Keywords: acute coronary syndrome, antithrombotic agents, antiplatelet agents

INTRODUCTION AND DEFINITIONS.

Unstable angina and myocardial infarction - forms ischemic disease hearts demanding emergency care to prevent dangerous complications, incl. deadly. Usually, although not always, the cause of these conditions is rupture of an atherosclerotic plaque or endothelial erosion followed by thrombosis. coronary artery and the development of acute ischemia. As numerous studies have shown, the earlier started necessary treatment, the more hope for a favorable prognosis in a particular patient. Hence, special attention to the early recognition of acute myocardial ischemia, which is extremely important to carry out already at the stage of the initial examination of the patient. It is for this purpose that the term "acute coronary syndrome" (ACS) was introduced.

So, OKS - any combination clinical symptoms or signs suggestive of myocardial infarction (MI) or unstable angina pectoris (HC). Includes MI (with persistent ST elevation or without persistent ST elevation, diagnosed by changes in enzymes or biomarkers, by late ECG signs) and NS (Fig. 1).

The term OKS was introduced in connection with:

· With the need to start treatment before the final diagnosis of the listed conditions is established;
Used to indicate patients at first contact with them, and
· Implies the need for their management, as patients with MI or NA.

Since at the preliminary stage of diagnosis it is not always possible to differentiate between NA and MI, as well as other diseases that have a similar clinic, it is advisable to distinguish PROBABLE ACS as a preliminary diagnosis in an emergency hospitalization of the patient, and PROSPECTED ACS as a secondary diagnosis in the event that it is more probable the cause of treatment is another disease, but ACS has not yet been excluded.

Acute myocardial ischemia can be a sign of developing myocardial infarction (with or without the formation of a Q wave), but does not always mean cardiomyocyte necrosis (unstable angina pectoris).

From a clinical point of view, it is important to differentiate ACS with persistent ST-segment elevation on ECG and ACS without persistent ST-segment elevation (Fig. 1).

Sick with ACS with stable ST rise- these are patients with pain or discomfort in the chest and persistent elevation of the ST segment or "new" (new or presumably new) complete left bundle branch block on the ECG. Persistent ST-segment elevation implies acute complete occlusion of a coronary artery by a thrombus. The main task of treatment in this situation is a quick and stable restoration of the vessel lumen (reocclusion). For this, thrombolytic agents are used (in the absence of contraindications) or direct angioplasty (percutaneous coronary intervention - PCI). ST-elevation ACS indicates the development of MI (ST-elevation MI)

Sick with ACS without stable ST rise- these are patients with pain or discomfort in the chest and ECG changes indicating acute myocardial ischemia, but without ST segment elevations. These patients may have persistent or transient ST depression, inversion, flattening, or pseudo-normalization of the T wave, although some patients may have normal ECG on admission. Thrombolytic agents are not used in the treatment of such patients due to unproven efficacy. The main objectives of treatment are to maintain the patency of the coronary artery by limiting and preventing intracoronary thrombosis and distal thromboembolism, eliminating ischemia (conservative or operatively - PCI). ACS without ST elevation may result in NA or MI (MI without ST elevation). It is advisable to give precise definitions of the listed clinical forms.

Picture 1
CLASSIFICATION AND COURSE OF ACUTE CORONARY SYNDROMES

Myocardial infarction (acute, developing or recent) by clinical signs is established on the basis of typical changes biochemical markers myocardial necrosis(rise and gradual decrease in troponin level or faster rise and decrease in CPK-MB level), in combination with at least one of the following signs:

(a) ischemic symptoms;
(b) the development of pathological Q waves on the ECG;
(c) ECG changes indicative of ischemia (ST elevation or depression, T changes);
(d) coronary artery interventions (PCI).

STEMI with persistent ST elevation (STEMI)- "new" or presumably "new" persistent ST elevation in two or more adjacent leads at the level of the J-point of 0.2 mV (2 mm) or more in leads V1, V2 or V3, or 0.1 mV (1 mm ) in other leads (in combination with typical changes in necrosis markers).

MI without persistent ST elevation (IBMP ST)- "new" or presumably "new" ST segment depression or only T wave changes (symmetric inversion of 0.1 mV or more) in 2 or more adjacent leads in combination with ischemic symptoms in the form of retrosternal discomfort (pain) or clinical equivalents in the form of:

- "causeless" nausea, vomiting;
- persistent shortness of breath associated with left ventricular failure;
- "causeless" weakness, dizziness or syncope.

A combination of these symptoms with typical changes in necrosis markers is imperative.

The terms STEMI and STEMI are used temporarily until the final definition of the type of MI (with or without the formation of a Q wave, undefined type)

Unstable angina in contrast to STEMI, it is not accompanied by significant changes in myocardial necrosis markers. It provides:

Resting angina pectoris and protracted (usually more than 20 minutes);
- for the first time arising angina pectoris at the level of at least 3 FC;
- progressive angina pectoris, in the form of its amplification from 1 FC to at least 3 FC.

As you know, the modern tactics of managing patients with ACS implies the possibility of early surgical intervention, especially in patients with a high risk of an unfavorable outcome. However, today in Russia there are only a limited number of large medical centers have the ability to perform urgent interventions on the coronary arteries (PCI, CABG). Therefore, for most patients, adequate conservative therapy is the only possible treatment option.

The goal of ACS treatment is to eliminate ischemia and its complications, prevent the development of myocardial necrosis (or its further spread), improve and stabilize coronary blood flow, and ultimately improve the prognosis of patients.

