An open-label study to assess the effect of a single dose of Nebivolol and Ivabradine on heart rate and pulse wave velocity in hypertensive patients receiving amlodipine
Keywords:Nebivolol, Ivabradine, Arterial stiffness, Carotid femoral pulse wave velocity, Amlodipine
Background:Increased resting heart rate (HR) has emerged as an independent risk factor in the general population and in patients with hypertension, coronary artery disease, and myocardial infarction. HR is strongly and directly associated with arterial rigidity in hypertensive patients. Nebivolol (N) and Ivabradine (I) were established HR lowering agents. In this study, we have evaluated Nebivolol and Ivabradine on HR and pulse wave velocity in hypertensive patients who were receiving Amlodipine.
Methods: A total of 18 hypertensive patients on Amlodipine participated in our study. Nine received Nebivolol and others received Ivabradine. We measured HR, blood pressures (BPs) and carotid-femoral pulse wave velocity (cf PWV - an index of large artery stiffness) non-invasively at baseline and 2 hrs after administration of single oral dose of 5 mg N and 5 mg of I.
Results: The mean change in HR (−21.7±7.1 vs. −13.89±7.4 beats/min p=0.03) and cf PWV (−0.27±0.58 vs. −2.31±2.1 m/s p=0.01) was statistically significant after treatment in N and I groups respectively. However, there was no significant change in systolic BP (−17.3±9.1 vs. −15.1±11.1 mmHg p=0.65) and diastolic BP (−3.5±5.0 vs. −8.0±6.4 mmHg p=0.11) after treatment in N and I groups, respectively.
Conclusions: Nebivolol is an effective HR lowering agent compared to Ivabradine. However, significant decrease in arterial stiffness was observed with Ivabradine.
Slawson DC, Shaughnessy AF. Obtaining useful information from expert based sources. BMJ. 1997;314(7085):947-9.
Robertson RM, Robertson D. Treatment of myocardial ischemia and hypertension. In: Laurence LB, Bruce AC, Bjorn CK, editors. Goodman and Gillman’s The Pharmacological Basis of Therapeutics. 12th Edition. New York: McGraw-Hill; 2010: 767-79.
Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, double-blind, crossover study. Circulation. 2001;104(5):511-4.
Laurent S. Arterial wall hypertrophy and stiffness in essential hypertensive patients. Hypertension. 1995;26(2):355-62.
Dominguez-Rodriguez A, Blanco-Palacios G, Abreu-Gonzalez P Increased heart rate and atherosclerosis: potential implications of ivabradine therapy. World J Cardiol. 2011;3(4):101-4.
Schram MT, Henry RM, van Dijk RA, Kostense PJ, Dekker JM, Nijpels G, et al. Increased central artery stiffness in impaired glucose metabolism and type 2 diabetes: the Hoorn Study. Hypertension. 2004;43(2):176-81.
Pannier B, Guérin AP, Marchais SJ, Safar ME, London GM. Stiffness of capacitive and conduit arteries: prognostic significance for end-stage renal disease patients. Hypertension. 2005;45(4):592-6.
Georgescu A, Pluteanu F, Flonta ML, Badila E, Dorobantu M, Popov D. The cellular mechanisms involved in the vasodilator effect of nebivolol on the renal artery. Eur J Pharmacol. 2005;508(1-3):159-66.
Ignarro LJ. Experimental evidences of nitric oxide-dependent vasodilatory activity of nebivolol, a third-generation beta-blocker. Blood Press Suppl. 2004;1:2-16.
Frishman WH. Beta-adrenergic blocker withdrawal. Am J Cardiol. 1987;59:26F-32.
Egstrup K. Transient myocardial ischemia after abrupt withdrawal of antianginal therapy in chronic stable angina. Am J Cardiol. 1988;61:1219-22.
Dawes M, Chowienczyk PJ, Ritter JM. Effects of inhibition of the L-arginine/nitric oxide pathway on vasodilation caused by beta-adrenergic agonists in human forearm. Circulation. 1997;95(9):2293-7.
Savelieva I, Camm AJ. Novel If current inhibitor ivabradine: safety considerations. Adv Cardiol. 2006;43:79-96.
Naidu MU, Reddy BM, Yashmaina S, Patnaik AN, Rani PU. Validity and reproducibility of arterial pulse wave velocity measurement using new device with oscillometric technique: a pilot study. Biomed Eng Online. 2005;4:49.
Sa Cunha R, Pannier B, Benetos A, Siché JP, London GM, Mallion JM, et al. Association between high heart rate and high arterial rigidity in normotensive and hypertensive subjects. J Hypertens. 1997;15:1423-30.
Benetos A, Laurent S, Hoeks AP, Boutouyrie PH, Safar ME. Arterial alterations with aging and high blood pressure. A noninvasive study of carotid and femoral arteries. Arterioscler Thromb. 1993;13(1):90-7.
Tomiyama H, Hashimoto H, Tanaka H, Matsumoto C, Odaira M, Yamada J, et al. Synergistic relationship between changes in the pulse wave velocity and changes in the heart rate in middle-aged Japanese adults: a prospective study. J Hypertens. 2010;28(4):687-94.
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.
Zaza A, Rocchetti M. Regulation of the sinoatrial pacemaker: selective if inhibition by ivabradine. In: Fox K, Ferrari R, editors. Heart Rate Management in Stable Angina. Abingdon: Taylor & Francis; 2005: 51-67.
Manz M, Reuter M, Lauck G, Omran H, Jung W. A single intravenous dose of ivabradine, a novel I(f) inhibitor, lowers heart rate but does not depress left ventricular function in patients with left ventricular dysfunction. Cardiology. 2003;100(3):149-55.
Fox KM, Ferrari R. Heart rate: a forgotten link in coronary artery disease? Nat Rev Cardiol. 2011;8(7):369-79.
Thollon C, Vilaine JP. I(f) inhibition in cardiovascular diseases. Adv Pharmacol. 2010;59:53-92.
Colin P, Ghaleh B, Monnet X, Su J, Hittinger L, Giudicelli JF, et al. Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol. 2003;284(2):H676-82.
Custodis F, Baumhäkel M, Schlimmer N, List F, Gensch C, Böhm M, et al. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2008;117:2377-87.
Schirmer SH, Degen A, Baumhäkel M, Custodis F, Schuh L, Kohlhaas M, et al. Heart-rate reduction by If-channel inhibition with ivabradine restores collateral artery growth in hypercholesterolemic atherosclerosis. Eur Heart J. 2012;33(10):1223-31.
Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113(9):1213-25.
Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K, Initiative Investigators. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26(23):2529-36.