Cardiology

Ivabradine

General (including evidence of efficacy)

Ivabradine (Corlanor®) is a novel selective inhibitor of the I f channel current in the pacemaker cells of the sinoatrial (SA) node. Its predominant effect is to reduce heart rate without affecting contractility. Heart rate reduction with beta blockers has been identified in clinical literature and trials as a contributor to better prognosis in patients with heart failure. However, beta blockers have undesirable adverse effects (i.e., hypotension and fatigue), which often lead to patient intolerance or medication non-adherence. In patients in normal sinus rhythm who cannot tolerate target doses of beta blockers or who experience high heart rates despite optimal beta blocker therapy, ivabradine may be a useful addition to standard heart failure therapy.

The efficacy of ivabradine in heart failure patients is demonstrated via a randomized, multi-center, double-blind, placebo-controlled, parallel-group trial - SHIFT - which was published in 2010. Over 6,000 patients were randomized and followed for about 22.9 months. Patients were enrolled if they were in normal sinus rhythm with a resting heart rate of at least 70 beats per minute (bpm) or more, had stable, symptomatic chronic heart failure (CHF) for at least 4-weeks' duration, had a previous hospital admission for worsening heart failure within the previous 12 months, and a left ventricular ejection fraction (LVEF) of 35% or less. The primary composite endpoint was cardiovascular death or hospital admission for worsening heart failure. The secondary endpoints were all-cause hospital admission, hospital admission for worsening heart failure, any cardiovascular hospital admission, or composite cardiovascular death, or hospital admission for worsening heart failure, or hospital admission for non-fatal myocardial infarction (MI). Patients assigned to ivabradine were started on 5 mg twice daily and the dose was modified according to the heart rate, which was assessed in 2 weeks.

At baseline, the average age of the patients was 60 years old, 77% male, 89% Caucasian, average baseline resting heart rate of 79-80 bpm, and average LVEF of 29%. At baseline, 89% of patients were taking a beta blocker with 56% of patients at 50% or more of the target beta blocker dose and 26% of patients at the target dose. The dose of beta blockers was maintained during the trial; no reduction in dosage was observed while titrating ivabradine. In addition, 22% of the patients were on a cardiac glycoside.

At the end of the study duration, 24% of patients in the ivabradine group experienced the primary composite endpoint versus 29% in the placebo group for a risk reduction of 18% (p< 0.0001). The results were primarily driven by the reduction in hospitalizations for worsening heart failure with ivabradine versus placebo (16% vs. 21%; p< 0.0001); although they trended in favor of ivabradine, the differences in all-cause mortality and cardiovascular mortality were not statistically significant (p = 0.092 and p = 0.128, respectively). The ivabradine group did achieve a statistically significant reduction in death from heart failure compared to placebo (3% vs. 5%; p = 0.014) (Figure 1).

Figure 1.

In addition, there was a significant treatment effect in patients with a baseline heart rate of 77 bpm or greater versus patients with a baseline heart rate of less than 77 bpm (p = 0.029 for interaction). There was no statistically significant difference in the primary endpoint with ivabradine compared to placebo in the subgroup of patients who received at least 50% or more of the target beta blocker dose (p = 0.155); however, there was a statistically significant reduction in hospitalizations due to worsening heart failure within this subgroup with ivabradine reducing admissions by 19% in this group (p = 0.021).

The BEAUTIFUL trial was a randomized, double-blind, placebo-controlled study that evaluated 10,917 patients with coronary artery disease (CAD), LVEF less than 40%, and normal sinus rhythm with a resting heart rate of at least 60 bpm or more. The primary outcome was time to first cardiovascular death, admission to the hospital for acute MI, and admission to the hospital for new onset or worsening heart failure. There were no statistically significant differences between the two groups for the primary endpoint. A sub-analysis showed that patients with a baseline heart rate of at least 70 bpm or greater demonstrated a significant difference in favor of ivabradine with regards to hospital admissions for MI (p = 0.001), admission for MI or stable angina (p = 0.023), and reduction in coronary re-vascularization (p = 0.016).

