Ivabradine in Heart Failure Treatment

    Authors

    Abstract

    Ivabradine is the first specific heart rate-lowering agent that selectively and specifically inhibiting the pacemaker (lf) current, which regulates spontaneous diastolic depolarization in the sinus node and the heart rate. It directly affects the sinus node, with no effect on the interatrial, atrioventricular, or intraventricular conduction times, myocardial contractility, or ventricular repolarization. Ivabradine is indicated for patients with chronic heart failure, New York Heart Association (NYHA) classification II to IV, with systolic dysfunction and in patients with sinus rhythm with heart rate ≥75/min, in combination with standard therapy that includes beta blockers, or when beta-blockers are contraindicated or poorly tolerated. Ivabradine improves the prognosis in such patients, reducing the risk of mortality from all causes and mortality from cardiovascular events and heart failure. It improves quality of life by increasing tolerance for physical exertion and prevents progression of the disease by reducing the volume of the left ventricle and improving the ejection fraction.

    Keywords

    ivabradine, heart frequency, heart failure

    DOI

    https://doi.org/10.15836/ccar.2015.148

    Full Text

    Ivabradine is the first specific heart rate-lowering agent that selectively and specifically inhibiting the pacemaker (lf) current, which regulates spontaneous diastolic depolarization in the sinus node and the heart rate. It directly affects the sinus node, with no effect on the interatrial, atrioventricular, or intraventricular conduction times, myocardial contractility, or ventricular repolarization. (1) The main pharmacodynamical characteristic of ivabradine is the specific reduction in heart rate that depends on the dosage. Analysis of the reduction in heart rate using doses up to 2 x 20 mg indicates that there is a trend towards a plateau effect, which is in line with the reduced risk of severe bradycardia with less than 40/min. At common recommended doses, heart frequency at rest and during physical exertion is reduced by about 10/min. This leads to a reduction of the cardiac workload and myocardial oxygen consumption. Ivabradine does not affect intracardiac conduction, contractility (there is no negative inotropic effect), or ventricular repolarization. During electrophysiological clinical testing, ivabradine had no effect on atrioventricular and intraventricular conduction times or on corrected QT intervals, and patients with dysfunction of the left ventricle (LVEF; left ventricular ejection fraction from 30% to 45%) showed no negative effect on LVEF when treated with ivabradine. (2) ## Antianginal and anti-ischemic effectiveness of Ivabradine The antianginal and anti-ischemic effectiveness of ivabradine was tested in five double-blind, randomized trials (three in comparison with placebo, and one each in comparison with atenolol and amlodipine). A total of 4111 patients with chronic stable angina pectoris took part in these trials, 2617 of whom were treated with ivabradine. Ivabradine was shown to have an effect on physical exertion test parameters within 3 to 4 weeks of treatment in doses of 2 x 5 mg. The effectiveness of 2 x 7.5 mg doses was shown as well. An additional advantage compared with the 2 x 5 mg dose was shown in a reference study that compared it with atenolol: the total duration of physical exertion at the lowest dosage increased by about 1 minute after a month of treatment with the 2 x 5 mg dose, and improved further by almost 25 seconds after an additional three-month treatment with faster titration to 2 x 7.5 mg. That study also showed the antianginal and anti-ischemic advantages of ivabradine in patients over 65 years of age. The efficacy of the doses of 5 mg and 7.5 mg b.i.d. in improving physical exertion test parameters was consistent throughout the study period (total duration of physical exertion, time to limiting angina, time to angina onset, and time to ST-segment depression of 1 mm) and correlated with an improvement in the time before the advent of angina pain by about 70%. The dosage of two ivabradine doses per day resulted in a consistent efficacy over 24 hours. (3) In a randomized placebo-controlled trial on 889 patients, treatment with ivabradine in conjunction with an existing atenolol treatment dosed at 50 mg once per day showed improvement in the exertion test across all parameters at the nadir effect of the medication (12 hours after oral ingestion). (4) A randomized placebo-controlled study on 725 patients showed that ivabradin has no additional effect over the effects of amlodipine 10 mg once per day at the nadir concentration (12 hours after administration of the drug), but at there was an additional effect at the highest concentration (3-4 hours after administration). In a randomized placebo-controlled trial on 1277 patients, the administration of ivabradine in conjunction with existing amlodipine therapy 5 mg once a day or nifedipine 30 mg once a day at the nadir concentration (12 hours after oral ingestion of ivabradine) showed a statistically significant added effect in treatment response (defined as a reduction of at least 3 angina attacks and/or increased period to 1 mm ST-segment depression by at least 60 s during an exertion tests) over a 6 week treatment period. Ivabradine showed no added effect in secondary outcomes of exertion test parameters at the nadir concentration, whereas