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Abstract

Heart failure affects over 5 million people in the United States and carries a high rate of mortality. Ivabradine, a new agent has been added to the current medical options for managing heart failure. It is a selective funny current (I_f) inhibitor in sinoatrial node and slows its firing rate, prolonging diastolic depolarization without a negative inotropic effect. Ivabradine was only recently approved by Food and Drug administration after the results of Systolic Heart Failure Treatment with the I_f Inhibitor Ivabradine (SHIFT) trial, for a reduction in rehospitalizations from chronic heart failure. This trial assessed patients with stable heart failure with reduced ejection fraction and a heart rate of at least 70 beats per minute at rest on maximally tolerated beta-blocker therapy and demonstrated statistically significant reduction in heart failure hospitalization and deaths. Additionally, ivabradine has been associated with reduced cardiac remodeling, reduced heart rate variability, improvement in exercise tolerance, improved heart failure class of New York Heart Association, and better quality of life. It has also been tried in other conditions, such as inappropriate sinus tachycardia and cardiogenic shock, and is currently in phase II trial for patients with newly diagnosed multiple organ dysfunction syndrome.

Keywords

ivabradine funny current HCN heart failure SIGNIFY SHIFT

Background

Heart failure (HF) affects over 5 million individuals in the United States with an incidence of more than 400,000 per year. Mortality associated with HF reaches as high as 250,000 per year in the United States alone.¹ The current treatment options for the management of HF include beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (ARBs), diuretics, aldosterone receptor blockers, and the most recently approved angiotensin receptor-neprilysin inhibitor. Elevated resting heart rate has been linked to increased rates of morbidity and mortality.² Studies have also observed that it is an independent predictor of left ventricular systolic dysfunction and HF.^3,4 Theoretically, lower resting heart rate should be beneficial among patients with ischemic heart disease or HF syndrome as it prolongs the diastolic filling time, reduces myocardial oxygen demand and, eventually, wall stress. Traditionally, beta-blockers and nondihydropyridine calcium channel blockers have been efficacious in reducing heart rate; however, their use is limited in view of their negative inotropic effect. Ivabradine is the new therapeutic agent which was approved by Food and Drug Administration (FDA) for patients with stable chronic HF with reduced ejection fraction (HFrEF) < 35% who are unable to tolerate beta-blockers or are on maximally tolerated beta-blockers with a resting heart rate more than 70 beats per minute (bpm).⁵

Mechanism of Action

Ivabradine selectively inhibits hyperpolarization-activated cyclic nucleotide gated (HCN) channel 4 and HCN1 (f-channels) channels (which belongs to voltage-gated potassium and cyclic nucleotide-gated channels family). There are 4 known isoforms of HCN channels: HCN1 through HCN4.⁶ HCN1 to HCN4 are involved in the conductance of hyperpolarizing currents (I _h) at different locations in the body (predominantly in the nervous system and the heart). HCN1 is expressed primarily in the brain neocortex, hippocampus, cerebellar cortex, and brainstem. HCN2 channels are expressed diffusely in the atrium and ventricles and certain parts of the brain including the neocortex, olfactory bulb, hippocampus, thalamus, and brain stem. HCN3 channels are expressed at very low levels and are diffusely distributed throughout the brain.^7

–11 HCN4 is highly expressed in various thalamic nuclei and mitral cell layers of the olfactory bulb^8
–10 as well as constitutes about 80% of the sinoatrial (SA) node’s “funny current” (I _f) responsible for pacemaker activity.^12

–15 This channel is also the predominant isoform expressed in the atrioventricular (AV) node¹⁶ and the Purkinje fibers.¹⁷ The HCN4 channels, which generates the I _f current, have a mixed permeability to sodium and potassium ions. In an open state, sodium ions carry the net depolarizing current inward.^18,19 This current (I _f) controls the heart rate due to its effect on the slope of diastolic depolarization and hence heart rate.²⁰ Ivabradine is a preferential HCN4 inhibitor (I _f/I _h inhibitor), which reduces the SA nodal discharge, thus reducing the heart rate and prolongation of diastolic depolarization without any negative inotropic effects.²¹