Based on the commonality of the pathogenesis of ACS, the main directions of their drug therapy should be considered:

· Lysis of a thrombus obstructing the coronary artery (for ACS with ST elevation);
· Prevention of further thrombus formation, microembolization, and creation of conditions for spontaneous lysis of a thrombus that does not close the lumen of the vessel;
· Elimination of ischemia and prevention of its occurrence;
Symptomatic therapy (pain relief, treatment of heart failure, shock, arrhythmias, etc.)
Initiation of measures for the secondary prevention of myocardial infarction

Main groups pharmacological agents used in the treatment of ACS, these are antithrombotic agents, antianginal agents, as well as drugs of other groups.

DRUGS USED IN TREATMENT OF ACS:

1. Antithrombotic agents:

2. Antianginal drugs:

3. Other funds:

CHARACTERISTICS OF THE MAIN GROUPS OF PHARMACOLOGICAL AGENTS USED IN THE TREATMENT OF ACS

Antithrombotic agents

Antithrombotic agents are intended to prevent or limit thrombus formation, as well as the destruction of the formed thrombus. They can be divided into 3 large groups: antiplatelet agents, anticoagulants and thrombolytics. Before touching on the points of application of the action of drugs of each of the groups, it is necessary to briefly dwell on the main stages and mechanisms of blood coagulation.

Hemostasis is carried out through the regulated interaction of vascular, platelet and plasma factors (Fig. 2.).

The vascular component of hemostasis helps to reduce bleeding from the damaged vessel due to its contraction and compression by the outflowing blood, but what is especially important, the exposure of the subendothelial layer, rich in collagen and tissue thromboplastin, triggers a cascade of coagulation reactions.

The platelet component of hemostasis ensures the rapid formation of platelet clots at the site of vessel damage. In addition, platelets secrete vasoconstrictor substances, and their membranes provide a surface and phospholipid components for the formation of enzyme-cofactor complexes at the next stage of coagulation. The interaction of plasma coagulation factors leads to the completion of the formation of a thrombus by reinforcing it with fibrin threads. A typical arterial intracoronary stenosing thrombus consists of a white head (a platelet clot at the site of endothelial injury) and a red tail caused by blood stasis.

Platelet hemostasis includes 2 stages: adhesion (adhesion) of platelets to the exposed collagen of the vascular wall (through the von Willebrand factor using Ib receptors, as well as Ia receptors) and their subsequent aggregation (through the binding of IIb and IIIa platelet receptors with molecules of fibrinogen and other adherent proteins ). The most powerful stimulators of aggregation are thromboxane A 2 and ADP, secreted by the platelets themselves, as a result of the interaction of their membranes with collagen and thrombin. Thromboxane A2 is synthesized from arachidonic acid by the enzyme cyclooxygenase (inhibited by aspirin).

The "plasma" stage of coagulation can be initiated in two ways: by an internal mechanism, activated by the intrinsic coagulation factors of blood upon contact with a negatively charged platelet surface, and by an external mechanism, activated by tissue thromboplastin, which appears in the circulating blood only when a vessel is damaged.

Picture 2
MAIN POINTS OF APPLICATION OF EFFECTS OF BASIC ANTITROMBOTIC AGENTS

Common in alternative pathways of blood coagulation is the activation of factor X. The latter, in combination with activated factor V, procoagulant phospholipid and Ca 2+ ions, causes the conversion of prothrombin to thrombin (factor II) on the platelet surface, which, in turn, converts fibrinogen to fibrin ( factor I) and activates fibrin-stabilizing factor (factor XIII).

In the internal coagulation pathway, factor X is activated through sequential activation of factors XII (in the presence of high molecular weight kininogen and precallikrein), XI and IX, under the action of a complex consisting of activated factors IX, VIII, procoagulant phospholipid and calcium ions. At outward path coagulation factor X becomes active under the action of activated factor VII in combination with tissue thromboplastin.

Plasma coagulation inhibitors are: inhibitor of the tissue factor pathway - TFPI (inhibits Xa, as well as the complex VIIa + tissue thromboplastin), anti-thrombin III (inhibits thrombin, factors Xa and IXa), protein C (inactivates factors Va and VIIIa ), protein S and thrombomodulin, as well as heparin-like compounds, which in combination with thrombin and antithrombin III enhance the activity of the latter. Fibrin degradation products (soluble fibrin, fibrin-monomer complexes) also have an antithrombin effect.

Excess fibrin clots are removed by the fibrinolytic system to restore vessel patency.

The development and progression of coronary atherosclerosis is closely associated with thrombosis. It is known that thrombotic artery occlusion develops only in the area of ​​atherosclerotic plaque (usually due to its rupture or dissection). Therefore, anti-thrombotic agents occupy one of the central places in the prevention and treatment of IHD complications.

Antiplatelet agents (antiplatelet agents)

The accumulated data indicate that the role of platelets in the pathogenesis of ischemic heart disease is not limited to the formation of intracoronary thrombus. It is known that platelets are involved in the development of the atherosclerotic plaque itself by stimulating the proliferation of smooth muscle cells (platelet growth factor), as well as the occurrence of intramural thrombi. Therefore, antiplatelet agents are necessary not only to prevent intravascular thrombosis, but also to slow the progression of atherosclerosis. These drugs have proven to be effective in affecting both coronary and cerebral and peripheral arteries. These funds reduce the functional activity of platelets, primarily their ability to aggregate. Aggregation blockade can be achieved by inhibiting the effects of thromboxane A2 (aspirin), ADP (thienopyridines), or by neutralizing the IIb / IIIa glycoprotein receptors of platelets (absiximab, etc.).

