IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved.

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial / Nicholls, Stephen J.; Kastelein, John J. P.; Schwartz, Gregory G.; Bash, Dianna; Rosenson, Robert S.; Cavender, Matthew A.; Brennan, Danielle M.; Koenig, Wolfgang; Jukema, J. Wouter; Nambi, Vijay; Wright, R. Scott; Menon, Venu; Lincoff, A. Michael; Nissen, ; Steven E., Hennekens C; Brown, Wv; Demets, D; Pfeffer, M; Roleau, J; Abraham, J; Gebel, J; Huff, C; Katzan, I; Shishehbor, M; Rassi, A; Uchino, K; Vest, A; Zishiri, E; Heckman, Mj; Balog, C; Dart, A; Amerena, J; Prasad, C; Farshid, A; Gunalingam, B; Thompson, P; Collins, N; Arstall, M; van Gaal, W; Aroney, C; Mahar, L; Youssef, G; Horowitz, J; Anand, D; Rodes-Cabau, J; Polasek, P; Lai, C; Huynh, T; Hubacek, J; Kokis, A; Paradis, Jm; Mukherjee, A; Senaratne, M; Constance, C; Gosselin, G; Lavi, S; Parker, J; Zadra, R; Abramson, B; Della-Siega, A; Spinar, J; Pudil, R; Motovska, Z; Maly, M; Hutyra, M; Pleva, L; Mayer, O; Semenka, J; Klimovic, T; Horak, D; Cervinka, P; Klimsa, Z; Hulinsky, V; Reichert, P; Monhart, Z; Rotterova, H; Kobulia, B; Shaburishvili, T; Mamatsashvili, M; Chapidze, G; Chumburidze, V; Megreladze, I; Khintibidze, I; Leithäuser, B; Voehringer, Hf; Wachter, R; Nogai, K; Lapp, H; Haltern, G; Gielen, S; Dorsel, T; Möllmann, H; Stellbrink, C; Hengstenberg, C; Dengler, T; Heuer, H; Kreuzer, J; Leschke, M; Mudra, H; Werner, N; Braun-Dullaeus, R; Rosenberg, M; Frey, N; Koenig, W; Strasser, R; Genth-Zotz, S; Kiss, R; Nagy, A; Kovacs, Z; Csapo, K; Edes, I; Sereg, M; Vertes, A; Ronaszeki, A; Kancz, S; Benczur, B; Polgar, P; Muller, G; Simonyi, G; Dezsi, C; Merkely, B; Dinnyes, J; Lupkovics, G; Kahali, D; Banker, D; Trivedi, S; Rajput, R; Premchand, R; Dani, S; Vadaganelli, P; Gupta, S; Chandra, S; Fulwani, M; Chawla, K; Parikh, K; Prati, F; Speciale, G; Valgimigli, M; Suriano, P; Sangiorgi, G; Fineschi, M; Merenda, R; Marenzi, G; Berti, S; Corrada, E; Cuccia, C; Testa, R; Moretti, L; Mennuni, M; Biasucci, Lm; Lioy, E; Auguadro, C; Magagnini, E; Fedele, F; Piscione, F; Azar, R; Trip, Md; Liem, A; den Hartoog, M; Lenderink, T; van de Wetering, Ml; Lok, D; Oei, F; Tans, Jg; Ilmer, B; Keijzers, M; Monraats, P; Kedhi, E; Breedveld, Rw; Herrman, J; van Wijk, L; Ronner, E; Nierop, P; Bosschaert, M; Hermans, W; Doevendans, P; Troquay, R; van der Heijden, R; Veen, G; Bokern, Mj; Bronzwaer, Pn; Kie, Sh; Den