Rate control with ivabradine: Angina pectoris and beyond

American Journal of Cardiovascular Drugs

Volumn 11, Issue 1, 2011, Pages 1-12

  Parakh, Neeraj ^a   Bhargava, Balram ^b  

^a G B PANT HOSPITAL   (India)

^b ALL INDIA INSTITUTE OF MEDICAL SCIENCES   (India)

Author keywords

Acute coronary syndromes, treatment; Angina pectoris, treatment; Arrhythmias, treatment; Heart failure, treatment; Ivabradine, pharmacodynamics; Ivabradine, therapeutic use; Research and development.

Indexed keywords

AMLODIPINE; ATENOLOL; BARBITURIC ACID DERIVATIVE; BETA ADRENERGIC RECEPTOR BLOCKING AGENT; FLUCONAZOLE; GRAPEFRUIT EXTRACT; IVABRADINE; KETOCONAZOLE; METOPROLOL; PHENYTOIN; PLACEBO; RIFAMPICIN;

ACUTE CORONARY SYNDROME; ANGINA PECTORIS; ATHEROSCLEROSIS; BRADYCARDIA; CARDIOVASCULAR DISEASE; CLINICAL TRIAL; CORONARY ARTERY DISEASE; CREATININE BLOOD LEVEL; DIZZINESS; DRUG ABSORPTION; DRUG DISTRIBUTION; DRUG DOSE REDUCTION; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG MECHANISM; DRUG METABOLISM; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; EOSINOPHILIA; FORCED EXPIRATORY VOLUME; GLUCOSE METABOLISM; HEADACHE; HEART ARRHYTHMIA; HEART ATRIUM FIBRILLATION; HEART FAILURE; HEART LEFT VENTRICLE FAILURE; HEART RATE; HEART VENTRICLE TACHYCARDIA; HEMOGLOBIN BLOOD LEVEL; HUMAN; HYPERURICEMIA; MORBIDITY; MORTALITY; MUSCLE CRAMP; NONHUMAN; PEAK EXPIRATORY FLOW; PHARMACODYNAMICS; PRIORITY JOURNAL; RECOMMENDED DRUG DOSE; REVIEW; SIDE EFFECT; SINUS TACHYCARDIA; ST SEGMENT ELEVATION MYOCARDIAL INFARCTION; STABLE ANGINA PECTORIS; SYSTOLIC HEART FAILURE; VISION; VISUAL DISORDER;

ACUTE CORONARY SYNDROME; ANGINA PECTORIS; ARRHYTHMIAS, CARDIAC; BENZAZEPINES; CYCLIC NUCLEOTIDE-GATED CATION CHANNELS; HEART FAILURE; HEART RATE; HUMANS;

EID: 79251601377     PISSN: 11753277     EISSN: 1179187X     Source Type: Journal    
DOI: 10.2165/11584840-000000000-00000     Document Type: Review

References (91)

