Weakness syndrome and sinus node dysfunction: causes and development, symptoms and consequences, treatment. Inhibitors of I f -channels

Clinical pharmacology

A New Class of Cardiovascular Drugs: Selective S-Inhibitor of Sinus Node Canals

In 2005, the European Agency for the Registration of Medicines and the Pharmacological Committee of the Russian Federation registered Coraxan (the active ingredient is ivabradine), the first β-inhibitor of the selective and specific action of the channels of sinoatrial compound. Coraxan was registered as a remedy for the symptomatic treatment of stable angina pectoris in patients with sinus rhythm who have contraindications to the use of β-blockers or their intolerance. Ivabradine has anti-ischemic and antianginal effects due to a decrease in heart rate (HR).

An increase in heart rate significantly increases myocardial oxygen demand and an increase in coronary blood flow in patients with ischemic heart disease (IHD). Large epidemiological studies confirm the role of high resting heart rate as an important predictor of general and cardiovascular mortality in patients with coronary artery disease, arterial hypertension, metabolic syndrome, as well as in healthy people. The use of P-blockers in patients after myocardial infarction (MI) confirmed that a decrease in heart rate leads to a decrease in mortality.

In the BEAUTIFUL study, it was shown that in patients with coronary artery disease and left ventricular (LV) dysfunction, it is heart rate> 70 bpm that is an independent unfavorable factor that significantly worsens the prognosis. Risk of cardiovascular

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ON THE. Egorova

Department of Clinical Pharmacology, Russian State Medical University

Distal mortality in these patients increases by 34%, the risk of fatal and non-fatal MI - by 46%, the need for revascularization by 38%, even with optimal therapy. Adding Coraxan to treatment in patients with coronary artery disease and heart rate> 70 beats / min improves the prognosis, reducing the risk of fatal and non-fatal myocardial infarction, as well as the need for revascularization. At the same time, Coraxan can be safely combined with any drugs for the treatment of coronary artery disease, including calcium antagonists and P-blockers.

Electrophysiological properties of cardiomyocytes

High heart rate as a factor of low physical fitness or poor general health is accompanied by a higher level of coronary, cardiovascular and sudden death, is associated with an increase in mortality in patients with coronary artery disease, MI, in the elderly.

Heart rate determines:

Myocardial oxygen consumption and myocardial ischemic threshold;

Time of diastolic filling of the coronary arteries (and, accordingly, the time of coronary blood flow);

Increased influence of catecholamines (a determining factor in reducing heart rate variability - a marker of life-threatening arrhythmias);

Atherogenic action associated with an increase in blood levels of low density lipoprotein cholesterol;

Hemodynamic stress in the form of tachycardia (factor of "shear stress") leads to the development of atherosclerosis of the coronary, iliac and renal arteries due to changes in the release of growth factors by the endothelium;

Decreased extensibility of the carotid arteries as one of the signs of atherosclerotic lesions.

The generation of impulses by specialized pacemaker cells of the sinus node occurs as a result of a change in the potential difference between the inner and outer surfaces of the cell membrane - transient depolarization of cell membranes (phase I of the action potential).

At rest, cardiomyocytes have a constant electrical potential difference between the inner and outer surfaces of the cell membrane - a resting transmembrane potential of about -90 mV. This potential is maintained by transmembrane ion currents with the participation of the N + -K + -pump. Depolarization of the cell occurs when positive ions enter the cell, continues until the electrochemical gradient is balanced and determines the action potential, which then moves along the pathways and stimulates the contraction of cardiomyocytes.

In the electrophysiology of cardiomyocytes, phases of rapid depolarization, rapid repolarization, plateau and phases of slow repolarization, related to the action potential, as well as the phase of the resting potential, are distinguished. In specialized pacemaker cells of the heart, the phase of slow re-polarization passes into the phase of spontaneous diastolic (pacemaker) depolarization, which brings the membrane potential to a threshold value at which

rum triggers action potential. Spontaneous diastolic depolarization occurs due to the action of the ionic N + -K + -pump, which provides a flow of positive ions into the cell.

The mechanism of action of Coraxan

Ivabradine (Coraxan) is the first selective 1g inhibitor that has a pulse-reducing effect and does not have a negative inotropic effect, as well as does not affect atrioventricular conductivity and blood pressure (BP). The anti-ischemic and antianginal effect of ivabradine is due to a decrease in heart rate due to inhibition of ionic 1r-currents in the sinoatrial compound.

Inhibition of ionic Ig currents plays a key role in heart rate control. Catecholamines, by stimulating the activity of adenylate cyclase, increase the production of cyclic adenosine monophosphate (cAMP), which promotes the opening of G-channels, while the suppression of cAMP production by acetylcholine inhibits their opening. Coraxan specifically binds to the G-channels of the sinus node and thus reduces the heart rate.

When the membrane potential is maintained at -35 mV (i.e. with closed G-channels), Coraxan does not bind to the cells of the sinus node. The ability to inhibit G-channels occurs at a lower transmembrane potential when the channel is open. Then Coraxan is able to reach the binding site located inside the pore of the G-channel, suppress the 1r-current and provide an effective decrease in heart rate.

Such features of the binding of Korak-san to the G-channels determined the concept of "dependent therapeutic utility": the level of binding of Coraxan depends on

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Clinical pharmacology

the level of opening of the H-channels and heart rate, and the effectiveness of Coraxan increases with a higher heart rate. In practice, this means that in patients with an initially higher heart rate, its decrease will be more pronounced and will allow it to be as close as possible to the target level.<60 уд./мин. В то же время у пациентов с исходно не очень высоким уровнем ЧСС эта особенность Кораксана обеспечивает высокую безопасность в плане возникновения брадикардии.

By selectively suppressing ionic 1r-currents at the level of the sinus node, Coraxan reduces the rate of spontaneous diastolic depolarization without changing the maximum diastolic potential. As a result, the time interval between the action potentials increases and the heart rate decreases, depending on the severity of tachycardia and in proportion to the concentration of the active substance.

At a concentration of Coraxan 100 times higher than the therapeutic one, there was a slight decrease in the activity of L-type calcium channels, which did not lead to a significant suppression of the current of calcium ions. These data suggest the absence of a negative effect of Coraxan on myocardial contractile function, however, additional clinical confirmation is required for the use of Coraxan in patients with systolic myocardial dysfunction.

No effect of Coraxan on T-type calcium channels in the formation of the action potential of the sinus node was revealed. The effect of Coraxan on the 1-potassium current of the repolarization phase of the action potential was observed only when the therapeutic concentration was exceeded by more than 30 times.

Pharmacokinetics of ivabradine

Ivabradine is rapidly absorbed after oral administration. Peak plasma concentration is reached after 1-1.5 hours, not

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depending on the dose of the drug. The bioavailability of the drug after oral administration is close to 40% and does not depend on the dose or food intake.

The average volume of distribution of ivabradine is 1.4 l / kg. The average plasma concentration upon reaching an equilibrium state is 10 mg / ml, the connection with plasma proteins is about 70%. The equilibrium concentration of the drug is achieved within 24 hours.

