Clinical benefits of Procoralan (ivabradine): evidence and perspectives






Irina ELYUBAEVA,MD
Ekaterini A. KRITIKOU,1MD, PhD
Servier International
Division of Medical Information
Suresnes, FRANCE

Clinical benefits of Procoralan (ivabradine): evidence and perspectives


by I. Elyubaeva, France



Procoralan (ivabradine) is the first selective and specific If inhibitor, and provides pure heart rate (HR) reduction without altering myocardial contractility, the cardiac conduction system, or coronary vascular resistance. Experimental data have demonstrated the specific nature of the HR lowering action of ivabradine and suggest that the selective mechanism by which HR slowing is achieved allows the maximum realization of benefits from HR reduction for improved coronary perfusion and pump efficiency. The ability of ivabradine to affect angina symptoms and myocardial ischemia and to prevent coronary events makes it an important agent in the management of patients with coronary artery disease (CAD). With its pharmacological and clinical properties, ivabradine is a disease-modifying treatment for patients with chronic heart failure (CHF). The results of SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) show that ivabradine is particularly suited to fulfill unmet needs in the treatment of CHF patients, improving symptoms and well-being along with outcomes. This evidence supports ivabradine’s importance as an essential therapeutic modality to enhance management of patients with CAD or CHF. The ongoing SIGNIFY trial (Study assessInG the morbidity- mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease) seeks to advance a new treatment paradigm by testing the hypothesis that HR reduction improves long-term clinical outcome in stable CAD patients without clinical HF. The results should provide insight into a role for ivabradine in the management of patients with stable CAD.

Medicographia. 2014;36:89-97 (see French abstract on page 97)


Pure heart rate reduction with ivabradine:
anti-ischemic effect and cardiovascular protection

Procoralan (ivabradine) is a specific heart rate (HR)-lowering agent, which has selective action on pacemaker activity in the sinoatrial node of the heart, resulting in important differences compared with nonselective HR-reducing agents, such as β-blockers.1 By inhibiting If—an ionic current that modulates pacemaking activity—in the sinus node, ivabradine lowers HR without directly affecting myocardial contractility (or relaxation), ventricular repolarization, or intracardiac conduction.2

Physiological changes in HR affect mainly the duration of diastole, with lower HR leading to prolongation of diastolic time, both in absolute terms and as a fraction of the cardiac cycle, facilitating myocardial perfusion.3 Ivabradine, similarly to physiological HR reduction, lowers HR essentially by prolonging diastole.4 In addition, ivabradine maintains coronary vasodilation during exercise. By contrast, β-blockers, due to their negative effect on myocardial contractility, tend to prolong systole as well, reducing their beneficial effect on diastolic time as a fraction of the cardiac cycle. β-Blockers may affect vasomotion in the coronary circulation by unmasking &qlpha;-adrenergic vasoconstriction, resulting in constriction of large and small coronary arteries during exercise.3 The experimental data suggest that pharmacological HR reduction with ivabradine resembles physiological change in HR more closely than what occurs with β-blockade, in that physiological changes in diastolic time fraction, LV relaxation, and coronary vasomotion are not compromised by other unwanted cardiac effects.5 In consequence, maximum benefits of HR reduction for improved coronary perfusion can be realized.

By reducing HR, ivabradine decreases myocardial oxygen consumption and increases myocardial perfusion, both of which preserve cardiac energy metabolism, which is profoundly depleted during HF. Sustained HR reduction with ivabradine was found to improve cardiac function by significantly decreasing left ventricular (LV) systolic diameter and increasing fractional shortening.6 Ivabradine preserved cardiac output due to increased stroke volume, reduced LV collagen density, and increased LV capillary density. These experimental data show that long-term HR reduction with ivabradine optimizes energy consumption, reverses remodeling, and prevents disease progression in HF.

