Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial.
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Serval ID
serval:BIB_080E4D2A257F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial.
Journal
Lancet
Working group(s)
BEAUTIFUL Investigators
Contributor(s)
Grancelli H., Freedman B., Eber B., Vanoverschelde J.L., Finkov B., Yotov Y., Tardif J.C., Hu D., Lau C., Hradec J., Hildebrandt P., Eha J., Peuhkurinen K., Danchin N., Steg P.G., Meinertz T., Vardas P., Borbola J., Mulcahy D., Maggioni A., Erglis A., Jirgensons J., Kalnins U., Laucevicius A., Dickstein K., Ruzyllo W., Tendera M., Seabra-Gomes R., Capalneanu R., Belenkov Y., Mareev Y., Murin J., Rakovec P., Macaya C., Dellborg M., Lüscher T.U., van Gilst W., Oto A., Ford I., Fox K., Hall A., Parkhomenko A., Robertson M., Weir C., Aziz J., Kean S., Wilson R., Thygesen K., Frenneaux M., Jondeau G., Camm A.J., Dargie H., Kjekshus J., Murray G., Ahuad Guerrero R.A., Allall O.A., Amuchastegui M., Buscema J.J., Bustos B., Cartasegna L.R., Cohen Arazi H., Fernandez A.A., Fuselli J.J., Guzmén L.A., Hasbani E., Ibañez J.O., Iglesias R.M., Lembo L.A., Luciardi H.L., Luquez H.A., Montaña O.R., Nul D.R., Orlandini A.D., Perna E.R., Sanchez A., Sanjurjo M.S., Schygiel P.O., Sinisi V.A., Sokn F.J., Thierer J., Del Valle Lobo Marquez L.L., Varini S., Vogel D., Alford K., Amerena J., Arnolda L., Atherton J., Bradley J., Cameron J., Colquhoun D., Counsell J., Fitzpatrick A., Horowitz J., Ireland M., Karrasch J., Kaye D., Lattimore J.D., Marwick T., O'Shea J., Owensby D., de Pasquale C., Prior D., Rogers J., Sindone A., Singh B.B., Stickland J., Szto G., Tofler G., Vogl E., Waites J., Walsh W., Eber E., Huber K., Lang I., Pichler M., Chenu P., Dendale P.A., François P.A., Friart A., Goethals M., Materne P., van Mieghem W., Missault L., Vachiery J.L., Vanderheyden M., Chompalova B., Denchev S., Donova T., Dzhurzdhev A., Georgiev B., Gotchev D., Goudev A., Grigorov M., Guenova D., Hergeldjieva V., Kamenova Z., Nachev C., Penkov N., Perchev I., Raev D., Sirakova V., Taseva T., Torbova S., Tzekova M., Baird M., Bernstein V., Chehayeb R., Constance C., Coutu B., Desrochers D., Fortin C., Glanz A., Haddad H., Heath J., Hill L.L., Klinke W.P., Kouz S., Lalani A., Lauzon C., Lepage S., Lonn E., Ma P., Matangi M., Nawaz S., Pandey S., Parker J.D., Parker J.O., Poirier P., Raco D., Rajda M., Rebane T., Rupka D., Savard D., Syan G.S., Talbot P., Tardif J.C., To T.B., Vakani M.T., Vertes G.E., Yao L., Dong Y., Gai L., Ge J.B., Hu D., Lv S., Sun Y., Wang W., Wang X., Yan X., Yuan Z., Zhang F., Ballek L., Drazka J., Fébik L., Florian J., Hradec J., Kaislerová M., Karetová D., Jerábek O., Kotík L., Krejcova H., Kryza R., Kuchar J., Lavicka V., Maratka T., Marcinek G., Penicka M., Povolný J., Sochor K., Soucek M., Spacek R., Spinar J., Stípal R., Sulda M., Vencour D., Vitovec J., Vojacek J., Vojtísek P., Agner E., Asklund M., Brønnum