Ivabradine undergoes active metabolism in the liver with the participation of cytochrome CYP3A4. Concomitant administration of CYP3A4 inhibitors leads to an increase in the maximum concentration and half-life of the drug, increasing the degree of heart rate reduction. The use of inducers of hepatic metabolism can reduce the area under the pharmacokinetic curve of ivabradine without affecting the ECG parameters.

The half-life of ivabradine with regular administration is about 2 hours. The drug is excreted in the form of metabolites equally by the liver and kidneys, less than 10% of the dose taken is found in the urine unchanged.

Hemodynamic properties of Koraxan

The hemodynamic properties of Coraxan are determined by an increase in the time interval between two action potentials of the sinus node. This provides a decrease in heart rate without systemic hemodynamic effects, a dose-dependent decrease in oxygen consumption by the myocardium, an improvement in regional myocardial contractility in the area of ​​reduced coronary blood flow.

During therapy with Coraxan, there is no change in mean blood pressure and a decrease in myocardial contractility, a more favorable dynamics of relaxation of the LV myocardium remains (which is important for

Selective sinus node channel I inhibitor

storage of LV volume in heart failure).

With LV dysfunction under the influence of inotropic drugs, the release of norepinephrine may increase, tachycardia and hypotension may increase, which will cause an increase in myocardial ischemia. In such a situation, the use of Coraxan will play an important role in limiting the heart rate without reducing the positive inotropic effect. This will provide an improvement in myocardial blood flow and stabilization of hemodynamics in patients with heart failure and cardiogenic shock.

The advantages of ivabradine are also revealed in the treatment of patients with postural orthostatic hypotension syndrome, sinus nodal tachycardia by the "re-entry" mechanism, persistent sinus tachycardia, when it is impossible to prescribe P-blockers or slow calcium channel blockers (drugs with negative inotropic and / or hypotensive effects that can increase the symptoms of the disease).

Effect of ivabradine on the QT interval

Prolongation of the corrected (correlated with heart rate) QT interval (QT ^ under the influence of drugs with a negative chronotropic effect is associated with a higher risk of death both in patients with heart disease and in the general population. of the ventricles predisposing to the occurrence of potentially fatal ventricular tachycardia of the “pirouette.” A clinical study of ivabradine confirmed the absence of changes in the Q ^ interval during therapy.

In patients with stable angina pectoris and normal electrophysiological parameters, Coraxan did not cause a significant slowdown in the conduction of impulses through the atria or ventricles of the heart. This

speaks of the ability of ivabradine to maintain the refractory periods of the atria, the time of atrioventricular conduction and the duration of the repolarization period.

It is not recommended to use Coraxan simultaneously with drugs that prolong the QT interval (quinidine, disopyramide, bepredil, sotalol, ibutilide, amiodarone, pentamidine, cisapride, erythromycin, etc.). The combined use of Co-raxan with similar drugs can increase the decrease in heart rate, which requires more careful monitoring of the patient's condition. At the same time, according to the BEAUTIFUL study, the combined use of Coraxan with P-blockers and calcium antagonists is safe and does not require additional monitoring.

Antianginal and anti-ischemic effects

The antianginal and antiischemic effects of Coraxan (at a dose of 7.5 or 10 mg 2 times a day) in patients with stable angina pectoris are comparable to those of atenolol (100 mg / day) and amlodipine (10 mg / day).

The heart rate and the value of the double product (HR x BP) at rest and at maximum physical activity as an indicator of oxygen consumption by the myocardium were significantly lower in the group of patients receiving Coraxan compared with amlodipine. The frequency of undesirable effects (NE) was comparable, and Coraxan was well tolerated.

The antianginal effect of Coraxan persists with prolonged regular use without the development of pharmacological tolerance. There was no withdrawal syndrome after discontinuation of the drug.

Unwanted effects

The most frequent NEs during the use of Coraxan were visual impairment.

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Clinical pharmacology

perceptions (photopsies), moderately expressed and disappearing spontaneously during therapy. Photopsies (transient changes in brightness in a limited area of ​​the visual field) were initiated by a sharp change in the intensity of illumination when viewing shiny objects in bright light and occurred in 14.5% of patients. In only 1% of patients, the appearance of photopsies was the reason for refusing treatment or changing the usual daily routine. The mechanism of occurrence of photopsies is the inhibition of G-channels in the cells of the retina. Blurred vision is a common NE. NE from the side of vision can restrict the use of the drug in patients who drive various vehicles or work on conveyor belts.

On the part of the cardiovascular system, frequent NEs were bradycardia, pre-cardiovascular blockade of the 1st degree, ventricular premature beats; rare - palpitations, supraventricular extrasystole. Rare gastrointestinal NEs were nausea, constipation, or diarrhea. Among the common NEs, headache, dizziness, and rarely shortness of breath, muscle cramps were often observed. Rare laboratory changes include hyperuricemia, blood eosinophilia, and increased plasma creatinine levels.

Indications and contraindications

The advantages of Coraxan over R-adrenoblockers are possible with stable angina pectoris in combination with the following conditions:

Bronchial asthma or chronic obstructive pulmonary disease;

Erectile dysfunction;

Atherosclerosis of the peripheral arteries;

Weakness symptoms;

Depression;

Sleep disturbances;

Lack of effect from P-blockers;

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Moderate violations of atrioventricular conduction;

Diabetes mellitus with significant fluctuations in glycemia;

Normal blood pressure.

Care must be taken when prescribing Coraxan in the following cases:

II degree atrioventricular block;

Concomitant use of other drugs that reduce heart rate;

Arterial hypotension;

Acute period of stroke;

Moderate hepatic impairment;

Severe renal failure;

Retinal pigment degeneration.

Contraindications to the use of Korak-san:

Hypersensitivity to ivabradine or any of the auxiliary components of the drug;

Resting heart rate<60 уд./мин (до начала лечения);

Sick sinus syndrome;

Sinoauricular block;

III degree atrioventricular block;

The presence of an artificial pacemaker;

Acute myocardial infarction;

Cardiogenic shock;

Unstable angina;

Severe arterial hypotension (BP<90/50 мм рт. ст.);

Chronic heart failure stage III-IV according to NYHA classification;

Severe liver failure (more than 9 points according to the Chile-da-Pugh classification);

Simultaneous use of strong inhibitors of the cytochrome P450 isoenzyme CYP3A4 (antifungal agents of the azole group - ketoconazole, it-raconazole; macrolides - clarithromycin, erythromycin for oral administration,

Clinical pharmacology

josamycin, telithromycin; inhibitors of HIV proteases - nelfinavir, rito-navir; nefazadone); pregnancy, breastfeeding.

Research data BEAUTIFUL

In January 2005, an international multicenter, randomized, double-blind, placebo-controlled study of ivabradine in patients with stable coronary artery disease and LV systolic dysfunction was launched. The BEAUTIFUL study evaluated the efficacy of ivabradine versus placebo for cardiovascular events in patients with stable coronary artery disease and LV systolic dysfunction (ejection fraction<39%). Это первое исследование, изучавшее влияние изолированного снижения ЧСС иваб-радином на прогноз у пациентов с ИБС и дисфункцией ЛЖ. Первичная комбинированная конечная точка исследования - время до возникновения первого из следующих событий: смерть вследствие сердечно-сосудистых причин, госпитализация по поводу острого ИМ, госпитализация по поводу манифестации или прогрессирования сердечной недостаточности.