Pharmacokinetics and Metabolism

Ivabradine is a water-soluble compound with a rapid intestinal absorption and a bioavailability of approximately 40% due to a high first pass metabolism. Ivabradine is the S-enantiomer without any demonstrable bioconversion in vivo. The main active metabolite identified in humans is the N-desmethylated derivative of ivabradine.²² Ivabradine is primarily metabolized by the cytochrome p450 system (CYP3A4) in the liver and gastrointestinal tract.²² Its plasma concentration peaks in approximately 1 hour under fasting conditions, and food intake can delay this peak by 1 hour.

Ivabradine is predominantly plasma protein bound (approximately 70%) with a steady state volume of distribution of about 100 liters. The average plasma concentration at steady state after a dosage of 5 mg 2 times a day is 10 ng/mL. Although metabolized by CYP3A4, it has a low affinity for induction or inhibition of this enzyme complex. However, when coadministered with potent inhibitors or inducers, the bioavailability and plasma concentration of ivabradine can be significantly affected.^23

–27 Ivabradine is eliminated via both feces and urine, with approximately 4% of oral dose being excreted unchanged in the urine. The drug has an effective half-life of 11 hours. The total clearance is about 400 mL/min with a renal clearance about 70 mL/min. Since renal clearance only contributes to about 20% of ivabradine elimination, the impact of renal impairment (creatinine clearance 15 mL/min to 60 mL/min) on its pharmacokinetics is minimal. However, it has been shown that mild hepatic impairment (Child Pugh score ≤ 7) can increase the levels of ivabradine by up to 20%. However, there are limited data in moderate or severe hepatic impairment.

Bradycardia from ivabradine follows a linear dose-dependent effect up to 24 mg twice daily. With higher doses, the effect on lowering heart rate reaches a plateau.²²

Pharmacodynamics

The blockade of HCN channels by ivabradine has been shown to be dependent on its plasma concentration. It inhibits the HCN channels by diffusing across the cellular membrane and interacting intracellularly within the pore loop with the channel in the open state.^28,29 This is particularly important as the number of open channels directly correlates with the frequency of diastolic depolarization of SA node and hence heart rate. Due to this mechanism of action, ivabradine is considered to have a “rate-dependent” effect with a more pronounced action at higher heart rates. At the same time, this mechanism of action also minimizes the risk of severe bradycardia.³⁰

Cyclic adenosine monophosphate (cAMP) is an important regulator of HCN channels, with an increased likelihood of the channel being in an open configuration when cAMP is bound to it. Thus, the frequency of the HCN channel in the open state is dependent on intracellular concentration of cAMP and therefore affects the rate of diastolic depolarization of SA node and heart rate.^31,32 Beta 1-receptors, in the heart, act by increasing the concentration of intracellular cAMP therefore causing an increased heart rate, and an opposite effect occurs with stimulation of muscarinic receptors.^23,33
–35 Ivabradine uniquely reduces the heart rate without affecting myocardial contractility.

