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N Engl J Med. 2017 May 4;376(18):1713-1722. doi: 10.1056/NEJMoa1615664. Epub 2017 Mar 17.

Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease.

Collaborators (1268)

Fish MP, Abrahamsen TE, Im K, Kanevsky E, Bonaca MP, Lira Pineda A, Hanlon K, Knusel B, Somaratne R, Kurtz C, Scott R, Accini Mendoza JL, Amerena J, Badariene J, Burgess L, Ceska R, Charng MJ, Choi D, Cobos JL, Dan GA, De Ferrari GM, Deedwania PC, Chopra VK, Erglis A, Ezhov MV, Ferreira J, Filipová S, Gaciong ZA, Pasierski T, Georgiev BG, Gonzalez-Galvez G, Gouni-Berthold I, Schäufele T, Hirayama A, Huber K, Rammer M, Kjaerulf Jensen H, Wermuth S, Jiang L, Jukema JW, Kraydashenko O, Leiter LA, Lewis BS, López-Miranda J, Lorenzatti AJ, Mach F, McAdam B, Nilsson L, Olsson Å, Rallidis L, Rogelio GG, Kerr Saraiva JF, Scheen A, Schiele F, Scott RS, Connolly D, Siu CW, Tay L, Thorgeirsson G, Tikkanen MJ, Tokgozoglu SL, Toth K, Viigimaa M, Wan Ahmad WA, Hennekens CH, Andreotti F, Baigent C, Brown WV, Davis BR, Newcomer JW, Wood SK, LaRosa J, Ansell B, Olsson A, Lowe C, Zahn L, Awtry E, Berger C, Croce K, Desai A, Gelfand E, Ho C, Leeman D, Link M, Norden A, Pande A, Rost N, Ruberg F, Silverman S, Singhal A, Vita J, Mackinnon I, Vogel DR, Leon de la Fuente R, Perna E, Amuchastegui M, Pacora F, Hershson A, Blumberg E, Glenny JA, Colombo H, Cuadrado JA, Nicolosi L, Rojas CG, Ulla MR, Hasbani EG, Cuneo C, Lopez Santi RG, Sanabria HD, Hrabar A, Lozada A, Begg A, Lehman S, Wittert G, Juergens C, Kostner K, Beltrame J, Simpson R, Sinhal A, Adams M, Kritharides L, Roberts Thomson P, Cross D, Thompson P, Van Gaal W, Cox N, Farshid A, Hammett C, Garrahy P, Prasan A, Horrigan M, Ebenbichler C, Hanusch U, Prager R, Schernthaner G, Luger A, Siostrzonek P, Toplak H, Bergler-Klein J, Paulweber B, Sinzinger H, Buysschaert I, Thoeng J, Vandekerckhove H, Catez E, Verheye S, Descamps O, Hoffer E, Wollaert B, Chenu P, van de Borne P, De Meulemeester M, Friart A, Charlier F, De Raedt H, Rietzschel E, Roelandt R, Lalmand J, Tavares Russo LA, Reis G, Duarte Barbosa EC, Vidotti MH, Fernandes Manenti ER, Dutra O, Leaes PE, Rech RL, Bertolim Precoma D, Nicolau JC, Amoedo R, Eliaschewitz FG, Pereira A, Kurtz Lisboa HR, Soares Piegas L, Cunha Borges JL, Ferreira Rossi PR, Pimentel Filho P, Bodanese LC, de Sa Cunha R, Moura Jorge JC, Ardito WR, Barroso de Souza WK, Hissa M, Izar MC, Manolova A, Kitova L, Kinova E, Tzekova M, Velchev V, Tarnovska-Kadreva R, Gotchev D, Petrov I, Raev D, Trendafilova-Lazarova D, Yotov Y, Lazov P, Rahimi S, St Amour E, Constance C, Pesant Y, Hess A, Anderson T, Sussex B, Henein S, Tsoukas G, Pandey AS, Bergeron J, Hart R, Gosselin G, Chehayeb R, Hamet P, Hartleib M, Mukherjee A, Halperin F, Petrella R, Bhargava R, Lonn E, Sabbah E, Bata I, Cha J, Gaudet D, Chapman K, Murthy D, Nigro F, Rupka D, Gossard D, Gupta M, Dowell A, Mansour S, Baass A, Geadah C, Huynh T, Peterson S, Poirier P, Sabe-Affaki G, Vertes G, Crowley D, Duchesne L, Pincetti