Hartog, F; Elliott, J; Wilkins, G; Hart, H; Devlin, G; Harding, S; Ponikowski, P; Madej, A; Kochmanski, M; Witkowski, A; Pluta, W; Bronisz, M; Kornacewicz-Jach, Z; Wysokinski, A; Ujda, M; Drozdz, J; Derlaga, B; Gessek, J; Dabrowski, M; Miekus, P; Kozlowski, A; Gniot, J; Musial, W; Dobrzycki, S; Rynkiewicz, A; Psuja, P; Rekosz, J; Drzewiecki, A; Kuznetsov, V; Gordeev, I; Goloshchekin, B; Markov, V; Barbarich, V; Belenky, D; Mikhin, V; Volkova, E; Timofeev, A; Ermoshkina, L; Barbarash, O; Klein, G; Libis, R; Vishnevsky, A; Linev, K; Khaisheva, L; Ruda, M; Dovgalevskiy, Y; Shvarts, Y; Zateyshchikov, D; Kostenko, V; Shalnev, V; Simanenkov, V; Arkhipov, M; Ovcharenko, E; Guseva, G; Akhunova, S; Ortiz, Ai; Navarro, Mj; Romero, Aj; Goya, Il; Peñaranda, As; Cendon, Aa; Rubio, Am; Zubiri, Jj; Soriano, Fr; Sanz, Rr; Genís, Ab; Lago, Vn; Fernández, Jd; Romo, Ai; Franco, Sn; Martin, Ih; Montero, Js; Martin Mde, M; González, Mj; Antolin, Jm; Areses, El; Miranda, Jm; Alonso-Pulpón, L; Esquivias, Gb; Jarne, Ef; Cortés, Jm; Pérez, Mb; Gormaz, Cl; Alegret, Jm; Nava, Js; Ingelmo, Jm; Urbano, Rh; Sanmartín, M; Katerenchuk, O; Vakaliuk, I; Karpenko, O; Prokhorov, O; Koval, O; Faynyk, A; Kopytsya, M; Karpenko, Y; Kraiz, I; Feskov, O; Rudenko, L; Kozhukhov, S; Goloborodko, B; Rivera, E; Broadwater, S; Crowley, S; Vijay, N; Goswami, R; Ferrier, L; Blanchard, A; Mccullum, K; Chernick, R; Bertolet, B; Battaglia, J; Richardson, J; Lochridge, S; Lieberman, S; Amkieh, A; Cavender, Jb; Denning, S; Treasure, C; Kmetzo, J; Stillabower, M; Brilakis, E; Schwartz, G; Acheatel, R; Kukuy, E; Ashchi, M; Skelding, K; Martin, L; Gillespie, E; French, W; Pollock, S; Polk, D; Black, R; Drenning, D; Anderson, J; Sanz, M; Korban, E; Wiley, M; Rezkalla, S; Minisi, A; Shah, A; Silverman, P; Amlani, M; Eaton, G; Brown, A; Jay, D; Loussararian, A; Lamas, G; Lauer, M; Williams, J; Asfour, A; Runquist, L; Robertson, R; Blonder, R; Davies, C; Downes, T; Chronos, N; Marso, S; Haldis, T; Eich, D; Ahmed, M; East, C; Macdonald, L; Seigel, P; White, M; Camp, A; Kleiman, N; Burtt, D; Strain, J; Go, B; Henry, P; Sultan, P; Delafontaine, P; Kashou, H; Lambert, C; Movahed, M; Saucedo, J; Thadani, U; Chandrashekhar, Y; Lu, D; Chandna, H; Mann, J; Ramaswamy, G; Browne, K; Janik, M; Cannon, K; Tolerico, P.; Berni, Andrea. - In: JAMA. - ISSN 0098-7484. - STAMPA. - 311:3(2014), pp. 252-262. [10.1001/jama.2013.282836]

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

Huynh T;Mukherjee A;Parker J;Strasser R;Simonyi G;Lioy E;Fedele F;Fernández JD;Schwartz G;Martin L;Brown A;Lauer M;White M;Lambert C;BERNI, Andrea
2014

Abstract

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved.