Ivabradine in HF: Clinical Trials and FDA Approval

Systolic Heart Failure Treatment with the I _f Inhibitor Ivabradine Trial (SHIFT) included all patients with HF (left ventricular ejection fraction [LVEF] < 35%, New York Heart Association II-IV) irrespective of their coronary artery disease (CAD) status (Table 1). Results from this trial led to the approval of ivabradine in April 2015 by FDA to reduce HF hospitalizations.³⁶ The current approved indication for ivabradine includes patients with chronic stable HFrEF (ejection fraction [EF] <35%) who are unable to tolerate beta-blockers or are on maximally tolerated beta-blockers with a resting heart rate more than 70 bpm. This trial studied 6,558 patients in a randomized fashion with NYHA functional class II to class IV, LVEF <35%, resting heart rate more than 70 bpm, and an episode of HF hospitalization within the last year. Patients were divided to receive either placebo or ivabradine. Ivabradine was initiated at 5 mg 2 times daily and was titrated to achieve a resting heart rate between 50 and 60 bpm in combination with optimal medical therapy. The study demonstrated a significant reduction in HF hospitalization in the ivabradine arm as compared to placebo (16% vs 21%, respectively, hazards ratio [HR] = 0.74; 95% confidence interval [CI] of 0.66-0.83, P < .0001). The study also demonstrated an 18% relative risk reduction in the primary end point (composite of HF hospitalization and cardiovascular deaths) and a statistically significant reduction in deaths due to HF (secondary outcome; receiving at least 50% of target beta-blocker medication) in the ivabradine arm as compared to the placebo arm (3% vs 5%, respectively, HR = 0.74; 95% CI = 0.58-0.94; P = .014). The beneficial effects of ivabradine appeared to be directly linked to a baseline elevated heart rate (HR = 0.75; 95% CI = 0.67-0.85) especially in patients with a heart rate more than 77 bpm when compared to a heart rate of less than or equal to 77 bpm (HR = 0.93; 95% CI = 0.80-1.08; P = .029). Of all patients, only 49% received >50% of target beta-blocker dosage. Although a majority of population was not at the maximally tolerated dose of beta-blockers, these numbers closely mirrored the current outpatient clinical practice.³⁷ In another interesting analysis from the SHIFT study by Swedberg et al, the effect of ivabradine across various baseline beta-blocker dosages was studied to examine if beta-blocker dose had influenced the outcomes of the original study.³⁸ It was concluded that the effects of ivabradine were primarily driven by the resting heart rate and there was, at the most, a minimal interaction of baseline beta-blocker treatment.

Table 1.

Major Trials on Ivabradine, Their Primary, and Secondary Outcomes.

Trials	SHIFT-HF	BEAUTIFUL CAD and LVSD	SIGNIFY	ADD-IFI
Inclusion	All HF NYHA II-IV; LVEF < 35%; HR > 70 bpm; hospitalization for worsening HF	All CAD; LVEF<40%; NYHA I-III; HR > 60	All CAD; No HF; LVEF >40%; HR>70	Documented CAD and stable angina (on atenolol 50 mg daily)
Dosing regimen	5 mg BID titrated to 2.5 mg or 7.5 mg BID	5 mg BID titrated to 7.5 mg BID	7.5 mg BID titrated to 5 mg or 10 mg BID	5 mg BID titrated to 7.5 mg BID
Study arms	Ivabradine vs placebo	Ivabradine vs placebo	Ivabradine vs placebo	Ivabradine vs placebo
Primary end point	Composite of CV death or hospitalization for worsening HF	Composite of CV death or hospitalization for worsening HF or MI	Composite of CV death or nonfatal MI	Changes in: 1. TED (min) 2. TLA (min) 3. TAO (min) 4. TST (min)
Results	HR 0.82 (95% CI 0.75-0.9)	No difference; HR = 1.00; (95% CI 0.91-1.10)	No difference; HR 1.08; (95% CI 0.96-1.20)	Ivabradine vs placebo 1. TED: 24 ± 65 vs 8 ± 64; P < .001 2. TLA: 49 ± 83 vs 23 ± 79; P < .001 3. TAO: 26 ± 66 vs 9 ± 64; P < .001 4. TST: 46 ± 93 vs 15 ± 87; P < .001
Secondary end points and results	(1) All-cause mortality: NS (HR = 0.90, CI 0.80-1.02) (2) Cardiovascular mortality: NS (HR = 0.91, CI 0.80-1.03) (3) Death from heart failure: HR = 0.74 (CI 0.58-0.94) (4) All-cause hospital admission: HR = 0.89 (CI 0.82-0.96) (5) Hospital admission for worsening heart failure: HR = 0.74 (CI 0.66-0.83) (6) Any cardiovascular hospital admission: HR = 0.85 (CI 0.78-0.92) (7) Cardiovascular death, hospital admission for worsening heart failure, or hospital admission for nonfatal myocardial infarction: HR = 0.82 (CI 0.74-0.89)	(1) All-cause mortality: NS (HR 1.04, CI 0.92-1·16) (2) Cardiac death (death from MI or HF or death related to a cardiac procedure): NS (HR = 0.89, CI 0.71-1.12) (3) Cardiovascular death (defined as cardiac death, death from a vascular procedure, presumed arrhythmic death, stroke death, other vascular death, or sudden death of unknown cause) or admission to hospital for new-onset or worsening heart failure: NS (HR = 1.07, CI 0.94-1.22) (4) Composite of admission to hospital for fatal and nonfatal acute myocardial infarction or unstable angina: HR = 0.78 (CI 0.62-0.97) (5) Coronary revascularization: HR = 0.70 (CI 0.52-0.93) (6) Cardiovascular death: NS (HR = 1.04, CI 0.94-1.15) (7) Admission to hospital for heart failure: NS (HR = 0.99, CI 0.86-1.13) (8) Admission to hospital for myocardial infarction: HR = 0.64 (CI 0.49-0.84)	(1) All-cause mortality: NS (HR 1.06, CI 0.94-1.21) (2) Cardiovascular mortality: NS (HR 1.10, CI 0.94-1.28) (3) Coronary death: NS (HR 1.06, CI 0.89-1.26) (4) Fatal or non-fatal myocardial infarction: NS (HR 1.06, CI 0.92-1.22) (5) Coronary revascularization (any or elective): NS (HR 1.00, CI 0.89-1.12; HR 0.89, CI 0.75-1.04 respectively) (6) Admission to hospital for heart failure: NS (HR 1.20, CI 0.99-1.46) (7) Unstable angina: NS (8) Stroke: NS	N/A