an effect was found at the highest concentration of the medication (3-4 hours after administration). In efficacy studies, ivabradine was shown to be effective during a treatment period of 3 or 4 months. Development of pharmacological tolerance was not noted during the treatment, and neither were rebound phenomena after sudden cessation of treatment. The antianginal and anti-ischemic of ivabradine corresponded to reduced heart rate, which was dependent on the dose and a significant decrease of the product of frequency Ą systolic pressure at rest and during exertion. Effects on the arterial pressure and peripheral vascular resistance were not clinically significant. Patients treated with ivabradine for at least a year showed extended heart rate reduction (n = 713). There was no effect on glucose values in the blood of lipid metabolism. The antianginal and anti-ischemic efficacy of ivabradine was also shown in diabetics (n = 457) with a similar safety profile as with other patients. ## Ivabradine and coronary heart disease The large BEAUTIFUL trial was performed on 10 917 patients with coronary heart disease (CHD) and left ventricle dysfunction (LVEF 2 in comparison with the control group, and benefit as measured by the ejection fraction of 2.7%. A reduction in heart rate in patients with HF and systolic dysfunction had a positive effect on left ventricle remodeling. The reduction in left ventricular volume and an improvement in the ejection fraction indicate an improvement in the disease prognosis as well. (15) The CARVIVA trial, a prospective, randomized, open, blinded study in which the patients received an optimal dose of ACE inhibitors and ivabradine or a combined treatment with carvedilol showed a significant improvement in tolerance for physical exertion in comparison with patients who received only beta blockers (27% vs. 15%). (16) NICE guidelines recommend ivabradine as an additional medication for patients with resting heart rates ≥75/min who are already taking standard beta-blockers at a maximal tolerated dose. (17) Finally, ivabradine is indicated for symptomatic treatment of chronic stable angina pectoris in adult patients with CHD with a normal sinus rhythm and a heart rate ≥70/min. Ivabradine is indicated in adult patients who do not tolerate beta-blockers or when their use is contraindicated, and in combination with beta-blockers in patients who were not adequately controlled by the optimal dose. (14) Ivabradine is also indicated in chronic HF of classes II to IV according to the NYHA classification with systolic dysfunction in patients in sinus rhythm with a heart rate ≥75/min, in combination with standard treatment, including beta-blockers or when beta-blockers are contraindicated and poorly tolerated. Treatment should be started in patients with stable HF. It is recommended that the physician has experience in treating chronic HF. The usual starting ivabradine dose is 2 x 5 mg. After two weeks of treatment, the dose can be increased to 2 x 7.5 mg if the resting heart rate is constantly above 60/min, or reduced to 2 x 2.5 mg if the heart rate is constantly lower than 50/min or if symptoms associated with bradycardia present themselves, such as light headedness, fatigue, or hypotension. If the heart rate is between 50 and 60/min, the 2 x 5 mg dose should be maintained. If the resting heart rate falls below 50/min, the dose should be titrated to a lower level in patients that are taking doses of 2 x 7.5 mg or 2 x 5 mg. If the resting heart rate is constantly above 60/min, the dose can be titrated to a higher level in patients taking 2 x 2.5 mg and 2 x 5 mg doses. Treatment must be discontinued if the heart rate falls below 50/min or if bradycardic symptoms persist. (9) In pharmacological conversion of atrial fibrillation to sinus rhythm, patients treated with ivabradine showed no danger of developing (significant) bradycardia. However, since the data on this issue are not sufficient, elective direct-current cardioversion can be performed 24 hours after administering the last dose of ivabradine. In the SHIFT trial, a somewhat larger number of patients treated with ivabradine experienced episodes of elevated arterial pressure (7.1%) compared with the control group (6.1%). These episodes most commonly occurred after a change in the treatment for arterial hypertension, were transitory, and did not influence the therapeutic effect of ivabradine. When introducing changes in treatment for arterial hypertension in patients with chronic HF treated with ivabradine, it is necessary to monitor arterial pressure at appropriate intervals. (18) ## Conclusion We can conclude that ivabradine is indicated in patients with chronic HF classes II to IV according to the NYHA classification with systolic dysfunction, in patients in sinus rhythm with a frequency ≥75/min, in combination with standard therapy including beta-blockers, or when beta-blockers are contraindicated or poorly tolerated. In such patients, ivabradine improves the prognosis by reducing mortality from all causes, cardiovascular death, and death due to HF. It improves quality of life by increasing tolerance for physical exertion and prevents disease progression by reducing the volume of the left ventricles and improving the ejection fraction. Ivabradine is well tolerated, with minimal risk of bradycardia and no risk of hypotension. It is easy to titrate and can be combined with a large number of other cardiovascular medication. (19, 20)

