a leading cohort (n = 3503) to provide an initial assessment of safety and exploratory efficacy before considering progression to part B (approximately 22 000 patients). Patients were considered potentially eligible for enrollment if they had been hospitalized with an acute MI and had at least 1 additional predictor of cardiovascular risk. INTERVENTIONS Patients were randomized to either twice-daily losmapimod (7.5mg; n = 1738) or matching placebo (n = 1765) on a background of guideline-recommended therapy. Patients were treated for 12 weeks and followed up for an additional 12 weeks. MAIN OUTCOMES AND MEASURES The primary end pointwas the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization with the principal analysis specified at week 12. RESULTS In part A, among the 3503 patients randomized (median age, 66 years; 1036 [ 29.6%] were women), 99.1% had complete ascertainment for the primary outcome. The primary end point occurred by 12 weeks in 123 patients treated with placebo (7.0%) and 139 patients treated with losmapimod (8.1%; hazard ratio, 1.16; 95% CI, 0.91-1.47; P =.24). The on-treatment rates of serious adverse events were 16.0% with losmapimod and 14.2% with placebo. CONCLUSIONS AND RELEVANCE Among patients with acute MI, use of losmapimod compared with placebo did not reduce the risk of major ischemic cardiovascular events. The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population.
ER  -

DONOGHUE, M.L., R. GLASER, M.A. CAVENDER, P.E. AYLWARD, M.P. BONACA, A. BUDAJ, R.Y. DAVIES, M. DELLBORG, K.A.A. FOX, J.A.T. GUTIERREZ, Ch. HAMM, R.G. KISS, F. KOVAR, J.F. KUDER, K.A. IM, J.J. LEPORE, J.L. LOPEZ-SENDON, T.O. OPHUIS, A. PARKHOMENKO, J.B. SHANNON, Jindřich ŠPINAR, J.F. TANGUAY, M. RUDA, P.G. STEG, P. THEROUX, S.D. WIVIOTT, I. LAWS, M.S. SABATINE and D.A. MORROW. Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction A Randomized Clinical Trial. \textit{JAMA-Journal of the American Medical Association}. Chicago, USA: American Medical Association, 2016, vol.~315, No~15, p.~1591-1599. ISSN~0098-7484. Available from: https://dx.doi.org/10.1001/jama.2016.3609.

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