Endothelial dysfunction is a common feature of all cardiac diseases, including coronary artery disease (CAD) and chronic heart failure (CHF). HR lowering with ivabradine may improve endothelial function and inhibit development and progression of atherosclerotic plaque. In dyslipidemic mice expressing human apoprotein B-100, 3 months’ treatment with ivabradine completely prevented deterioration of endothelial dependent vasodilation in the renal and cerebral arteries.7 In another model, with severe hypercholesterolemia in apolipoprotein E–deficient mice, ivabradine treatment improved endothelial function, and reduced atherosclerotic plaque area in the aortic root (by >40%) and ascending aorta (by >70%).8 These beneficial effects on endothelial function and slowing of development of atherosclerosis may contribute to the reduction in cardiac events seen in the clinical setting.

Clinical benefits of pure HR reduction with ivabradine

The results of clinical trials are consistent with the importance of HR in pathophysiology of CAD and CHF, supporting the value of pure HR reduction in management of these patients.

◆ Clinical benefits of HR reduction with ivabradine in stable CAD
Consistent with this advanced understanding of the importance of HR in the pathophysiology of CAD, HR reduction should clearly be considered as a key therapeutic goal in patients with CAD: the short-term implication is better prevention of ischemia, and the long-term implication is better prevention of cardiovascular (CV) events.9

◆ Reduction in angina attacks and improvement in quality of life
Ivabradine substantially reduced the frequency of angina attacks and the consumption of short-acting nitrates compared with placebo.10 Antianginal efficacy of ivabradine was confirmed in the INITIATIVE study (INternatIonal TrIAl on the Treatment of angina with IVabradinE versus atenolol), which included 939 patients with stable angina: the number of angina attacks was decreased at 4 months by 1.6 with ivabradine and by 1.2 with atenolol 100 mg once daily.11





In another double-blind, parallel-group, noninferiority trial in 1195 patients with chronic stable angina and documented CAD, ivabradine 7.5 mg twice daily produced substantial antianginal efficacy similar to amlodipine 10 mg once daily, reducing the number of angina attacks by about two-thirds and the short-acting nitrates consumption by about one-half across the study.12

The efficacy of ivabradine in reducing the frequency of angina symptoms was also confirmed in a 1-year study.13 Treatment with ivabradine 5 mg and 7.5 mg twice daily showed significant reductions in angina attack frequency from 50% to 67%, approximately relative to baseline at 1 year of treatment.

Substantial antianginal efficacy of ivabradine is confirmed under conditions seen in day-to-day practice as well, in the large open-label, multicenter ADDITIONS study (prActical Daily efficacy anD safety of Procoralan In combinaTION with betablockerS [trial]) conducted in a broad range of patients with stable angina.14 Ivabradine added to β-blockers in 2330 patients with stable angina resulted in significant reduction of angina attacks and short-acting nitrate consumption (from 1.7 to 0.3 and from 2.3 to 0.4 units per week, respectively).14 In line with reduction in angina attacks, ivabradine improved quality of life (QOL) assessed by the EuroQol 5 Dimension (EQ-5D) questionnaire (both the EQ-AD index [EuroQol Anxiety/ Depression dimension score], as well as visual analog scale) throughout 4 months of therapy with ivabradine (Figure 1).14

◆ Anti-ischemic efficacy and improvement of exercise capacity
Ivabradine showed significant anti-ischemic efficacy compared with placebo in the randomized, double-blind study.10 The efficacy of ivabradine was confirmed compared with representative examples of β-blockers and calcium antagonists, which are widely used for angina therapy. A relevant anti-ischemic effect of ivabradine, indicated by the increase in time to 1-mm ST-segment depression by approximately 1.5 minutes, was demonstrated in the INITIATIVE study.11 At peak drug activity at 4 months, the time to 1-mm ST-segment depression was increased by 108.4 seconds with ivabradine 7.5 mg twice daily, and 140.5 seconds with atenolol100 mg once daily. The group receiving ivabradine 7.5 mg twice daily showed an increase in total exercise duration at the trough of drug activity of 86.8 seconds compared with 78.8 seconds in the atenolol 100 mg once daily group, and noninferiority was demonstrated for all exercise tolerance test parameters (P<0.001). The ASSOCIATE trial (evaluation of the Antianginal efficacy and Safety of the aSsociation Of the If Current Inhibitor ivAbradine with a beTa-blockEr) examined the effects of ivabradine in patients with chronic stable angina pectoris receiving β-blocker therapy.15 This double-blind, randomized, placebocontrolled trial in 889 patients clearly demonstrates that ivabradine in patients with stable angina receiving the β-blocker atenolol provides further significant improvement in all parameters of the exercise test at 2 and 4 months. Importantly, despite the fact that combination therapy is widely used in clinical practice to achieve adequate control of angina, clinical trials evaluating combination therapy have yielded inconsistent results. This makes ivabradine with β-blockers the best evidence-based combination therapy for angina patients.