    Literature

    1. Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, et al. American Heart Association Task Force on Practice Guidelines. Committee on the Management of Patients With Chronic Stable Angina. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina–summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation. 2003;107(1):149–58. https://doi.org/10.1161/01.CIR.0000047041.66447.29
    2. Fox K, Borer JS, Camm AJ, Danchin N, Ferrari R, Lopez Sendon JL, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol. 2007;50:823–30. https://doi.org/10.1016/j.jacc.2007.04.079
    3. Borer JS, Fox K, Jaillon P, Lerebours G, 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;107:817–23. https://doi.org/10.1161/01.CIR.0000048143.25023.87
    4. 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;26:2529–36. https://doi.org/10.1093/eurheartj/ehi586
    5. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R, BEAUTIFUL investigators. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet. 2008;372:817–21. https://doi.org/10.1016/S0140-6736(08)61171-X
    6. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Rationale, design, and baseline characteristics of the Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease (SIGNIFY trial): a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease without clinical heart failure. Am Heart J. 2013;166(4):654–661.e6. https://doi.org/10.1016/j.ahj.2013.06.024
    7. Clarck AL. Almanac 2013: heart failure. Cardiol Croat. 2013;8(12):448–55. https://doi.org/10.15836/ccar.2013.448
    8. Šikić J. Chronic heart failure – therapeutic approaches. Cardiol Croat. 2015;10(1-2):46–50. https://doi.org/10.15836/ccar.2015.46
    9. Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Tavazzi L. 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;12(1):75–81. https://doi.org/10.1093/eurjhf/hfp154
    10. Böhm M, Swedberg K, Komajda M, Borer JS, Ford I, Dubost-Brama A, et al. SHIFT Investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010;376(9744):886–94. https://doi.org/10.1016/S0140-6736(10)61259-7
    11. Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, et al. SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376(9744):875–85. https://doi.org/10.1016/S0140-6736(10)61198-1
    12. Böhm M, Borer J, Ford I, Gonzalez-Juanatey JR, Komajda M, Lopez-Sendon J, et al. Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study. Clin Res Cardiol. 2013;102(1):11–22. https://doi.org/10.1007/s00392-012-0467-8
    13. Borer JS, Böhm M, Ford I, Komajda M, Tavazzi L, Sendon JL, et al. SHIFT Investigators. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT Study. Eur Heart J. 2012;33(22):2813–20. https://doi.org/10.1093/eurheartj/ehs259
    14. Reil JC, Tardif JC, Ford I, Lloyd SM, O'Meara E, Komajda M, et al. Selective heart rate reduction with ivabradine unloads the left ventricle in heart failure patients. J Am Coll Cardiol. 2013;62(21):1977–85. https://doi.org/10.1016/j.jacc.2013.07.027
    15. Tardif JC, O'Meara E, Komajda M, Böhm M, Borer JS, Ford I, et al. 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;32(20):2507–15. https://doi.org/10.1093/eurheartj/ehr311
    16. Volterrani M, Cice G, Caminiti G, Vitale C, D'Isa S, Perrone Filardi P, et al. Effect of Carvedilol, Ivabradine or their combination on exercise capacity in patients with Heart Failure (the CARVIVA HF trial). Int J Cardiol. 2011;151(2):218–24. https://doi.org/10.1016/j.ijcard.2011.06.098
    17. National Institute for Health and Clinical Excellence (NICE). Ivabradine for treating chronic heart failure. London (UK): National Institute for Health and Clinical Excellence (NICE); 2012 Nov. 49 p. (Technology appraisal guidance; no. 267). (10.6.2015). http://www.nice.org.uk/guidance/ta267
    18. Komajda M, Böhm M, Borer JS, Ford I, Robertson M, Manolis AJ, et al. SHIFT Investigators. Efficacy and safety of ivabradine in patients with chronic systolic heart failure according to blood pressure level in SHIFT. Eur J Heart Fail. 2014;16(7):810–6. https://doi.org/10.1002/ejhf.114
    19. Ekman I, Chassany O, Komajda M, Böhm M, Borer JS, Ford I, et al. Heart rate reduction with ivabradine and health related quality of life in patients with chronic heart failure: results from the SHIFT study. Eur Heart J. 2011;32(19):2395–404. https://doi.org/10.1093/eurheartj/ehr343
    20. Borer JS, Swedberg M, Komajda M, Ford I, Tavazzi L, Boehm M, et al. Efficacy profile of ivabradine in patients with heart failure plus angina pectoris. J Am Coll Cardiol. 2015;65 10S:A791. https://doi.org/10.1016/S0735-1097(15)60791-4
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    Ivabradine in Heart Failure Treatment