Schou J., Dahlstrøm C.G., Dodt K.K., Egstrup K., Gøtzsche L., Gøtzsche O., Haghfelt T., Hildebrandt P., Jakobsen T., Jensen G., Klarlund K., Køber L., Larsen C.T., Larsen J., Lind Rasmussen S., Lysko Svendsen T., Markenvard J., McNair A., Nielson H., Pedersen L., Petersen J., Ralfkiaer N., Rickers H., Rokkedal J., Romer F., Roseva Nielsen N., Scheibel M., Sejersen H., Skagen K., Stentebjerg S.E., Torp-Pedersen C., Tuxen C., Vigholt E., Averina O., Eha J., Kolbassova O., Sildmäe S., Vahula V., Viigimaa M., Harjola V.P., Luoma J., Melin J., Peuhkurinen K., Aliot E., Barthelemy J.C., Bauer F., Beaune J., Belin A., Bodur G., Boudahne A., Bourdon A., Bouvier J.M., Carlioz R., Chati Z., Cherbi C., Chevalier J.M., Chevrier J., Claudon O., Colin P., Dambrine P., Danchin N., Decoulx E., Demarcq J.M., Doucet B., Drawin T., Dubois-Rande J.L., El Mansour N., Escande M., Fournier P.Y., Funck F., Gabrovescu M., Galinier M., Galley D., Gay A., Genest M., Godenir J.P., Guillot J.P., Gully C., Habib G., Huyghe de Mahenge A., Jaboureck O., Kahn J.C., Khalife K., Khanoyan P., Koenig A., Leborgne L., Lemoine C., Magnin D., Mann H., Mansourati J., Martelet M., Matina D., Meurice T., Olive T.G., Ovize M., Perret T., Pierre-Justin E., Riou A., Roudaut R., Roul G., Roynard J.L., Sellier P., Slama M., Soto F.X., Thisse J.Y., Wolf J.E., Ammer K., Appel K.F., Baar M., Bauknecht C., Baumann G., Bergmann K., Böhm M., Bosch R., Bott J., Cieslinski G., Deissner M., Drescher T., Droese K., Figulla H.R., Frick H.M., Fries P., Gärtner J., Gola G., Gonska B.D., Grooterhorst P., Hasenfuss G., Haverkamp W., Heckel D., Hengstenberg C., Hering R., Heuer H., Hoppe U., Jahnke N., Jeserich M., Katus H., Kleinertz K., Kombächer H.D., Lange R., Lehmann G., Meinertz T., Müller O., Münzel T., Natour M., Nienaber C., Oeff M., Pötsch T., Proskynitopoulos N., Rüdell U., Rummel R., Rupprecht H.J., von Schacky C., Schenkenberger I., Schmidt J., Schreckenberg A., Schuler G., Schultheiss H.P., Seidl K., Spanier C., Spengler U., Steindorf J., Strasser R., Taggeselle J., Tammen A., Werdan K., Windstetter U., Winkelmann B.R., Wolde C.H., Zahorsky R., Al-Zoebi A., Alexopoulos D., Anastasiou-Nana M., Apostolou T., Fotiadis I., Hatzinikolaou-Kotsakou E., Kallikazaros I., Kapordelis C., Karvounis H., Kolettis T., Koliopoulos N., Kremastinos D., Kyriakides Z., Manolis A., Papadopoulos C., Pras A., Pyrgakis V.N., Siogas K., Theodorakis G., Tryposkiadis F., Tziakas D., Vardas P., Lee K., Barsi B., Borbola J., Cziráki A., Dézsi C.A., Edes I., Farsang C., Harmati L., Juhász A., Kovács A., Lakatos F., Lippai J., Lupkovics G., Matoltsy A., Mohácsi A., Mohay A., Nagy A., Nagy K., Nagy L., Nyárádi A., Pálinkás A., Piros G., Polgár P., Préda I., Regos L., Rumi G., Sármán P., Sereg M., Sidó Z., Tahy A., Takács J., Tomcsányi J., Tóth K., Váradi A., Vegh G., Veress G., Zámolyi K., Barton J., Crean P., Daly K., Foley D., Alberti E., Ambrosio