ANTI-PLATE AGENTS (ANTI-AGGREGANTS):

Inhibitors of arachidonic acid metabolism:

1) cyclooxygenase inhibitors:
acetylsalicylic acid (ASA), indobufen, triflusal

2) thromboxane blockers:
picotamide, ridogrel, vapiprost

Drugs that increase the content of cAMP in platelets:

1) platelet PDE inhibitors
dipyridamole, triflusal

2) stimulants of adenylate cyclase
iloprost

ADP receptor blockers (thienopyridines):

Ticlopidine; clopidogrel

Antagonists IIb / IIIa of platelet glycoprotein receptors:

Abciximab; eptifibatid, tirofiban, lamifiban

V complex treatment ACS actively use only a limited list of antiplatelet agents: this is a cyclooxygenase inhibitor - acetylsalicylic acid, ADP receptor blockers thienopyridines - clopidogrel and ticlopidine, as well as antagonists of IIb / IIIa glycoprotein receptors - asciximab, eptifibanatide and thiene.

Dipyridamole and prostacyclin analogues were ineffective in the treatment of ACS, and thromboxane blockers did not show any advantages over aspirin.

It is advisable to give some principles for the use of antiplatelet drugs in ACS:

· Antiplatelet agents - a cornerstone in the treatment of acute coronary syndromes, and, therefore, an indispensable component of therapy;

· They should be prescribed as early as possible, while treatment begins with loading doses;

· Aspirin is prescribed to all patients with ACS in the absence of contraindications; in case of intolerance to aspirin, it is replaced with clopidogrel;

· Antiplatelet agents, as a rule, are combined with the introduction of heparin or its low molecular weight fractions;

With conservative tactics for the introduction of ACS, it is advisable to combine antiplatelet agents with different mechanisms of action, although this is associated with a high risk of hemorrhagic complications;

The activity of antiplatelet therapy is determined by the severity of the patient's prognosis with mandatory registration possible risk bleeding.

Acetylsalicylic acid (Aspirin, Acuprin, Ecotrin, Plidol, Bufferin; enteric forms - Aspirin Cardio and Thrombo ACC; for intravenous administration - Aspirin-DL-lysine).

Pharmacodynamics: Acetylsalicylic acid (ASA) inhibits cyclooxygenase in tissues and platelets, which blocks the formation of thromboxane A2, one of the main inducers of platelet aggregation. The blockade of platelet cyclooxygenase is irreversible and persists throughout the life of the platelets, i.e. for 7-10 days, which causes a significant duration of the effect, which persists even after the drug is removed from the body. At doses above 300 mg / day, ASA inhibits the production of the antiplatelet agent and the vasodilator prostacyclin by the endothelium, which is one of the additional reasons for using lower doses of the drug (75-160 mg / day) as an antiplatelet agent. Aspirin doses below 75 mg are likely to be less effective, and doses above 160 mg / day increase the risk of bleeding.

The action of ASA begins within 5 minutes after ingestion and reaches a maximum after 30-60 minutes, remaining stable for the next 24 hours. To restore the functional state of platelets, at least 72 hours after a single dose of ASA are required.

Aspirin reduces the incidence of MI and death from cardiovascular causes in patients with NS, therefore, aspirin is prescribed to all patients with suspected ACS in the absence of contraindications. With continued intake of aspirin after stabilization of the patient's condition, a long-term prophylactic effect is achieved.

Pharmacokinetics: The bioavailability of ASA when taken orally is 50-68%, the maximum plasma concentration is created after 15-25 minutes (4-6 hours for enteric forms with sustained release). When absorbed, ASA is partially metabolized in the liver and intestines with the formation of salicylic acid, a weaker antiplatelet agent. Therefore, in an urgent situation, to increase the bioavailability and accelerate the onset of the effect, the first ASA tablet is chewed in the mouth, which ensures the absorption of the drug into the systemic circulation, bypassing the liver. The half-life of ASA is 15-20 minutes, salicylic acid - 2-3 hours. ASA is excreted in the form of free salicylic acid through the kidneys.

Indications: ACS treatment; secondary prevention of myocardial infarction; prevention of thrombosis and reocclusion after CABG, PCI, peripheral artery plasty; prevention of thromboembolism in chronic form atrial fibrillation, after prosthetics of heart valves, with transient cerebral ischemia, peripheral vascular disease.

Contraindications: intolerance to ASA, severe allergy in the form of attacks of bronchospasm (including bronchial asthma, combined with rhinosinusopathy - "aspirin asthma"); hemophilia and thrombocytopenia; active bleeding, incl. retinal hemorrhage; erosive and ulcerative processes in gastrointestinal tract or other sources of gastrointestinal bleeding or urinary tract; severe uncontrolled hypertension; severe renal and hepatic impairment.

Application for ACS: if the patient has not taken ASA before admission, the first dose of the drug (325-500 mg) should be chewed in the mouth (using regular, not enteric aspirin). The maintenance dose is 75-162 mg (enteric forms can be used) once a day after meals. In studies that have proven the positive effect of aspirin in ACS, mainly "simple" (non-enteric) forms of the drug have been used. The advantages of enteric forms of ASA over conventional ones in terms of the incidence of hemorrhagic complications have not been proven.

There are indications that some patients may be resistant to aspirin, although there are no reliable clinical tests to verify this condition. In patients with a high risk of thrombotic complications, it is necessary to supplement ASA with other antiplatelet agents (clopidogrel, antagonists of IIb / IIIa platelet glycoprotein receptors).

Side effects: bleeding, dyspepsia and erosive and ulcerative lesions of the esophagogastroduodenal zone, bronchospasm, acute gout attack due to impaired urate excretion, allergic reactions.

Drug interactions: weakening the action of antihypertensive and diuretics, increasing the risk of bleeding when administered with indirect anticoagulants, other NSAIDs, potentiation of the action of hypoglycemic agents, etc.

Ticlopidine (Tiklid, Tiklin)

Pharmacodynamics: Ticlopidine, a drug from the thienopyridine group, blocks ADP receptors on platelet membranes, inhibiting aggregation and degranulation. The drug increases the formation of nitric oxide by endothelial cells, reduces blood viscosity.

