Instructions for use of RAENOM®
No effect on clinical outcomes in patients with symptomatic chronic stable angina
Raenom® is indicated only for the symptomatic treatment of chronic stable angina, as it does not have a beneficial effect on cardiovascular outcomes (eg, myocardial infarction or cardiovascular mortality).
Heart rate control
Taking into account the variability of heart rate throughout the day, periodic heart rate measurements, ECG or 24-hour monitoring should be considered to determine resting heart rate before starting treatment with Raen®, as well as in patients receiving treatment with ivabradine when dose titration is necessary . This also applies to patients with low heart rate, in particular when heart rate is less than 50 beats/min, or when the dose is reduced (see Dosage Regimen).
Heart rhythm disturbances
Raenom® is not effective for the treatment or prevention of arrhythmias. There is a high probability of a decrease in its effectiveness due to the development of tachyarrhythmia (for example, ventricular or supraventricular tachycardia). Therefore, Raenom® is not recommended for patients with atrial fibrillation or other types of cardiac arrhythmias associated with sinus node function.
Patients receiving treatment with Raen® have an increased risk of developing atrial fibrillation. Atrial fibrillation was more common among patients who were taking amiodarone or class I antiarrhythmic drugs concomitantly with ivabradine. It is recommended to conduct regular clinical monitoring of patients receiving treatment with Raen® for the detection of atrial fibrillation (persistent or paroxysmal), which, if clinically indicated, should also include ECG monitoring (for example, in the case of worsening angina, palpitations, irregular pulse).
Patients should be informed about the signs and symptoms of atrial fibrillation and should be advised to seek medical attention if such symptoms occur.
If atrial fibrillation occurs during therapy, it is necessary to assess the benefit-risk ratio of further treatment with Raen®.
Patients with CHF and intraventricular conduction disorders (left bundle branch block, right bundle branch block) and ventricular dyssynchrony should be closely monitored.
2nd degree AV block
Prescribing Raenom® to patients with second degree AV block is not recommended.
Use in patients with bradycardia
Raenom® should not be prescribed to patients if, before starting therapy, the resting heart rate is less than 70 beats/min.
If during therapy the resting heart rate decreases to values less than 50 beats/min or the patient experiences symptoms associated with bradycardia (such as dizziness, fatigue or hypotension), the dose of the drug must be reduced. If, when the dose of the drug is reduced, the heart rate remains less than 50 beats/min or symptoms of bradycardia persist, the drug should be discontinued.
Combination therapy with calcium channel blockers
The use of Raenom® in combination with calcium channel blockers (CCBs) that reduce heart rate, such as verapamil or diltiazem, is contraindicated. When using the drug Raenom® in combination with nitrates and dihydropyridine CCBs, such as amlodipine, no changes in the safety profile were noted. It has not been established that simultaneous use with CCBs increases the effectiveness of ivabradine.
Chronic heart failure
The use of Raenom® should be considered only in cases of stable CHF. Caution should be exercised when using the drug Raenom® in patients with NYHA functional class IV CHF due to limited data on the use of the drug in this group of patients.
Stroke
It is not recommended to use the drug Raenom® immediately after a stroke, because There are no data on the use of the drug in such situations.
Functions of visual perception
Ivabradine affects the function of the retina. There is no evidence that ivabradine treatment causes long-term retinal toxicity. If visual impairments not described in these instructions occur, you should consider stopping the drug. Caution should be exercised when prescribing Raenom® to patients with retinal pigmentary degeneration.
Arterial hypotension
There is insufficient data on use in patients with mild or moderate arterial hypotension, so caution should be exercised when prescribing Raenom® to such patients. Raenom® is contraindicated in patients with severe arterial hypotension (BP < 90/50 mm Hg).
Atrial fibrillation
–
cardiac arrhythmias
There was no risk of developing severe bradycardia while taking ivabradine when restoring sinus rhythm through pharmacological cardioversion. However, due to the lack of sufficient data, if it is possible to delay elective electrical cardioversion, Raenom should be discontinued 24 hours before it is performed.
Congenital long QT syndrome or treatment with drugs that prolong the QT interval
Avoid prescribing Raenom® to patients with congenital long QT syndrome or patients taking drugs that prolong the QT interval. If it is necessary to use such a combination, careful monitoring of cardiac function should be performed.