In 660 research centers, 10,947 people (aged> 55 years without diabetes and> 18 years with diabetes) were randomized to placebo or ivabradine (5 mg twice daily for 2 weeks, then 7.5 mg twice per day). In both groups, patients received antiplatelet therapy (94%), statins (74%), angiotensin-converting enzyme inhibitors (90%), P-blockers (87%). Among P-blockers, the most commonly used were carvedilol, bisoprolol and metoprolol, doses of P-blockers averaged about 50% of the maximum. The observation period lasted from 18 to 36 months.

The results of the BEAUTIFUL study were presented at the European

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the progress of cardiologists in September 2008. Prescribing Coraxan to patients with coronary artery disease, LV dysfunction and heart rate> 70 beats / min improved the prognosis in these patients. Although there were no differences in the primary endpoint, the study results showed an improved prognosis for coronary complications. Coraxan reduced the risk of fatal and non-fatal myocardial infarction by 35%, the need for revascularization by 30%, and the frequency of hospitalizations for myocardial infarction or unstable angina pectoris by 22%.

It is important to note that these results were obtained in patients who initially received the optimal therapy from the modern point of view, including statins, antiplatelet agents, P-blockers, and angiotensin-converting enzyme inhibitors. These results prove not only the predictive value of increased heart rate, but also the importance of effective control of this indicator. Selective reduction of heart rate by Coraxan can significantly improve the prognosis in patients with coronary artery disease with heart rate> 70 beats / min. Coraxan is safe to use simultaneously with pulse-reducing drugs, including P-blockers and calcium antagonists.

Erofeeva S.B., Maneshina O.A., Belousov Yu.B. The place of ivabradine - the first If inhibitor of selective and specific action in the treatment of cardiovascular diseases // Qualitative clinical practice. 2006. No. 1. C. 10-22. Cook S., Togni M., Schaub M.C. et al. High heart rate: cardiovascular rick factor? // Eur. Heart J. 2006. No. 27. P. 2387-2393. DiFrancesco D. If current inhibitors: properties of drug-channel interaction // Selective and Specific if Channel Inhibitor in Cardiology / Ed. by Fox K. L .: Science Press Ltd., 2004. P. 1-13.

Fox K., Ferrari R., Tendera M. et al. Rationale and design of a randomized double-blind, placebo-controlled trial of ivabradine in patient with sta-

Selective sinus node channel I inhibitor

ble coronary artery disease and left ventricular systolic dysfunction: the morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) study // Amer. Heart J. 2006. P. 860-866.

Fox K., Ford I., Steg P.G. et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomized, double-blind, placebo-controlled trial // Lancet. 2008. V. 372. P. 807-816.

Kannel W.B., Kannel C., Paffenbarger R.S. Jr., Cupples L.A. Heart rate and cardiovascular mortality: the Framingham Study // Amer. Heart J. 1987. V. 113. P. 1489-1494.

McGovern P. G., Pankow J. S., Shahar E. et al. Recent trends in acute coronary heart disease - mortality, morbidity, medical care, and risk factors. The Minnesota Heart Survey Investigators // N. Engl. J. Med. 1996. V. 334. P. 884-890.

Ruzyllo W., Tendera M., Ford I. et al. Antianginal efficacy and safety of ivabradine compared with amlodipine in patient with stable effort angina pectoris: a 3-month randomized double-blind, multicetre noninferiority trial // Drugs. 2007. V. 67. No. 3. P. 393-405.

Tardif J. C., Ford I., Tendera M. et al. Efficacy of ivabradine, a new selective If inhibitor compared with atenolol in patients with chronic stable angina // Eur. Heart J. 2005. V. 26. P. 2529-2536.

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The spontaneous generation of electricity in the heart seems unrealistic and impossible, but it is - the heart is able to independently generate electrical impulses, and the sinus node rightfully plays the leading role in this.

The basis of the contraction of the heart muscle is the transfer of electrical energy into kinetic, that is, the electrical excitation of the smallest cells of the myocardium leads to their synchronous contraction, capable of pushing blood into the vessels of the body with a certain force and frequency. Such energy arises in the cells of the sinus node, which are not designed to contract, but to generate an electrical impulse due to the work of ion channels that pass potassium, sodium and calcium ions into and out of the cell.

Sinus node - what is it?

The sinus node, also called the pacemaker, is a mass about 15 x 3 mm in the wall of the right atrium. The impulses arising in this place are transmitted to the nearby contractile cells of the myocardium and spread to the next section of the cardiac conduction system - to the atrioventricular node. The sinus node contributes to the contraction of the atria in a certain rhythm - with a frequency of 60-90 beats per minute. The contraction of the ventricles in the same rhythm is carried out by conducting impulses along the atrioventricular node and the bundle of His.

The regulation of the sinus node activity is closely related to the autonomic nervous system, represented by sympathetic and parasympathetic nerve fibers that regulate all internal organs. The latter fibers are represented by the vagus nerve, which slows down the heart rate and strength. Sympathetic fibers, on the other hand, accelerate the rhythm and increase the strength of myocardial contractions. That is why a slowdown (bradycardia) and an increase (tachycardia) of the heart rate is possible in practically healthy individuals with, or - a violation of the normal coordination of the autonomic nervous system.

If we are talking about damage to the heart muscle, then it is possible to develop a pathological condition called dysfunction (DSU), or sick sinus syndrome (SSS). These concepts are not practically equivalent, but in general we are talking about the same thing - about bradycardia with varying degrees of severity, capable of causing a catastrophic decrease in blood flow in the vessels of internal organs, and, first of all, in the brain.

Causes of weakness of the sinus node

Previously, the concepts of sinus node dysfunction and weakness were combined, but now it is generally accepted that dysfunction is a potentially reversible condition and is caused by functional disorders, while node weakness syndrome is caused by organic damage to the myocardium in the pacemaker area.

Causes of sinus node dysfunction(more common in childhood and adolescents):

• Age-related involution of the sinus node - a decrease in the activity of pacemaker cells due to age-related characteristics,
• Age-related or congenital dysfunction of the autonomic nervous system, manifested not only by a violation of the regulation of sinus activity, but also by a change in vascular tone, as a result of which there is a decrease or increase in blood pressure.

Causes of sick sinus syndrome (SSS) in children:

1. Amyloidosis with damage to the heart muscle - deposition in the myocardium of a pathological protein - amyloid,
2. Autoimmune damage to the heart muscle due to systemic processes -, systemic,
3. Post-viral - inflammatory changes in the thickness of the heart muscle, capturing the right atrium,
4. The toxic effect of certain substances - phosphorogenic compounds (FOS), (verapamil, diltiazem, etc.) - as a rule, clinical manifestations disappear after the cessation of the action of the substance and the conduct of detoxification therapy.