Jofre CP, Potthoff Cardenas S, Conejeros Kindel C, Saavedra Gajardo VA, Lanas Zanetti F, Sepulveda Varela PA, Stockins Fernandez BA, Li W, Li D, Zhao S, Li Z, Wang J, Yang Y, Zhang L, Yang P, Zhang X, Huang H, Xue L, Zheng Z, Huang W, Dai H, Su H, Zeng X, Zheng Y, Tang Y, Yao Z, Sun Y, Du Y, Ge Z, Yan J, Chen X, Liu F, Pei H, Yang X, Cui H, Gu Y, Yang Z, Li J, Lian Y, Cui Y, Wang D, Jiang J, Li X, Chen J, Mo Z, Xu P, He Y, Zhou C, Qu P, Zhu Y, Liu Y, Shen X, Gao X, Terront Lozano MA, Moncada Corredor MA, Hernandez Triana E, Botero Lopez R, Coronel Arroyo JA, Quintero Baiz AE, Sanchez Vallejo G, Arana Londoño C, Molina de Salazar DI, Castellanos Bueno R, Manzur Jattin F, Cure Cure CA, Sotomayor Herazo A, Spinar J, Hala T, Machkova M, Klimsa Z, Polasek R, Jerabek O, Kazdera P, Pozdisek Z, Vaclavik J, Frana P, Elbl L, Kucera D, Kryza R, Malecha J, Reichert P, Sochor K, Ludka O, Kellnerova I, Peterka K, Zidkova E, Cech V, Brabec T, Fiserova N, Kvasnicka J, Rosolova H, Nemecek E, Adamkova V, Dunaj M, Pojsl S, Cepelak M, Podpera I, Kuchar L, Rysava D, Burianova H, Spinarova L, Skrobakova J, Charvat J, Homza M, Zemanek J, Koleckar P, Karen I, Krupicka J, Blaha V, Matuska J, Brotanek J, Cifkova R, Kuchar R, Vomacka Z, Kosek Z, Hulinsky V, Krejcova H, Kuchar J, Jelinek Z, Jelinek P, Markdanner Lindgren L, Saetre Lihn A, Korsgaard Thomsen K, Bronnum-Schou J, Nielsen H, Nielsen T, Egstrup K, Klausen IC, Mickley H, Hove J, Jeppesen J, Melchior T, Schmidt EB, Valter I, Rosenthal A, Kaik J, Kork A, Alt I, Strand J, Nieminen S, Kahri J, Suomi J, Nyman K, Strandberg TE, Piippo T, Savolainen M, Vikman S, Pucheu Y, Cariou B, Henry P, Ferrari E, Montalescot G, Ferrieres J, Roubille F, Bonnet B, Angoulvant D, Range G, Bammert A, Delarche N, Mariat C, Cayla G, Durlach V, Coisne D, Paillard F, Rouzier R, Goralski M, Khanoyan P, Cottin Y, Ziegler O, Khalife K, Le Corvoisier P, Motreff P, Spaulding C, VanBelle E, Bourhaial H, Opitz C, Kahrmann G, Contzen C, Appel K, Schenkenberger I, Rinke A, Trenk D, Maus O, Karakas M, Hanefeld M, Darius H, Hetzel G, Münzel T, Wöhrle J, Stawowy P, Marten I, Isermann B, Kast P, Vorpahl M, Bosiljanoff P, Hengstenberg C, Kassner U, Salbach P, Fischer M, Steiner S, Wagner S, Kraatz U, von Hodenberg E, Weyland K, Mantas I, Tziakas D, Bousboulas S, Patsilinakos S, Mertzanos G, Panagoulis C, Bilianou H, Skoumas I, Elisaf M, Manolis A, Moschos N, Kochiadakis G, Ntaios G, Richter D, Athyros V, Kolovou G, Danias P, Melidonis A, Fan KYY, Siu SC, Hornyik A, Lakatos F, Zilahi Z, Nagy K, Laszlo Z, Peterfai E, Lupkovics G, Andreka P, Merkely B, Herczeg B, Piros GA, Salamon C, Mark L, Papp A, Szakal I, Edes I, Mohacsi A, Tomcsanyi J, Hajko E, Nagy A, Papp E, Kiss R, Karadi I, Sigurdsson A, Jain A, Pai R, Kothiwale V, Kulkarni G, Mahajan A, Aggarwal S, Mehta V, Rajadhyaksha G, Joshi A, Khandait V, Parmar M, Tyagi S, Airody Govinda R, Dwivedi SK, Parikh K, Pothineni RB, Solanki B, O’Donnell M, Crean P, Barton J, Shechter M, Shotan A, Klutstein M, Chorin E, Gavish