2014
Acetates; Acute Coronary Syndrome; Aged; Angina, Unstable; Atherosclerosis; Atorvastatin Calcium; Double-Blind Method; Early Termination of Clinical Trials; Female; Heptanoic Acids; Humans; Indoles; Male; Middle Aged; Phospholipases A; Phospholipases A2, Secretory; Pyrroles; Risk; Stroke; Survival Analysis; Treatment Outcome; Myocardial Infarction; Medicine (all)
01 Pubblicazione su rivista::01l Trial clinico
Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial / Nicholls, Stephen J.; Kastelein, John J. P.; Schwartz, Gregory G.; Bash, Dianna; Rosenson, Robert S.; Cavender, Matthew A.; Brennan, Danielle M.; Koenig, Wolfgang; Jukema, J. Wouter; Nambi, Vijay; Wright, R. Scott; Menon, Venu; Lincoff, A. Michael; Nissen, ; Steven E., Hennekens C; Brown, Wv; Demets, D; Pfeffer, M; Roleau, J; Abraham, J; Gebel, J; Huff, C; Katzan, I; Shishehbor, M; Rassi, A; Uchino, K; Vest, A; Zishiri, E; Heckman, Mj; Balog, C; Dart, A; Amerena, J; Prasad, C; Farshid, A; Gunalingam, B; Thompson, P; Collins, N; Arstall, M; van Gaal, W; Aroney, C; Mahar, L; Youssef, G; Horowitz, J; Anand, D; Rodes-Cabau, J; Polasek, P; Lai, C; Huynh, T; Hubacek, J; Kokis, A; Paradis, Jm; Mukherjee, A; Senaratne, M; Constance, C; Gosselin, G; Lavi, S; Parker, J; Zadra, R; Abramson, B; Della-Siega, A; Spinar, J; Pudil, R; Motovska, Z; Maly, M; Hutyra, M; Pleva, L; Mayer, O; Semenka, J; Klimovic, T; Horak, D; Cervinka, P; Klimsa, Z; Hulinsky, V; Reichert, P; Monhart, Z; Rotterova, H; Kobulia, B; Shaburishvili, T; Mamatsashvili, M; Chapidze, G; Chumburidze, V; Megreladze, I; Khintibidze, I; Leithäuser, B; Voehringer, Hf; Wachter, R; Nogai, K; Lapp, H; Haltern, G; Gielen, S; Dorsel, T; Möllmann, H; Stellbrink, C; Hengstenberg, C; Dengler, T; Heuer, H; Kreuzer, J; Leschke, M; Mudra, H; Werner, N; Braun-Dullaeus, R; Rosenberg, M; Frey, N; Koenig, W; Strasser, R; Genth-Zotz, S; Kiss, R; Nagy, A; Kovacs, Z; Csapo, K; Edes, I; Sereg, M; Vertes, A; Ronaszeki, A; Kancz, S; Benczur, B; Polgar, P; Muller, G; Simonyi, G; Dezsi, C; Merkely, B; Dinnyes, J; Lupkovics, G; Kahali, D; Banker, D; Trivedi, S; Rajput, R; Premchand, R; Dani, S; Vadaganelli, P; Gupta, S; Chandra, S; Fulwani, M; Chawla, K; Parikh, K; Prati, F; Speciale, G; Valgimigli, M; Suriano, P; Sangiorgi, G; Fineschi, M; Merenda, R; Marenzi, G; Berti, S; Corrada, E; Cuccia, C; Testa, R; Moretti, L; Mennuni, M; Biasucci, Lm; Lioy, E; Auguadro, C; Magagnini, E; Fedele, F; Piscione, F; Azar, R; Trip, Md; Liem, A; den Hartoog, M; Lenderink, T; van de Wetering, Ml; Lok, D; Oei, F; Tans, Jg; Ilmer, B; Keijzers, M; Monraats, P; Kedhi, E; Breedveld, Rw; Herrman, J; van