Abbreviations: CAD, coronary artery disease; LVSD, left ventricular systolic dysfunction; HF, heart failure; LVEF, left ventricular ejection fraction; HR, heart rate; NYHA, New York Heart Association; CV, cardiovascular; MI, myocardial infarction; CI, confidence Interval; NS, not significant; TED, total exercise duration; TLA, time to limiting angina; TAO, time to angina onset; TST, time to 1-mm ST-segment depression at trough of drug activity.

Ivabradine in CAD: Clinical Trials

There are 2 major clinical trials assessing the role of ivabradine in patients with CAD: morBidity-mortality EvAlUaTion of the If inhibitor Ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) and Study assessInG the morbidity-mortality beNefits of the If inhibitor Ivabradine in patients with coronarY artery disease (SIGNIFY; Table 1). Each of these trials has studied different patient populations and end points. BEAUTIFUL trial assessed patients with CAD and left ventricular dysfunction whereas SIGNIFY trial evaluated patients with CAD without any evidence of left ventricular dysfunction.

Ivabradine has been approved in Europe by European Medicines Agency (EMA) for chronic stable angina in 2006 and was approved for patients with chronic stable HF in 2012. However, in the United States, this agent is only approved for reduction in rehospitalization rates in patients with chronic stable HF in April 2015.

The first major study for ivabradine was the BEAUTIFUL trial in 2008 that randomized 10,917 patients with stable CAD and left ventricular dysfunction (EF < 40%) into 2 groups: placebo and ivabradine in addition to standard medical therapy. Ivabradine failed to demonstrate a significant reduction in the primary end point of cardiovascular death, admission to hospital for acute myocardial infarction (MI), and admission to the hospital for new onset or worsening HF. However, a subgroup analysis of patients with a heart rate of more than 70 beats per minute demonstrated a significant reduction in coronary events by 22% (P = .023), fatal and nonfatal MI by 36% (P = .001), and coronary revascularization by 30% (P = .016).²

In 2014, SIGNIFY trial reported an increased incidence of nonfatal MI and cardiovascular death in patients experiencing angina (Canadian Cardiovascular Society II or higher) on ivabradine in addition to standard medical therapy as compared to placebo (7.6% vs. 6.5%; HR = 1.18; 95% CI = 1.03-1.35; P = .02). Moreover, there was an associated increased risk of symptomatic bradycardia (7.9% vs 2.1%; P < .001), phosphenes (5.4% vs 5%; P < .001), and atrial fibrillation (5.3% vs 3.8%; P < .001).³⁹ Following the results of this study, EMA suggested that ivabradine use should only be restricted to patients with a heart rate more than 70 bpm for symptomatic anginal relief and discontinuation if it fails to alleviate symptoms after 3 months of therapy.⁴⁰ The underlying reasons delaying approval of this agent in the United States for patients with HF is because of fundamental differences in the functioning and regulatory roles of FDA and EMA.