    Review Article
    Issue5-6
    Published
    Pages148-154
    PDF via DOIhttps://doi.org/10.15836/ccar.2015.148
    ivabradine
    heart frequency
    heart failure

    Authors

    Goran Krstačić*ORCIDInstitute for Cardiovascular Prevention and Rehabilitation, Zagreb, Croatia

    *Correspondence email: goran.krstacic@srcana.hr

    Abstract

    Ivabradine is the first specific heart rate-lowering agent that selectively and specifically inhibiting the pacemaker (lf) current, which regulates spontaneous diastolic depolarization in the sinus node and the heart rate. It directly affects the sinus node, with no effect on the interatrial, atrioventricular, or intraventricular conduction times, myocardial contractility, or ventricular repolarization. Ivabradine is indicated for patients with chronic heart failure, New York Heart Association (NYHA) classification II to IV, with systolic dysfunction and in patients with sinus rhythm with heart rate ≥75/min, in combination with standard therapy that includes beta blockers, or when beta-blockers are contraindicated or poorly tolerated. Ivabradine improves the prognosis in such patients, reducing the risk of mortality from all causes and mortality from cardiovascular events and heart failure. It improves quality of life by increasing tolerance for physical exertion and prevents progression of the disease by reducing the volume of the left ventricle and improving the ejection fraction.

    Full Text

    Ivabradine is the first specific heart rate-lowering agent that selectively and specifically inhibiting the pacemaker (lf) current, which regulates spontaneous diastolic depolarization in the sinus node and the heart rate. It directly affects the sinus node, with no effect on the interatrial, atrioventricular, or intraventricular conduction times, myocardial contractility, or ventricular repolarization. (1)

    The main pharmacodynamical characteristic of ivabradine is the specific reduction in heart rate that depends on the dosage. Analysis of the reduction in heart rate using doses up to 2 x 20 mg indicates that there is a trend towards a plateau effect, which is in line with the reduced risk of severe bradycardia with less than 40/min. At common recommended doses, heart frequency at rest and during physical exertion is reduced by about 10/min. This leads to a reduction of the cardiac workload and myocardial oxygen consumption. Ivabradine does not affect intracardiac conduction, contractility (there is no negative inotropic effect), or ventricular repolarization. During electrophysiological clinical testing, ivabradine had no effect on atrioventricular and intraventricular conduction times or on corrected QT intervals, and patients with dysfunction of the left ventricle (LVEF; left ventricular ejection fraction from 30% to 45%) showed no negative effect on LVEF when treated with ivabradine. (2)