According to large studies, ticlopidine reduces the risk of complications in patients after PCI with stenting, as well as the frequency of vascular complications in patients with cerebrovascular diseases. The drug is effective in the treatment of vascular obliterating diseases. lower limbs, and in patients with glomerulonephritis, it increases creatinine clearance and reduces the severity of proteinuria.

The action of ticlopidine begins slowly, 1-2 days after administration, the peak of the effect falls on days 3-6 of treatment, and the duration of action reaches 4-10 days. Therefore, the drug is not a "first line" drug for the treatment of ACS.

Pharmacokinetics: The bioavailability of ticlopidine is 80-90% (increases when taken after meals), and the maximum plasma concentration is reached after 2 hours. The half-life after taking the first dose is 12-13 hours, it increases to 4-5 days with regular medication. A stable concentration of the drug in plasma is created in the 2-3rd week of treatment. The metabolism of the drug occurs in the liver, the excretion of metabolites is carried out in the urine, part of the drug is excreted unchanged in the bile.

Indications: secondary prevention of myocardial infarction; prevention of thrombosis and reocclusion after PCI, CABG; ACS treatment; prevention of stroke in patients with transient cerebral ischemia; prevention of thrombosis in obliterating diseases of peripheral arteries.

Contraindications: hemorrhagic diathesis; hematological disorders: neutropenia, agranulocytosis, thrombocytopenia; gastrointestinal bleeding, intracranial hemorrhage (and a history of them); severe liver failure; age under 18; pregnancy and breastfeeding; hypersensitivity to the drug.

Application for ACS: 250 mg 2 times a day after meals. In renal failure, the dose of ticlopidine is reduced. Co-administration with ASA requires great care due to the high risk of bleeding. In the first 3 months of treatment, once every 2 weeks, a blood test is performed with the counting of formed elements, incl. platelets.

Side effects: occur in half of patients, this is dyspepsia (30-40%), bleeding (the drug is canceled 10-14 days before planned surgery), neutropenia (2.5%), agranulocytosis (0.8%) and thrombocytopenia in the first 3 months of treatment (fever, sore throat, aphthous stomatitis, purpura), liver dysfunctions, hemolysis, dizziness, headache, tinnitus.

Clopidogrel (Plavix)

Pharmacodynamics: Clopidogrel, a representative of the thienopyridine group, inhibits platelet aggregation by irreversible and selective blockade of their ADP receptors.

The antiplatelet effect develops 2 hours after taking the loading dose of the drug (reduction of aggregation by 40%). The maximum effect (60% suppression of aggregation) is observed on the 4-7th day of continuous administration of a maintenance dose of the drug and lasts for 7-10 days (platelet life).

According to the large CAPRIE study, clopidogrel is as effective as aspirin, and perhaps even slightly more effective, in the secondary prevention of MI, ischemic stroke and death from vascular causes.

In comparison with ticlopidine, the action occurs faster, and the tolerance is better (hematological and dyspeptic complications are much less common), therefore, clopidogrel is preferable for the treatment of ACS.

The combination of clopidogrel with ASA is safer than the combination of ASA with ticlopidine, although the risk of bleeding still increases. However, concomitant administration of clopidogrel and aspirin is more effective in the treatment of non-ST elevation ACS than aspirin alone. In addition, the drug in combination with aspirin significantly improves the results of PCI.

Pharmacokinetics: The bioavailability of the drug is high, the maximum plasma concentration is created after 1 hour. Clopidogrel is a prodrug, its metabolite is active after biotransformation in the liver. The half-life is 8 hours. The drug is excreted in urine and faeces.

Indications: ACS treatment; secondary prevention of MI, stroke, peripheral arterial thrombosis; prevention of thrombosis and reocclusion after PCI.

Contraindications: individual intolerance; active bleeding; erosive and ulcerative processes in the gastrointestinal tract; severe liver failure; age less than 18 years.

Application for ACS: if the patient did not take clopidogrel before admission, then the first dose of the drug is 300 mg (4 tablets) orally once (loading dose), then the daily maintenance dose is 75 mg (1 tablet) once a day, regardless of food intake for 1 up to 9 months

If the patient is planned to undergo CABG (but not PCI), clopidogrel is not prescribed or canceled 5, and preferably 7 days before the operation to prevent dangerous bleeding.

Side effects: dyspepsia and diarrhea, gastrointestinal bleeding, intracranial hemorrhage, neutropenia (mainly in the first 2 weeks of treatment), skin rash.

Drug interactions: increased risk of bleeding when administered with ASA and NSAIDs

Abciximab (Abtsiximab, ReoPro)

Pharmacodynamics: Abciximab (AB) is a representative of the group of antagonists of platelet glycoprotein IIb / IIIa receptors. IIb / IIIa receptors (alpha IIb beta 3 integrins) are located on the surface of the platelets. As a result of platelet activation, the configuration of these receptors changes, which increases their ability to fix fibrinogen and other adhesive proteins. The binding of fibrinogen molecules to IIb / IIIa receptors of various platelets leads to the connection of the plates with each other - aggregation. This process does not depend on the type of activator and is the final and only mechanism of platelet aggregation.

AB- Fab-fragment of chimeric human-mouse monoclonal antibodies 7E3, it has a high affinity for IIb / IIIa glycoprotein platelet receptors and binds to them for a long time (up to 10-14 days). As a result of blockade of more than 80% of receptors, platelet aggregation is disrupted at its final stage. After stopping the administration of the drug, there is a gradual (within 1-2 days) restoration of the aggregation ability of platelets.