D, Kracoff O, Atar S, Rigler S, Hasin Y, Schiff E, Merlini P, Rapezzi C, Pirro M, Gonnelli S, Floresta AM, Mennuni M, Ardissino D, Senni M, Marenzi G, Marcucci R, Sampietro T, Cosmi F, Perrone Filardi P, De Caterina R, Fedele F, Moretti L, Biasucci LM, Ferri C, Go Y, Kiyosue A, Higashi Y, Tokunaga T, Kawasaki T, Sakagami S, Namba S, Saku K, Oku K, Arakawa T, Iida H, Nakamura Y, Yamamoto K, Hata Y, Katsuda Y, Koga Y, Shimizu M, Uehara H, Kajiyama S, Okamoto H, Shinozaki T, Fujino Y, Funazaki T, Higa N, Kaigawa K, Koike A, Nakane H, Sato K, Satoh Y, Shirasawa K, Sugino H, Tanabe J, Uemura O, Yoshimichi G, Akai A, Himeno H, Inage T, Inoko M, Kadokami T, Noguchi Y, Yamashita K, Yasumura Y, Yuge M, Hosokawa S, Kawamitsu K, Kozuma K, Matsuo H, Nakashima E, Okada M, Wada A, Yokoya K, Iwade K, Kawabata K, Tanno H, Ako J, Fujita H, Izumiya Y, Kanno M, Nunohiro T, Ohmura H, Ueno T, Kakurina N, Jasinkevica I, Stukena I, Veze I, Eglite R, Teterovska D, Sime I, Strazdiene V, Venceviciene L, Gustiene O, Radzeviciene-Jurgute R, Kucinskiene A, Maskon O, Lee CY, Erng T, Gan HW, Mohamed Yusof AK, Ramanathan GL, Liew H, Lopez Alvarado A, Nevarez Ruiz LA, De los Rios Ibarra MO, Bazzoni Ruiz AE, Ramos Lopez GA, Llamas Esperon GA, De la Peña Topete GDJ, Violante Ortiz RM, Illescas Diaz JJ, Leon Gonzalez S, Sanchez Diaz CJ, Mendez Machado GF, Venegas Carrillo LA, Aldrete Velasco JA, Cardona Muñoz EG, Leiva Pons JL, Perez Alva JC, van der Zwaan C, Oomen A, van de Wal R, Magro M, Boswijk D, Janus C, Groutars R, Tonino W, Cornel JH, Oude Ophuis A, Troquay R, Liem A, Westendorp I, Van Hessen M, Lok D, De Nooijer C, Den Hartog F, Van Beek E, Bendermacher P, Jansen R, Römer T, Rensing B, Hersbach F, Herrman J, Ladyjanskaia G, Karalis I, Linssen G, Bokern M, Visman A, Kooij A, Monajemi H, Lieverse A, Baker J, Tie S, Risberg K, Hysing J, Pedersen T, Hoivik HO, Norheim P, Solnor L, Hovland A, Kjaernli T, Jocson G, Coching RM, Batalla E, Go A, Habaluyas R, Barcinas R, Sy RA, Estepar RA, Germar A, Trebacz J, Szymkowiak K, Wnetrzak-Michalska R, Kopaczewski J, Przekwas-Jaruchowska M, Kania G, Zabowka M, Mirek-Bryniarska E, Dabrowska M, Napora P, Konieczny M, Spyra J, Lysek R, Pijanowski Z, Grzegorzewski B, Bednarkiewicz Z, Kinasz L, Antkowiak-Piatyszek K, Stania K, Szpajer M, Staneta P, Skonieczny G, Ksiezycka-Majczynska E, Blicharski T, Piepiorka M, Wozakowska-Kaplon B, Zechowicz T, Ilkowski J, Lubiszewska B, Hiczkiewicz J, Wierzbicka K, Kosior D, Garbocz P, Kubica J, Raczak G, Wozniak I, Cygler J, Kramarczuk E, Bystryk L, Pentela-Nowicka J, Dabrowski M, Podolec P, Zieba B, Mosiewicz J, Dubaniewicz W, Banach M, Tyszecka G, Lepich T, Rychlewska-Hanczewska A, Guzik T, Monteiro P, Pereira H, Oliveira L, Matos P, Soares Goncalves S, Leitao A, Vasco Salgado A, Timoteo AT, Pintilei E, Badila E, Militaru C, Tudoran M, Arsenescu-Georgescu C, Mitu F, Zdrenghea D, Lighezan D, Teodorescu I, Popescu MI, Coman I, Vintila MM, Vishnevsky A, Lukyanov Y, Blokhin A, Kostenko V, Shvarts Y, Markov V, Motylev