Causes of Weak Sinus Nodes in Adulthood(as a rule, in persons over 50 years old) - in addition to the possible conditions listed above, most often the development of the disease is provoked by:

• , as a result of which the blood flow in the sinus node is disrupted,
• Transferred with the subsequent development of cicatricial changes affecting the area of ​​the sinus node.

Symptoms of the disease

Clinical signs of weakness of the sinus node depend on the type and degree of disturbances in its work. So, according to the type of clinical and electrocardiographic changes, there are:

1. Persistent expressed,
2. Takhi-bradi syndrome - alternating attacks of a rare and fast heartbeat,
3. The bradystolic form is a condition characterized by the fact that the functions of the pacemaker are taken over by the smallest areas of electrically active tissue in the atria, but as a result of this, the muscle fibers of the atria do not contract synchronously, but chaotically, and even less frequently than should be normal.
4. - a state in which a block appears for conducting pulses either in the node itself or at the exit from it.

Clinically, bradycardia begins when the heart rate is less than 45 to 50 beats per minute. Symptoms include increased fatigue, dizziness, severe weakness, flashing flies before the eyes, light-headedness, especially with physical exertion. At a rhythm of less than 40, attacks of MES (MAS, Morgagni - Adems - Stokes) develop - loss of consciousness due to a sharp decrease in blood flow to the brain. The danger of such attacks is that at this time the period of absence of electrical activity of the heart is more than 3-4 seconds, which is fraught with the development of complete asystole (cardiac arrest) and clinical death.

Sinoauricular block of the 1st degree clinically does not manifest itself in any way, but the II and III degrees are characterized by attacks of dizziness and fainting.

Takhi-brady syndrome manifested by sharp sensations of interruptions in the work of the heart, a feeling of rapid heartbeat (tachycardia), and then a sharp slowdown in the pulse, causing dizziness or fainting. Similar violations are manifested and atrial fibrillation- sharp interruptions in the heart with subsequent loss of consciousness or without it.

Diagnostics

The examination plan for suspected sinus node syndrome (SSS) includes the following diagnostic methods:

• - can be informative in case of pronounced conduction disturbances in the sinoatrial connection, since, for example, with I degree blockade, it is not always possible to fix electrocardiographic signs.

ECG tape: tachy-brady syndrome - with stopping the sinus node after an attack of tachycardia, followed by sinus bradycardia

• Daily monitoring of ECG and blood pressure more informative, however, it also cannot always register rhythm disturbances, especially when it comes to short paroxysms of tachycardia with subsequent significant pauses in the contraction of the heart.
• ECG recording after dosed physical activity, for example, after doing a treadmill test (walking on a treadmill) or (pedaling on a stable bike). The increase in tachycardia is estimated, which should normally be observed after exercise, and in the presence of SSS is absent or insignificantly expressed.
• Endocardial EFI (endoEPI)- an invasive research method, the essence of which is the introduction of a microelectrode through the vessels into the cavity of the heart and in the subsequent stimulation of cardiac contractions. After artificially induced tachycardia, the presence and degree of conduction delays in the sinus node are assessed, which appear on the ECG with pauses lasting more than 3 seconds in the presence of sick sinus syndrome.
• (CHEFI)- the essence of the method is approximately the same, only the electrode is inserted through the esophagus at the site of its anatomical proximity to the right atrium.

Treatment of sick sinus syndrome

If a patient is diagnosed with sinus node dysfunction caused by vegetative-vascular dystonia, a neurologist and cardiologist should be consulted. Usually, in such cases, it is recommended to maintain a healthy lifestyle and take vitamins, sedatives and restorative drugs. Tinctures of valerian, motherwort, ginseng, eleutherococcus, echinacea purpurea, etc. are usually prescribed. Glycine and magne B6 are also shown.

In the case of an organic pathology that caused the development of sick sinus syndrome, especially with life-threatening long pauses in the heart rhythm, recommended drug treatment of the underlying pathology(heart defects, myocardial ischemia, etc.).

Due to the fact that in most cases, SSSS progresses to clinically significant blockages and prolonged periods of asystole, accompanied by attacks of MES, most of these patients are shown implantation of a pacemaker - an artificial pacemaker - as the only effective method of treatment.

The operation can currently be performed free of charge in the compulsory medical insurance system, if the patient has an approved application for a quota.

MES (Morgagni Adams Stokes) attack - emergency

In case of loss of consciousness (with a direct attack) or a sharp sudden dizziness (with equivalent), the patient needs to count the pulse, or, if it is difficult to palpate on the carotid artery, count the heart rate by probing or listening to the chest on the left under the nipple. If the pulse is less than 45-50 per minute, you should immediately call an ambulance.

Upon the arrival of the ambulance team or if the patient has the necessary medications, it is necessary to inject 2 ml of a 0.1% solution of atropine sulfate subcutaneously (often such patients have everything they need with them, knowing that they can have an attack at any time). This drug neutralizes the action of the vagus nerve that slows down the heart rate, so that the sinus node starts to work at a normal frequency.

If the injection was ineffective, and the patient continues to be unconscious for more than 3-4 minutes, you should start immediately, since a long pause in the sinus node can turn into a complete one.

In most cases, the rhythm is restored without any intervention. thanks to impulses either from the sinus node itself, or from additional sources of excitation in the wall of the right atrium. Nevertheless, if the patient has developed at least one attack of MES, the patient should be examined in the hospital and the question of whether it should be resolved.

Lifestyle

If the patient has sick sinus syndrome, he should take care of a healthy lifestyle. It is necessary to eat right, observe the regime of work and rest, and also exclude sports and extreme physical activity. Minor exertion, such as walking on foot, is not contraindicated if the patient is in good health.

Staying in the army for young men and young men is contraindicated, since the disease carries a potential danger to life.

Forecast

With dysfunction of the sinus node, the prognosis is more favorable than with the syndrome of its weakness, due to organic damage to the heart. In the latter case, a rapid progression of the frequency of MES attacks is possible, which may result in an unfavorable outcome. After installing a pacemaker, the prognosis is favorable, and the potential life expectancy increases.

Video: lecture on sick sinus syndrome / dysfunction

Ivabradin(Koraksan).

In recent years, the study of selective I f - inhibitors (specific blockers of the incoming ion current through the mixed Na + / K + channels, activated at the time of hyperpolarization) has been intensively carried out. Ionic current I f plays an important role in pacemaker activity, since it is responsible for the onset of the spontaneous slow diastolic depolarization phase in the cells of the sinus node, and therefore determines the heart rate. As a result of blockade of I f-channels in the sinoatrial node, due to a decrease in heart rate, myocardial oxygen demand decreases without a concomitant decrease in the strength of heart contractions (dose-dependent effect).

One of the drugs - blockers of I f -channels - is Ivabradin(Coraxan), prescribed 5-10 mg 2 times a day. When using the usual recommended dose (7.5 mg 2 times a day), there is a decrease in heart rate by about 10 beats / min at rest and during exercise. This reduces the work of the heart and reduces myocardial oxygen consumption.