The reduction in heart rate caused by ivabradine may exacerbate the prolongation of the QT interval, which can cause the development of severe arrhythmias, in particular, torsades de pointes (TdP).
.
Patients with arterial hypertension requiring adjustment of antihypertensive therapy
In the SHIFT study, increased blood pressure was more common in the ivabradine group (7.1%) compared with placebo (6.1%). Most often, these cases were observed immediately after changing antihypertensive therapy; they were temporary and did not affect the effectiveness of ivabradine. When changing antihypertensive therapy in patients with CHF taking ivabradine, blood pressure monitoring is necessary at appropriate time intervals.
Excipients
Raenom® film-coated tablets,
contain lactose.
The drug is not recommended for patients with lactase deficiency, lactose intolerance, or glucose-galactose malabsorption syndrome.
Impact on the ability to drive vehicles and machinery
A special study to evaluate the effect of ivabradine on the ability to drive a car was conducted with the participation of healthy volunteers. According to its results, the ability to drive a car did not change. However, in the post-registration period, there were cases of deterioration in the ability to drive vehicles due to symptoms associated with visual impairment. Ivabradine may cause a temporary change in light perception, predominantly in the form of phosphenes. The possible occurrence of such a change in light perception should be taken into account when driving vehicles or other mechanisms when there is a sharp change in light intensity, especially at night.
Ivabradine does not affect the ability to operate machinery.
Raenom, 56 pcs., 5 mg, film-coated tablets
Ivabradine is a medicine that slows the heart rate.
The mechanism of action of ivabradine is the selective and specific inhibition of If
channels of the sinus node that control spontaneous diastolic depolarization in the sinus node and regulate heart rate (HR).
Ivabradine has a selective effect on the sinus node, without affecting the timing of impulses along the intra-atrial, atrioventricular and intraventricular pathways, as well as on myocardial contractility and ventricular repolarization. Ivabradine can also interact with the Ih
channels of the retina, which are similar in structure to
the If
channels of the heart. They are involved in the mechanisms of temporary adaptation of the visual perception system by changing the retinal response to bright light stimuli.
Under provoking circumstances (for example, a sharp change in illumination intensity in the visual field), partial inhibition of Ih
channels with ivabradine leads to
the phenomenon of changes in light perception (photopsia)
. Photopsia is characterized by a transient change in brightness in a limited area of the visual field (see section “Side effects”).
The main pharmacological effect of ivabradine is a dose-dependent decrease in heart rate. An analysis of the dependence of the magnitude of the decrease in heart rate on the dose of the drug was carried out with a gradual increase in the dose of ivabradine to 20 mg 2 times a day and revealed a tendency to achieve a “plateau” effect (no increase in the therapeutic effect with a further increase in the dose of the drug), which reduces the risk of developing severe bradycardia (HR less than 40 beats/min) (see section “Side effects”).
When using the drug in recommended doses, the degree of decrease in heart rate depends on its initial value and is approximately 10–15 beats/min both at rest and during physical activity, as a result of which the work of the heart and the myocardial oxygen demand decreases.
Ivabradine does not affect intracardiac conduction, myocardial contractility (does not have a negative inotropic effect) and the process of ventricular repolarization. In clinical electrophysiological studies, ivabradine had no effect on the timing of impulses along the atrioventricular or intraventricular pathways, as well as on corrected QT intervals.
In studies in patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) 30–45%), ivabradine has been shown to have no effect on myocardial contractility.
It was found that ivabradine at a dose of 5 mg 2 times a day improved the performance of stress tests after 3–4 weeks of treatment. Efficacy was also confirmed for a dose of 7.5 mg 2 times a day. An additional effect when increasing the dose from 5 mg to 7.5 mg 2 times a day was established in a comparative study with atenolol. The time spent performing physical activity increased by approximately 1 minute after 1 month of using ivabradine at a dose of 5 mg 2 times a day, while after an additional 3-month course of taking ivabradine at a dose of 7.5 mg 2 times a day orally, a further increase in this indicator was noted for 25 seconds. The antianginal and anti-ischemic activity of ivabradine has also been confirmed in patients aged 65 years and older. The effectiveness of ivabradine when used in doses of 5 mg and 7.5 mg 2 times a day was observed in relation to all indicators of stress tests (total duration of physical activity, time to a limiting attack of angina, time to the onset of an attack of angina and time to the development of ST segment depression at 1 mm) and was accompanied by a decrease in the incidence of angina attacks by approximately 70%. The use of ivabradine 2 times a day provided constant therapeutic efficacy for 24 hours.
