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Lancet. 2008 Sep 6;372(9641):807-16. doi: 10.1016/S0140-6736(08)61170-8. Epub 2008 Aug 29.

Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial.

Collaborators (838)

Grancelli H, Freedman B, Eber B, Vanoverschelde JL, Finkov B, Yotov Y, Tardif JC, Hu D, Lau C, Hradec J, Hildebrandt P, Eha J, Peuhkurinen K, Danchin N, Steg PG, 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 TU, 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 AJ, Dargie H, Kjekshus J, Murray G, Ahuad Guerrero RA, Allall OA, Amuchastegui M, Buscema JJ, Bustos B, Cartasegna LR, Cohen Arazi H, Fernandez AA, Fuselli JJ, Guzmén LA, Hasbani E, Ibañez JO, Iglesias RM, Lembo LA, Luciardi HL, Luquez HA, Montaña OR, Nul DR, Orlandini AD, Perna ER, Sanchez A, Sanjurjo MS, Schygiel PO, Sinisi VA, Sokn FJ, Thierer J, Del Valle Lobo Marquez LL, 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 JD, Marwick T, O'Shea J, Owensby D, de Pasquale C, Prior D, Rogers J, Sindone A, Singh BB, Stickland J, Szto G, Tofler G, Vogl E, Waites J, Walsh W, Eber E, Huber K, Lang I, Pichler M, Chenu P, Dendale PA, François PA, Friart A, Goethals M, Materne P, van Mieghem W, Missault L, Vachiery JL, 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 LL, Klinke WP, Kouz S, Lalani A, Lauzon C, Lepage S, Lonn E, Ma P, Matangi M, Nawaz S, Pandey S, Parker JD, Parker JO, Poirier P, Raco D, Rajda M, Rebane T, Rupka D, Savard D, Syan GS, Talbot P, Tardif JC, To TB, Vakani MT, Vertes GE, Yao L, Dong Y, Gai L, Ge JB, 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 CG, Dodt KK, Egstrup K, Gøtzsche L, Gøtzsche O, Haghfelt T, Hildebrandt P, Jakobsen T, Jensen G, Klarlund K, Køber L, Larsen CT, 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 SE, Torp-Pedersen C, Tuxen C, Vigholt E, Averina O, Eha J, Kolbassova O, Sildmäe S, Vahula V, Viigimaa M, Harjola VP, Luoma J, Melin J, Peuhkurinen K, Aliot E, Barthelemy JC, Bauer F, Beaune J, Belin A, Bodur G, Boudahne A, Bourdon A, Bouvier JM, Carlioz R, Chati Z, Cherbi C, Chevalier JM, Chevrier J, Claudon O, Colin P, Dambrine P, Danchin N, Decoulx E, Demarcq JM, Doucet B, Drawin T, Dubois-Rande JL, El Mansour N, Escande M, Fournier PY, Funck F, Gabrovescu M, Galinier M, Galley D, Gay A, Genest M, Godenir JP, Guillot JP, Gully C, Habib G, Huyghe de Mahenge A, Jaboureck O, Kahn JC, Khalife K, Khanoyan P, Koenig A, Leborgne L, Lemoine C, Magnin D, Mann H, Mansourati J, Martelet M, Matina D, Meurice T, Olive TG, Ovize M, Perret T, Pierre-Justin E, Riou A, Roudaut R, Roul G, Roynard JL, Sellier P, Slama M, Soto FX, Thisse JY, Wolf JE, Ammer K, Appel KF, Baar M, Bauknecht C, Baumann G, Bergmann K, Böhm M, Bosch R, Bott J, Cieslinski G, Deissner M, Drescher T, Droese K, Figulla HR, Frick HM, Fries P, Gärtner J, Gola G, Gonska BD, 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 HD, 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 HJ, von Schacky C, Schenkenberger I, Schmidt J, Schreckenberg A, Schuler G, Schultheiss HP, Seidl K, Spanier C, Spengler U, Steindorf J, Strasser R, Taggeselle J, Tammen A, Werdan K, Windstetter U, Winkelmann BR, Wolde CH, 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 