The importance of increases in HR during daily activity due to physical or emotional stress as a trigger of myocardial ischemia is well established and explains the crucial need to prevent excessive increases in HR.16 A recent analysis from the ASSOCIATE trial further reinforced the importance of HR reduction to ensure anti-ischemic efficacy and demonstrated that ivabradine significantly improves exercise capacity whatever the baseline HR, whether it was above or below the median level of 65 beats per minute (bpm) (Figure 2, page 92).16


Figure 1
Figure 1. Quality of life index EQ-5D at baseline and after 1 and 4
months of treatment with ivabradine.

Abbreviation: EQ-5D, EuroQol 5 Dimension (questionnaire).
After reference 14: Werdan et al. Clin Res Cardiol. 2012;101(5):365-373.
© 2012, Springer-Verlag.



In a study comparing the efficacy of a combination of ivabradine 7.5 mg twice daily plus bisoprolol 5 mg once daily versus the full dose of bisoprolol (10 mg once daily) in patients with stable angina and LV systolic dysfunction (LVSD), 2 months of treatment with ivabradine substantially reduced the mean weekly number of angina attacks compared with bisoprolol alone (from 3.3 to 1.7 vs from 3.2 to 2.5, respectively; P between groups is 0.041).17

◆ Improvement in coronary flow reserve
The effect of ivabradine on coronary flow velocity and coronary flow reserve was evaluated in a study in 21 patients with stable CAD. Coronary flow velocity measurements in a non- culprit vessel were taken using a Doppler guidewire, at rest and after adenosine administration to achieve maximal hyperemia.18 There was a significant increase in coronary flow reserve after short-term treatment with ivabradine (1 week). Improvement in coronary flow reserve may have profound clinical implications, as it predicts long-term adverse CV outcomes.19


Figure 2
Figure 2. Treatment effect (ivabradine versus
placebo) on change in exercise tolerance test
criteria between baseline and study’s end
(4 months), according to resting HR at baseline
(≤65 bpm or >65 bpm).

Abbreviations: bpm, beats per minute; ETT, exercise tolerance
test.
After reference 16: Tardif et al. Int J Cardiol. 2013;168(2):
789-794. © 2012, Elsevier Ireland Ltd.



◆ Prevention of CV events in symptomatic patients with LVSD
An analysis in 1507 patients with symptoms of angina at baseline in the BEAUTIFUL trial (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) evaluated the prognostic benefit of ivabradine in this population.20 The reduction in the primary end point of the study (CV death, myocardial infarction [MI], or hospitalization for heart failure [HF]) was 24% in the whole group of patients with limiting angina and 31% in the group with baseline HR ≥70 bpm. The primary end point appears to be driven by the coronary outcomes, as there was a 42% reduction in the risk for hospitalization for fatal and nonfatal MI in patients with limiting angina treated with ivabradine (Figure 3A).20 The reduction in the risk of CV outcomes was even greater in patients with angina and HR ≥70 bpm, notably with a significant 73% ivabradine-related reduction in hospitalization for fatal and nonfatal MI (Figure 3B) and a 59% reduction in coronary revascularization.20 These findings suggest benefits of ivabradine beyond the control of anginal symptoms and show the potential of ivabradine to modify the clinical course of CAD. Important insight into the role of ivabradine in the management of patients with stable CAD will be provided by the ongoing SIGNIFY trial (Study assess- InG the morbidity–mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease). SIGNIFY is currently evaluating the efficacy of ivabradine in patients without HF and LVSD.21 It includes more than 16 850 patients from 47 countries with stable CAD, an ejection fraction above 40%, and no clinical sign of HF. The results of this trial will provide new insight into the role for ivabradine in the management of patients with stable CAD.