In patients taking ivabradine, additional effectiveness was shown in relation to all indicators of stress tests when added to the maximum dose of atenolol (50 mg) at the decline of its therapeutic activity (12 hours after oral administration).
There was no improvement in the effectiveness of ivabradine when added to the maximum dose of amlodipine at the decline of its therapeutic activity (12 hours after oral administration), while at the maximum activity of amlodipine (3-4 hours after oral administration), additional effectiveness of ivabradine was proven.
In studies of the clinical effectiveness of ivabradine, its therapeutic effect was fully maintained over 3–4 months of therapy. During treatment, there were no signs of decreased effectiveness, and after cessation of treatment, no withdrawal syndrome was observed. The antianginal and anti-ischemic effects of ivabradine were associated with both a dose-dependent decrease in heart rate and a significant decrease in the work product (heart rate × systolic blood pressure) both at rest and during exercise. The effect on blood pressure (BP) and total peripheral vascular resistance (TPVR) was minor and clinically insignificant. A sustained decrease in heart rate was observed in patients who took ivabradine for at least 1 year. No effect on carbohydrate metabolism and lipid profile was observed.
In patients with diabetes mellitus, the efficacy and safety of ivabradine were similar to those in the general population. There were no differences between the groups of patients taking ivabradine against the background of standard therapy, and in patients with stable angina and left ventricular dysfunction (LVEF less than 40%), 86.9% of whom received beta-blockers and placebo, in the total incidence of cardiac deaths -vascular diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or worsening of chronic heart failure (CHF) and in the subgroup of patients with a heart rate of at least 70 beats/min.
The use of ivabradine in patients with a heart rate of at least 70 beats/min showed a reduction in the frequency of hospitalizations for fatal and non-fatal myocardial infarction by 36% and the frequency of revascularization by 30%. In patients with exertional angina, the use of ivabradine showed a reduction in the relative risk of complications (the incidence of deaths from cardiovascular diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or worsening of CHF) by 24%. The noted therapeutic benefit is achieved primarily by reducing the frequency of hospitalizations for acute myocardial infarction by 42%.
The reduction in the rate of hospitalization for fatal and non-fatal myocardial infarction in patients with heart rate more than 70 beats/min is even more significant and reaches 73%. In general, the drug was well tolerated and safe.
The use of ivabradine in patients with CHF II–IV functional class according to the NYHA classification with LVEF less than 35% showed a clinically and statistically significant reduction in the relative risk of complications (the incidence of deaths from cardiovascular diseases and a reduction in the frequency of hospitalizations due to worsening CHF ) by 18%. The absolute risk reduction was 4.2%. A pronounced therapeutic effect was observed 3 months after the start of ivabradine therapy.
A decrease in mortality from cardiovascular diseases and the frequency of hospitalizations due to worsening CHF was observed regardless of age, gender, functional class of CHF, the use of beta-blockers, ischemic or non-ischemic etiology of CHF, the presence of diabetes mellitus or a history of arterial hypertension.
Patients with symptoms of CHF in sinus rhythm and with a heart rate of at least 70 beats/min received standard therapy, which included beta-blockers (89%), angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor antagonists (91%), diuretics ( 83%) and aldosterone antagonists (60%).
It has been shown that use of ivabradine for 1 year can prevent one death or one hospitalization due to cardiovascular disease for every 26 patients taking the drug.
The use of ivabradine showed an improvement in the functional class of CHF according to the NYHA classification.
In patients with a heart rate of 80 beats/min, a decrease in heart rate by an average of 15 beats/min was noted.
Ryan
An antianginal drug that slows the heart rate. The mechanism of action of ivabradine is the selective and specific inhibition of If channels of the sinus node, which control spontaneous diastolic depolarization in the sinus node and regulate heart rate.