1. Lad VD. Secrets of the pulse: the ancient art of the ayurvedic pulse diagnosis. 2nd ed. Delhi: Lotus Press, Motilal Banarasi Dass Publishers, 2005: 10-8
2. Kannel WB, KannelC, Paffenbarger Jr RS, et al Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J 1987 Jun; 113 (6): 1489-94
3. Gillum RF, Makuc DM, Feldman JJ. Pulse rate, coronary heart disease, and death: the NHANES I Epidemiologic Follow-Up Study. Am Heart J 1991 Jan; 121 (1 Pt 1): 172-7
4. Dyer AR, Persky V, Stamler J, et al Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies. Am J Epidemiol 1980 Dec; 112 (6): 736-49
5. Wilhelmsen L, Berglund G, Elmfeldt D, et al The multifactor primary prevention trial in Goteborg, Sweden. Eur Heart J 1986 Apr; 7 (4): 279-88
6. Tverdal A, Hjellvik V, Selmer R. Heart rate and mortality from cardiovascular causes: a 12 year follow-up study of 379 843 men and women aged 40-45 years. Eur Heart J 2008 Nov; 29 (22): 2772-81
7. HozawaA, Ohkubo T, Kikuya M, et al Prognostic value of home heart rate for cardiovascular mortality in the general population: the Ohasama study. Am J Hypertens 2004 Nov; 17 (11 Pt 1): 1005-10
8. Kristal-Boneh E, Silber H, Harari G, et al The association of resting heart rate with cardiovascular, cancer and all-cause mortality: eight year follow-up of 3527 male Israeli employees (the CORDIS Study). Eur Heart J 2000 Jan; 21 (2): 116-24
9. Gillman MW, Kannel WB, Belanger A, et al Influence of heart rate on mortality among persons with hypertension: the Framingham Study. Am Heart J 1993 Apr; 125: 1148-54
10. Fox K, Ford I, Steg PG, et al BEAUTIFUL investigators Heart rate as a prognostic risk factor in patients with coronary artery disease and leftventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet 2008 Sep; 372 (9641): 817-21
11. Palatini P, Benetos A, Grassi G, et al Identification and management of the hypertensive patient with elevated heart rate: statement of a European Society of Hypertension Consensus Meeting. J Hypertens 2006 Apr; 24 (4): 603-10
12. Jouven X, Empana JP, Schwartz PJ, et al Heart-rate profile during exercise as a predictor of sudden death. N Engl J Med 2005 May; 352 (19): 1951-8 (Pubitemid 40638365)
13. Beere PA, Glagov S, Zarins CK. Experimental atherosclerosis at the carotid bifurcation of the cynomolgus monkey: localization, compensatory enlargement, and the sparing effect of lowered heart rate. Arterioscler Thromb 1992 Nov; 12 (11): 1245-53
14. Traub O, Berk BC. Laminar shear stress: mechanisms by which endothelial cells transduce an atheroprotective force. Arterioscler Thromb Vasc Biol 1998 May; 18 (5): 677-85
15. Kaplan JR, Manuck SB, Adams MR, et al Inhibition of coronary atherosclerosis by propranolol in behaviorally predisposed monkeys fed an atherogenic diet. Circulation 1987 Dec; 76 (6): 1364-72
16. Bassiouny HS, Zarins CK, Kadowaki MH, et al Hemodynamic stress and experimental aortoiliac atherosclerosis. J Vasc Surg 1994 Mar; 19 (3): 426-34
17. Brown HF, DiFrancesco D, Noble SJ. How does adrenaline accelerate the heart? Nature 1979 Jul; 280 (57): 235-6
18. Nerbonne JM, Kass RS. Molecular physiology of cardiac repolarization. Physiol Rev 2005 Oct; 85 (4): 1205-53
19. Baruscotti M, Bucchi A, DiFrancesco D. Physiology and pharmacology of the cardiac pacemaker (funny) current. Pharmacol Ther 2005 Jul; 107 (1): 59-79
20. Dobrzynski H, Nikolski VP, Sambelashvilli AT, et al Site of origin and molecular substrate of atrioventricular junctional rhythm in the rabbit heart. Circ Res 2003 Nov; 93 (11): 1102-10
21. Munk AA, Adjemian RA, Zhao J, et al Electrophysiological properties of morphologically distinct cells isolated from the rabbit atrioventricular node. J Physiol 1996 Jun; 493 (Pt 3): 801-18
22. ShiW,Wymore R, Yu H, et al Distribution and prevalence of hyperpolarizationactivated cation channel (HCN) mRNA expression in cardiac tissue. Circ Res 1999 Jul; 85 (1): e1-6
23. Robinson RB, Siegelbaum SA. Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol 2003; 65: 453-80
24. Pape HC. Queer current and the pacemaker: hyperpolarization-activated cation current in neurons. Annu Rev Physiol 1996; 58: 299-327
25. Snyders DJ, Van Bogaert PP. Alinidine modifies the pacemaker current in sheep Purkinje fibers. Pflügers Arch 1987 Sep; 410 (1-2): 83-91
26. Goethals M, Raes A, van Bogaert PP. Use-dependent block of the pacemaker current If in rabbit sinoatrial node cells by zatebradine (UL-FS 49): on the mode of action of sinus node inhibitors. Circulation 1993 Nov; 88 (5 Pt 1): 2389-401