Figure 3
Figure 3. Kaplan-Meier time-to-event curves by treatment group
for hospitalization for fatal and nonfatal myocardial infarction
in patients with limiting angina at baseline (A) and in patients with
limiting angina and resting heart rate ≥bpm at baseline (B).

Abbreviations: bpm, beats per minute; CI, confidence interval;
HR, heart rate; MI, myocardial infarction.
After reference 20: Fox et al. Eur Heart J. 2009;30(19):2337-2345.
© 2009, The Author.



◆ Clinical benefits of HR reduction with ivabradine in HF
◆ Reduction in the risk of major outcomes related to HF
The effect of ivabradine in improvement of prognosis in HF has been successfully tested in the SHIFT trial (Systolic Heart failure treatment with If inhibitor ivabradine Trial). This randomized placebo-controlled clinical trial evaluated the effects of ivabradine, in addition to guideline-recommended therapies, on morbidity and mortality in 6558 patients with moderate to severe chronic HF and LVSD (LV ejection fraction [LVEF] <35%) and a resting HR ≥70 bpm (median follow-up was 22.9 months).22 After 28 days, ivabradine reduced HR by 15.4 bpm (10.9 bpm placebo-corrected). The primary composite end point (CV death or hospital admission for worsening HF) was significantly reduced by 18% (P<0.0001) (Figure 4A).22 Ivabradine significantly reduced both hospitalization for HF (relative risk reduction [RRR], 26%; P<0.0001) and HF death (RRR, 26%; P=0.014) (Figure 4B and C).22


Figure 4
Figure 4. Kaplan-Meier cumulative event curves for different
end points in SHIFT.
(A) Primary composite outcome (cardiovascular mortality or heart failure
hospitalization), (B) heart failure hospitalizations, and (C) heart failure deaths in
the ivabradine and the placebo arms of SHIFT.

Abbreviations: CI, confidence interval; CV, cardiovascular; HR, heart rate;
SHIFT, Systolic Heart failure treatment with the If inhibitor ivabradine Trial.
After reference 22: Swedberg et al. Lancet. 2010;376(9744):875-885.
© 2010, Elsevier Ltd.



◆ Reduction in the burden of hospitalizations related to worsening HF
Despite current intensive multidrug therapies, readmission rates following HF remain very high.23 SHIFT analysis explored the effect of ivabradine on recurrent hospitalizations for HF as well as on the total HF hospitalization burden.24 The results show that ivabradine substantially reduced the total number of HF hospitalizations by 25% (P=0.0002). Over 2 years of follow-up, ivabradine substantially reduced the risk of recurrent HF hospitalization: 34% reduction (P<0.001) in the risk of second hospitalization, 29% reduction (P<0.012) in the risk of third hospitalization (Figure 5).24 Similar results for HF hospitalization were seen in the higher risk subgroup of patients with a HR of ≥75 bpm (27% reduction; P=0.0006). Ivabradine also reduced hospitalizations for any cause (by 15%; P=0.001) and CV hospitalizations (by 16%; P=0.002). These findings are very important for clinical practice as hospital admissions are not only distressing for patients and their families, but they are also harbingers of accelerated disease progression (manifest by increased risk of readmission and death) and the major driver of the economic burden of HF.


Figure 5
Figure 5.
The effect of ivabradine on recurrence of hospitalizations for worsening heart failure in patients with chronic heart failure.

Abbreviation: CI, confidence interval.
After reference 24: Borer et al. Eur Heart J. 2012;33(22): 2813-2820. © 2012, The Author.



Figure 6
Figure 6. The effect of ivabradine on outcomes in patients with chronic heart failure and resting heart rate ≥75 bpm.

