How should Ivabradine be used?💔💔💔

The end stages of various cardiovascular diseases lead to heart failure. Patients with heart failure are characterized by high mortality and poor prognosis. One of the important predictors of death from heart failure is heart rate. Therefore, how to effectively control the heart rate of the patient is extremely critical. The guidelines for the diagnosis and treatment of heart failure set the resting heart rate down to about 60 beats per minute as the goal of heart rate management in patients with chronic stable heart failure. β-blockers and ivabradine are clinically mainly used to lower heart rate. 

What is the difference between β-blockers and ivabradine?

β-blockers reduce sympathetic activity and resting heart rate. It will benefit patients with heart failure by reducing myocardial oxygen consumption, reducing cardiac work, delaying and improving ventricular structural remodeling. The guidelines for the treatment of heart failure state that all symptomatic patients with chronic heart failure need long-term use of β-blockers unless the patient is intolerable or contraindicated. At present, it is clinically recommended that the dose for patients with heart failure to reduce the heart rate to 60 beats/min is the target dose or maximum tolerated dose of β-blockers. When treating patients with heart failure, the tolerable target dose should be reached as soon as possible to reduce the resting heart rate. It will result in the greatest benefit to the patient. During the treatment of patients, attention should be paid to whether they may develop worsening heart failure, bradycardia, atrioventricular block, etc., especially at the beginning of treatment and when the dose is increased. β receptors are also distributed in blood vessels. Therefore, peripheral vasculature, coronary resistance and blood pressure are all affected by beta-blockers. Due to the decline of the patient's heart function, too fast increase of the dose of β-blockers can induce or aggravate the risk of heart failure. The dose of β-receptor blockers can reduce the work of myocardial cells and oxygen consumption rate by controlling the heart rate, but it is also necessary to avoid excessive inhibition of myocardial contractility by β-receptor blockers to affect cardiac output and blood pressure. 

Ivabradine is a pure sinoatrial node If-channel blocker. It generally only acts on the ion channel of the sinoatrial node, but in large doses it will also act on the Ih-channel of the retina, resulting in phosphenes. Ivabradine reduces sinus node excitability. It has the characteristic that the faster the base heart rate, the more obvious the effect. No negative inotropic and negative conduction effects are its important features and it will not affect blood pressure.

What is the usual usage of ivabradine?

Many treatment guidelines recommend the use of ivabradine for heart failure with reduced ejection fraction (HFrEF). For patients with sinus rhythm failure of New York heart function class II to IV and left ventricular ejection fraction (LVEF) ≤ 35%, ivabradine can be added with one of the following conditions:

1. The patient has been treated with angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers/angiotensin receptor neprilysin inhibitors, aldosterone receptor antagonists, and β-blockers. The patient has used the target dose or the maximum tolerated dose of β-blockers but the heart rate is still ≥70 beats/min.
2. Heart rate ≥ 70 beats/min in patients who are contraindicated or intolerant of β-blockers.

The guidelines for the use of ivabradine in patients with heart failure are as follows:

1. Patients with chronic HFrEF on ACE inhibitors/ARBs, β-blockers, and spironolactone who have significantly increased resting heart rate (≥80 beats/min) and who cannot increase the dose of β-blockers, the dose of β-blockers can be considered as the maximum tolerated dose in the current state. Early combined use of ivabradine can improve cardiac function and control heart rate. It is also beneficial for patients to subsequently increase the dose of β-blockers.
2. When β-blockers are used in the treatment of patients in the vulnerable stage of heart failure, the dose should not be increased too rapidly. Patients achieved target heart rate more quickly when ivabradine was used in combination. Patients will also more quickly enter into compensation and stabilization.
3. When patients with acute heart failure enter the pre-discharge stage (the patient's hemodynamic status is stable, after orthopnea is relieved, and vasoactive drugs and vasoactive drugs are stopped), ACEI/ARB,  β-blockers and spironolactone therapy can be started on the patient. If the patient has previously used ACEI/ARB, β-blockers and spironolactone, the dose can be increased. However, if the patient has tachycardia, the dose of beta-blockers should not be increased too rapidly. Combined use of ivabradine is beneficial to control the heart rate of patients with tachycardia and further improve cardiac function.
4. Some studies have pointed out that when patients with heart failure and chronic obstructive pulmonary disease are intolerant to β-blockers or can no longer increase the dose, ivabradine can be used in combination or switched. It can control patients' heart rate, improve symptoms and benefit their prognosis.

The recommended starting dose for patients with chronic HFrEF is 5 mg twice daily with meals. The starting dose for elderly patients ≥75 years is 2.5 mg twice daily. Patients were evaluated and dose adjusted two weeks after treatment. The patient's resting heart rate should be controlled at about 60 beats per minute. The maximum dose of ivabradine is 7.5 mg twice daily. Ivabradine is only metabolized by CYP3A4. Ivabradine is only metabolized by CYP3A4. It interacts with inhibitors and inducers of CYP3A4. CYP3A4 inducers decrease the plasma concentration of ivabradine whereas CYP3A4 inhibitors increase its plasma concentration. Elevated plasma concentrations of ivabradine may cause bradycardia in patients.

What other cardiovascular diseases can ivabradine be used for?

The general indication of ivabradine is for sinus rhythm and heart rate ≥ 75 beats/min, accompanied by New York Heart Function Class II to IV chronic heart failure patients with systolic dysfunction. In order to control the patient's condition early or improve the patient's prognosis, there are several practical clinical applications as follows:

1. Stable coronary artery disease: ivabradine or nicorandil can be used for patients who have contraindications to the use of β-blockers, poor treatment effect or adverse reactions. Ivabradine can reduce the heart rate of patients with coronary heart disease to reduce oxygen consumption, increase coronary blood flow, improve coronary microcirculation, prevent ischemia and improve exercise tolerance.
2. After the symptoms of acute heart failure are relieved: when the heart rate of a patient with acute heart failure is still fast after systemic treatment, the treatment guidelines require that the patient should use β-blockers as soon as possible. In patients with acute heart failure who are hemodynamically stable after hospitalization, if the patient cannot tolerate β-blockers, low-dose ivabradine (2.5 mg twice a day) may be considered initially . Ivabradine can be adjusted according to the blood pressure and heart rate of the patient. At the same time, the β-blockers used by patients should be evaluated in time, so that the two can be used in combination reasonably. It can further improve the symptoms of heart failure decompensation and reduce the risk of rehospitalization.
3. Focal atrial tachycardia, inappropriate sinus tachycardia, and orthostatic tachycardia syndrome: Guidelines recommend ivabradine alone or in combination with beta-blockers in patients with symptomatic inappropriate sinus tachycardia. Guidelines recommend ivabradine alone or in combination with beta-blockers in patients with symptomatic inappropriate sinus tachycardia. Ivabradine may be considered in patients with postural tachycardia syndrome. Patients with chronic focal atrial tachycardia may consider using ivabradine combined with β-blockers.
4. Heart rate preconditioning before coronary CT angiography: Excessive heart rate will affect coronary CT angiography. Therefore, metoprolol and propranolol are general pretreatment drugs. Ivabradine safely, rapidly and consistently lowers the patient's heart rate. The regimen of using ivabradine alone or in combination may be a better choice.