Ivabradine has a selective effect on the sinus node, without affecting the timing of impulses along the intra-atrial, atrioventricular and intraventricular pathways, as well as on myocardial contractility and ventricular repolarization.
Ivabradine can also interact with the Ih channels of the retina, similar in structure to the If channels of the heart, which are involved in the mechanisms of temporary adaptation of the visual perception system by changing the retinal response to bright light stimuli.
Under provoking circumstances (for example, a sharp change in light intensity in the visual field), partial inhibition of Ih channels by ivabradine leads to the phenomenon of changes in light perception (photopsia). Photopsia is characterized by a transient change in brightness in a limited area of the visual field.
The main pharmacological effect of ivabradine is a dose-dependent decrease in heart rate. An analysis of the dependence of the magnitude of the decrease in heart rate on the dose of the drug was carried out with a gradual increase in the dose of ivabradine to 20 mg 2 times a day and revealed a tendency to achieve a plateau effect (no increase in the therapeutic effect with a further increase in the dose of the drug), which reduces the risk of developing severe bradycardia (heart rate less than 40 beats/min).
When using the drug in recommended doses, the degree of decrease in heart rate depends on its initial value and is approximately 10-15 beats/min both at rest and during physical activity, as a result of which the work of the heart and the myocardial oxygen demand decreases.
Ivabradine does not affect intracardiac conduction, myocardial contractility (does not have a negative inotropic effect) and the process of ventricular repolarization. In clinical electrophysiological studies, ivabradine had no effect on the timing of impulses along the atrioventricular or intraventricular pathways, as well as on corrected QT intervals. In studies in patients with left ventricular dysfunction (LVEF 30-45%), it was shown that ivabradine does not affect myocardial contractility.
It was found that ivabradine at a dose of 5 mg 2 times a day improved the performance of stress tests after 3-4 weeks of treatment. Efficacy was also confirmed for a dose of 7.5 mg 2 times a day. An additional effect when increasing the dose from 5 mg to 7.5 mg 2 times / day was established in a comparative study with atenolol. The time for performing physical activity increased by approximately 1 min after 1 month of using ivabradine at a dose of 5 mg 2 times a day, while after an additional 3-month course of using ivabradine orally at a dose of 7.5 mg 2 times a day, a further increase in this indicator by 25 seconds was noted . The antianginal and anti-ischemic activity of ivabradine has also been confirmed in patients aged 65 years and older. The effectiveness of ivabradine when used in doses of 5 mg and 7.5 mg 2 times a day was noted in relation to all indicators of stress tests (total duration of physical activity, time to a limiting attack of angina, time to the onset of an attack of angina and time to the development of ST segment depression by 1 mm ) and was accompanied by a decrease in the incidence of angina attacks by approximately 70%. The use of ivabradine 2 times a day provided constant therapeutic efficacy for 24 hours.
In patients taking ivabradine, additional effectiveness was shown in relation to all indicators of stress tests when added to the maximum dose of atenolol (50 mg) at the decline of its therapeutic activity (12 hours after oral administration).
There was no improvement in the effectiveness of ivabradine when added to the maximum dose of amlodipine at the decline of its therapeutic activity (12 hours after oral administration), while at the maximum activity of amlodipine (3-4 hours after oral administration), additional effectiveness of ivabradine was proven.
In studies of the clinical effectiveness of ivabradine, its therapeutic effect was fully maintained for 3-4 months of therapy. There were no signs of decreased effectiveness during treatment, and no withdrawal syndrome was observed after cessation of treatment. The antianginal and anti-ischemic effects of ivabradine were associated with both a dose-dependent decrease in heart rate and a significant decrease in the work product (heart rate x systolic blood pressure) both at rest and during exercise. The effect on blood pressure and peripheral vascular resistance was minor and clinically insignificant.
A sustained decrease in heart rate was observed in patients who took ivabradine for at least 1 year. No effect on carbohydrate metabolism and lipid profile was observed.
In patients with diabetes mellitus, the efficacy and safety of ivabradine were similar to those in the general population.