Abbreviations: bpm, beats per minute; CI, confidence interval; HF, heart failure. Based on data from reference 25: Böhm et al. Clin Res Cardiol. 2013;102(1):11-22.



◆ Reduction in the risk of total and CV mortality in patients with HR of 75 bpm and higher
Patients with higher HR and therefore at higher CV risk will have the most benefits from HR reduction with ivabradine. The effect of ivabradine was also assessed in the high-risk SHIFT patients (HR ≥75 bpm).25 The results of this analysis show that in patients with baseline HR ≥75 bpm, ivabradine significantly reduces all clinical outcomes, including the composite primary end point of CV death or hospitalization for HF by 24% (P<0.0001), all-cause death by 17% (P=0.0109), CV death by 17% (P=0.0166), death from HF by 39% (P=0.006), and hospitalization for HF by 30% (P<0.0001) (Figure 6).25 Only 17 patients need to be treated with ivabradine for 1 year to prevent 1 primary outcome, 19 patients to prevent 1 hospitalization for HF, 52 patients to prevent 1 CV death, and 51 patients to prevent 1 all-cause death. Risk reduction with ivabradine was related to both HR level achieved and magnitude of HR reduction. Patients achieving a HR <60 bpm or a HR reduction of more than 10 bpm had the best prognosis. The exceptional benefits of ivabradine in the population with HR ≥75 bpm led the European Medicine Agency to grant a new indication for symptomatic patients with CHF and HR ≥75 bpm. ◆ Reduction in the risk of major outcomes related to HF whatever the background treatment
The SHIFT trial has demonstrated a beneficial prognostic effect of ivabradine in the population receiving contemporary HF treatments, including a high rate being prescribed angiotensin- converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers and β-blockers.

The special analysis evaluated whether the dose of background β-blocker therapy had an impacton the effectof ivabradine in the SHIFT population.26 After adjusting for the previously identified interaction between baseline HR and the effect of treatment with ivabradine, there was no evidence of a trend for differing effect of ivabradine across β-blocker categories (P=0.135 for the primary end point, P=0.19 for hospital admission for worsening HF, and P=0.30 for CV death). This analysis indicates that magnitude of HR reduction with ivabradine beyond what is achieved by a β-blocker, rather than the dose of background β-blocker therapy itself, primarily determines subsequent outcome.

Another analysis assessed the effect of ivabradine in SHIFT patients treated by neurohormonal modulation with multiple drugs, including mineralocorticoid receptor antagonists (MRA).27 The results of this analysis show that the beneficial effect on outcomes observed with ivabradine in the overall SHIFT population is maintained in patients treated with MRAs, with significant reductions in primary composite end point by 18%, death from HF by 27%, hospitalization for HF by 23%, hospitalization for all causes by 14%, and hospitalization for CV cause by 16%.

◆ Improvement of symptoms and quality of life in patients with HF
Symptoms and well-being are other important targets for therapy, together with improvement of outcomes. SHIFT found that New York Heart Association (NYHA) class improved in 29.0% of patients treated with ivabradine vs 24.2% in the placebo group (P<0.0156), and patient-reported global assessment improved in 65.9% of patients treated with ivabradine vs 61.3% in the placebo group (P<0.0345) in the overall SHIFT population.28 Furthermore, a substudy of the SHIFT trial in 1944 patients demonstrated that in parallel to a reduction in outcomes in the SHIFT trial, ivabradine improved healthrelated QOL (HQOL) in patients with HF, assessed by the spe-cific Kansas City Cardiomyopathy Questionnaire (KCCQ).28 Treatment with ivabradine significantly improved both scores assessed by the KCCQ: the overall summary score (OSS) and the clinical summary score (CSS). The OSS—which includes physical limitation, total symptoms, QOL, and social limitation scores—was 6.7 in the ivabradine group vs 4.3 in the placebo group (P<0.001) at 12 months. The CSS—which includes the physical limitation and the total symptom domain scores—was 5.0 with ivabradine vs 3.3 with placebo (P=0.018) at 12 months.