The drug is comparable in antianginal activity with atenolol, but unlike β-blockers, it does not cause bronchospasm, AV blockade and erectile dysfunction. Ivabradine is contraindicated for bradycardia (heart rate less than 50 beats / min), AV-blockade II-III degree, sick sinus syndrome.

Side effects are mainly due to the effect of the drug on the retinal h-channels related to f-channels, which is the cause of visual symptoms of varying severity in 10-15% of patients (photopsies, increased brightness in the visual field, blurred vision). These symptoms, as a rule, appear in the first 2 months of therapy, are moderately pronounced, reversible and do not require special treatment.

Indications for use

Therapy for stable angina in patients with normal sinus rhythm:

In case of intolerance or contraindications to the use of beta-blockers.
In combination with beta-blockers with inadequate control of stable angina pectoris against the background of the optimal dose of beta-blocker.

Chronic heart failure:

To reduce the incidence of cardiovascular complications in patients with chronic heart failure, with sinus rhythm and heart rate of at least 70 beats / min.

Description of the effect on the body

Ivabradine is a drug that slows down the heart rhythm, the mechanism of action of which is the selective and specific inhibition of the 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 myocardial contractility and ventricular repolarization. Ivabradine may also interact with Ih channels of the retina, similar to the If channels of the heart, involved in the occurrence of a temporary change in the visual perception system due to changes in the retinal response to bright light stimuli. Under provocative circumstances, partial inhibition of Ih channels by ivabradine causes the phenomenon of changes in light perception .
Photopsy is characterized by a transient change in brightness in a limited area of ​​the visual field. The main pharmacological feature of ivabradine is its ability to dose-dependently reduce heart rate.
Analysis of the dependence of the rate of 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 / day and revealed a tendency to achieve a plateau effect, which reduces the risk of developing severe bradycardia. When the drug is prescribed in recommended doses, the degree of heart rate decrease depends on its initial value and is approximately 10-15 beats / min at rest and during physical activity.
As a result, the work of the heart decreases and the demand for oxygen in the myocardium decreases.
Ivabradine does not affect intracardiac conduction, myocardial contractility or the process of repolarization of the ventricles of the heart.
In clinical electrophysiological studies, ivabradine did not affect the timing of impulses along the atrioventricular or intraventricular pathways, as well as the corrected QT intervals.
In studies involving patients with left ventricular dysfunction (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 / day improved the performance of stress tests after 3-4 weeks of therapy.
The efficacy was also confirmed for a dose of 7.5 mg 2 times / day.
In particular, an additional effect with an increase in 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 about 1 minute after 1 month of using ivabradine at a dose of 5 mg 2 times / day, while after an additional 3-month course of taking ivabradine at a dose of 7.5 mg 2 times / day by mouth, a further increase in this indicator was noted by 25 sec.
The antianginal and antiischemic efficacy of ivabradine was also confirmed for patients aged 65 years and older.
The effectiveness of ivabradine when used in doses of 5 mg and 7.5 mg 2 times / day was noted in these studies in relation to all indicators of stress tests, and was also accompanied by a decrease in the incidence of angina attacks by about 70%.
The use of ivabradine 2 times / day provided constant therapeutic efficacy for 24 hours. In patients taking ivabradine, additional efficacy of ivabradine was shown in relation to all indicators of exercise tests when added to the maximum dose of atenolol during the decline in therapeutic activity. An improvement in the effectiveness of ivabradine has not been shown when added to the maximum dose of amlodipine on the decline in therapeutic activity, while at the maximum activity, additional effectiveness of ivabradine has been proven. In studies of the clinical efficacy of the drug, the effects of ivabradine were fully preserved over 3 and 4 month periods of treatment.
During treatment, there were no signs of tolerance development, and after cessation of treatment, there was no "withdrawal" syndrome.
The antianginal and antiischemic effects of ivabradine were associated with a dose-dependent decrease in heart rate, as well as with a significant decrease in work work, both at rest and during physical activity.
The effect on blood pressure and systemic vascular resistance was insignificant and clinically insignificant.
A sustained decrease in heart rate has been demonstrated in patients taking 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 indicators of ivabradine were similar to those in the general patient population.
There were no differences between the groups of patients taking ivabradine against the background of standard therapy, and in patients with stable angina pectoris and left ventricular dysfunction, 86.9% of whom received beta-blockers and placebo, in the total incidence of deaths from cardiovascular diseases, hospitalization for acute myocardial infarction, hospitalization for the occurrence of new cases of heart failure or increased symptoms of chronic heart failure and in the subgroup of patients with a heart rate of at least 70 beats / min. Against the background of the use of ivabradine in patients with a heart rate of at least 70 beats / min, a decrease in the frequency of hospitalizations for fatal and non-fatal myocardial infarction by 36% and the frequency of revascularization by 30% was shown. In patients with exertional angina while taking ivabradine, the relative risk of complications decreased by 24%.
The noted therapeutic advantage is achieved primarily by reducing the frequency of hospitalization for acute myocardial infarction by 42%. Reducing the frequency of hospitalization for fatal and non-fatal myocardial infarction in patients with a heart rate of more than 70 beats / min.
even more significant and reaches 73%.
In general, the drug was well tolerated and safe. Against the background of the use of ivabradine in patients with CHF II-IV functional class according to the NYHA classification with LVEF less than 35%, a clinically and statistically significant decrease in the relative risk of complications by 18% was shown.
The absolute risk reduction was 4.2%.
A pronounced therapeutic effect was observed 3 months after the start of therapy. A decrease in mortality from cardiovascular diseases and a decrease in the frequency of hospitalizations due to increased symptoms of the course of CHF were observed regardless of age, gender, functional class of CHF, use of beta-blockers, ischemic or non-ischemic etiology of CHF, history of diabetes mellitus or arterial hypertension. Patients with CHF symptoms with sinus rhythm and with a heart rate of at least 70 beats / min received standard therapy, including the use of beta-blockers, ACE inhibitors and / or angiotensin II receptor antagonists, diuretics and aldosterone antagonists. It has been shown that the use of ivabradine for 1 year can prevent one death or one hospitalization due to cardiovascular disease for every 26 patients taking the drug Against the background of the use of ivabradine, an improvement in the functional class of CHF according to the NYHA classification has been shown. In patients with a heart rate of 80 beats / min, a decrease in heart rate by an average of 15 beats / min was noted.

Contraindications to the drug

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Simultaneous use with strong inhibitors of the isoenzyme of the cytochrome P450 3A4 system, such as antifungal agents of the azole group, antibiotics from the macrolide group, inhibitors of HIV proteases and nefazodone.
Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.
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Hypersensitivity to ivabradine or any component of the drug.

WITH caution the drug should be prescribed for moderate hepatic impairment, severe renal failure, congenital prolongation of the QT interval, concomitant use of drugs that prolong the QT interval, concomitant use of moderate inhibitors of the CYP 3A4 isoenzyme and grapefruit juice, asymptomatic left ventricular dysfunction, AV block II degree stroke, retinal pigment degeneration, arterial hypotension, simultaneous use with blockers of "slow" calcium channels that slow down the heart rate, such as verapamil or diltiazem.