Another study (ADD-IFI study) evaluated patients with CAD for improvement in exercise capacity by addition of ivabradine beyond standard medical therapy (Table 1). Primary outcome of the study was assessment of exercise capacity (using treadmill exercise test—Bruce protocol) at baseline and 4 months. Patients with CAD and stable angina on atenolol 50 mg/d (n = 889) were randomized to receive ivabradine (n = 431) 5 mg twice daily for 2 months (which was increased to 7.5 mg twice daily if heart rate was >50 bpm after 2 months of therapy for an additional 2 months) versus placebo (n = 432). Treatment with the ivabradine 5-mg dose was associated with reduction in resting heart rate by 7 beats per minute, while the 7.5-mg dose lowered heart rate by 9 beats per minute. At 4 months, follow-up of ivabradine demonstrated an increase total exercise duration, reduction in time to angina limiting exercise, time to angina onset, and time to ST-segment depression as compared to placebo.⁴¹

Effects of Ivabradine on Pathophysiology of HF and CAD

Heart failure is characterized by cardiac remodeling, which plays a predominant role in its pathophysiology. The beneficial effects of beta-blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists (spironolactone) in HF are secondary to inhibition of cardiac remodeling.^42

–45 Clinical data supporting the effects of ivabradine in HF is provided by an improvement in physical performance and increase in exercise capacity with addition of ivabradine. De Luca et al showed that addition of ivabradine to optimal medical therapy in patients with NYHA functional class II, LVEF > 50%, and heart rate > 70 bpm resulted in a statistically significant improvement in physical performance and increase in their exercise capacity.⁴⁶ Another study of patients with stable ischemic HF with NYHA functional class II and LVEF ≤ 40%, authors demonstrated an improved gaseous exchange (with improvement in peak oxygen consumption), improvement in functional NYHA class, quality of life, improvement in physical performance, and exercise capacity.⁴⁷ Heart failure is associated with an increased sympathetic response resulting in tachycardia. Tachycardia by itself can lead to worsening of HF and hence becomes a part of vicious cycle of tachycardia exacerbating HF and vice versa. This causes alterations in the excitation-contraction (EC) coupling of cardiomyocytes, thus adversely affecting cardiac contractility. Ivabradine improves EC coupling by breaking this vicious cycle without having any effects on contractility (unlike beta-blockers).⁴⁸ Ivabradine has also been shown to reduce heart rate variability (HRV) that could be contributing to reduction of cardiac remodeling with HF as demonstrated by Kurtoglu et al.⁴⁹ Of interest, in a recent study published by Silva et al,⁵⁰ ivabradine was associated with increase sympathetic nervous system activation secondary to baroreceptor unloading in a mouse model. Since the baroreceptor unloading mechanism is also found in humans, chronic use of ivabradine may eventually result in increased sympathetic activity and increase in HRV—whether this would result in long-term detrimental effects remains to be determined. This finding contradicts the results of Kurtoglu et al. However, since these findings were only demonstrated in a mouse model, it remains to be determined whether ivabradine will result in similar changes in HRV.⁵⁰ The mechanisms, which contribute to the antiremodeling effects of ivabradine, remain unclear.