The randomized, open, blinded—end point CARVIVA HF study (effect of CARVedilol, IVAbradine or their combination on exercise capacity in patients with Heart Failure) assessed the effect of HR reduction with carvedilol (25 mg twice daily), ivabradine (7.5 mg twice daily), and their combination (12.5/ 7.5 mg twice daily) on exercise capacity and QOL in 121 HF patients receiving ACE inhibitor at maximal dose.29 After 3 months of therapy, the NYHA class improved significantly more in patients receiving ivabradine and combination therapy compared with those allocated to carvedilol. Ivabradine alone or in combination was also more effective for improvement in exercise capacity and QOL compared with carvedilol alone.

The results of the recent study suggest that addition of ivabradine to carvedilol improves exercise capacity in patients with CHF compared with carvedilol alone: the change in distance for the 6-minutewalking test was 68.3±12.7 meters in the combination arm vs 32.4 with carvedilol alone (P<0.05) (Table I).30 In addition, the combination of ivabradine with carvedilol resulted in more than twice the number of patients attaining at least half of the carvedilol target dose (80% of patients vs 38% with carvedilol alone) and shortens the duration of carvedilol uptitration (from 2.7 months with carvedilol alone to 1.9 months in the combination arm).

◆ Reversing ventricular remodeling in patients with HF
Aside from the clinical standpoint, SHIFT also has important pathophysiological implications, demonstrated by the reverse remodeling observed with ivabradine. An echocardiography substudy in 611 patients from SHIFT demonstrated that 8 months of therapy with ivabradine resulted in a 7 mL/m2 reduction in LVend-systolic volume index (LVESVI), as comparedwith 0.9 mL/m2 in the placebo group.31 The LV end-diastolic volume index (LVEDVI) was also reduced by 7.9 mL/m2 as compared with 1.8 mL/m2 in the placebo group; LVEF was improved by 2.4%, whereas there was no change at all in the placebo group. Moreover, these results occurred despite treatment with β-blockers and renin-angiotensin-aldosterone system (RAAS) antagonists, each used in more than 90% of patients.

Reversal of LV remodeling has important clinical implications, as cardiac remodeling is a central feature in the progression of HF and is an established prognostic factor in HF patients. The beneficial impact of ivabradine on LV remodeling and function may contribute to the reduction in cardiac morbidity and mortality found in HF patients treated with ivabradine.

◆ Improvement in major outcomes in a wide range of patients with LVSD
The recent analysis in the large pooled population of nearly 12 000 patients from BEAUTIFUL and SHIFT trials with LVSD and HR ≥70 bpm demonstrated that ivabradine substantially reduced risk for major outcomes in the broad population of patients with LVSD, whatever the primary clinical presentation (CAD or HF) or clinical status (NYHA class).32 The results show that ivabradine substantially lowers the risk of major outcomes: the risk of CV death or hospitalization for HF (SHIFT primary end point) decreased by 13% (P<0.001), the risk of CV death or hospitalization for HF or MI (BEAUTIFUL end point) decreased by 15% (P<0.001), the risk of hospitalization for HF decreased by 19% (P<0.001), and the risk of hospitalization for MI decreased by 23% (P=0.009). In patients with HR ≥75 bpm, the magnitude of risk reduction with ivabradine was more pronounced, including a 12% reduction in CV mortality (P=0.049) and an 11% reduction in total mortality (P=0.048). Moreover, the improvement in outcomes observed with ivabradine was not confined to the most severe, symptomatic patients with the worst outcomes, but was observed in patients with less severe profiles as well (eg, LVEF ≤40% and NYHA class ≥I). Ivabradine was well tolerated with a low rate of symptomatic (4%) or asymptomatic bradycardia (4%), leading to withdrawal in less than 0.9% of patients.