    Antianginal and anti-ischemic effectiveness of Ivabradine

    The antianginal and anti-ischemic effectiveness of ivabradine was tested in five double-blind, randomized trials (three in comparison with placebo, and one each in comparison with atenolol and amlodipine). A total of 4111 patients with chronic stable angina pectoris took part in these trials, 2617 of whom were treated with ivabradine. Ivabradine was shown to have an effect on physical exertion test parameters within 3 to 4 weeks of treatment in doses of 2 x 5 mg. The effectiveness of 2 x 7.5 mg doses was shown as well. An additional advantage compared with the 2 x 5 mg dose was shown in a reference study that compared it with atenolol: the total duration of physical exertion at the lowest dosage increased by about 1 minute after a month of treatment with the 2 x 5 mg dose, and improved further by almost 25 seconds after an additional three-month treatment with faster titration to 2 x 7.5 mg. That study also showed the antianginal and anti-ischemic advantages of ivabradine in patients over 65 years of age. The efficacy of the doses of 5 mg and 7.5 mg b.i.d. in improving physical exertion test parameters was consistent throughout the study period (total duration of physical exertion, time to limiting angina, time to angina onset, and time to ST-segment depression of 1 mm) and correlated with an improvement in the time before the advent of angina pain by about 70%. The dosage of two ivabradine doses per day resulted in a consistent efficacy over 24 hours. (3)

    In a randomized placebo-controlled trial on 889 patients, treatment with ivabradine in conjunction with an existing atenolol treatment dosed at 50 mg once per day showed improvement in the exertion test across all parameters at the nadir effect of the medication (12 hours after oral ingestion). (4) A randomized placebo-controlled study on 725 patients showed that ivabradin has no additional effect over the effects of amlodipine 10 mg once per day at the nadir concentration (12 hours after administration of the drug), but at there was an additional effect at the highest concentration (3-4 hours after administration). In a randomized placebo-controlled trial on 1277 patients, the administration of ivabradine in conjunction with existing amlodipine therapy 5 mg once a day or nifedipine 30 mg once a day at the nadir concentration (12 hours after oral ingestion of ivabradine) showed a statistically significant added effect in treatment response (defined as a reduction of at least 3 angina attacks and/or increased period to 1 mm ST-segment depression by at least 60 s during an exertion tests) over a 6 week treatment period. Ivabradine showed no added effect in secondary outcomes of exertion test parameters at the nadir concentration, whereas an effect was found at the highest concentration of the medication (3-4 hours after administration).

    In efficacy studies, ivabradine was shown to be effective during a treatment period of 3 or 4 months. Development of pharmacological tolerance was not noted during the treatment, and neither were rebound phenomena after sudden cessation of treatment. The antianginal and anti-ischemic of ivabradine corresponded to reduced heart rate, which was dependent on the dose and a significant decrease of the product of frequency Ą systolic pressure at rest and during exertion. Effects on the arterial pressure and peripheral vascular resistance were not clinically significant.

    Patients treated with ivabradine for at least a year showed extended heart rate reduction (n = 713). There was no effect on glucose values in the blood of lipid metabolism. The antianginal and anti-ischemic efficacy of ivabradine was also shown in diabetics (n = 457) with a similar safety profile as with other patients.

    Ivabradine and coronary heart disease

    The large BEAUTIFUL trial was performed on 10 917 patients with coronary heart disease (CHD) and left ventricle dysfunction (LVEF <40%) treated with the standard treatment, of which 86.9% received beta-blockers as well. The main criterion of efficacy was the effect on cardiovascular mortality, hospitalization for acute myocardial infarction, or hospitalization for newly-appeared or deteriorating heart failure (HF). The study showed no difference in primary outcomes between the ivabradine and placebo groups (relative risk ivabradine vs. placebo 1.00, p = 0.945). In post hoc analysis of the subgroup of patients with symptomatic angina at randomization (p = 0.945), the safety of patients was not compromised regarding cardiovascular mortality, hospitalization for acute myocardial infarction, or HF (ivabradine 12.0% compared with placebo 15.5%, p = 0.005). (5)