There were no differences between the groups of patients taking ivabradine against the background of standard therapy, and in patients with stable angina and left ventricular dysfunction (LVEF less than 40%), 86.9% of whom received beta-blockers and placebo, in the total incidence of deaths from cardiovascular diseases diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or worsening of chronic heart failure (CHF) and in the subgroup of patients with a heart rate of at least 70 beats/min.
The use of ivabradine in patients with a heart rate of at least 70 beats/min showed a reduction in the frequency of hospitalizations for fatal and non-fatal myocardial infarction by 36% and the frequency of revascularization by 30%.
In patients with exertional angina, the use of ivabradine showed a reduction in the relative risk of complications (the incidence of deaths from cardiovascular diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or worsening of CHF) by 24%. The noted therapeutic benefit is achieved primarily by reducing the frequency of hospitalizations for acute myocardial infarction by 42%.
The reduction in the incidence of hospitalization for fatal and non-fatal myocardial infarction in patients with heart rate more than 70 beats/min is even more significant and reaches 73%. In general, the drug was well tolerated and safe.
The use of ivabradine in patients with CHF II-IV functional class according to the NYHA classification with LVEF less than 35% showed a clinically and statistically significant reduction in the relative risk of complications (the frequency of deaths from cardiovascular diseases and a reduction in the frequency of hospitalizations due to worsening CHF ) by 18%. The absolute risk reduction was 4.2%. A pronounced therapeutic effect was observed 3 months after the start of ivabradine therapy.
A decrease in mortality from cardiovascular diseases and the frequency of hospitalizations due to worsening CHF was observed regardless of age, gender, functional class of CHF, the use of beta-blockers, ischemic or non-ischemic etiology of CHF, the presence of diabetes mellitus or a history of arterial hypertension.
Patients with symptoms of CHF in sinus rhythm and with a heart rate of at least 70 beats/min received standard therapy, which included beta-blockers (89%), ACE inhibitors and/or angiotensin II receptor antagonists (91%), diuretics (83%) and aldosterone antagonists (60%).
It has been shown that use of ivabradine for 1 year can prevent one death or one hospitalization due to cardiovascular disease for every 26 patients taking the drug. The use of ivabradine showed an improvement in the functional class of CHF according to the NYHA classification.
In patients with a heart rate of 80 beats/min, a decrease in heart rate by an average of 15 beats/min was noted.
Pharmacokinetics
Ivabradine is an S-enantiomer with no signs of bioconversion (according to in vivo studies). The main active metabolite is the N-desmethylated derivative of ivabradine.
Suction
After oral administration, ivabradine is quickly and almost completely absorbed from the gastrointestinal tract. Cmax in blood plasma is achieved within 1 hour after oral administration on an empty stomach. Bioavailability is approximately 40% due to the “first pass” effect through the liver. Eating increases the absorption time by approximately 1 hour and increases the plasma concentration from 20% to 30%. To reduce the variability of concentration, it is recommended to take the drug simultaneously with meals.
Distribution
Plasma protein binding is approximately 70%. Vd in equilibrium is about 100 l. Cmax in blood plasma with long-term use at the recommended dose of 5 mg 2 times a day is approximately 22 ng/ml (coefficient of variation = 29%). The average Css in blood plasma is 10 ng/ml (coefficient of variation = 38%).
The pharmacokinetics of ivabradine is linear over the dose range from 0.5 to 24 mg.
Metabolism
Ivabradine is predominantly metabolized in the liver and intestines by oxidation involving the CYP3A4 isoenzyme. The main active metabolite is the N-desmethylated derivative (S 18982), which accounts for 40% of the ivabradine dose. Metabolism of the active metabolite ivabradine also involves the CYP3A4 isoenzyme. Ivabradine has low affinity for the CYP3A4 isoenzyme and does not induce or inhibit it. In this regard, it is unlikely that ivabradine affects the metabolism or concentration of CYP3A4 isoenzyme substrates in blood plasma. At the same time, simultaneous use of ivabradine with potent inhibitors or inducers of cytochrome P450 can significantly affect the concentration of ivabradine in the blood plasma.
Removal
T1/2 of ivabradine is, on average, 2 hours (70-75% AUC), effective T1/2 is 11 hours. Total clearance is approximately 400 ml/min, renal clearance is about 70 ml/min. Metabolites are excreted at the same rate through the kidneys and intestines. About 4% of the dose taken is excreted unchanged by the kidneys.
