Effect of Ivabradine in Stage D HF/Cardiogenic Shock Patients on Dobutamine

Summary

This is a randomized, double blind, single center trial to study of the effects of Ivabradine vs. Placebo on patients hospitalized for Stage D heart failure (HF)/ and cardiogenic shock (CS) who will require continuous infusion of Dobutamine and have developed sinus tachycardia (ST) (heart rate \>100 beats/min). The aim of the study will be to assess the potential of Ivabradine to slow ST and improve hemodynamics in patients with stage D HF/CS on Dobutamine treatment.

Timeline

Start

2018-03-15

Primary completion

2020-01

Completion

2020-06

Publications

• Background Reynolds HR, Hochman JS. Cardiogenic shock: current concepts and improving outcomes. Circulation. 2008 Feb 5;117(5):686-97. doi: 10.1161/CIRCULATIONAHA.106.613596. No abstract available.
• Background Vasquez A, Kern KB, Hilwig RW, Heidenreich J, Berg RA, Ewy GA. Optimal dosing of dobutamine for treating post-resuscitation left ventricular dysfunction. Resuscitation. 2004 May;61(2):199-207. doi: 10.1016/j.resuscitation.2004.01.002.
• Background Leier CV, Webel J, Bush CA. The cardiovascular effects of the continuous infusion of dobutamine in patients with severe cardiac failure. Circulation. 1977 Sep;56(3):468-72. doi: 10.1161/01.cir.56.3.468.
• Background Metra M, Nodari S, D'Aloia A, Muneretto C, Robertson AD, Bristow MR, Dei Cas L. Beta-blocker therapy influences the hemodynamic response to inotropic agents in patients with heart failure: a randomized comparison of dobutamine and enoximone before and after chronic treatment with metoprolol or carvedilol. J Am Coll Cardiol. 2002 Oct 2;40(7):1248-58. doi: 10.1016/s0735-1097(02)02134-4.
• Background Wynsen JC, O'Brien PD, Warltier DC. Zatebradine, a specific bradycardic agent, enhances the positive inotropic actions of dobutamine in ischemic myocardium. J Am Coll Cardiol. 1994 Jan;23(1):233-41. doi: 10.1016/0735-1097(94)90526-6.
• Background Aidonidis I, Brachmann J, Rizos I, Zacharoulis A, Stavridis I, Toutouzas P, Kubler W. Electropharmacology of the bradycardic agents alinidine and zatebradine (UL-FS 49) in a conscious canine ventricular arrhythmia model of permanent coronary artery occlusion. Cardiovasc Drugs Ther. 1995 Aug;9(4):555-63. doi: 10.1007/BF00878087.
• Background Hettrick DA, Pagel PS, Lowe D, Tessmer JP, Warltier DC. Increases in inotropic state without change in heart rate: combined use of dobutamine and zatebradine in conscious dogs. Eur J Pharmacol. 1996 Dec 5;316(2-3):237-44. doi: 10.1016/s0014-2999(96)00688-7.
• Background Neustein SM, Dimich I, Shiang H, Mezrow C. Role of zatebradine and propranolol in attenuation of tachycardia produced by dobutamine in pigs. Acta Anaesthesiol Scand. 1997 Aug;41(7):849-52. doi: 10.1111/j.1399-6576.1997.tb04799.x.
• Background Zhang Y, Mazgalev TN. Cardiac vagal stimulation eliminates detrimental tachycardia effects of dobutamine used for inotropic support. Ann Thorac Surg. 2009 Jul;88(1):117-22. doi: 10.1016/j.athoracsur.2009.04.009.
• Background DiFrancesco D, Camm JA. Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs. 2004;64(16):1757-65. doi: 10.2165/00003495-200464160-00003.
• Background Fox K, Ford I, Steg PG, Tendera M, Ferrari R; BEAUTIFUL Investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008 Sep 6;372(9641):807-16. doi: 10.1016/S0140-6736(08)61170-8. Epub 2008 Aug 29.
• Background Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010 Sep 11;376(9744):875-85. doi: 10.1016/S0140-6736(10)61198-1.
• Background Henri C, O'Meara E, De Denus S, Elzir L, Tardif JC. Ivabradine for the treatment of chronic heart failure. Expert Rev Cardiovasc Ther. 2016;14(5):553-61. doi: 10.1586/14779072.2016.1165092. Epub 2016 Mar 28.