G., Barbuzzi S., Bellone E., Buia E., Capucci A., Carbonieri E., Cardona N., Della Casa S., Cocchieri M., Colombo A., Cosmi F., De Cristofaro M., Ferrari R., Fuscaldo G., Gavazzi A., Giannuzzi P., Giustiniani S., Ingrilli F., Leghissa R., De Luca I., Maresta A., De Matteis C., Minneci C., Mos L., Paparoni S., Perna B., Pettinati G., Pinelli G., Pizzimenti G., Porcu M., Proietti G., Proto C., Pulitano G., Reggianini L., Santini M., Uguccioni M., Urbinati S., Zanetta M., Zanini R., Erglis A., Gailiss E., Gersamija A., Keisa M., Libins A., Ozolina M.A., Stoma M., Volans E., Berukstis E., Grabauskiene V., Kibarskis A., Kirkutis A., Marcinkeviciene J., Naudziunas A., Petrulioniene Z., Varoneckas G., Zaliunas R., Bartels G.L., van Beek G.J., van den Berg B.J., Bruning T.A., Cornel J.H., Daniels M.C., Dijkgraaf R., Fast J., Freericks M.P., Galema T.W., Göbel E.J., Hamer L.H., van der Heijden R., Herrman J.P., Hoedemaker G., Holwerda N.J., Hoogslag P.A., Jaarsma W., Jap Tjoen San W.T., van Kempen L.H., Kirkels J.H., Kragten J.A., Leenders C.M., Linssen G.C., Lionarons R.J., Maas A.H., Michels H.M., de Milliano P.A., Nagelsmit M.J., Nierop P.R., Pinto Y.M., Robles De Medina R., van Rossum P., van Rugge F.P., Somer S.T., Swart H., Thijssen H., van der Veen M., Verheul J.A., van Vlies B., Voors A.A., Wesdorp J.C., van Wijk L.M., Willems A.R., Winter J.B., Withagen A.J., van der Zwaan C., Zwart P.A., Atar D., Dickstein K., Myhre E.P., Achremczyk P., Andrzejak R., Baska J., Bloch C., Dluzniewski M., Drozdowski P., Goch J.H., Janik K., Janion M., Jaworska K., Kalarus Z., Kawecka-Jaszcz K., Kozlowski A., Krupa E., Krynicki R., Krzciuk M., Krzeminska-Pakula M., Kubica J., Kurowski M., Kuzniar J., Loboz-Grudzien K., Mazurek W., Miekus P., Musial W., Opolski G., Piepiorka M., Piotrowski W., Piwowarska W., Pluta W., Ponikowski P., Pulkowski G., Pusz T., Ruszkowski P., Ruzyllo W., Rynkiewicz A., Sinkiewicz W., Skura M., Slowinski S., Szolkiewicz M., Szpajer M., Targonski R., Tendera M., Tracz W., Trojnar R., Trusz-Gluza M., Wodniecki J., Wrabec K., Zadrozna Z., Zinka E., Aguiar J., Carvalho N., Ferreira Da Silva G., Freitas J., Lousada N., Oliveira Soares A., Paisana Lopes J.P., Providencia L.A., Salgado A., Teixeira M., Apetrei E., Arsenescu C., Avram R., Babes K., Bruckner I., Capalneanu R., Carasca E., Cinteza M., Craiu E., Dan G.A., Datcu M.D., Dimulescu D.R., Dorobantu M., Dragomor D., Dragulescu I.S., Dumitrascu D.L., Georgescu I.M., Ionescu D.D., Ionascu-Fometescu C.R., Kiss L., Macarie C., Manitiu I., Minescu B., Nanea T., Olariu C., Olinic N.C., Opris M., Pop C., Radoi M., Radu I., Sinescu C.J., Tanaseanu C.M., Tase A., Tintoiu I., Tomescu M., Topolnitchi L., Vintila M., Vladoianu M., Arkhipov M.V., Aroutiounov G.P., Azarin O.G., Barbarash O.L., Bart B.Y., Beloussov Y.B., Bychkova L., Chumakova G.A., Glezer M.G., Golukhova E., Gorbachenkov A.A., Gordeev I.G., Ivleva A.Y., Karpov