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JAMA. 2014 Jan 15;311(3):252-62. doi: 10.1001/jama.2013.282836.

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

Collaborators (356)

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, Berni A, 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.

Author information

1
South Australian Health and Medical Research Institute and University of Adelaide, Adelaide, Australia.
2
Academic Medical Center, Amsterdam, the Netherlands.
3
Veterans Affairs Medical Center and University of Colorado, Colorado, Denver.
4
Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio.
5
Icahn School of Medicine at Mount Sinai, New York, New York.
6
Brigham and Women's Hospital, Boston, Massachusetts.
7
University of Ulm Medical Center, Ulm, Germany.
8
Leiden University Medical Center, Leiden, and Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.
9
Michael E. DeBakey Veterans Affairs Hospital and Baylor College of Medicine, Houston, Texas.
10
Mayo Clinic, Rochester, Minnesota.

Abstract

IMPORTANCE:

Secretory phospholipase A2 (sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2 inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown.

OBJECTIVE:

To determine the effects of sPLA2 inhibition 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 measure was 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 sPLA2 inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS.

TRIAL REGISTRATION:

clinicaltrials.gov Identifier: NCT01130246.

PMID:
24247616
DOI:
10.1001/jama.2013.282836
[Indexed for MEDLINE]
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