Table I

Good tolerability profile and easy use in practice

Throughout its entire clinical development program, ivabradine has always been found to have a good safety profile consistent with its highly specific and selective mode of action on the If current. Ivabradine fully preserves the main electrophysiological parameters, including the refractory period of the atrium, atrioventricular conduction time, and repolariza-tion duration.33 The absence of changes in the corrected QT interval throughout the follow-up period provides strong evidence of the lack of any significant direct effects of ivabradine on the duration of ventricular repolarization, indicating absence of any proarrhythmic action. In some patients, ivabradine can induce visual symptoms, mainly phosphenes, related to the inhibition of the Ih current in retinal hyperpolarization- activated and cyclic nucleotide–gated (HCN) channels.33 They were generally mild and well tolerated, resolving spontaneously during or after treatment, and leading to withdrawal in less than 1% of patients without safety concern.

Bradycardia was reported in 2.2% of patients with angina treated with ivabradine 7.5 mg twice daily compared with 4.4% with atenolol 100 mg once daily.14 In HF patients in the SHIFT trial, bradycardia led to permanent withdrawal from the study in only 1% of patients on ivabradine.22 This low percentage is explained by a clear plateau in the dose-response curve of If-current inhibition and by the direct rate-related dynamics of the HR-lowering effect, limiting the risk of excessive bradycardia and ensuring the greatest HR reduction in patients with the highest pretreatment HR.

Achievement of target dose of ivabradine is simple in comparison with other treatments, with uptitration from 5 mg (starting dose) to 7.5 mg twice daily if HR remains above 60 bpm, which simplifies the management of angina or HF patients. Importantly, the abrupt discontinuation of ivabradine does not result in a rebound phenomenon.34 The absence of rebound tachycardia with ivabradine not only simplifies the management of antianginal treatment, but also reduces the risk of adverse effects following missed doses or unscheduled gaps in medication administration.

These characteristics of the HR-lowering action of ivabradine make it suitable and simple to use in most symptomatic patients with CAD or HF.

Conclusion

The existing evidence supports ivabradine as an important therapeutic modality to enhance management of patients with CAD or CHF. SHIFT shows ivabradine to be an effective treatment that can fulfill unmet needs in the management of CHF patients: improvement of symptoms and well-being together with outcomes. Due to ivabradine’s beneficial effects on angina symptoms and myocardial ischemia and its ability to prevent coronary events, it is an important agent in the management of patients with angina. The ongoing SIGNIFY trial is assessing the potential of ivabradine to improve prognosis in a large population of patients with stable CAD and HR ≥70 bpm. The results of this trial will provide new insight into the role of ivabradine in the management of patients with stable CAD.