The SIGNIFY trial was a randomized, double-blind, placebo-controlled study that enrolled 19,102 patients with CAD, preserved LVEF, heart rate of 70 bpm or greater, and at least one of the following: symptomatic patients in Canadian Cardiovascular Society (CCS) class II or higher, objective evidence of ischemia induced by stress testing, or discharged from a hospital with a documented diagnosis of a major coronary event within 12 months prior to selection or at least two of the following: low HDL and/or high LDL despite lipid-lowering treatment, type 1 or type 2 diabetes, peripheral artery disease (PAD), a current smoker, or age greater than 70 years old. The primary composite endpoint was death from cardiovascular causes or non-fatal MI. No significant difference was seen with regards to the primary outcome. Of note, patients with activity-limiting angina CCS class II or higher actually had a higher risk for the primary endpoint with ivabradine compared to placebo (p = 0.02). However, it is noted that the study allowed patients to be titrated to a higher dose of ivabradine (i.e., 10 mg twice daily), which exceeds the FDA recommended maximum daily dose.

In general, ivabradine was shown, as an adjunctive therapy to guideline-based regimen, to reduce the risk for re-hospitalization due to worsening heart failure in patients with symptomatic heart failure and a LVEF of 35% or less, who are in normal sinus rhythm and have a resting baseline heart rate of 70 bpm or greater.

Differences between drugs within the class

Ivabradine is the only selective I fchannel inhibitor to date. There are no other medications within this class.

Administration

The recommended starting dose of ivabradine is 5 mg by mouth twice daily with meals. Assess the patient after 2 weeks and adjust the dose to achieve a resting heart rate between 50-60 beats per minute (Table I). Adjust the dose as needed based on resting heart rate and tolerability. The maximum recommended dose is 7.5 mg by mouth twice daily with meals.

Table I.

Recommended dose adjustment according to heart rate

In patients with a history of conduction defects, or other patients in whom bradycardia could lead to hemodynamic compromise, initiate therapy at 2.5 mg by mouth twice daily with meals before increasing the dose based on heart rate.

Pharmacologic action

Ivabradine blocks the hyperpolarization-activated cyclic nucleotide-gated channel responsible for the cardiac pacemaker I f current, which regulates heart rate. Ivabradine crosses the cell membrane and interacts within the pore loop from the intracellular side. The inhibition slows down depolarization and reduces heart rate. Binding and un-binding of ivabradine at the channel site only occurs when the channel is in an "open" state. Given that the number of open channels directly correlates with heart rate, the actions of ivabradine are considered "rate-dependent" and the pharmacological reduction of heart rate is a function of heart rate at baseline.

Indications and contraindications

Ivabradine received FDA approval in April 2015 to reduce the risk of hospitalization for worsening heart failure in patients with stable symptomatic CHF with a left ventricular ejection fraction of 35% or less, who are in sinus rhythm with a resting heart rate of 70 bpm or greater, and are either on maximally-tolerated doses of beta blockers or have a contraindication to beta blocker use.

Ivabradine is approved in Europe for the symptomatic treatment of chronic stable angina in coronary artery disease (CAD) patients who are in normal sinus rhythm and have a resting heart rate of 70 bpm or greater. It is also approved for the treatment of CHF in patients with class NYHA II-IV, in sinus rhythm, and whose resting heart rate is 75 bpm or greater. Patients may take ivabradine in combination with standard therapy, including beta blockers, or when beta blocker therapy is contraindicated or not tolerated.

Ivabradine is contraindicated in patients with acute decompensated heart failure, blood pressure less than 90/50 mmHg, sick sinus syndrome, sinoatrial block or 3rd degree atrioventricular block (unless a functioning demand pacemaker is present), resting heart rate less than 60 bpm prior to treatment, severe hepatic impairment (Child-Pugh class 3), pacemaker dependence (heart rate maintained exclusively by the pacemaker), and concomitant use of strong cytochrome P450 3A4 inhibitors.

Undesirable effects

The most commonly reported adverse events with ivabradine were bradycardia (10%), hypertension (8.9%), atrial fibrillation (8.3%), and visual brightness (2.8%).

Additional warnings and precautions include: fetal toxicity (women of child-bearing age should be on contraception), increased risk for atrial fibrillation that requires close cardiac rhythm monitoring (discontinue ivabradine if atrial fibrillation develops), bradycardia, sinus arrest, and heart block; thus, heart rate and symptoms of bradycardia should be monitored during treatment.