Pharmacokinetics in special groups of patients
Pharmacokinetic parameters (AUC and Cmax) do not differ significantly in groups of patients aged 65 years and older, 75 years and older, and the general patient population.
The effect of renal failure (creatinine clearance from 15 to 60 ml/min) on the kinetics of ivabradine is minimal, because only about 20% of ivabradine and its active metabolite S 18982 is excreted by the kidneys.
In patients with mild hepatic impairment (up to 7 points on the Child-Pugh scale), the AUC of free ivabradine and its active metabolite is 20% greater than in patients with normal liver function. Data on the use of ivabradine in patients with moderate liver failure (7-9 points on the Child-Pugh scale) are limited and do not allow us to evaluate the pharmacokinetics of the drug in this group of patients. There are currently no data on the use of ivabradine in patients with severe hepatic impairment (Child-Pugh score greater than 9).
Relationship between pharmacokinetic and pharmacodynamic properties
Analysis of the relationship between the pharmacokinetic and pharmacodynamic properties of ivabradine made it possible to establish that the decrease in heart rate is directly proportional to the increase in the concentration of ivabradine and the active metabolite S 18982 in the blood plasma when used in doses of up to 15-20 mg 2 times a day. At higher doses of the drug, the slowing of heart rate is not proportional to the concentration of ivabradine in the blood plasma and is characterized by a tendency to reach a plateau. High concentrations of ivabradine, which can be achieved when used simultaneously with strong inhibitors of the CYP3A4 isoenzyme, can lead to a pronounced decrease in heart rate, but this risk is lower when combined with moderate inhibitors of the CYP3A4 isoenzyme.
Raenom®
Ivabradine is a medicine that slows the heart rate.
The mechanism of action of ivabradine is the selective and specific inhibition of Iƒ channels of the sinus node, which control spontaneous diastolic depolarization in the sinus node and regulate heart rate (HR).
Ivabradine has a selective effect on the sinus node, without affecting the conduction time of impulses along the intraatrial, atrioventricular and intraventricular pathways, as well as on myocardial contractility and ventricular repolarization.
Ivabradine can also interact with the Ih channels of the retina, which are similar in structure to the If channels of the heart. They are involved in the mechanisms of temporary adaptation of the visual perception system by changing the retinal response to bright light stimuli.
Under provoking circumstances (for example, a sharp change in illumination intensity in the visual field), partial inhibition of Ih channels by ivabradine leads to the phenomenon of changes in light perception (photopsia). Photopsia is characterized by a transient change in brightness in a limited area of the visual field (see section “Side effects”).
The main pharmacological effect of ivabradine is a dose-dependent decrease in heart rate. An analysis of the dependence of the magnitude of the decrease in heart rate on the dose of the drug was carried out with a gradual increase in the dose of ivabradine to 20 mg 2 times a day and revealed a tendency to achieve a “plateau” effect (no increase in the therapeutic effect with a further increase in the dose of the drug), which reduces the risk of developing severe bradycardia (HR less than 40 beats/min) (see section “Side effects”).
When using the drug in recommended doses, the degree of decrease in heart rate depends on its initial value and is approximately 10-15 beats/min both at rest and during physical activity, as a result of which the work of the heart and the myocardial oxygen demand decreases.
Ivabradine does not affect intracardiac conduction, myocardial contractility (does not have a negative inotropic effect) and the process of ventricular repolarization. In clinical electrophysiological studies, ivabradine had no effect on the timing of impulses along the atrioventricular or intraventricular pathways, as well as on corrected QT intervals.
In studies in patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) 30-45%) it was shown that ivabradine does not affect myocardial contractility.
It was found that ivabradine at a dose of 5 mg 2 times a day improved the performance of stress tests after 3-4 weeks of treatment. Efficacy was also confirmed for a dose of 7.5 mg 2 times a day. An additional effect when increasing the dose from 5 mg to 7.5 mg 2 times a day was established in a comparative study with atenolol. The time spent performing physical activity increased by approximately 1 minute after 1 month of using ivabradine at a dose of 5 mg 2 times a day, while after an additional 3-month course of taking ivabradine at a dose of 7.5 mg 2 times a day orally, a further increase in this indicator was noted for 25 seconds.