References
1. DiFrancesco D. Cardiac pacemaker If current and its inhibition by heart ratereducing agents. Curr Med Res Opin. 2005;21(7):1115-1122.
2. Berdeaux A. Preclinical results with If current inhibition by ivabradine. Drugs. 2007;67(suppl 2):25-33.
3. Heusch G. Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents. r J Pharmacol. 2008;153(8):1589-1601.
4. Colin P, Ghaleh B, Monnet X, et al. Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol. 2003;284(2):H676-H682.
5. Simon L, Ghaleh B, Puybasset L, Giudicelli JF, Berdeaux A. Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. J Pharmacol Exp Ther. 1995;275(2):659-666.
6. 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; 109(13):1674-1679.
7. Drouin A, Gendron ME, Thorin E, Gillis MA, Mahlberg-Gaudin F, Tardif JC. Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice. Br J Pharmacol. 2008;154(4):749-757.
8. Custodis F, Baumhäkel M, Schlimmer N, et al. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoproteinE-deficient mice. Circulation. 2008;117(18):2377-2387.
9. Fox KM, Ferrari R. Heart rate: a forgotten link in coronary artery disease? Nat Rev Cardiol. 2011;8(7):369-379.
10. Borer JS, Fox K, Jaillon P, Lerebours G; Ivabradine Investigators Group. Antianginal and antiischemic effects of ivabradine, an If inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003;107(6):817-823.
11. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K; INITIATIVE Investigators. Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26(23):2529-2536.
12. Ruzyllo W, Tendera M, Ford I, Fox KM. Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial. Drugs. 2007;67(3):393-405.
13. López-Bescós L, Filipova S, Martos R. Long-term safety and efficacy of ivabradine in patients with chronic stable angina. Cardiology. 2007;108(4):387-396.
14. Werdan K, Ebelt H, Nuding S, Höpfner F, Hack G, Müller-Werdan U. Ivabradine in combination with beta-blocker improves symptoms and quality of life in patients with stable angina pectoris: results from the ADDITIONS study. Clin Res Cardiol. 2012;101(5):365-373.
15. Tardif JC, Ponikowski P, Kahan T; ASSOCIATE Study Investigators. Efficacy of the If current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebo-controlled trial. Eur Heart J. 2009;30(5):540-548.
16. Tardif JC, Ponikowski P, Kahan T; on behalf of the ASSOCIATE Investigators. Effects of ivabradine in patients with stable angina receiving beta-blockers according to baseline heart rate: an analysis of the ASSOCIATE study. Int J Cardiol. 2013;168(2):789-794.
17. Amosova E, Andrejev E, Zaderey I, Rudenko U, Ceconi C, Ferrari R. Efficacy of ivabradine in combination with beta-blocker versus uptitration of beta-blocker in patients with stable angina. Cardiovasc Drugs Ther. 2011;25(6):531-537.
18. Skalidis EI, Hamilos MI, Chlouverakis G, Zacharis EA, Vardas PE. Ivabradine improves coronary flow reserve in patients with stable coronary artery disease. Atherosclerosis. 2011;215(1):160-165.
19. Britten MB, Zeiher AM, Schächinger V. Microvascular dysfunction in angiographically normal or mildly diseased coronary arteries predicts adverse cardiovascular long-term outcome. Coron Artery Dis. 2004;15:259-264.
20. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R; BEAUTIFUL Investigators. 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;30(19):2337-2345.
21. Website registration: \ISRCTN61576291 – Effects of ivabradine in patients with stable coronary artery disease without heart failure.
22. Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376(9744):875-885.
23. Heidenreich PA, Sahay A, Kapoor JR, Pham MX, Massie B. Divergent trends insurvival and readmission following a hospitalization for heart failure in the Veterans Affairs health care system 2002 to 2006. J Am Coll Cardiol. 2010;56(5): 362-368.
24. Borer JS, Bohm M, Ford I, et al. 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):2813-2820.
25. Böhm M, Borer J, Ford I, 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.
26. Swedberg K, Komajda M, Bohm M, et al. Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose?: findings from the shift (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) study. J Am Coll Cardiol. 2012;59(22): 1938-1945.
27. Komajda M, Bohm M, Borer J, et al. Influence of background treatment with mineralocorticoid receptor antagonists on ivabradine’s effects in patients with chronic heart failure. Eur J Heart Fail. 2013;15(1):79-84.
28. Ekman I, Chassany O, Komajda M, 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):2395-2404.
29. Volterrani M, Cice G, Caminiti G, 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):218-224.
30. Bagriy AE, Shchukina EV, Malovichko SI, Prikolota AV. Addition of ivabradine to carvedilol reduces duration of carvedilol uptitration and improves exercise capacity in patients with chronic heart failure. J Am Coll Cardiol. 2013;61(10_S). doi:10.1016/S0735-1097(13)60700-7.
31. Tardif JC, O’Meara E, Komajda M, 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):2507-2515.
32. Fox K, Komajda M, Ford I, et al. Effect of ivabradine in patients with left-ventricular systolic dysfunction: a pooled analysis of individual patient data from the BEAUTIFUL and SHIFT trials. Eur Heart J. 2013;34(29):2263-2270.
33. Savelieva I, Camm AJ. If inhibition with ivabradine: electrophysiological effects and safety. Drug Saf. 2008;31(2):95-107.
34. Borer JS, Le Heuzey JY. Characterization of the heart rate-lowering action of ivabradine, a selective If current inhibitor. Am J Ther. 2008;15(5):461-473.


Keywords: coronary artery disease; heart failure, heart rate reduction; If current; ivabradine; Procoralan; sinus node; stable angina