AB is a nonspecific ligand; it also blocks endothelial vitronectin receptors involved in the migration of endothelial and smooth muscle cells, as well as Mac-1 receptors on activated monocytes and neutrophils. However, the clinical significance of these effects is not yet clear. The presence of antibodies to AB or to its complex with the platelet receptor can cause anaphylaxis and dangerous thrombocytopenia.

The ability of the drug has been proven to significantly improve the prognosis in patients undergoing PCI, primarily in patients with ACS, as well as in patients with a high risk of cardiovascular complications.

Battery efficiency at conservative treatment ACS has not been proven (unlike eptifibatid and tirofiban). The possibilities of combining the drug and other antagonists of glycoprotein IIb / IIIa receptors with thrombolytics in the treatment of ST-elevation ACS are being investigated.

Pharmacokinetics: With intravenous administration, a stable concentration of AB is maintained only by continuous infusion, after its termination, it decreases rapidly within 6 hours, and then slowly (over 10-14 days) due to the fraction of the drug associated with platelets. The drug is excreted in the urine.

Indications: Prevention of thrombosis and reocclusion in connection with PCI (including stent placement) in patients with ACS (with and without ST segment elevation), as well as in high-risk patients.

Contraindications: Internal bleeding; a history of gastrointestinal bleeding (within the last 6 weeks); violation of cerebral circulation (including a history within 2 years, or in the presence of significant residual neurological manifestations); intracranial neoplasm; previous coagulation disorders (hemorrhagic diathesis, thrombocytopenia
Application for ACS: IV bolus (10-60 minutes before PCI) at a dose of 0.25 mg / kg, then 0.125 mcg / kg / min (max 10 mcg / min) for 12-24 hours.

Precautionary measures. The drug must be drawn into a syringe through a 0.2-0.22 micron filter with low level protein binding to reduce the likelihood of thrombocytopenia due to the presence of protein impurities. It is not recommended to use AB after angioplasty if dextran was injected after surgery. Coagulation control is carried out initially, every 15-30 minutes during angioplasty and every 12 hours until the removal of catheters. Estimated parameters: activated blood clotting time (at the level of 300-350 s), hemoglobin content, hematocrit, platelet count.

Side effects: bleeding (including intracranial, retroperitoneal), bradycardia, AV blockade, hypotension, dyspepsia (nausea, vomiting), confusion, visual impairment, hyperimmune reactions (thrombocytopenia, anemia, leukocytosis, pleural effusion, pneumonitis, cutaneous rash, anaphylactic shock). The risk of bleeding is increased in people over 70 years of age and weighing less than 70 kg. Treatment for severe bleeding involves platelet transfusion.

Eptifibatid (Integrilin)

Pharmacodynamics: Eptifibatide (EP) is a blocker of platelet glycoprotein IIb / IIIa receptors from the class of RGD mimetics. In principle, the mechanism of action is similar to that of Ab, but Ep is selective for IIb / IIIa receptors.

The effect of EP occurs immediately after intravenous administration at a dose of 180 μg / kg. The suppression of aggregation is reversible. 4 hours after cessation of intravenous infusion at a dose of 2 μg / kg / min, platelet function reaches more than 50% of the initial level.

Unlike AB, the drug is probably effective in the conservative treatment of ACS.

Pharmacokinetics: The pharmacokinetics of EP when administered at recommended doses is linear, and the maximum concentration is reached quickly. The degree of binding to proteins is 25%. The half-life is 2.5 hours. The drug is excreted by about 50% in the urine.

Indications: Prevention of thrombosis and reocclusion in connection with PCI (including with the installation of a stent); acute coronary syndrome without ST elevation (in combination with ASA, UFH or LMWH, and possibly with ticlopidine).

Contraindications: Hemorrhagic diathesis or severe pathological bleeding in the next 30 days; severe arterial hypertension (systolic blood pressure more than 200 mm Hg or diastolic blood pressure more than 110 mm Hg) against the background of antihypertensive therapy; major surgical interventions within the last 6 weeks; a stroke within the previous 30 days or a history of hemorrhagic stroke; dependence on hemodialysis due to renal failure; simultaneous use of another inhibitor of IIb / IIIa platelet receptors for parenteral administration; hypersensitivity to the drug.

Application for ACS: IV bolus bolus at a dose of 180 mcg / kg for 1-2 minutes, then drip at a dose of 2 mcg / kg / min (at a serum creatinine level of up to 2 mg / dl), at a dose of 1 mcg / kg / min ( at a creatinine level of 2-4 mg / dL) for 72 hours or until discharge. If necessary, the treatment time can be increased to a maximum of 96 hours. If PCI is planned, ep begins to be administered immediately before the operation and continues for at least 12 hours. The activated blood clotting time must be monitored at the level of 200-300 s.

Side effects: mostly bleeding.

Anticoagulants

The purpose of anticoagulant therapy is to inhibit plasma coagulation factors in order to prevent the formation or limit the spread of blood clots. These drugs include direct and indirect anticoagulants. The former act by directly inhibiting thrombin and other coagulation factors, the latter disrupt the synthesis of coagulation factors, as a result of which the latter lose their activity. Anticoagulants have proven their effectiveness in the prevention and treatment of both venous and arterial thrombosis and embolism, in particular in the treatment of ACS.

LITERATURE

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11) Braunwald E. et al. ACC / AHA Guidelines for the Management of Patients With Unstable Anginaand Non-ST-Segment Elevation Myocardial Infarction. A Report of the American College of Cardiology / American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina) // Journal of the American College of Cardiology. - 2000. -Vol. 36, no. 3. - P.970-1062.