    SIGNIFY, a large outcome trial, included 19 102 patients with CHD with no clinical signs of HF (LVEF < 40%) with optimal basic treatment. The applied therapeutic scheme was higher than the approved dosage (starting dose 2 x 7.5 mg twice a day or 2 x 5 mg for age ≥ 75; titration to 2 x 10 mg). The main primary composite outcomes (PCO) of was the sum of cardiovascular mortality or non-fatal myocardial infarction. The trial found no difference in PCO between the ivabradine and control groups (relative risk ivabradine vs. placebo 1.08; p = 0.197). Bradycardia was noted in 17.9% of the patients on ivabradine (2.1% in the control group). Verapamil, diltiazem, or strong CYP3A4 inhibitors were administered to 7.1% of the patients during the trial. A small but significant increase in PCO was found in a previously defined subgroup with initially diagnosed angina pectoris CCS class II or higher (n = 12 049) (annual rates 3.4% compared with 2.9%, relative risk ivabradine vs. placebo 1.18; p = 0.018), but not in the subgroup of the total patient population with angina pectoris CCS class ≥I (n = 14 286) (relative risk ivabradine vs. placebo 1.11; p = 0.110). Higher doses than approved that were used in the study did not fully account for these results. (6)

    Ivabradine and heart failure

    Heart failure is one of the greatest public health issues in developed and developing countries, despite the advancements in modern pharmacological treatment and risk factor control. There is a constant need for the development of new therapeutic approaches in the treatment of chronic HF, so any newly discovered medication effect on the course of this disease is worth noting.

    In 2010, the results of the SHIFT (Systolic Heart failure treatment with the IF inhibitor ivabradine Trial) trial were published, which looked at the effect of adding ivabradine treatment to patients with HF, previously treated according to existing guidelines. The trial showed that the additional reduction in heart rate from ivabradine can amplify the positive effects of neurohormonal blockade in chronic HF. (7, 8)

    The SHIFT trial was a large multicentric, international, randomized, double blind, placebo-controlled outcome trial performed on 6505 adult patients with stable chronic HF (duration ≥4 weeks) of NYHA classes II to IV, with reduced ejection fraction of the left ventricle (LVEF ≤ 35%) and resting heart rate ≥70/min. (9)

    Patients were treated using a standard therapeutic approach that included beta-blockers (89%), ACE inhibitors and/or angiotensin II inhibitors (91%), diuretics (83%), and aldosterone antagonists (60%). In the group of patients treated with ivabradine, 67% were treated with a 2 x 7.5 mg dose. The median follow-up period was 22.9 months. Ivabradine treatment was associated with an average reduction in heart rate of 15/min from the initial 80/min. The difference in heart rate between the ivabradine and placebo groups was 10.8/min after 28 days; 9.1/min after 12 months, and 8.3/min after 24 months. This study showed a clinically and statistically significant reduction in relative risk of 18% for PCO (cardiovascular mortality and hospitalization for deteriorating HF), which became clear within the first three months of the treatment. The reduction in absolute risk was 4.2%. Results related to PCO were mostly a consequence of HF outcomes, outcomes of hospitalization for deteriorating HF (4.7% reduction in absolute risk), and death due to HF (reduction in absolute risk of 1.1%). (9–11)

    The reduction in PCO was consistent regardless of gender, NYHA class, HF etiology, or the presence of diabetes or arterial hypertension. In the subgroup of patients with a heart rate ≥75/min (n = 4150) a more significant reduction in PCO of 24% was noted, as well as of other secondary outcomes, including total mortality and mortality from cardiovascular causes. The safety profile of ivabradine in this subgroup was the same as in the other groups.

    A significant effect on PCO was noted in the whole group of patients taking beta-blockers. In the subgroup of patients with heart rate ≥75/min that received the recommended target dose of beta-blockers, there was no significant improvement in PCO or other secondary outcomes. A significant improvement in NYHA class was found in the last recorded value; 887 (28%) patients treated with ivabradine achieved improvement, in comparison with 776 (24%) of patients in the placebo group (p = 0.001).