Y.A., Karpov Y.B., Kastanaian A.A., Kisliak O.A., Kobalava J.D., Konyakhin A.Y., Khrustalev O.A., Kuimov A.D., Kukes A.G., Lopatin Y.M., Mareev V.Y., Moiseeva O.M., Mkrtchyan V.R., Nedogoda S.V., Orlov V.A., Perepech N.B., Pimenov L.T., Pozdnyakov Y.M., Rodoman G.V., Rudnev D.V., Sayganov S.A., Shlyakhto E.V., Shostak N.A., Shpektor A.V., Sidorenko B.A., Sorokin L.A., Stryuk R.I., Svistov A.S., Tankhilevich B.M., Tereschenko S.N., Tsyba L.P., Vasyuk Y.A., Vertkine A.L., Yakhontova P.K., Yakusevich V.V., Yakushin S.S., Zadionchenko V.S., Zateyshchikov D.A., Zhilyaev E.V., Bada V., Bugán V., Gonsorcík J., Kamenský G., Kmec J., Micko K., Murín J., Pella D., Sojka G., Vahala P., Bombek M., Kanic V., Markez J., Melihen-Bartolic C., Rakove P., Skrabl-Mocnik F., Slemenik-Pusnik C., Balaguer Recena J., Bertomeu Martinez V., Bruguera Cortada J., Calvo Gomez C., Calvo Iglesias F., Caparros Valderrama J., Casares Garcia G., Fernandez Alvarez R., Galve E., Garcia De Burgos F., Grande A., Gusi Tragant G., Iglesias Alonso L.F., Iglesias Cubero G., Illa Gay J., Jimenez Navarro M., López Bescós L., López García-Aranda V., Macaya De Miguel C., Noriega Peiro F., Paz Bermejo M.A., Perez Villa F., Romero Hinojosa J.A., San Román Calvar A., Sevilla Toral B., Sola Casado R., Bandh A., Blomgren J., Dellborg M., Herlitz J., Ohlin H., Ullman B., Delabays A., Dubach P., Eeckhout E., Gallino A., Hess O., Moccetti T., Vontobel H., Acarturk E., Ergene O., Erol K., Kozan O., Mutlu B., Ural D., Yilmaz H., Amosova K., Barna O., Batushkin V., Bazylevych A., Bereznyakov I., Dyadyk A., Dzyak G., Girina O., Glushko L., Goloborodko B., Karpenko O., Khomazyuk T., Kolchin Y., Kolomiets S., Korkushko O., Korzh O., Kovalenko V., Kovalsky I., Krayz I., Kubyshkin V., Lutay M., Mostovoy Y., Netyazhenko V., Parkhomenko A., Perepelytsya M., Pertseva T., Polyvoda S., Putintsev V., Rishko L.M., Rudyk Y., Sakharchuk I., Semidotska Z., Seredyuk N., Serkova V., Sharuk O., Slyvka Y., Soldatchenko S., Stadnyuk L., Storozhuk B., Tashchuk V., Tseluyko V., Vatutin M., Vizir V., Vlasenko M., Voronkov L., Yurlov V., Zharinov O., Baig M.W., Brady A., Brooks N., Brooksby P., Crook J.R., Dutka D., Francis C.M., Greaves K., Groves P., Hall A., Kadr H., Lindsay S., Moriarty A., Purvis J., Rozkovec A., Saltissi S., Stewart M., Timmis A., Williams S.
ISSN
1474-547X (Electronic)
ISSN-L
0140-6736
Publication state
Published
Issued date
06/09/2008
Peer-reviewed
Oui
Volume
372
Number
9641
Pages
807-816
Language
english
Notes
Publication types: Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
Ivabradine specifically inhibits the I(f) current in the sinoatrial node to lower heart rate, without affecting other aspects of cardiac function. We aimed to test whether lowering the heart rate with ivabradine reduces cardiovascular death and morbidity in patients with coronary artery disease and left-ventricular systolic dysfunction.