• Background Tardif JC, O'Meara E, Komajda M, Bohm M, Borer JS, Ford I, Tavazzi L, Swedberg K; SHIFT Investigators. Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy. Eur Heart J. 2011 Oct;32(20):2507-15. doi: 10.1093/eurheartj/ehr311. Epub 2011 Aug 29.
• Background Fang Y, Debunne M, Vercauteren M, Brakenhielm E, Richard V, Lallemand F, Henry JP, Mulder P, Thuillez C. Heart rate reduction induced by the if current inhibitor ivabradine improves diastolic function and attenuates cardiac tissue hypoxia. J Cardiovasc Pharmacol. 2012 Mar;59(3):260-7. doi: 10.1097/FJC.0b013e31823e5e01.
• Background Mulder P, Barbier S, Chagraoui A, Richard V, Henry JP, Lallemand F, Renet S, Lerebours G, Mahlberg-Gaudin F, Thuillez C. Long-term heart rate reduction induced by the selective I(f) current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure. Circulation. 2004 Apr 6;109(13):1674-9. doi: 10.1161/01.CIR.0000118464.48959.1C. Epub 2004 Feb 23.
• Background Boldt A, Gergs U, Ponicke K, Simm A, Silber RE, Neumann J. Inotropic effects of ivabradine in the mammalian heart. Pharmacology. 2010;86(5-6):249-58. doi: 10.1159/000320454. Epub 2010 Oct 21.
• Background Reil JC, Tardif JC, Ford I, Lloyd SM, O'Meara E, Komajda M, Borer JS, Tavazzi L, Swedberg K, Bohm M. Selective heart rate reduction with ivabradine unloads the left ventricle in heart failure patients. J Am Coll Cardiol. 2013 Nov 19;62(21):1977-1985. doi: 10.1016/j.jacc.2013.07.027. Epub 2013 Aug 7.
• Background De Ferrari GM, Mazzuero A, Agnesina L, Bertoletti A, Lettino M, Campana C, Schwartz PJ, Tavazzi L. Favourable effects of heart rate reduction with intravenous administration of ivabradine in patients with advanced heart failure. Eur J Heart Fail. 2008 Jun;10(6):550-5. doi: 10.1016/j.ejheart.2008.04.005. Epub 2008 May 16.
• Background Cavusoglu Y, Mert U, Nadir A, Mutlu F, Morrad B, Ulus T. Ivabradine treatment prevents dobutamine-induced increase in heart rate in patients with acute decompensated heart failure. J Cardiovasc Med (Hagerstown). 2015 Sep;16(9):603-9. doi: 10.2459/JCM.0000000000000033.
• Background Roubille F, Lattuca B, Busseuil D, Leclercq F, Davy JM, Rheaume E, Tardif JC. Is ivabradine suitable to control undesirable tachycardia induced by dobutamine in cardiogenic shock treatment? Med Hypotheses. 2013 Aug;81(2):202-6. doi: 10.1016/j.mehy.2013.05.002. Epub 2013 May 26.
• Background Franke J, Schmahl D, Lehrke S, Pribe R, Bekeredjian R, Doesch AO, Ehlermann P, Schnabel P, Katus HA, Zugck C. Adjuvant Use of Ivabradine in Acute Heart Failure due to Myocarditis. Case Rep Med. 2011;2011:203690. doi: 10.1155/2011/203690. Epub 2011 Sep 27.
• Background Link A, Reil JC, Selejan S, Bohm M. Effect of ivabradine in dobutamine induced sinus tachycardia in a case of acute heart failure. Clin Res Cardiol. 2009 Aug;98(8):513-5. doi: 10.1007/s00392-009-0038-9. Epub 2009 Jun 23. No abstract available.
• Background Vitale D, De Santis V, Guarracino F, Fontana A, Pellegrini F, Tritapepe L. Use of ivabradine in catecholamine-induced tachycardia after high-risk cardiac surgery. Clin Res Cardiol. 2010 Dec;99(12):853-5. doi: 10.1007/s00392-010-0208-9. Epub 2010 Sep 7. No abstract available.
• Background Gallet R, Ternacle J, Damy T, Guendouz S, Bremont C, Seemann A, Gueret P, Dubois-Rande JL, Lim P. Hemodynamic effects of Ivabradine in addition to dobutamine in patients with severe systolic dysfunction. Int J Cardiol. 2014 Sep 20;176(2):450-5. doi: 10.1016/j.ijcard.2014.07.093. Epub 2014 Aug 1.
• Background Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail. 2010 Sep;3(5):588-95. doi: 10.1161/CIRCHEARTFAILURE.109.930701. Epub 2010 Jun 11.
• Background Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Heart Fail Clin. 2008 Jan;4(1):23-36. doi: 10.1016/j.hfc.2007.10.001.

Drugs

Indications