    The SHIFT trial brought to attention the fact that adding ivabradine, which reduces heart rate by inhibiting the depolarization of the sinus node, improves outcomes in patients with HF caused by systolic dysfunction of the left ventricle with sinus rhythm and a heart rate ≥70/min. The positive outcome of the trial also indicated a positive effect on survival of patients with a resting heart rate ≥75/min. (9, 12, 13)

    As part of the SHIFT trial, 275 patients receiving ivabradine 2 x 7.5 mg were included in an echocardiographic substudy. A reduction in heart rate was found, but also an increase in cardiac output (stroke volume), resulting in a stable minute volume. (14)

    A second echocardiographic substudy on 411 patients found, over a 8 month follow-up, a statistically significant reduction in left ventricular end-diastolic volume of 5.5 mL/m2 in comparison with the control group, and benefit as measured by the ejection fraction of 2.7%. A reduction in heart rate in patients with HF and systolic dysfunction had a positive effect on left ventricle remodeling. The reduction in left ventricular volume and an improvement in the ejection fraction indicate an improvement in the disease prognosis as well. (15)

    The CARVIVA trial, a prospective, randomized, open, blinded study in which the patients received an optimal dose of ACE inhibitors and ivabradine or a combined treatment with carvedilol showed a significant improvement in tolerance for physical exertion in comparison with patients who received only beta blockers (27% vs. 15%). (16)

    NICE guidelines recommend ivabradine as an additional medication for patients with resting heart rates ≥75/min who are already taking standard beta-blockers at a maximal tolerated dose. (17)

    Finally, ivabradine is indicated for symptomatic treatment of chronic stable angina pectoris in adult patients with CHD with a normal sinus rhythm and a heart rate ≥70/min. Ivabradine is indicated in adult patients who do not tolerate beta-blockers or when their use is contraindicated, and in combination with beta-blockers in patients who were not adequately controlled by the optimal dose. (14)

    Ivabradine is also indicated in chronic HF of classes II to IV according to the NYHA classification with systolic dysfunction in patients in sinus rhythm with a heart rate ≥75/min, in combination with standard treatment, including beta-blockers or when beta-blockers are contraindicated and poorly tolerated. Treatment should be started in patients with stable HF. It is recommended that the physician has experience in treating chronic HF. The usual starting ivabradine dose is 2 x 5 mg. After two weeks of treatment, the dose can be increased to 2 x 7.5 mg if the resting heart rate is constantly above 60/min, or reduced to 2 x 2.5 mg if the heart rate is constantly lower than 50/min or if symptoms associated with bradycardia present themselves, such as light headedness, fatigue, or hypotension. If the heart rate is between 50 and 60/min, the 2 x 5 mg dose should be maintained. If the resting heart rate falls below 50/min, the dose should be titrated to a lower level in patients that are taking doses of 2 x 7.5 mg or 2 x 5 mg. If the resting heart rate is constantly above 60/min, the dose can be titrated to a higher level in patients taking 2 x 2.5 mg and 2 x 5 mg doses. Treatment must be discontinued if the heart rate falls below 50/min or if bradycardic symptoms persist. (9)

    In pharmacological conversion of atrial fibrillation to sinus rhythm, patients treated with ivabradine showed no danger of developing (significant) bradycardia. However, since the data on this issue are not sufficient, elective direct-current cardioversion can be performed 24 hours after administering the last dose of ivabradine.

    In the SHIFT trial, a somewhat larger number of patients treated with ivabradine experienced episodes of elevated arterial pressure (7.1%) compared with the control group (6.1%). These episodes most commonly occurred after a change in the treatment for arterial hypertension, were transitory, and did not influence the therapeutic effect of ivabradine. When introducing changes in treatment for arterial hypertension in patients with chronic HF treated with ivabradine, it is necessary to monitor arterial pressure at appropriate intervals. (18)

    Conclusion

    We can conclude that ivabradine is indicated in patients with chronic HF classes II to IV according to the NYHA classification with systolic dysfunction, in patients in sinus rhythm with a frequency ≥75/min, in combination with standard therapy including beta-blockers, or when beta-blockers are contraindicated or poorly tolerated. In such patients, ivabradine improves the prognosis by reducing mortality from all causes, cardiovascular death, and death due to HF. It improves quality of life by increasing tolerance for physical exertion and prevents disease progression by reducing the volume of the left ventricles and improving the ejection fraction.

    Ivabradine is well tolerated, with minimal risk of bradycardia and no risk of hypotension. It is easy to titrate and can be combined with a large number of other cardiovascular medication. (19, 20)

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