Side effects on the body

The use of the drug has been studied in studies involving almost 14,000 patients. The most common side effects of ivabradine were dose-dependent and were associated with the mechanism of action of the drug.

The frequency of adverse reactions that have been observed in clinical trials is given in the form of the following gradation: very often; often; infrequently; rarely; rarely; unspecified frequency.

On the part of the organ of vision:
Very often - changes in light perception.

The following adverse events identified in clinical trials occurred with the same frequency both in the group of patients treated with ivabradine and in the comparison group, which suggests their relationship with the disease as such, and not with taking ivabradine: sinus arrhythmia, angina pectoris, incl. h. unstable, atrial fibrillation, myocardial ischemia, myocardial infarction and ventricular tachycardia.

Cautions for use

During pregnancy:

Coraxan ® is contraindicated for use during pregnancy. At the moment, there is insufficient data on the use of the drug during pregnancy.

In preclinical studies of ivabradine, embryotoxic and teratogenic effects have been identified.

The use of Coraxan ® during breastfeeding is contraindicated. There is no information on the penetration of ivabradine into breast milk.

Heart rhythm disorders:

Coraxan ® is ineffective for the treatment or prevention of arrhythmias. Its effectiveness decreases against the background of the development of tachyarrhythmias. The drug is not recommended for patients with atrial fibrillation or other types of arrhythmias associated with sinus node function.

During therapy, patients should be clinically monitored for atrial fibrillation. If clinically indicated, ECG should be included in the current monitoring.

Application in patients with bradycardia:

Coraxan® is contraindicated if the resting heart rate is less than 60 beats / min before starting therapy. If, during therapy, the resting heart rate drops to values ​​less than 50 beats / min, or the patient develops symptoms associated with bradycardia, it is necessary to reduce the dose of the drug. If, with a decrease in the dose of the drug, the heart rate remains less than 50 beats / min, or symptoms associated with bradycardia persist, then the drug Coraxan should be discontinued.

Combined use as part of antianginal therapy:

The use of Coraxan ® in conjunction with blockers of "slow" calcium channels that reduce heart rate, such as verapamil or diltiazem, is not recommended.

With the combined use of ivabradine with nitrates and blockers of "slow" calcium channels - derivatives of the dihydropyridine series, such as amlodipine, there was no change in the safety profile of the therapy. It has not been established that the combined use with blockers of "slow" calcium channels increases the effectiveness of ivabradine.

Visual perception functions:

Coraxan ® affects the function of the retina. At present, no toxic effects of ivabradine on the retina have been identified, however, the effect of the drug on the retina with prolonged use is currently unknown. In case of visual impairment that is not described in this instruction, it is necessary to consider discontinuing the use of Coraxan ®. Patients with retinal pigmentary degeneration should take Coraxan® with caution.

Excipients:

The preparation contains lactose, therefore Coraxan ® is not recommended for patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

Arterial hypotension:

Due to the insufficient amount of clinical data, the drug should be prescribed with caution in patients with arterial hypotension.

Coraxan ® is contraindicated in severe arterial hypotension.

Atrial fibrillation - cardiac arrhythmias:

An increase in the risk of developing severe bradycardia while taking Coraxan® during the restoration of sinus rhythm during pharmacological cardioversion has not been proven. However, due to the lack of sufficient data, if possible, to delay electrical cardioversion, the drug Coraxan should be discontinued 24 hours before it.

Use in patients with congenital long QT interval syndrome or in patients taking drugs that prolong the QT interval:

Coraxan® should not be prescribed for congenital prolonged QT interval syndrome, as well as in combination with drugs that prolong the QT interval. If necessary, such therapy requires strict ECG monitoring.

Moderate liver failure:

In case of moderately severe hepatic insufficiency, therapy with Coraxan® should be carried out with caution.

Severe renal failure:

In severe renal failure, therapy with Coraxan® should be carried out with caution.

Influence on the ability to drive vehicles and use mechanisms:

The use of Coraxan ® does not impair the quality of driving. Coraxan ® does not affect the ability to drive vehicles and perform work requiring a high speed of psychomotor reactions. However, one should be aware of the possibility of photopsia occurring with a sharp change in the intensity of illumination, especially when driving at night.

How to apply

Coraxan® should be taken orally 2 times / day, in the morning and in the evening during meals.

With stable angina pectoris, the recommended initial dose of the drug is 10 mg / day. Depending on the therapeutic effect, after 3-4 weeks of use, the dose of the drug can be increased to 15 mg. If during therapy with Coraxan ® the resting heart rate decreases to less than 50 beats / min, or the patient develops symptoms associated with bradycardia, it is necessary to reduce the dose of Coraxan ® 2 times / day). If, with a decrease in the dose of Coraxan ®, the heart rate remains less than 50 beats / min or symptoms of severe bradycardia persist, the drug should be discontinued .:

If the heart rate is stable no more than 50 beats / min or in case of symptoms of bradycardia, such as dizziness, fatigue or arterial hypotension, the dose can be reduced to 2.5 mg 2 times / day.

If the heart rate is in the range from 50 to 60 beats / min, it is recommended to use Coraxan® at a dose of 5 mg 2 times / day.

If, during the use of the drug, the heart rate at rest is stably less than 50 beats / min or if the patient has symptoms of bradycardia, for patients receiving Coraxan® at a dose of 5 mg 2 times / day or 7.5 mg 2 times / day, the dose of the drug should be reduced.

If in patients receiving Coraxan® at a dose of 2.5 mg 2 times / day or 5 mg 2 times / day, the resting heart rate is consistently more than 60 beats / min, the dose of the drug may be increased.

If the heart rate is not more than 50 beats / min or the patient has symptoms of bradycardia, the drug should be discontinued.

Have patients aged 75 and over The recommended initial dose of Coraxan® is 2.5 mg (1/2 tab. 5 mg) 2 times / day. In the future, it is possible to increase the dose of the drug.

Patients with impaired renal function with CC more than 15 ml / min The recommended initial dose of Coraxan® is 10 mg / day (1 tab. 5 mg 2 times / day). Depending on the therapeutic effect, after 3-4 weeks of use, the dose of the drug can be increased to 15 mg (1 tab. 7.5 mg 2 times / day).

Due to the lack of clinical data on the use of Coraxan ® in patients with CC less than 15 ml / min, the drug should be used with caution.

Patients with mild hepatic failure (up to 7 points on the Child-Pugh scale) the usual dosage regimen is recommended. The recommended initial dose of Coraxan ® is 10 mg / day (1 tab. 5 mg 2 times / day). Depending on the therapeutic effect, after 3-4 weeks of use, the dose of the drug can be increased to 15 mg (1 tab. 7.5 mg 2 times / day).

Caution should be exercised when using the drug in patients with moderate hepatic impairment (7-9 points on the Child-Pugh scale).

Coraxan ® is contraindicated in patients with severe liver failure (more than 9 points on the Child-Pugh scale), since the use of the drug in such patients has not been studied (a significant increase in the concentration of the drug in the blood plasma can be expected).