Between December, 2004, and December, 2006, we screened 12 473 patients at 781 centres in 33 countries. We enrolled 10 917 eligible patients who had coronary artery disease and a left-ventricular ejection fraction of less than 40% in a randomised, double-blind, placebo-controlled, parallel-group trial. 5479 patients received 5 mg ivabradine, with the intention of increasing to the target dose of 7.5 mg twice a day, and 5438 received matched placebo in addition to appropriate cardiovascular medication. The primary endpoint was a composite of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening heart failure. We analysed patients by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00143507.
Mean heart rate at baseline was 71.6 (SD 9.9) beats per minute (bpm). Median follow-up was 19 months (IQR 16-24). Ivabradine reduced heart rate by 6 bpm (SE 0.2) at 12 months, corrected for placebo. Most (87%) patients were receiving beta blockers in addition to study drugs, and no safety concerns were identified. Ivabradine did not affect the primary composite endpoint (hazard ratio 1.00, 95% CI 0.91-1.1, p=0.94). 1233 (22.5%) patients in the ivabradine group had serious adverse events, compared with 1239 (22.8%) controls (p=0.70). In a prespecified subgroup of patients with heart rate of 70 bpm or greater, ivabradine treatment did not affect the primary composite outcome (hazard ratio 0.91, 95% CI 0.81-1.04, p=0.17), cardiovascular death, or admission to hospital for new-onset or worsening heart failure. However, it did reduce secondary endpoints: admission to hospital for fatal and non-fatal myocardial infarction (0.64, 95% CI 0.49-0.84, p=0.001) and coronary revascularisation (0.70, 95% CI 0.52-0.93, p=0.016).
Reduction in heart rate with ivabradine does not improve cardiac outcomes in all patients with stable coronary artery disease and left-ventricular systolic dysfunction, but could be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 bpm or greater.
Between December, 2004, and December, 2006, we screened 12 473 patients at 781 centres in 33 countries. We enrolled 10 917 eligible patients who had coronary artery disease and a left-ventricular ejection fraction of less than 40% in a randomised, double-blind, placebo-controlled, parallel-group trial. 5479 patients received 5 mg ivabradine, with the intention of increasing to the target dose of 7.5 mg twice a day, and 5438 received matched placebo in addition to appropriate cardiovascular medication. The primary endpoint was a composite of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening heart failure. We analysed patients by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00143507.
Mean heart rate at baseline was 71.6 (SD 9.9) beats per minute (bpm). Median follow-up was 19 months (IQR 16-24). Ivabradine reduced heart rate by 6 bpm (SE 0.2) at 12 months, corrected for placebo. Most (87%) patients were receiving beta blockers in addition to study drugs, and no safety concerns were identified. Ivabradine did not affect the primary composite endpoint (hazard ratio 1.00, 95% CI 0.91-1.1, p=0.94). 1233 (22.5%) patients in the ivabradine group had serious adverse events, compared with 1239 (22.8%) controls (p=0.70). In a prespecified subgroup of patients with heart rate of 70 bpm or greater, ivabradine treatment did not affect the primary composite outcome (hazard ratio 0.91, 95% CI 0.81-1.04, p=0.17), cardiovascular death, or admission to hospital for new-onset or worsening heart failure. However, it did reduce secondary endpoints: admission to hospital for fatal and non-fatal myocardial infarction (0.64, 95% CI 0.49-0.84, p=0.001) and coronary revascularisation (0.70, 95% CI 0.52-0.93, p=0.016).
Reduction in heart rate with ivabradine does not improve cardiac outcomes in all patients with stable coronary artery disease and left-ventricular systolic dysfunction, but could be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 bpm or greater.
Keywords
Aged, Benzazepines/adverse effects, Benzazepines/pharmacology, Benzazepines/therapeutic use, Coronary Disease/complications, Coronary Disease/drug therapy, Double-Blind Method, Female, Follow-Up Studies, Heart Rate/drug effects, Hospital Mortality, Humans, Ivabradine, Kaplan-Meier Estimate, Male, Middle Aged, Ventricular Dysfunction, Left/complications, Ventricular Dysfunction, Left/drug therapy
Pubmed
Web of science
Create date
15/02/2010 14:45
Last modification date
09/03/2024 8:10
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