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The "gold standard" for assessing myocardial reperfusion is direct coronary angiography (CAG) with an assessment of antegrade blood flow according to the TIMI scale. In real clinical practice, the treatment of ST-segment elevation myocardial infarction (MI) (STEMI) CAG is performed not for routine assessment of the effectiveness of thrombolytic therapy (TLT), but as an integral part of the intervention strategy in general. On the other hand, the successes or failures of thrombolysis determine the further tactics of managing a particular patient as a whole: the urgency and sequence of percutaneous coronary intervention, drug support, the volume of additional examinations, etc. In this regard, a number of non-invasive (indirect) signs are proposed that allow to evaluate the effectiveness of TLT directly at the patient's bedside. According to the available literature data, non-invasive signs of the completed reperfusion can be divided into the following main groups: clinical; electrocardiographic; laboratory. At the same time, it is obvious that the final judgment about the effectiveness of TLT is made on the basis of the totality of the available features. The clinical criteria for a completed reperfusion include the final relief of pain and signs of acute heart failure within the next 30-60 minutes after thrombolysis. When evaluating clinical criteria, it should be borne in mind that TLT is only one of the components of complex intensive therapy for STEMI, i.e., stabilization of the patient's condition may not occur due to effective reperfusion, but against the background of the introduction of narcotic analgesics, inotropic support, the use of peripheral vasodilators and β -blockers. Thus, clinical criteria for the effectiveness of TLT are highly subjective and do not rely on a strict evidence base. The electrocardiographic criteria for a completed myocardial reperfusion is a normalization or significant, ≥ 50% of baseline, decrease in ST segment elevation from baseline within 60-180 minutes after TLT. In addition, the appearance on the ECG of "new" Q-waves during the same period of time is of practical importance. The study of new ECG criteria for the completed reperfusion seems to most experts to be the most promising direction.

The subject of study is such ECG indicators as the total decrease in the amplitude of ST-segments in all infarction-associated leads; decrease in the amplitude of the ST-segment in the lead, where the maximum rise was recorded; the number of leads where "new" Q-waves appeared. The use of ECG data to assess the effectiveness of TLT began with the ISAM study (1986), in which researchers established a relationship between the degree of ST segment reduction on an ECG 3 hours after the onset of thrombolysis and mortality. In 1988 A.A. Smirnov et al. proposed an indirect method for assessing myocardial reperfusion, which was based on the rate of decrease in ST segment elevation. EKG indices were assessed 90 and 180 minutes after the onset of thrombolysis. A decrease in the ST segment by more than 50% from the initial one in the lead with a maximum rise 3 hours after the start of TLT with a 92% probability indicated effective reperfusion with restoration of blood flow through the infarcted coronary artery (ISCA) on the TIMI scale at the level of 2-3. This criterion formed the basis modern guidelines Russian Society of Cardiology for Evaluation of the Effectiveness of TLT. In the HIT-4 (Hirudin for Improvement of Thrombolysis Trial) study, which included 1208 patients with myocardial infarction, from the onset of which did not take more than 6 hours, who underwent systemic TLT, compared the degree of decrease in ST segment elevation relative to the baseline 90 minutes after the onset of TLT with data from KAG. If the decrease in ST segment elevation to the isoline 90 min after the onset of TLT is ≥ 70% of the baseline in the lead with the maximum elevation, the intervention was proposed to be regarded as effective. The blood flow in the ISKA according to the CAG data corresponded to TIMI 3 in 69% of cases. With a decrease in ST segment from 70% to 30%, the effectiveness of TLT was considered doubtful. With a decrease in the ST segment to the isoline of less than 30%, the blood flow according to ISCA in 84% of patients corresponded to TIMI 0-1.

R. Clemmensen et al. proposed to summarize the amplitude of ST segment elevation in all conduction with ST elevation. At the same time, after thrombolysis, a decrease in the total amplitude of ST segment elevation by 20% from the initial value correlated with the restoration of blood flow according to ISAA at the TIMI 2-3 level according to angiography data and was a more reliable criterion than the assessment of the absolute deviation of the ST segment relative to the isoline. Another approach is to assess not only the total elevation, but also the total ST segment depression. In the work of A.A. Shevchenko, it was shown that the calculation of the total deviation of the ST segment in all leads, and not only in the lead with the maximum deviation, makes it possible to more accurately determine the possible volume of myocardial damage and the dynamics of ST segment displacement during thrombolysis. A decrease in the total ST segment elevation by 50% or more after 180 minutes from the beginning of TLT is regarded as a criterion for the effectiveness of TLT, less than 50% - as a dubious result. With ineffective reperfusion therapy, an increase in the total ST segment reduction was noted. It was proved that it is the dynamics of the total ST segment elevation that is a significant criterion for the effectiveness of TLT, while there were no significant differences in the dynamics of the total ST segment decrease in patients with effective and ineffective TLT. According to some authors, infarctions of different localization with effective TLT are characterized by different degrees of ST segment reduction: for anterior localized STEMI, the optimal degree of ST segment elevation reduction is 50% or more, and for lower infarctions - 70% or more. Analysis of the dynamics of the ST segment by a changing ECG, which is recorded at fixed time intervals after thrombolysis, is currently the most accessible and simple method for indirectly assessing the effectiveness of reperfusion in patients with STEMI, which has proven in a number of studies its high specificity and prognostic value. However, the question of what time is optimal for assessing the dynamics of the ECG remains open - according to different researchers, it ranges from 30 to 180 minutes, and some authors suggest making a final judgment no earlier than 24 hours after TLT.

According to a number of experts, changes in the T wave can also indirectly testify in favor of the restoration of coronary blood flow. The use of more sophisticated approaches to ECG analysis for this purpose, for example, the Anderson-Wilkins scoring of the severity of myocardial ischemia, continues to be the subject of study.

