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.

Základní údaje

Originální název

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

Autoři

DONOGHUE, M.L. (840 Spojené státy), R. GLASER (840 Spojené státy), M.A. CAVENDER (840 Spojené státy), P.E. AYLWARD (36 Austrálie), M.P. BONACA (840 Spojené státy), A. BUDAJ (616 Polsko), R.Y. DAVIES (840 Spojené státy), M. DELLBORG (752 Švédsko), K.A.A. FOX (826 Velká Británie a Severní Irsko), J.A.T. GUTIERREZ (840 Spojené státy), Ch. HAMM (276 Německo), R.G. KISS (348 Maďarsko), F. KOVAR (703 Slovensko), J.F. KUDER (840 Spojené státy), K.A. IM (840 Spojené státy), J.J. LEPORE (840 Spojené státy), J.L. LOPEZ-SENDON (724 Španělsko), T.O. OPHUIS (528 Nizozemské království), A. PARKHOMENKO (804 Ukrajina), J.B. SHANNON (840 Spojené státy), Jindřich ŠPINAR (203 Česká republika, garant, domácí), J.F. TANGUAY (124 Kanada), M. RUDA (643 Rusko), P.G. STEG (250 Francie), P. THEROUX (124 Kanada), S.D. WIVIOTT (840 Spojené státy), I. LAWS (840 Spojené státy), M.S. SABATINE (840 Spojené státy) a D.A. MORROW (840 Spojené státy)

Vydání

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

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30201 Cardiac and Cardiovascular systems

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 44.405

Kód RIV

RIV/00216224:14110/16:00090655

Organizační jednotka

Lékařská fakulta

DOI

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

UT WoS

000374289300019

Klíčová slova anglicky

Losmapimod

Štítky

EL OK

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 29. 8. 2016 16:49, Soňa Böhmová

Anotace

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 a 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, roč. 315, č. 15, s. 1591-1599. ISSN 0098-7484. Dostupné z: 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 a 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, roč.~315, č.~15, s.~1591-1599. ISSN~0098-7484. Dostupné z: https://dx.doi.org/10.1001/jama.2016.3609.

Podrobný výpis o publikaci