Alternative approaches

To date, there are no well-established, head-to-head studies comparing ivabradine with other rate-lowering medications used in heart failure, such as digoxin. Currently, digoxin is listed in the 2013 ACCF/AHA Heart Failure Guidelines as a class IIa recommendation for patients with reduced ejection fraction, unless contraindicated, to decrease hospitalizations for heart failure (level of evidence: B). Digoxin may also be used in concomitant atrial fibrillation, whereas ivabradine cannot.

Per the Digitalis Investigators Group (DIG) trial, which evaluated the benefit of digoxin in 6,800 patients with heart failure and LVEF of 45% or less, in addition to standard guideline-based therapy, the results showed that there was a statistically significant decrease in re-hospitalizations due to worsening heart failure, with 26.8% in the digoxin group versus 34.7% in the placebo group (p < 0.001). However, there was no statistically significant difference in the primary outcome of all-cause or cardiovascular mortality. Due to having a narrow therapeutic index window in heart failure, in contrast to ivabradine, digoxin requires close monitoring with regards to serum drug levels, renal function, and electrolytes.

What's the Evidence?

Rosa, GM, Ferrero, S, Ghione, P, Valbusa, A, Brunelli, C. "An evaluation of the pharmacokinetic and pharmacodynamics of ivabradine for the treatment of heart failure. Expert Opin. Drug Metab". Toxicol. vol. 10. 2014. pp. 279-291.

(A systematic review on the role of ivabradine in heart failure, highlighting the mechanism of action and specific pharmacodynamics and kinetics of the drug.)

McAlister, FA, Wiebe, N, Ezekowitz, JA. "β-Blocker Dose, Heart Rate Reduction, and Death in Patients with Heart Failure". Ann Intern Med. vol. 150. 2009. pp. 784-794.

(A meta-analysis conducted to determine whether the mortality benefits of beta blockers are associated with the extent of heart rate reduction or the dose itself.)

Pocock, SJ, Wang, D, Pfeffer, MA. "Predictors of mortality and morbidity in patients with chronic heart failure". Eur Heart J. vol. 27. 2005. pp. 65-75.

(A study that examined patients enrolled in the CHARM trial with the purpose of developing prognostic models and understanding factors that have an independent influence on mortality outcomes, including heart rate reduction.)

Swedberg, K, Komajda, M, Bohm, M. "Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized, placebo-controlled study". Lancet. vol. 376. 2010. pp. 875-885.

(The 2010 SHIFT trial that compared ivabradine versus placebo in heart failure patients with an LVEF of ≤ 35%, in normal sinus rhythm with a resting heart of at least 70 bpm and on optimized CHF medications for at least 1 month and observed any differences in cardiovascular death or hospital admission for worsening heart failure.)

Fox, K, Ford, I, Steg, PG, Tendera, M, Ferrari, R. "Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomized, double-blind, placebo-controlled trial". Lancet. vol. 372. 2008. pp. 807-816.

(The 2008 BEAUTIFUL trial that compared ivabradine versus placebo in patients with CAD, LVEF less than 40%, and normal sinus rhythm with a resting heart rate of at least 60 bpm and observed for any differences with regards to cardiovascular death or hospital admission for MI or heart failure.)

Fox, K, Ford, I, Steg, PG. "Ivabradine in Stable Coronary Artery Disease without Clinical Heart Failure". NEJM. vol. 371. 2014. pp. 1091-1099.

(The 2014 SIGNIFY trial that compared ivabradine versus placebo in patients with stable CAD and observed for any differences with regards to cardiovascular death or non-fatal MI.)

(References the FDA-approved administration, pharmacologic action, indications, contraindications, and undesirable effects of ivabradine.)

(The European package insert about ivabradine and the specific indications that differ from the US-based package insert.)

vol. 128. 2013. pp. e240-e327.

(References the place of digoxin within the current heart failure guidelines.)

"The Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure". NEJM. vol. 336. 1997. pp. 525-533.

(The 1997 DIG trial that compared digoxin versus placebo in heart failure patients with an LVEF of ≤ 45% and in normal sinus rhythm to observe any differences in all-cause mortality and hospitalization for worsening heart failure.)
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