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N Engl J Med. 2017 Aug 17;377(7):633-643. doi: 10.1056/NEJMoa1701131.

Cognitive Function in a Randomized Trial of Evolocumab.

Collaborators (461)

Wittert G, Begg A, Simpson R, Lehman S, Cross D, Sinhal A, Roberts Thomson P, De Meulemeester M, De Meulemeester E, Dufrasnes P, van de Borne P, De Clippel M, Catez E, Charlier F, Roelandt R, St Amour E, Pesant Y, Sardin V, Henein S, Dowell A, Dowell M, Peterson S, Chilvers M, VanSickle L, Sussex B, Williams A, Cole J, Hartleib M, Petrella R, Keast D, Dihel C, Machkova M, Brabec T, Stepek D, Kucera D, Elbl L, Balcarkova P, Matuska J, Ceska R, Zlatohlavek L, Tvrdikova J, Skrobakova J, Polak M, Skrobak I, Vaclavik J, Fiserova N, Kopcikova Y, Hala T, Kvasnicka J, Kvasnickova H, Polasek R, Adamkova V, Krupicka J, Franc P, Budkova J, Vomacka Z, Peterka K, Cech V, Dufka A, Masarikova L, Dunaj M, Svatosova A, Sochor K, Markdanner Lindgren L, Schmidt U, Korsgaard Thomsen K, Hummelshøj J, Saetre Lihn A, Bronnum-Schou J, Wermuth S, Hove J, Valter I, Rosenthal A, Pajos A, Rajasalu R, Viigimaa M, Alt I, Kork A, Reimand M, Nieminen S, Strand J, Heiskanen R, Piippo T, Kylkilahti S, Suomi J, Maunu V, Aalto M, Kahri J, Strandberg TE, Punkka A, Savolainen M, Nyman K, Vänttinen E, Kaakkomäki A, Montalescot G, Cariou B, Roubille F, Schiele F, Range G, Pucheu Y, Carpentier C, Ferrieres J, Opitz C, Contzen C, Gouni-Berthold I, Burst V, Karakas M, Rinke A, Kahrmann G, Hanefeld M, Schenkenberger I, Trenk D, Maus O, Vorpahl M, Schäufele TG, Melidonis A, Elisaf M, Tziakas D, Mertzanos G, Lakatos F, Zilahi Z, Hornyik A, Nagy K, Salamon C, Kis E, Nemedine Kolman E, Toth K, Piros GA, Balogh J, De Ferrari GM, Kiyosue A, Sato K, Go Y, Yasumura Y, Yamamoto K, Tokunaga T, Kajiyama S, Noguchi Y, Katsuda Y, Hosokawa S, Arakawa T, Kaigawa K, Funazaki T, Uehara H, Higa N, Yokoya K, Ito S, Saku K, Higashi Y, Fujita H, Koga Y, Fujino Y, Teterovska D, Mora L, Vecteva Liepniece I, Veze I, Jasinkevica I, Pavulans A, Kakurina N, Stukena I, Sime I, Flaksa I, Eglite R, Jansone L, Strazdiene V, Maskon O, van de Wal R, Janus C, Den Hartog F, Tonino W, Monajemi H, Hovens M, Van Den Berg A, Scott R, Tie S, Hysing J, Thalamus J, Flagstad E, Kjaernli T, Solnor L, Simonsen E, Hoivik HO, Hoye K, Myhrvold T, Pedersen T, Bergengen L, Szymkowiak K, Antkowiak-Piatyszek K, Trebacz J, Przekwas-Jaruchowska M, Wnetrzak-Michalska R, Konieczny M, Dabrowska M, Spyra J, Heince E, Zabowka M, Zabowka E, Grzegorzewski B, Kopaczewski J, Napora P, Blicharski T, Wierzbicka K, Bednarkiewicz Z, Pentela-Nowicka J, Bissinger A, Pijanowski Z, Pijanowska M, Lysek R, Kramarczuk E, Tyszecka G, Szpajer M, Raczak G, Wozniak I, Lepich T, Monteiro P, Oliveira L, Rodrigues B, Duarte A, Ferreira J, Guerreiro S, Pereira H, Vishnevsky A, Lukyanov Y, Shutemova E, Motylev I, Dronov D, Voevoda M, Shvarts Y, Markov V, Ezhov M, Kobalava Z, Shustov S, Solovev O, Barbarash O, Pimenov L, Tarasov N, Freidlin M, Runkova O, Zrazhevskiy K, Marchenko O, Lukacova J, Predmerska A, Sosovec D, Banik M, Pella D, Urgeova L, Urge M, Dzupina A, Oriesek R, Antalik L, Kockova Z, Banikova A, Micko K, Fulop P, Fulopova A, Zanonyova H, Lennerova J, Burgess L, du Toit M, Urbach D, Lipschitz S, Blignaut S, Coetzer TF, van der Walt E, Pinto Sala X, Civeira Murillo F, Gonzalez Juanatey JR, Ascaso Gimilio JF, Zamorano Gomez JL, Lindholm C, Dahlén G, Östergren J, Svensson P, Hennicks Jakobsson E, Bandh S, Olsson S, Wagner H, Svensson A, Sahin T, Dervis E, Altintas N, Kayikcioglu L, Yigit Z, Kirma C, Demir M, Douglas F, Blagden M, Mathew A, Ivan P, Thom S, Thompson D, James R, Fiore G, Lagocki S, McNally D, Heron M, Boyd B, Paul N, Lip G, McCormack T, Adlam D, Connolly D, Kondagunta V, Jaafar F, Trevelyan J, Davis G, Al-Bahrani A, Heller S, Saravanan P, Issa B, Thomas H, Caulfield M, McKinnon C, Gaunt R, Ramstad D, Khurana S, Pierpont B, Martin V, Dave K, Dave B, Levinson D, Haught WH, Mays M, Cheung D, Marcus A, Haddad T, Crater T, Shah A, Kereiakes D, Hershon K, Meengs M, Poock J, Forgosh L, Napoli M, Eaton C, Dill S, Blair E, Grubb S, Reschak M, Broughton R, Douyon H, Flock C, Torres M, Labrada H, Romero N, Herman L, Tami L, Krichmar P, Abdurrahman M, Bhagwat R, Desire A, Waters L, Shanchita S, Focil A, Remler R, Vora K, Vijay N, Mohammed A, Kohli N, Khan B, Rahman S, Binns M, Recknor C, Purdy D, Lawless A, Tarleton G, Schramm E, Srivastava S, Nadar V, Johnston J, Linsky R, Strader J, Gneiting A, Hearne S, Berlacher P, Dobkin L, Rubenfire M, Rogers W, Morgan T, Sherman H, Reza S, Reed C, Farris N, Koren M, Gupta D, Issa M, Reddy J, Nagajothi N, Davis M, Christensen T, Wise J, Rowe W, Joffe I, Hage-Korban E, Kozlowski L, Iteld B, Fritz R, Barnett S, Strobl D, Ord J, Zarich S, Gordon R, Assalone V, Aboufakher R, Snyder B, Gabra N, Andrawis N, Ghaly E, Singh I, Aneja B, Shapiro M, Ramos M, Little A, Brown C, Carr K, Davila W, Brezina B, Hitchcock J, Hick M, Onyema D, Cuji J, Stout E, Macasieb A, De Souza J, Tjaden J, Ward L, French J, Ballantyne C, Makam S, Kashyap M, Vo A, Bawa S, Zeig S, Isserman S, Potu R, Hamroff G, Fishbein G, Christofides E, Runquist L, Khan M, Rider J, Schantz M, Yeoman G, Wenocur H, DiDonato M, McLellan B, Hayden J, Henry B, Shalek M, Bhushan R, Walker N, Baird I, Kirstein J, Case C, Roseman H, Comer D, Yang E, Weinstein D, Molter D, Ramsbottom J, Hardee L.