VN, Siogas K, Theodorakis G, Tryposkiadis F, Tziakas D, Vardas P, Lee K, Barsi B, Borbola J, Cziráki A, Dézsi CA, 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 MA, Stoma M, Volans E, Berukstis E, Grabauskiene V, Kibarskis A, Kirkutis A, Marcinkeviciene J, Naudziunas A, Petrulioniene Z, Varoneckas G, Zaliunas R, Bartels GL, van Beek GJ, van den Berg BJ, Bruning TA, Cornel JH, Daniels MC, Dijkgraaf R, Fast J, Freericks MP, Galema TW, Göbel EJ, Hamer LH, van der Heijden R, Herrman JP, Hoedemaker G, Holwerda NJ, Hoogslag PA, Jaarsma W, Jap Tjoen San WT, van Kempen LH, Kirkels JH, Kragten JA, Leenders CM, Linssen GC, Lionarons RJ, Maas AH, Michels HM, de Milliano PA, Nagelsmit MJ, Nierop PR, Pinto YM, Robles De Medina R, van Rossum P, van Rugge FP, Somer ST, Swart H, Thijssen H, van der Veen M, Verheul JA, van Vlies B, Voors AA, Wesdorp JC, van Wijk LM, Willems AR, Winter JB, Withagen AJ, van der Zwaan C, Zwart PA, Atar D, Dickstein K, Myhre EP, Achremczyk P, Andrzejak R, Baska J, Bloch C, Dluzniewski M, Drozdowski P, Goch JH, 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 JP, Providencia LA, Salgado A, Teixeira M, Apetrei E, Arsenescu C, Avram R, Babes K, Bruckner I, Capalneanu R, Carasca E, Cinteza M, Craiu E, Dan GA, Datcu MD, Dimulescu DR, Dorobantu M, Dragomor D, Dragulescu IS, Dumitrascu DL, Georgescu IM, Ionescu DD, Ionascu-Fometescu CR, Kiss L, Macarie C, Manitiu I, Minescu B, Nanea T, Olariu C, Olinic NC, Opris M, Pop C, Radoi M, Radu I, Sinescu CJ, Tanaseanu CM, Tase A, Tintoiu I, Tomescu M, Topolnitchi L, Vintila M, Vladoianu M, Arkhipov MV, Aroutiounov GP, Azarin OG, Barbarash OL, Bart BY, Beloussov YB, Bychkova L, Chumakova GA, Glezer MG, Golukhova E, Gorbachenkov AA, Gordeev IG, Ivleva AY, Karpov YA, Karpov YB, Kastanaian AA, Kisliak OA, Kobalava JD, Konyakhin AY, Khrustalev OA, Kuimov AD, Kukes AG, Lopatin YM, Mareev VY, Moiseeva OM, Mkrtchyan VR, Nedogoda SV, Orlov VA, Perepech NB, Pimenov LT, Pozdnyakov YM, Rodoman GV, Rudnev DV, Sayganov SA, Shlyakhto EV, Shostak NA, Shpektor AV, Sidorenko BA, Sorokin LA, Stryuk RI, Svistov AS, Tankhilevich BM, Tereschenko SN, Tsyba LP, Vasyuk YA, Vertkine AL, Yakhontova PK, Yakusevich VV, Yakushin SS, Zadionchenko VS, Zateyshchikov DA, Zhilyaev EV, 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 LF, 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 MA, Perez Villa F, Romero Hinojosa JA, 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 LM, 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 MW, Brady A, Brooks N, Brooksby P, Crook JR, Dutka D, Francis CM, Greaves K, Groves P, Hall A, Kadr H, Lindsay S, Moriarty A, Purvis J, Rozkovec A, Saltissi S, Stewart M, Timmis A, Williams S.

Author information

  • 1Royal Brompton Hospital, London, UK.

Abstract

BACKGROUND:

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.

METHODS:

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.

FINDINGS:

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).

INTERPRETATION:

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.

Comment in

PMID:
18757088
[PubMed - indexed for MEDLINE]
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