Wijk, L; Ronner, E; Nierop, P; Bosschaert, M; Hermans, W; Doevendans, P; Troquay, R; van der Heijden, R; Veen, G; Bokern, Mj; Bronzwaer, Pn; Kie, Sh; Den Hartog, F; Elliott, J; Wilkins, G; Hart, H; Devlin, G; Harding, S; Ponikowski, P; Madej, A; Kochmanski, M; Witkowski, A; Pluta, W; Bronisz, M; Kornacewicz-Jach, Z; Wysokinski, A; Ujda, M; Drozdz, J; Derlaga, B; Gessek, J; Dabrowski, M; Miekus, P; Kozlowski, A; Gniot, J; Musial, W; Dobrzycki, S; Rynkiewicz, A; Psuja, P; Rekosz, J; Drzewiecki, A; Kuznetsov, V; Gordeev, I; Goloshchekin, B; Markov, V; Barbarich, V; Belenky, D; Mikhin, V; Volkova, E; Timofeev, A; Ermoshkina, L; Barbarash, O; Klein, G; Libis, R; Vishnevsky, A; Linev, K; Khaisheva, L; Ruda, M; Dovgalevskiy, Y; Shvarts, Y; Zateyshchikov, D; Kostenko, V; Shalnev, V; Simanenkov, V; Arkhipov, M; Ovcharenko, E; Guseva, G; Akhunova, S; Ortiz, Ai; Navarro, Mj; Romero, Aj; Goya, Il; Peñaranda, As; Cendon, Aa; Rubio, Am; Zubiri, Jj; Soriano, Fr; Sanz, Rr; Genís, Ab; Lago, Vn; Fernández, Jd; Romo, Ai; Franco, Sn; Martin, Ih; Montero, Js; Martin Mde, M; González, Mj; Antolin, Jm; Areses, El; Miranda, Jm; Alonso-Pulpón, L; Esquivias, Gb; Jarne, Ef; Cortés, Jm; Pérez, Mb; Gormaz, Cl; Alegret, Jm; Nava, Js; Ingelmo, Jm; Urbano, Rh; Sanmartín, M; Katerenchuk, O; Vakaliuk, I; Karpenko, O; Prokhorov, O; Koval, O; Faynyk, A; Kopytsya, M; Karpenko, Y; Kraiz, I; Feskov, O; Rudenko, L; Kozhukhov, S; Goloborodko, B; Rivera, E; Broadwater, S; Crowley, S; Vijay, N; Goswami, R; Ferrier, L; Blanchard, A; Mccullum, K; Chernick, R; Bertolet, B; Battaglia, J; Richardson, J; Lochridge, S; Lieberman, S; Amkieh, A; Cavender, Jb; Denning, S; Treasure, C; Kmetzo, J; Stillabower, M; Brilakis, E; Schwartz, G; Acheatel, R; Kukuy, E; Ashchi, M; Skelding, K; Martin, L; Gillespie, E; French, W; Pollock, S; Polk, D; Black, R; Drenning, D; Anderson, J; Sanz, M; Korban, E; Wiley, M; Rezkalla, S; Minisi, A; Shah, A; Silverman, P; Amlani, M; Eaton, G; Brown, A; Jay, D; Loussararian, A; Lamas, G; Lauer, M; Williams, J; Asfour, A; Runquist, L; Robertson, R; Blonder, R; Davies, C; Downes, T; Chronos, N; Marso, S; Haldis, T; Eich, D; Ahmed, M; East, C; Macdonald, L; Seigel, P; White, M; Camp, A; Kleiman, N; Burtt, D; Strain, J; Go, B; Henry, P; Sultan, P; Delafontaine, P; Kashou, H; Lambert, C; Movahed, M; Saucedo, J; Thadani, U; Chandrashekhar, Y; Lu, D; Chandna, H; Mann, J; Ramaswamy, G; Browne, K; Janik, M; Cannon, K; Tolerico, P.; Berni, Andrea. - In: JAMA. - ISSN 0098-7484. - STAMPA. - 311:3(2014), pp. 252-262. [10.1001/jama.2013.282836]
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