27. Thollon C, Bidouard JP, Cambarrat C, et al Stereospecific in vitro and in vivo effects of the new sinus node inhibitor (+)-S16257. Eur J Pharmacol 1997 Nov; 339 (19): 43-51
28. Fox K, Ford I, Steg PG, et al Ivabradine for patients with stable coronary artery disease and left ventricular dysfunction (BEAUTIFUL): a randomized, double-blind, placebo controlled trial. Lancet 2008 Sep; 372 (9641): 807-16
29. Tardif JC, Ford I, Tendera M, et al, for the INITIATIVE Investigators. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J 2005 Dec; 26 (23): 2529-36
30. Tardif JC, Ponikowski P, Kahan T, ASSOCIATE Study Investigators. Efficacy of the I(f) current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebocontrolled trial. Eur Heart J 2009 Mar; 30 (5): 540-8
31. Köster R, Kaehler J, Meinertz T. Treatment of stable angina pectoris by ivabradine in every day practice: The REDUCTION Study. Am Heart J 2009 Oct; 158 (4): e51-7
32. Ruzyllo W, Tendera M, Ford I, et al Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferioriry trial. Drugs 2007; 67 (3): 393-405
33. Borer JS, Fox K, Jaillon P, et al, Ivabradine Investigators Group. Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation 2003 Feb; 107 (6): 817-23
34. Lopez-Bescos L, Filipova S, Martos R. Long-term safety and efficacy of the If current inhibitor ivabradine in patients with chronic stable angina. Cardiology 2007; 108 (4): 387-96
35. Swedberg K, Komajda M, Bahm M, et al Rationale and design of a randomized, double-blind, placebo-controlled outcome trial of ivabradine in chronic heart failure: the Systolic Heart Failure Treatment with the I(f) Inhibitor Ivabradine Trial (SHIFT). Eur J Heart Fail 2010 Jan; 12 (1): 75-81
36. ISRCTN (International Standard Randomised Controlled Trial Number). Evaluation versus placebo of the effects on heart rate, haemodynamic parameters, safety and tolerability of 5mg bolus of ivabradine followed by 8-hour infusion of 5mg of ivabradine, given to patients undergoing a percutaneous coronary intervention following a myocardial infarction with ST segment elevation (STEMI): a pilot, blind, randomised, placebo-controlled, international, multi-centre study including the ancillary sub-study to the clinical study protocol. VIVIFY trial [online]. Available from URL: http://www.controlled- trials.com/ISRCTN66067800 [Accessed 2010 Apr 30]
37. Dominguez-Rodriguez A, Fard SS, Abreu-Gonzalez P, et al Randomised, double-blind, placebo-controlled trial of ivabradine in patients with acute coronary syndrome: effects of the If current inhibitor ivabradine on reduction of inflammation markers in patients with acute coronary syndrome. RIVIERA trial study design and rationale. Cardiovasc Drugs Ther 2009 Jun; 23 (3): 243-7
38. ISRCTN (International Standard Randomised Controlled Trial Number). Effects of ivabradine in patients with stable coronary artery disease without heart failure: SIGNIFY trial [online]. Available from URL: http://www. controlled-trials.com/ISRCTN6157629 [Accessed 2010 Apr 30]
39. Steg PG. Heart rate management in coronary artery disease: the CLARIFY registry. Eur Heart J 2009; 11 Suppl. D: D13-8
40. Bucchi A, Baruscotti M, DiFrancesco D. Current-dependent block of rabbit sino-atrial node If channels by ivabradine. J Gen Physiol 2002 Jul; 120 (1): 1-13
41. ThollonC, Cambarrat C, Vian J, et al Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison with UL-FS 49. Br J Pharmacol 1994 May; 112 (1): 37-42
42. Savelieva I, Camm AJ. Comparison of the effects of a selective If current inhibitor ivabradine and atenolol on theQT interval in patients with coronary artery disease [abstract no. P2-36]. Heart Rhythm 2005 May; 2 (5): S145-6
43. Camm AJ, Lau CP. Electrophysiological effects of a single intravenous administration of ivabradine (S 16257) in adult patients with normal baseline electrophysiology. Drugs R D 2003; 4 (2): 83-9
44. Mulder P, Barbier S, Chagraoui A, et al Long-term heart-rate reduction induced by the selective If current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure. Circulation 2004 Apr; 109 (13): 1674-9
45. Mulder P, Thuillez C. Heart rate slowing for myocardial dysfunction/heart failure: rationale and preclinical studies. In: Camm J, Tandera M, editors. Heart rate slowing by If current inhibition. Advances in Cardiology 43. Basel: Karger, 2006: 97-105