Consequences of incorrect dosage

Symptoms:
Severe and prolonged bradycardia.

Treatment:
Severe bradycardia should be symptomatic and carried out in specialized departments. In the case of the development of bradycardia in combination with impaired hemodynamic parameters, symptomatic treatment with intravenous administration of beta-adrenergic agonists, such as isoprenaline, is indicated. If necessary, an artificial pacemaker can be installed.

Combination with other medicines

The simultaneous use of ivabradine and drugs that prolong the QT interval should be avoided since a decrease in heart rate may cause an additional lengthening of the QT interval. If necessary, the joint appointment of these drugs should be carefully monitored ECG indicators:

Ivabradine is metabolized in the liver with the participation of isoenzymes of the cytochrome P450 system and is a very weak inhibitor of this isoenzyme. Ivabradine does not significantly affect the metabolism and plasma concentration of other substrates of cytochrome CYP3A4. At the same time, inhibitors and inducers of the CYP3A4 isoenzyme can interact with ivabradine and have a clinically significant effect on its metabolism and pharmacokinetic properties. It was found that inhibitors of the CYP3A4 isoenzyme increase, and inducers of the CYP3A4 isoenzyme reduce the plasma concentrations of ivabradine .:

An increase in the concentration of ivabradine in blood plasma may increase the risk of developing severe bradycardia.

Contraindicated drug combinations:

The simultaneous use of ivabradine with potent inhibitors of the CYP3A4 isoenzyme, such as antifungal agents of the azole group, antibiotics of the macrolide group, HIV protease inhibitors and nefazodone is contraindicated. Potent inhibitors of the isoenzyme CYP3A4 - ketoconazole or josamycin increase the average plasma concentrations of ivabradine by 7-8 times.

Unwanted drug combinations:

The combined use of ivabradine and moderate inhibitors of the CYP3A4 isoenzyme diltiazem or verapamil in healthy volunteers and patients was accompanied by an increase in the AUC of ivabradine by 2-3 times and an additional decrease in heart rate by 5 beats / min. This use is not recommended .:

Combinations of medicines requiring caution:

CYP3A4 isoenzyme inducers, such as rifampicin, barbiturates, phenytoin and herbal remedies containing St. With the combined use of ivabradine and preparations containing St. John's wort, a two-fold decrease in the AUC of ivabradine was noted. During the period of therapy with Coraxan ®, the use of drugs and products containing St. John's wort should be avoided if possible .:

Combined use with other drugs:

It has been shown that there is no clinically significant effect on the pharmacodynamics and pharmacokinetics of ivabradine with the simultaneous use of the following drugs: proton pump inhibitors, PDE5 inhibitors, HMG-CoA reductase inhibitors, slow calcium channel blockers - dihydropyridine derivatives, digoxin and warfarin. It was shown that ivabradine does not have a clinically significant effect on the pharmacokinetics of simvastatin, amlodipine, lacidipine, the pharmacokinetics and pharmacodynamics of digoxin, warfarin and the pharmacodynamics of acetylsalicylic acid.

Ivabradine was used in combination with ACE inhibitors, angiotensin II receptor antagonists, beta-blockers, diuretics, aldosterone antagonists, short- and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton acetyl glycemic acid pump inhibitors, and other peragillocytic acids means. The use of the above drugs was not accompanied by a change in the safety profile of the therapy.

Other types of interactions requiring caution when used together:

While taking grapefruit juice, there was a 2-fold increase in the concentration of ivabradine in the blood. During the period of therapy with Coraxan ®, if possible, you should avoid the use of grapefruit juice .:

A significant relationship between the level of heart rate (HR) at rest, on the one hand, and overall and cardiovascular mortality, on the other hand, has been noted in numerous epidemiological studies conducted over the past 25 years. This relationship has been demonstrated both for the general population and for patients with various cardiovascular disorders: arterial hypertension, acute myocardial infarction, chronic ischemic heart disease (IHD), chronic heart failure (CHF), asymptomatic left ventricular (LV) systolic dysfunction. Two recently published large studies with a particularly long follow-up period have significantly expanded our understanding of the predictive value of heart rate. In the first of them (X. Jouven et al., 2005), heart rate at rest and during exercise was assessed in 15,713 men aged 42-53 years (without cardiovascular diseases), who were then followed up for an average of 23 years. It was noted that overall mortality, the frequency of death from myocardial infarction, as well as the frequency of sudden death progressively increased with an increase in resting heart rate (in groups with an initial heart rate within< 60, 60-64, 65-69, 70-75 и >75 beats per minute), and this effect did not depend on age, diabetes mellitus, blood pressure, body weight, level of physical activity and other factors.

The second study (A. Diaz et al., 2005) included 24 913 men and women with a presumed or established diagnosis of coronary artery disease, the average follow-up period for them was 14.7 years. A direct relationship was shown between total and cardiovascular mortality, on the one hand, and the resting heart rate at the start of the study, on the other hand. This relationship did not depend on the presence of arterial hypertension, diabetes mellitus, smoking, level of LV ejection fraction; it was significant for people of both sexes, in more and less older age groups (≤ 65 and> 65 years), at different levels of body mass index (≤ 27 and> 27 kg / m2).

Taking into account these and similar data, elevated heart rate is currently considered as an independent cardiovascular risk factor. So, for the first time in 2007, tachycardia was included in the number of cardiovascular risk factors in the Recommendations for hypertension of the European Society of Cardiology. According to the recommendations of the US experts for the treatment of patients with stable angina pectoris (2007), an increased heart rate is also recognized as a factor of cardiovascular risk; for these patients, target heart rate values ​​are set within< 60 уд. в минуту.

Adverse effects of increased heart rate, which are associated with its adverse effect on the degree of cardiovascular risk (adapted from A. Hjalmarson, 2007; K. Foxet al., 2007):

Arteries, atherosclerosis:

- an increase in the rigidity of the arterial wall, a decrease in their compliance and extensibility;

- an increase in shear stress, an increase in mechanical stress on the vascular endothelium;

- an increase in the rate of progression of atherosclerotic plaque;

- increased risk of atherosclerotic plaque rupture.

Myocardial ischemia:

- an increase in oxygen consumption by the myocardium;

- an increase in the duration of diastole, a decrease in the time of diastolic perfusion, an increase in the ratio between the duration of systole and diastole;

- unfavorable redistribution of coronary blood flow with its decrease, especially in the subendocardium;

- an unfavorable change in the phase composition of diastole (to a lesser extent than other phases, the phase of isovolumic relaxation of the LV is shortened, while the period of extravasal compression of small coronary arteries lasts relatively longer).

Ventricular arrhythmias:

- an increase in the risk of developing life-threatening ventricular arrhythmias, especially those associated with myocardial ischemia.

Forecast:

- an increase in the risk of developing myocardial infarction, sudden death, cardiovascular and general mortality.

