Heart rate reduction through regulation of the funny current

Heart rate reduction improves outcomes in many CVD populations, including chronic stable angina, ischemic heart disease and HF.

Benefits include decreased oxygen demand; enhanced diastolic coronary perfusion and ventricular filling; prevention of arrhythmias; and improved cardiac output. Likewise, tachycardia is predictive of poor outcomes. Rate control has traditionally been achieved with beta-blockers, calcium-channel blockers, digoxin or amiodarone; however, these medications have hemodynamic and other effects that may be dose-limiting.

A mechanism of action

Michael P. Moranville

Ivabradine (Procoralan, Servier) reduces heart rate without affecting BP, contractility, conduction or repolarization. Pacemaker cells in the sinoatrial node control the inward funny current (I_f) with hyperpolarization-activated cyclic nucleotide gated channels or f-channels. The I_f current is activated at –60 to –70 mV during phase 4 of conduction and is responsible for spontaneous depolarization. I_f channels present in other atrial tissues, the atrioventricular node and purkinje fibers are affected less by ivabradine due to activation at greater hyperpolarization thresholds.

Transmembrane G-proteins coupled to adenylate cyclase increase intracellular cAMP concentrations when activated, which also activates f-channels by causing them to remain open. Stimulation of myocardial beta-1 receptors activate adenylate cyclase, increase cAMP and shift activation of the I_f current to less negative voltages. This causes faster diastolic depolarization and heart rate. Parasympathetic stimulation has the opposite effect on cAMP concentrations, resulting in less activity of f-channels.

Ivabradine is an inhibitor of I_f current via blockade of f-channels. This results in decreased frequency of sinoatrial node spontaneous depolarization. Ivabradine must bind to f-channels in the open state, making it more potent at high heart rate and reducing the likelihood of bradycardic events. Ivabradine only effects impulse generation and has no effect on P wave, PR, QRS or QT interval duration. Any effect it does have on these intervals is primarily due to slower heart rate. When given at doses of 5 mg to 7.5 mg twice daily, ivabradine lowers heart rate approximately 20% during exercise and at rest.

Pharmacokinetics, pharmacodynamics

Ivabradine is water soluble and reaches peak concentrations in approximately 1 hour. Food delays absorption and increases bioavailability, so ivabradine should be taken consistently regarding meals. Hepatic metabolism through cytochrome P450 3A4 in the gut and liver produces active metabolites. Ivabradine does not induce or inhibit 3A4 metabolism. The half-life is 11 hours. Excretion occurs through urine and feces. Dose reductions are not necessary for creatinine clearance of at least 15 mL/minute; ivabradine is contraindicated in patients with severe liver disease.

The starting dose is 5 mg twice daily with up-titration after 2 to 4 weeks to a maximum of 7.5 mg twice daily. If bradycardia occurs, doses can be reduced to 2.5 mg twice daily.

Therapeutic uses

CAD is the leading cause of death in the United States. Observational studies have shown a clear link between heart rate, ischemic events and mortality. Rapid heart rate increases myocardial oxygen requirement leading to angina and ischemic events. Benefits of beta-blockers and calcium-channel blockers include reduction in sudden cardiac death, ventricular fibrillation and infarct size. However, hemodynamic limitations, adverse effects and drug interactions can prohibit addition or up-titration of these agents.

Trials with ivabradine have demonstrated heart rate reduction in patients with chronic stable angina. Data support its use besides, or in lieu of, beta-blockers, nitrates or calcium-channel blockers for improving exercise capacity, increasing time to angina and ECG evidence of ischemia, and reducing the need for nitrates. The Morbidity-Mortality Evaluation of the I_f Inhibitor Ivabradine in Patients with Coronary Disease and Left Ventricular Dysfunction Study (BEAUTIFUL) assessed patients with stable CAD and ejection fraction of less than 40%. Ivabradine did not demonstrate a reduction in the primary endpoint of CV death, hospitalization for MI or hospitalization for new or worsening HF during a median of 19 months; however, it significantly reduced secondary endpoints, including admission for fatal or nonfatal MI and need for revascularization.

Patients with heart rate of more than 70 bpm had a nonsignificant trend toward benefit in the primary composite endpoint. Bradycardia occurred more often in patients receiving ivabradine than control groups overall, but was not a major limitation in trials when compared with or added to beta-blockers, especially with baseline heart rate of more than 70 bpm. Visual phosphenes, nausea and dizziness were other notable adverse effects. Ivabradine gained European Medicines Agency approval for chronic stable angina in patients unable to tolerate beta-blockers or inadequately controlled with heart rate of more than 60 bpm.

In patients with HF, tachycardia is a compensatory mechanism to maintain adequate cardiac output. Previous studies have shown an increased risk for death and hospital admissions for HF when heart rate is more than 70 bpm. Slowing heart rate reduces energy expenditure, improves ventricular diastolic filling and allows more coronary perfusion. It is unclear whether heart rate reduction with beta-blockers provides primary mortality advantages, given their known antiarrhythmic and neurohormonal benefits. Ivabradine can provide additional heart rate lowering without affecting contractility or hemodynamics. Early trials in HF patients have shown improvements in ejection fraction, exercise duration, maximum exercise capacity and quality of life when ivabradine was used alone or combined with carvedilol.

More recently, the Systolic Heart Failure Treatment with I_f Inhibitor Ivabradine Trial (SHIFT) evaluated the effect of ivabradine on morbidity and mortality in patients with symptomatic HF and ejection fraction of 35% or less. SHIFT was a randomized, double blind, placebo-controlled trial that included 6,558 patients who were followed for a median of 23 months. All patients were in sinus rhythm with heart rate of at least 70 bpm, were taking optimal background medications at baseline and had at least one hospital admission HF within the last year.

Key exclusion criteria were recent MI; ventricular or atrioventricular pacing; atrial fibrillation or flutter; and symptomatic hypotension. Mean heart rate reduction was 10.9 bpm with ivabradine. The primary composite endpoint (CV death or hospital admission for worsening HF) occurred significantly less often in the ivabradine group compared with placebo. In patients taking at least 50% of the recommended beta-blocker dose at baseline, only HF readmission was significantly reduced with ivabradine compared with placebo.

Multiple applications

Ivabradine has a novel mechanism of action and is hemodynamically neutral. Given the known benefits of heart rate reduction for cardiac disease, coupled with the intolerability of current options in many patients, ivabradine may be a significant addition to the pharmacologic armamentarium in the United States. Ivabradine has shown primary benefit in patients with chronic stable angina, but evidence is mounting for use in stable HF patients, as well. Studies are also under way in patients with acute coronary syndromes, HF and preserved ejection fraction, as well as in acute HF.

Michael P. Moranville, PharmD, BCPS, is clinical pharmacist specialist, cardiology, at University of Chicago Medical Center.

Rhonda M. Cooper-DeHoff, PharmD, MS, is associate professor at the University of Florida College of Pharmacy in Gainesville, and is the column editor for Cardiology Today’s Pharmacology Consult.

For more information:

• Baruscotti M. Pharmacol Ther. 2005;107:59-79.
• Fox K. Lancet. 2008;372:807-816.
• Parakh N. Am J Cardiovasc Drugs. 2011;11:1-12.
• Riccioni G. Adv Ther. 2009;26:12-24.
• Swedberg K. Lancet. 2010;376:875-885.

Disclosure: Drs. Moranville and Cooper-DeHoff report no relevant financial disclosures.