46. European Public Assessment Report (EPAR). Ivabradine hydrochloridestable angina pectoris: scientific discussion. EMEA 2005 [online]. Available from URL: http://www.emea.europa.eu/humandocs/Humans/EPAR/procoralan/procoralan.htn [Accessed 2010 Apr 30]
47. Baumhakel M, Custodis F, Schlimmer N, et al Heart-rate reduction with ivabradine improves erectile dysfunction in parallel to decrease in atherosclerotic plaque load in ApoE-knockout mice. Atherosclerosis. Epub 2010Mar
48. Drouin A, Gendron ME, Thorin E, et al Chronic heart-rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice. Br J Pharmacol 2008 Jun; 154 (4): 749-57
49. Procoralan-(ivabradine hydrochloride) [summary of product characteristics]. Servier Laboratories Ltd. Updated 13 November 2009 [online]. Available from URL: [Accessed 2010 Apr 30]
50. Borer JS, Tardif JC. Efficacy of ivabradine, a selective I(f) inhibitor, in patients with chronic stable angina pectoris and diabetes mellitus. Am J Cardiol 2010 Jan; 105 (1): 29-35
51. Portolos A, Terleira A, Calvo A, et al Effects of Hypericum perforatum on ivabradine pharmacokinetics in healthy volunteers: an open-label, pharmacokinetic interaction clinical trial. J Clin Pharmacol 2006 Oct; 46 (10): 1188-94
52. Portoles A, Calvo A, Terleira A, et al Lack of pharmacokinetic interaction between omeprazole or lansoprazole and ivabradine in healthy volunteers: an open-label, randomized, crossover, pharmacokinetic interaction clinical trial. J Clin Pharmacol 2006 Oct; 46 (10): 1195-203
53. Simon L, Ghaleh B, Puybasset L, et al Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. J Pharmacol Exp Ther 1995 Nov; 275 (2): 659-66
54. Fox K, Ford I, Steg PG, et al Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized controlled BEAUTIFUL trial. Eur Heart J 2009 Oct; 30 (19): 2337-45
55. Köster R, Kaehler J, Meinertz T, for the REDUCTION Study. Ivabradine reduces angina pectoris in patients after PCI: results from the reduction study [abstract no. 1213-298]. J Am Coll Cardiol 2010 Mar; 55 (10A): A121.E1132
56. Cerbai E, Barbieri M, Mugelli A. Characterization of the hyperpolarizationactivated current, If, in ventricular myocytes isolated from hypertensive rats. J Physiol 1994 Dec; 481 (Pt 3): 585-91
57. Cerbai E, Barbieri M, Mugelli A. Occurrence and properties of the hyperpolarization- activated current If in ventricular myocytes from normotensive and hypertensive rats during aging. Circulation 1996 Oct; 94 (7): 1674-81
58. Stilli D, Sgoifo A, Macchi E, et al Myocardial remodeling and arrhythmogenesis in moderate cardiac hypertrophy in rats. Am J Physiol Heart Circ Physiol 2001 Jan; 280 (1): H142-50
59. Fernandez-Velasco M, Goren N, Benito G, et al Regional distribution of hyperpolarization-activated current If and hyperpolarization-activated cyclic nucleotide-gated channel mRNA expression in ventricular cells from control and hypertrophied rat hearts. J Physiol 2003 Dec; 553 (Pt 2): 395-405
60. Cerbai E, Sartiani L, De Paoli P, et al Isolated cardiac cells for electropharmacological studies. Pharmacol Res 2000 Jul; 42 (1): 1-8
61. Sartiani L, DePaoli P, Stillitano F, et al Functional remodeling in postmyocardial infarcted rats: focus on beta-adrenoceptor subtypes. J Mol Cell Cardiol 2006 Feb; 40 (2): 258-66
62. Cerbai E, Pino R, Porciatti F, et al Characterization of the hyperpolarizationactivated current, If, in ventricular myocytes from human failing heart. Circulation 1997 Feb; 95 (3): 568-71
63. Hoppe UC, Jansen E, Sudkamp M, et al Hyperpolarization activated inward current in ventricular myocytes from normal and failing human hearts. Circulation 1998 Jan; 97 (1): 55-65
64. Cerbai E, Sartiani L, DePaoli P, et al The properties of the pacemaker current If in human ventricular myocytes are modulated by cardiac disease. JMol Cell Cardiol 2001 Mar; 33 (3): 441-8
65. Couvreur N, Tissier R, Pons S, et al Chronic heart-rate reduction with ivabradine improves systolic function of the reperfused heart through a dual mechanism involving a direct mechanical effect and a long-term increase in FKBP12/12.6 expression. Eur Heart J. Epub 2009 Dec
66. Fasullo S, Cannizzaro S, Maringhini G, et al Comparison of ivabradine versus metoprolol in early phases of reperfused anterior myocardial infarction with impaired left ventricular function:preliminary findings. J Card Fail 2009 Dec; 15 (10): 856-63
67. Reil JC,Reil GH, Bohm M. Heart-rate reduction by I(f)-channel inhibition and its potential role in heart failure with reduced and preserved ejection fraction. Trends Cardiovasc Med 2009 Jul; 19 (5): 152-7