Preclinical data on rats has demonstrated an improvement of cardiac remodeling from ivabradine by increasing capillary density, reducing interstitial collagen content, and improving left ventricle pressure-volume relationship.⁵¹ Gerbaud et al in his study of successfully reperfused patients with STEMI provided the first objective evidence of addition of ivabradine to standard medical therapy in reducing cardiac remodeling as seen on cardiac magnetic resonance imaging.⁵² Mouse models have shown ivabradine to improve endothelial dysfunction, decrease in the vascular oxidative stress biomarkers, and prevent atherosclerosis in apolipoprotein E-deficient mice.⁵³ Heart failure is also known to be associated with ventricular arrhythmias. In preclinical studies, HCN2 and HCN4 receptors were found to be upregulated in the atrial and ventricular myocardium^54

–60 and this overexpression could well be an important trigger of dysrhythmias observed in this patient population.^{15,54

–57,59,60} Hence by blocking HCN4 receptors, ivabradine should offer an additional theoretical advantage in prevention of arrhythmias in this population. Indeed, the antiarrhythmic effect on ivabradine, specifically ventricular fibrillation (VF) and ventricular tachycardia (VT) was demonstrated by Mackiewicz et al in a preclinical rat study. They demonstrated a reduced incidence and mortality due to combined VF and VT in rats with MI pretreated with ivabradine as compared to placebo.⁶¹

Ivabradine has also been shown to reduce infarct size when administered before reperfusion in preclinical studies with ST-segment elevation MI (STEMI) induced in pigs.⁶² Dedkov et al, in another study, demonstrated that mice with STEMI when treated with ivabradine resulted in improvement of LVEF, coronary reserve, and volume of interstitial and periarteriolar collagen network suggestive of ivabradine’s role in preventing left ventricular remodeling.⁶³ A similar conclusion was drawn in a pilot study of 124 patients investigating ivabradine’s role in successfully patients with reperfused STEMI . The study demonstrated promising results with lesser increase of left ventricular end-diastolic volume index (P = .04) and significant improvement in LVEF as compared to placebo (P = .04).⁵²

In normal myocardium, increased myocardial oxygen consumption is balanced by an increase in coronary blood flow via metabolic vasodilation. However, due to a reduction in diastolic time (in setting of tachycardia) the coronary blood flow per cardiac cycle decreases, this is matched by an enhanced myocardial oxygen extraction. Patients with coronary artery stenosis due to a sudden plaque rupture or due to chronic narrowing from progression of an atherosclerotic plaque exhaust their metabolic vasodilator reserve in the poststenotic segment and eventually supply demand mismatch. This results in metabolic dilation in the areas of normal myocardium and hence increased blood flow, that is, differential blood supply between normal and abnormal myocardium. Ivabradine increases the diastolic period and hence helps counteract this differential blood supply between abnormal and normal myocardium.^62,64,65 Also, the hypothesis of reduction in the infarct size could be secondary to reduced accumulation of extra mitochondrial reactive oxygen species. This is potentially beneficial as it increases mitochondrial capacity to produce adenosine triphosphate, which has been demonstrated by Kleinbongard et al. The study demonstrated that ivabradine has pleiotropic actions, which could potentially contribute in infarct size reduction following coronary ischemia independent of its heart rate lowering effect.⁶⁶

Side Effects and Contraindications

The common side effects observed with ivabradine are bradycardia, hypertension, atrial fibrillation, and temporary vision disturbances called phosphenes. Atrial fibrillation is an important side effect with a recent meta-analysis showing a 15% increase in its incidence with ivabradine.⁶⁷ Another combined analysis of SHIFT trial and BEAUTIFUL study reported an increase in atrial fibrillation incidence in this patient population (number needed to harm = 58).⁶⁸ The proposed mechanism of ivabradine leading to atrial fibrillation is genetic polymorphisms in HCN4 receptors resulting in an enhanced effect of ivabradine.⁶⁹ We hypothesize that individuals with genetic polymorphisms of HCN4 can have significant inhibition of the 2 primary pacemaker tissues of the heart (SA node and AV node). This would provide substrate for atrial tissue to discharge and convert sinus rhythm into atrial fibrillation.