I, Dronov D, Sherenkov A, Barbarash O, Shutemova E, Bolshakova O, Kobalava Z, Voevoda M, Treshkur T, Zrazhevskiy K, Pimenov L, Solovev O, Tarasov N, Arkhipov M, Freidlin M, Shalaev S, Yakhontova P, Shustov S, Goloshchekin B, Panov A, Bart B, Bubnova M, Gordeev I, Osipova I, Tereshenko S, Solovieva E, Meshkov A, Zateyshchikov D, Tan JL, Subramaniam T, Pella D, Fulop P, Antalik L, Dzupina A, Banikova A, Sosovec D, Urgeova L, Mazur J, Hranai M, Banik M, Vinanska D, Lennerova J, Kovar F, Pastrnakova E, Uhliar R, Blasko P, Gonsorcik J, Lukacova J, Oriesek R, Hatalova K, du Toit M, Ebrahim I, Vawda G, Lipschitz S, Blignaut S, Engelbrecht J, Coetzer TF, Pretorius M, Urbach D, Badat A, Pillay S, Van Zyl L, Abelson M, van der Walt E, Moodley R, Jacovides A, Oosthuysen WM, Klug E, Lottering H, Kok J, Saaiman J, Dawood S, De Jong DM, Kapp C, Makotoko E, Bayat J, Sarvan M, Vally T, Stapelberg A, Kim M, Bae J, Cho Y, Kim S, Han KH, Her S, Kim B, Lee S, Hong B, Kim W, Rha S, Jeong M, Shin GJ, Vida Gutierrez M, Valdes Chavarri M, Pinto Sala X, Gonzalez Juanatey JR, Civeira Murillo F, Zamorano Gomez JL, Lekuona Goya I, Iñiguez Romo A, Cordero Fort A, Ascaso Gimilio JF, Millan Nuñez-Cortes J, Lindholm C, Söderberg S, Suutari A, Berglund S, Mooe T, Kusiak D, Bandh S, Dahlén G, Olsson S, Witt N, Tydén P, Johansson P, Cizinsky S, Falck G, Pettersson SI, Rasmanis G, Östergren J, Moccetti T, Beer HJ, Eberli F, Krähenbühl S, Linka A, Ackermann D, Michel P, Yeh H, Tsai CF, Wu C, Hsia C, Juang J, Hsieh I, Lai W, Huang C, Hsieh Y, Sahin T, Duzenli M, Yigit Z, Demir M, Yilmaz MB, Muderrisoglu IH, Kirma C, Ercan E, Kayikcioglu L, Balbay Y, Lymar I, Kulynych O, Prokhorov O, Karpenko O, Kraіz I, Vakaliuk I, Stanislavchuk M, Korzh O, Rudyk I, Zhurba S, Svishchenko Y, Tseluyko V, Gyrina O, Reshotko D, Kopytsya M, Volkov V, Myshanych G, Rebrov B, Rishko M, Rudenko L, Shatylo V, Parkhomenko O, Yena L, Golovchenko O, Sorokina I, Malynovsky Y, Ivan P, Blagden M, Dear H, Mathew A, Lagocki S, Kondagunta V, Ahsan A, McKinnon C, Douglas F, Thom S, Fiore G, Caulfield M, Lynch M, Thomas H, Bain S, Hall A, McNally D, Fisher M, Keeling P, Al-Bahrani A, Lip G, Ellery A, Purohit J, Travill C, Cappuccio F, Davis G, Gaunt R, Adlam D, Asamoah N, Jaafar F, McCormack T, Jupp B, Pye M, Ainsworth P, Chauhan A, Paul N, Fairlie H, Fox C, Muzulu S, Trevelyan J, Aggarwal R, Issa B, Saravanan P, Cruickshank K, Gorog D, Heller S, Newby D, Nicolson A, Hare PO, Donnelly P, Rutherfurd S, de Belder M, Finlayson J, Harvey J, Hoye A, Kingston D, Sarkar D, Negahban A, Webster J, Wyatt N, Muir S, Cummings M, Mackenzie I, Senior R, Capps N, Fotherby K, McIntyre H, Aldegather J, Dixon L, Saksena R, Butler R, Ramstad D, Pierpont B, Levinson D, Mohammed A, Haddad T, Goel A, Dave K, Haught WH, Desire A, Hershon K, Napoli M, Tami L, Rothschild R, Khurana S, Gupta D, Cheung D, Hearne S, Grubb S, Miller A, Baird I, Marcus A, Srivastava S, Forgosh L, Fritz R, Mays M, Bertolet B, Reddy J, Khan M, Nakhle S, Dill S, Fishbein G, Khan