The antianginal and anti-ischemic activity of ivabradine has also been confirmed in patients aged 65 years and older.
The effectiveness of ivabradine when used in doses of 5 mg and 7.5 mg 2 times a day was observed in relation to all indicators of stress tests (total duration of physical activity, time to a limiting attack of angina, time to the onset of an attack of angina and time to the development of ST segment depression at 1 mm) and was accompanied by a decrease in the incidence of angina attacks by approximately 70%. The use of ivabradine 2 times a day provided constant therapeutic efficacy for 24 hours.
In patients taking ivabradine, additional effectiveness was shown in relation to all indicators of stress tests when added to the maximum dose of atenolol (50 mg) at the decline of its therapeutic activity (12 hours after oral administration).
There was no improvement in the effectiveness of ivabradine when added to the maximum dose of amlodipine at the decline of its therapeutic activity (12 hours after oral administration), while at the maximum activity of amlodipine (3-4 hours after oral administration), additional effectiveness of ivabradine was proven.
In studies of the clinical effectiveness of ivabradine, its therapeutic effect was fully maintained over 3-4 months of therapy. During treatment, there were no signs of decreased effectiveness, and after cessation of treatment, no withdrawal syndrome was observed.
The antianginal and anti-ischemic effects of ivabradine were associated with both a dose-dependent decrease in heart rate and a significant decrease in the work product (heart rate x systolic blood pressure) both at rest and during exercise.
The effect on blood pressure (BP) and total peripheral vascular resistance (TPVR) was minor and clinically insignificant.
A sustained decrease in heart rate was observed in patients who took ivabradine for at least 1 year.
No effect on carbohydrate metabolism and lipid profile was observed.
In patients with diabetes mellitus, the efficacy and safety of ivabradine were similar to those in the general population. There were no differences between the groups of patients taking ivabradine against the background of standard therapy, and in patients with stable angina and left ventricular dysfunction (LVEF less than 40%), 86.9% of whom received beta-blockers and placebo, in the total incidence of cardiac deaths -vascular diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or worsening of chronic heart failure (CHF) and in the subgroup of patients with a heart rate of at least 70 beats/min.
The use of ivabradine in patients with a heart rate of at least 70 beats/min showed a reduction in the frequency of hospitalizations for fatal and non-fatal myocardial infarction by 36% and the frequency of revascularization by 30%.
In patients with exertional angina, the use of ivabradine showed a reduction in the relative risk of complications (the incidence of deaths from cardiovascular diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or worsening of CHF) by 24%.
The noted therapeutic benefit is achieved primarily by reducing the frequency of hospitalizations for acute myocardial infarction by 42%. The reduction in the rate of hospitalization for fatal and non-fatal myocardial infarction in patients with heart rate more than 70 beats/min is even more significant and reaches 73%. In general, the drug was well tolerated and safe.
The use of ivabradine in patients with CHF II-IV functional class according to the NYHA classification with LVEF less than 35% showed a clinically and statistically significant reduction in the relative risk of complications (the incidence of deaths from cardiovascular diseases and a reduction in the frequency of hospitalizations due to worsening CHF ) by 18%. The absolute risk reduction was 4.2%. A pronounced therapeutic effect was observed 3 months after the start of ivabradine therapy.
A decrease in mortality from cardiovascular diseases and the frequency of hospitalizations due to worsening CHF was observed regardless of age, gender, functional class of CHF, the use of beta-blockers, ischemic or non-ischemic etiology of CHF, the presence of diabetes mellitus or a history of arterial hypertension.
Patients with symptoms of CHF in sinus rhythm and with a heart rate of at least 70 beats/min received standard therapy, which included beta-blockers (89%), angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor antagonists (91%), diuretics ( 83%) and aldosterone antagonists (60%).
It has been shown that use of ivabradine for 1 year can prevent one death or one hospitalization due to cardiovascular disease for every 26 patients taking the drug.
The use of ivabradine showed an improvement in the functional class of CHF according to the NYH A classification.
In patients with a heart rate of 80 beats/min, a decrease in heart rate by an average of 15 beats/min was noted.