Another marker of myocardial reperfusion is considered to be the appearance of so-called "reperfusion arrhythmias" that occur within 30-90 minutes after thrombolysis and can be represented by extrasystole of any topical affiliation, accelerated idioventricular rhythm, ventricular tachycardia jogging and ventricular fibrillation. Most experts believe that the reason for the development of "reperfusion arrhythmias" is the formation of zones of re-entry or trigger activity as a result of uneven restoration of blood flow in the ischemic myocardium. However, there is another point of view, according to which the appearance of fatal ventricular arrhythmias soon after TLT is a sign of unrecovered blood flow (no-reflow phenomenon) or reperfusion injury of the myocardium.

According to the ASSENT-2 and ASSENT Plus studies, ECG indicators in dynamics correlate precisely with mortality rates in patients with MI after TLT. Thus, the currently proposed ECG criteria for the success of reperfusion remain the subject of discussion.

The method of transthoracic echocardiography (EchoCG) is an integral part of the diagnostic arsenal of a doctor of the emergency cardiology department in working with patients with MI. However, the problem of maximizing the potential of the method remains relevant.

The laboratory criteria for the reperfusion that took place include a sharp increase in the activity of myocardial necrosis markers - cardiotroponins, CPK, its MV fraction - within the next 60-90 minutes after TLT. A similar phenomenon is explained by the restoration of coronary venous outflow and the elimination of destruction enzymes into the general blood circulation system. But there is also an opposite opinion, which explains the increase in the activity of cardiospecific enzymes by the development of reperfusion damage to the myocardium. In recent years, the attention of experts has been attracted by other probable markers of myocardial reperfusion - the dynamics of changes in the D-dimer, C-reactive protein, the ratio of neutrophils / leukocytes, and a number of other indicators.

Implementation in clinical practice systems for assessing the concentration of troponins T and I in blood plasma have revolutionized the diagnosis of myocardial infarction and the methods of allocating patients to high-risk groups. Troponins T and I are cardiospecific markers of myocardial necrosis, according to the latest recommendations of the Russian Cardiological Society, American Heart Association (AHA), and European Society of Cardiology (ESC).

According to the literature data, troponins are a universal protein structure for the myocardium and skeletal muscles, which is localized on the thin myofilaments of the contractile apparatus. The troponin complex consists of three subunits - troponin C, T and I. These proteins play a key role in the calcium-dependent regulation of muscle contraction. The amino acid sequence of myocardial troponin C is identical to that found in skeletal muscle. Troponin C does not have a cardiospecific isoform and therefore cannot be used to diagnose myocardial injury. Troponins T and I exist in myocardial-specific isoforms that differ from skeletal muscle isoforms. Their synthesis is encoded by specific genes, and these proteins have a unique amino acid sequence. This explains the absolute specificity of the methods used to detect myocardial isoforms of troponins T and I. The molecular weight of troponin T is 37,000 daltons, and the molecular weight of troponin I is 24,000 daltons. The content of troponin T in cardiac myocytes is approximately 2 times higher than the level of troponin I. Troponins are found in cells mainly in a structurally related form. Most of the troponins T and I are part of the contractile apparatus and are released as a result of its enzymatic degradation. There is also a cytosolic pool of unbound troponins, which are released acutely, like other cytosolic enzymes, such as CPK. The cytoplasm contains 6-8% troponin T and 2-4% troponin I. The release of cardiotroponins in the event of myocardial injury occurs in the following situations - with reversible damage, the integrity of the myocardiocyte membrane is disturbed, and this leads to the release of troponins of the cytosolic pool, and when the damage becomes irreversible, intracellular acidosis and activation of proteolytic enzymes lead to the destruction of the contractile apparatus with the subsequent release of bound troponins. Cytoplasmic isoforms of troponins are released from cardiomyocytes approximately 4 hours after the onset of potentially irreversible damage, reaching peak values ​​after 12 hours, and structurally related troponins - after 24-48 hours. Troponin I can be detected in the blood after 7-10 days, and troponin T - even 14 days after the onset of myocardial infarction. The duration of detection of elevated troponin concentrations depends on the volume of necrotic myocardium, reperfusion therapy or revascularization, and renal excretory capacity.

It is known that increased troponin levels can be detected in diseases such as myocarditis, pulmonary embolism, renal failure, and many other pathologies. Since 2000, the determination of troponins in blood serum has been the "gold standard" in the diagnosis and prognosis of acute myocardial infarction. The content of troponins in blood plasma is closely related to the volume of damaged MI. After reperfusion therapy, the assessment of the troponin content in the blood plasma can be difficult due to the implementation of the wash-out phenomenon. As a result, the assessment of the level of troponins T and I is not recommended for establishing the fact of microvascular myocardial damage, which may develop as a result of inadequate opening of ISCA after TLT.

At the moment, it is impossible to answer unequivocally, the determination of which of the cardiac troponins (T or I) is of greater importance. At first glance, troponin I is a more specific cardiac marker than troponin T, but the existing methods for the determination of troponin I are less standardized. Different manufacturers of troponin I tests use different antibodies in their reagents and different methods calibration, so their results are difficult to compare. The method for determining TNT is patented and this test is produced by only one manufacturer.

Creatine phosphokinase is an enzyme in muscle tissue. MV-CPK is a cardiac form of CPK (MV-CPK), which is a heterodimer with a molecular weight of 86 kDa. Skeletal muscle contains the muscular form of CPK (MM-CPK) and less than 3% MV-CPK. The share of MV-CPK among the total CPK of more than 5-6% is a specific sign of myocardial necrosis. However, it is known that diseases such as chronic renal failure, strokes, some oncological diseases, myasthenia gravis, traumatic operations can lead to an increase in the CF fraction of CPK and, as a consequence, overdiagnosis of MI. Determination of total CPK in the blood is recognized by most experts as inappropriate for the diagnosis of MI, since this enzyme is found in large quantities in skeletal muscles and it is low specific for myocardial necrosis. For the diagnosis of myocardial infarction, it is considered preferable to determine the mass of MV-CPK. The level of the CF-fraction of CPK in serum begins to increase after 4-8 hours from the onset of symptoms, reaches a peak after 24 hours, and then returns to normal after 48-72 hours. This temporal sequence is important, since MV-CPK from other sources or in other cardiac pathologies, for example, in myocarditis, usually does not obey this law. TLT in MI leads to a rapid washout of the enzyme and an earlier peak in the CF fraction of CPK.