B, Marais H, Reschak M, Malone M, Nadar V, Whitney R, Reichman A, Reyes H, El Shahawy M, Rabinowitz A, Weinstein D, Farhat N, Onyema D, Potu R, Runquist L, Barnum O, Crater T, Fialkow J, Shah A, Thompson C, Wiseman A, Doyle T, Henderson D, Herzog W, Schnitzler R, Carr K, Davis M, Nagajothi N, Olsen S, Rogers W, Rubino J, Singh I, Tarleton G, Bhagwat R, Clardy D, Jardula M, Robinson J, Torres M, Vijay N, Farris N, Lillo J, Moriarty P, Recknor C, Berlacher P, Christensen T, Gabra N, Issa M, Janik M, Lawless A, Molter D, Stout E, Brezina B, Claxton E, Linsky R, Poock J, Remler R, Roseman H, Schramm E, Al-Joundi T, Amin J, Hitchcock J, Isserman S, Kirstein J, Rider J, Shalek M, Sherman H, Bernstein M, Chandra L, Hatharasinghe R, Ibrahim H, Iteld B, Linzmeyer K, Seaton B, Zeig S, Christofides E, Dunbar R, Griffin S, Kohli N, Koren M, Pharr W, Purdy D, Spencer R, Yeoman G, Banerjee S, Cheek HB, Engel E, Hamroff G, Huling R, Kozlowski L, Levin P, Makam S, Meengs M, Bhushan R, Erickson B, Herman L, Lo E, McDowell E, McGrew F, Miller M, Ord J, Webel R, Wilhoit G, Wise J, Yang E, Budoff M, Collins J, Dauber I, Dobkin L, Focil A, Gandy W, Pasquini J, Ramos M, Rodriguez D, Rosenson R, Sanford K, Schlau A, Snyder B, Stonesifer L, Tang A, De Souza J, Elam M III, French J, Guyton J, Hage Korban E, Kereiakes D, King M, Loh I, Navarro J, Simons R, Tobin T, Younis L, Aboufakher R, Baldari D, Ballantyne C, Broughton R, Eaton C, Johnston J, Simon W, Thomson S, Vora K, Youngman D, Alzohaili O, Auerbach E, Brown C, Burrough B, Chen Y, Gilpatrick M, Landzberg J, Mitchell C, Rice L, Rubenfire M, Sofley CW, Strobl D, Atassi K, Davila W, Diogo J, Fagan T, Joffe I, Krishna J, Osea E, Penny W, Rowe W, Shapiro M, Welker J, Benton R, Dobratz D, Fortuin F, Graham J, Henry B, Kusnick B, Lutskiy M, McRae A, Saway W, Scott J, Shah M, Weinberg B, Zarich S, Acheatel R, Case C, Earl J, Fernandez S, Giugliano G, Handelsman Y, Hermany P, Holder S, Kashyap M, Khan A, Lader E, Peniston J, Raoof T, Sacco J, Shore K, Spriggs D, Stringam S, Tahirkheli N, Delgado E, Derian W, Greenwald J, Harris M, Jackson R, Marhefka G, McElveen W, Mooss A, Morris P, Murray J, Pearlstein P, Raisinghani A, Rezkalla S, Sakhrani L, Schreibman D, Shaoulian E, Steinsapir J, Yataco A, De La Cruz A, Fredrick M, Goldenberg E, Lee D, McCullum K, McLellan B, Stephens L, Wilson S, Alfieri A, Mandviwala M, ORourke D, Samal A, Schmedtje J, Waxman F, Carhart R, Clements B, Dyke C, Ghali J, Gruberg L, Hack T, Jehle A, Pogue B, Schooley C, Shifrin G.

Abstract

BACKGROUND:

Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain.

METHODS:

We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years.

RESULTS:

At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%).

CONCLUSIONS:

In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets. (Funded by Amgen; FOURIER ClinicalTrials.gov number, NCT01764633 .).

PMID:
28304224
DOI:
10.1056/NEJMoa1615664
[Indexed for MEDLINE]
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