68. Colin P, Ghaleh B, Monnet X, et al Effect of graded heart-rate reduction with ivabradine on myocardial oxygen consumption and diastolic time in exercising dogs. J Pharmacol Exp Ther 2004 Jan; 308 (1): 236-40
69. De Ferrari GM, Mazzuero A, Agnesina L, et al Favourable effects of heartrate reduction with intravenous administration of ivabradine in patients with advanced heart failure. Eur J Heart Fail 2008 Jun; 10 (6): 550-5
70. Arutyunov GP, Arutyunov AG, Volkova AG. Study evaluating the impact of a combination of inotropic support and heart rate monitoring on prognosis and stabilization rate in patients with decompensated chronic heart failure (LEGION). Ter Arkh 2010; 82 (3): 47-52
71. Link A, Reil JC, Selejan S, et al Effect of ivabradine in dobutamine induced sinus tachycardia in a case of acute heart failure. Clin Res Cardiol 2009 Aug; 98 (8): 513-5
72. Heidland UE, Stauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation 2001 Sep; 104 (13): 1477-82
73. Custodis F, Baumhakel M, Schlimmer N, et al Heart-rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice. Circulation 2008 May; 117 (18): 2377-87
74. Schulze-Bahr E,Neu A, Friederich P, et al Pacemaker channel dysfunction in a patient with sinus node disease. J Clin Invest 2003 May; 111 (10): 1537-45
75. Milanesi R, Baruscotti M, Gnecchi-Ruscone T, et al Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel [published rratum appears in N Engl J Med 2006 Jun; 354 (23): 2520
76. N Engl J Med 2006 Jan; 354 (2): 151-7
77. Nof E, Luria D, Brass D, et al Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia. Circulation 2007 Jul; 116 (5): 463-70
78. Plotnikov AN, Bucchi A, Shlapakova I, et al HCN212-channel biological pacemakers manifesting ventricular tachyarrhythmias are responsive to treatment with If blockade. Heart Rhythm 2008 Feb; 5 (2): 282-8
79. Vaillant F, Tabib A, Chevalier P, et al Heart-rate reduction with ivabradine protects against ventricular fibrillation during acute ischemia in pigs [abstract]. J Mol Cell Cardiol 2007 Jun; 42 (6 Suppl. 1): S14
80. Zellerhoff S, Hinterseer M, Krull BF, et al Selective inhibition of the funny current: a novel pharmacological intervention in patients with inadequate sinus tachycardia [abstract no. PO01-23].Heart Rhythm2009May; 6 (5) Suppl. 1: S103
81. Winum PF, Cayla G, Rubini M, et al A case of cardiomyopathy induced by inappropriate sinus tachycardia and cured by ivabradine. Pacing Clin Electrophysiol 2009 Jul; 32 (7): 942-4
82. Lai LP, Su MJ, Lin JL, et al Measurement of funny current (If) channel mRNA in human atrial tissue: correlation with left atrial filling pressure and atrial fibrillation. J Cardiovasc Electrophysiol 1999 Jul; 10 (7): 947-53
83. Porciatti F, Pelzmann B, Cerbai E, et al The pacemaker current If in single human atrial myocytes and the effect of beta-adrenoceptor and A1-adenosine receptor stimulation. Br J Pharmacol 1997 Nov; 122 (5): 963-9
84. Pino R, Cerbai E, Calamai G, et al Effect of 5-HT4 receptor stimulation on the pacemaker current If in human isolated atrial myocytes. Cardiovasc Res 1998 Dec; 40 (3): 516-22
85. Opthof T. The membrane current (If) in human atrial cells: implications for atrial arrhythmias. Cardiovasc Res 1998 Jun; 38 (3): 537-40
86. Doesch AO, Celik S, Ehlermann P, et al Heart-rate reduction after heart transplantation with beta-blocker versus the selective If channel antagonist ivabradine. Transplantation 2007 Oct; 84 (8): 988-96
87. Doesch AO, Ammon K, Konstandin M, et al Heart-rate reduction for 12 months with ivabradine reduces left ventricular mass in cardiac allograft recipients. Transplantation 2009 Sep; 88 (6): 835-41
88. Pasceri E, Curcio A, Achille F, et al Acute reduction of transmitral gradient after I(f) channel inhibition in patients with mitral valve stenosis or a mitral annuloplasty ring [abstract no. 974]. Europace 2009 Jun; 11 Suppl. 2: S6
89. Bel A, Perrault LP, Faris B, et al Inhibition of the pacemaker current: a bradycardic therapy for off-pump coronary operations. Ann Thorac Surg 1998 Jul; 66 (1): 148-52
90. Cervetto L, Demontis GC, Gargini C. Cellular mechanisms underlying the pharmacological induction of phosphenes. Br J Pharmacol 2007 Feb; 150 (4): 383-90
91. Babu KS, Gadzik F, Holgate ST. Absence of respiratory effects with ivabradine in patients with asthma. Br J Clin Pharmacol 2008 Jul; 66 (1): 96-101