Author information

1
From the Thrombolysis in Myocardial Infarction (TIMI) Study Group, Brigham and Women's Hospital, Boston (R.P.G., K.I., E.K., M.S.S.); Hôpital Cantonal, Hopitaux Universitaires de Genève, Geneva (F.M.); Cambridge Cognition, Cambridge (K.Z.), and International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London (P.S.S.) - both in the United Kingdom; Amgen, Thousand Oaks, CA (C.K., J.S., H.W., N.H., S.M.W.); Sydney Medical School, NHMRC Clinical Trials Centre, University of Sydney, Sydney (A.K.); Oslo University Hospital, Ullevål, and Medical Faculty, University of Oslo - both in Oslo (T.R.P.); University of Iowa, Iowa City (J.G.R.); and Rhode Island Hospital, Department of Neurology, Alpert Medical School of Brown University, Providence (B.R.O.).

Abstract

Background Findings from clinical trials of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors have led to concern that these drugs or the low levels of low-density lipoprotein (LDL) cholesterol that result from their use are associated with cognitive deficits. Methods In a subgroup of patients from a randomized, placebo-controlled trial of evolocumab added to statin therapy, we prospectively assessed cognitive function using the Cambridge Neuropsychological Test Automated Battery. The primary end point was the score on the spatial working memory strategy index of executive function (scores range from 4 to 28, with lower scores indicating a more efficient use of strategy and planning). Secondary end points were the scores for working memory (scores range from 0 to 279, with lower scores indicating fewer errors), episodic memory (scores range from 0 to 70, with lower scores indicating fewer errors), and psychomotor speed (scores range from 100 to 5100 msec, with faster times representing better performance). Assessments of cognitive function were performed at baseline, week 24, yearly, and at the end of the trial. The primary analysis was a noninferiority comparison of the mean change from baseline in the score on the spatial working memory strategy index of executive function between the patients who received evolocumab and those who received placebo; the noninferiority margin was set at 20% of the standard deviation of the score in the placebo group. Results A total of 1204 patients were followed for a median of 19 months; the mean (±SD) change from baseline over time in the raw score for the spatial working memory strategy index of executive function (primary end point) was -0.21±2.62 in the evolocumab group and -0.29±2.81 in the placebo group (P<0.001 for noninferiority; P=0.85 for superiority). There were no significant between-group differences in the secondary end points of scores for working memory (change in raw score, -0.52 in the evolocumab group and -0.93 in the placebo group), episodic memory (change in raw score, -1.53 and -1.53, respectively), or psychomotor speed (change in raw score, 5.2 msec and 0.9 msec, respectively). In an exploratory analysis, there were no associations between LDL cholesterol levels and cognitive changes. Conclusions In a randomized trial involving patients who received either evolocumab or placebo in addition to statin therapy, no significant between-group difference in cognitive function was observed over a median of 19 months. (Funded by Amgen; EBBINGHAUS ClinicalTrials.gov number, NCT02207634 .).

PMID:
28813214
DOI:
10.1056/NEJMoa1701131
[Indexed for MEDLINE]
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