General characteristics of ivabradine

Ivabradine is the only representative of a new pharmacological class approved for clinical use - blockers of I f -channels of pacemaker cells of the sinus node. Its action in relation to these channels is selective and specific, since it interacts only with them, without affecting other ionic channels of the cell membrane. Due to the effect on the I f -channels of the sinus node, ivabradine reduces heart rate during sinus rhythm at rest and during exercise; due to the selective nature of this effect, it does not affect the sympathetic system, does not cause vasodilation and hypotension, does not affect myocardial contractility and conductivity. Ivabradine does not increase the risk of developing episodes of atrial fibrillation, does not increase the frequency of supraventricular and ventricular premature beats. The standard initial dose is 5 mg 2 times a day, later it is possible to transfer to a dose of 7.5 mg 2 times a day. The effect of ivabradine on heart rate is long-term and stable - when the drug is used for many months, this effect does not weaken.

Ivabradine is well tolerated and rarely causes significant (< 40 уд. в минуту) брадикардию. С учетом того, что ивабрадин, влияя на I f (HCN4)-каналы синусового узла, в части случаев может также слабо взаимодействовать с HCN1- и HCN2-каналами, расположенными в структурах сетчатки, у небольшого числа больных (3-5 %) могут отмечаться так называемые визуальные симптомы, которые характеризуются появлением светлых пятен в поле зрения умеренной или средней интенсивности (их возникновение провоцирует внезапное изменение освещенности). Этот эффект дозозависим; если возникает, то в первые 2 месяца лечения; по характеру — транзиторен и обычно полностью исчезает без прекращения лечения (лишь в 1 % случаев требуется отмена препарата). Для ивабрадина отсутствуют синдромы отмены, рикошета и толерантности. Препарат хорошо комбинируется практически со всеми используемыми в кардиологической практике лекарственными препаратами, за исключением верапамила и дилтиазема.

The use of ivabradine for angina pectoris

The beneficial effects of a decrease in heart rate achieved with ivabradine in patients with angina pectoris (adapted from A. Hjal-marson, 2007; K. Fox et al., 2007):

- an increase in the duration of diastole, an increase in oxygen delivery to the myocardium;

- decrease in myocardial oxygen consumption;

- improvement of the phase composition of diastole (G. Heusch, 2007) - with lengthening of diastole in general, the phase of isovolumic relaxation is lengthened to a lesser extent than other phases of diastole; thus, the relative time of compression of small coronary arteries decreases (this effect is inherent in ivabradine, but not β-AB);

- reducing the progression and risk of rupture of atherosclerotic plaques;

- decrease in the number and intensity of episodes of angina pectoris;

- increased exercise tolerance.

Ivabradine is currently a full-fledged component of the treatment of patients with stable angina pectoris who have sinus rhythm (especially if there are contraindications to the use of β-AB or if they are intolerant). This drug was included in the latest Recommendations for the treatment of angina pectoris presented by experts from Europe (2006). Antiangi
The natural effect of ivabradine is quite significant - for a dose of 15 mg / day. in terms of severity, it is comparable to similar effects of 100 mg / day. atenolol and 10 mg / day. amlodipine or even surpasses them. The drug shows high antianginal efficacy and good tolerance both in patients with stable angina pectoris in general, and in groups of elderly people and patients with diabetes mellitus in particular.

Possible prospects for the use of ivabradine in CHF. BEAUTI f UL and SHI f T studies

The beneficial effect of β-AB on the prognosis in CHF is widely known. Representatives of this group of drugs are, in accordance with the already mentioned international recommendations, the standard in the treatment of patients with CHF. Currently, the point of view is widespread that at least part of the positive effects of β-AB in CHF is associated with the decrease in heart rate achieved with their use. Taking into account the important role of elimination of tachycardia in reducing myocardial ischemia, which is presented in more detail above, lowering heart rate as an independent approach seems especially attractive in the treatment of CHF of ischemic genesis. An important argument in favor of the possible use of ivabradine for selectively lowering heart rate is that some patients who need to eliminate tachycardia with CHF have contraindications to the use of β-AB (active asthma or COPD, hypotension, conduction disturbances) or side effects when using them ( e.g. erectile dysfunction). Thus, the theoretical prerequisites for the use of ivabradine in CHF are quite convincing.

Data from small studies on this use of ivabradine are already available. In a recent study by G. Jondeau et al. (2004) showed positive hemodynamic and clinical effects of ivabradine in a group of 65 patients with coronary artery disease who had CHF of functional class III (the average level of LV ejection fraction was 40%). The study was double-blind, placebo-controlled and lasted for 3 months. Patients received standard treatment for CHF (ACE inhibitors, diuretics, if necessary, digoxin), to which ivabradine (10 mg 2 times a day) or placebo was added. Against the background of the use of ivabradine, a decrease in heart rate, a significant increase in distance in the test with a 6-minute walk, a tendency to a decrease in LV volumes were noted, especially in patients with an initial LV ejection fraction.< 35 %. У этой категории больных за период лечения изменения конечно-диастолического объема ЛЖ составили для групп ивабрадина и плацебо соответственно -22 мл и +14 мл; конечно-систолического объема соответственно -24 мл и +9 мл.

Taking into account the data on the beneficial effects and good tolerability of ivabradine in CHD, the pathophysiological justification of selective decrease in heart rate in CHF, as well as preliminary data from small studies on the positive effect of ivabradine in CHF, BEAUTI f UL and SHI f T studies were planned and are currently being conducted, which we will briefly describe.

The randomized, placebo-controlled, double-blind study BEAUTI f UL aims to compare ivabradine with placebo (when added to standard CHF therapy) in terms of its effect on prognosis. This study included 10,917 patients (mean age 65 years, 37% with type 2 diabetes mellitus, 40% with metabolic syndrome) with proven chronic coronary artery disease with sinus rhythm with a frequency of ≥ 60 beats. per minute (on average - 72 beats per minute), having levels of LV ejection fraction ≤ 39% (average level of LV ejection fraction is 32%). Before being included in the study, the patients were in a stable clinical state for at least 3 months. Basic treatment includes ACE inhibitors or ARAII (89%), β-AB (87%), statins (76%), antiplatelet drugs (94%). Doses of ivabradine are 10 or 15 mg / day. depending on heart rate levels. The minimum observation period should be 12 months. In BEAUTI f UL there are sub-studies: one - with 24-hour ECG monitoring - to assess the effect of ivabradine on heart rate and another - with the definition of echocardiographic parameters - to assess the effect of ivabradine on the structure and function of the LV. BEAUTI f UL results are planned for publication in August - September 2008.

Another large study of ivabradine in CHF is SHI f T, which is also a randomized, placebo-controlled, double-blind. It assesses the effect of ivabradine (15 mg / day) on the prognosis in 2750 patients with moderate and severe CHF (at levels of LV ejection fraction< 35 %).

The results of these two studies will make it possible to more clearly present the prognostic value of heart rate in CHF, as well as the effect on the prognosis of a selective decrease in heart rate. If successfully completed, these studies can add a new class of drugs (selective inhibitors of I f -channels, in particular ivabradine) to the number recommended for CHF, and also expand the spectrum of drugs that can improve cardiovascular prognosis due to this drug.