Phosphenes, that is, perception of transient enhanced light brightness localized to small areas in visual field, is another potential side effect observed with ivabradine. The underlying mechanism of this side effect is an extension of the hyperpolarization current inhibition by ivabradine. The photoreceptors in retina utilize the hyperpolarization current to send neurological signals of light perception to the brain. However, this can be dysregulated in susceptible individuals with ivabradine. This side effect resolves shortly after drug discontinuation.

Other uncommon side effects include headaches, first-degree AV block, ventricular extra systoles, dizziness, and/or blurred vision. Ivabradine is contraindicated in patients with decompensated HF (as this was an exclusion criteria in all the trials), sick sinus syndrome, third-degree AV block (unless functioning demand pacemaker is present), sinoatrial block, blood pressure below 90/50 mm Hg, resting heart rate < 60 bpm prior to treatment, pacemaker dependence, severe hepatic impairment, and use of strong cytochrome P4503A4 inhibitors. It can also cause fetal toxicity and should be avoided in pregnancy (pregnancy class D, Lactation: unknown).

There has been only a single case reported for ivabradine intoxication so far. Intoxication from ivabradine is thought to induce severe bradycardia and acute HF; however, the patient in this case report self-administered 280 mg ivabradine, and his only symptoms were drowsiness and a mild sinus bradycardia (50 bpm) associated with a well-tolerated borderline low blood pressure (100/50 mm Hg), which resolved over a period of 3 days. Of note, the severity of presentation was not found to be associated with the serum concentration of ivabradine. Increasing experience with ivabradine will shed more light into the toxicity associated with this medication.⁷⁰

Future Directions for Ivabradine

Ivabradine, because of its unique mechanism of action, has been tried in other conditions including treatment of inappropriate sinus tachycardia, demonstrating a significant symptomatic improvement as compared to placebo.⁷¹ Other potential uses of ivabradine as reported by Zwicker et al include management of cardiogenic shock secondary to tachycardia-induced cardiomyopathy postheart transplantation⁷² and Roubile et al in acute idiopathic HF.⁷³

Post et al reported a successful reduction of catecholamine-induced tachycardia with inotrope use in patients with cardiogenic shock from treatment with ivabradine. This beneficial effect could potentially translate into reduction in need for inotropic agents and also the time requiring intra-aortic balloon pump support.⁷⁴ Along similar lines, MODI(f)Y is an ongoing trial evaluating ivabradine in multiorgan dysfunction syndrome (MODS). It is a prospective randomized controlled phase II-trial evaluating 70 patients with newly diagnosed MODS, with an elevated heart rate of more than or equal to 90 bpm in sinus rhythm and contraindication to beta blockers. The patients are divided into a study arm with ivabradine for 4 days in prespecified dosage according to heart rate compared to placebo, in addition to standard medical therapy. The patients will be followed for 6 months with primary end point of reduction in the mean heart rate by at least 10 bpm, for up to 96 hours after initiation of therapy. The secondary end points will evaluate for morbidity, hemodynamic parameters, vasopressor requirement, improvement in microcirculation and endothelial function, mean heart rate at 24 and 48 hours, mortality at 28 days and 6 months, and cardiac autonomic dysfunction.⁷⁵

Ivabradine has seen multiple benefits in large-scale trials and has found a place in the management algorithm for HF. Currently, it is recommended in patients who are on optimal medical therapy (including maximally tolerated beta-blockers, ACE/ARB inhibitors, mineralocorticoid receptor antagonists) and continue to have a heart rate >70 bpm in order to reduce HF re-hospitalization rates and provide symptomatic relief. However, there is an accumulating evidence of “off-label” use of ivabradine in other conditions like STEMI to reduce infarct size, cardiogenic shock complicated by vasopressors-induced significant tachycardia, and inappropriate sinus tachycardia.

In conclusion, due to its unique mechanism of action, ivabradine continues to have an expanding field of applications. With new trials in the horizon, exploring the “off label” use of this medication will help providing an insight into the yet unexplained pleiotropic effects seen and provide for wider indications of usage of this medication.

Footnotes

Author Contributions

Rahul Chaudhary, Jalaj Garg, and Parasuram Krishnamoorthy have contributed equally for the article.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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