D-dimer are fragments of the fibrin molecule that are formed during its degradation under the action of active plasmin. Accordingly, it can be attributed both to markers of activation of coagulation and fibrin formation, and to markers of fibrinolysis. D-dimer is formed during the activation of hemocoagulation due to damage to the endothelial lining, or getting into blood vessel from the surrounding tissues of a tissue factor - a component of cell membranes, or when the internal coagulation pathway is activated due to contact of blood with a foreign surface, or when active proteases enter the bloodstream. Thrombus formation begins when, under the action of thrombin, fibrinogen is converted to fibrin, and it forms the main framework of a blood clot and thrombus. This process has several stages. The dimeric fibrinogen molecule is converted to monomeric fibrin molecules, which are capable of polymerizing and ultimately forming an insoluble fibrin polymer. The change in fibrinogen to fibrin-monomeric molecules is accompanied by the cleavage of fibrinopeptides A and B. Fibrin, being the end product of the blood coagulation process, simultaneously serves as a substrate for plasmin, the main enzyme of fibrinolysis. The fibrinolytic system is adapted to fibrin lysis. However, with excessive activation of fibrinolysis, it is possible to start the process of fibrinogen lysis. Under the action of plasmin, there is a sequential cleavage of fibrinogen and fibrin. During this process, molecules are formed that have different molecular weights and are released as products of fibrin and fibrinogen degradation (FDP). Degradation products of fibrin (polymer molecule) are larger fragments - D-dimer and trimers, which contain a covalent bond between D-domains of fragments of the fibrin molecule. Lysis of fibrinogen produces smaller, individual oligopeptide fragments. The D-dimer is not formed from the fibrinogen molecule.

In some diseases, which are characterized by the activation of blood coagulation processes, there is a constant transition of fibrinogen to fibrin and, as a consequence, the appearance in the bloodstream of a large number of fibrinopeptides A and B, the accumulation of fibrin monomers. At the same time, the activation of fibrinolysis is accompanied by an increased formation of PDPs, which interact with monomeric fibrin molecules that have not undergone polymerization. Thus, soluble fibrin-monomeric complexes (RFMC) are formed, containing fibrin monomers, fibrinopeptides A and B, and their complexes with PDP. All of these protein molecules are formed as a result of the formation of a fibrin clot, and then its cleavage. The concentration in the blood of D-dimer, PDP and RFMK reflects two processes that continuously occur in the human body, this is thrombus formation and thrombolysis. Consequently, these indicators can be used in clinical and laboratory practice to assess these processes.

The dynamics of the level of D-dimer in the blood reflects the process of formation and destruction of an existing thrombus. According to G.P. Arutyunov et al. the dynamics of the increase in the level of D-dimer can be used as a marker of the effectiveness of the performed thrombolysis. In his study, an early increase in plasma D-dimer concentration after TLT coincided with an earlier onset of myocardial reperfusion and was associated with preserved left ventricular function. It has been proved that the D-dimer index in blood plasma reflects the presence of atherosclerotic lesions of the vascular bed as a whole, and the quantitative value of this indicator is comparable to the severity of atherosclerosis. The difference in D-dimer values ​​among patients is explained by the different degree of activity of the fibrinolysis system. With the normalization of the D-dimer value in patients with MI, which occurred spontaneously or was achieved due to thrombolytic therapy, there is a decrease in the risk of repeated thrombotic events. For patients with persistent high level D-dimer, it may be advisable to conduct more aggressive antiplatelet therapy. However, according to some authors, the question of the need to determine the D-dimer index in patients hospitalized for cardiovascular pathology remains unresolved. In their opinion, this indicator has average values ​​of sensitivity and specificity; it can be useful in diagnosing the risk of thromboembolic events, but requires further study and accumulation of experience.

Thus, the clinical significance of using the D-dimer index is enormous. Many reviews and articles have been devoted to this laboratory criterion. However, research works on the study of this indicator as laboratory confirmation of completed or failed reperfusion after TLT are few.

Timely dynamic assessment of clinical signs, ECG indicators, laboratory data for MI and TLT performed on this occasion will help identify patients at high risk of developing cardiovascular complications and promptly adjust therapy. In this regard, a search is underway for new markers, including laboratory ones, and the role of already known ones, which have a high predictive value in relation to the risk of complications, the course of the disease, and monitoring of the results of drug therapy in patients with acute coronary syndrome, is being clarified.

Conclusion

Summarizing the data of the review of modern literature, it is important to note that the clinical and instrumental assessment of the effectiveness of thrombolysis in STEMI is of practical importance and largely determines the success and tactics of further actions. Non-invasive approaches to assessing the effectiveness of TLT discussed in the literature require clarification, structuring, and comprehensive consideration.

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E. M. Podgornaya 1
L. I. Markova,
O. L. Belaya, Doctor of Medical Sciences, Professor
K. I. Tebloyev,Doctor of Medical Sciences, Professor

GBOU VO MGMSU them. A.I. Evdokimova, Ministry of Health of the Russian Federation, Moscow

Podgornaya E.M., Markova L.I., Belaya O.L., Tebloev K.I.
For citation: Attending physician No. 11/2018; Page numbers in the issue: 74-78
Tags: heart, thrombolysis, myocardial reperfusion

This is a group of clinical and laboratory-instrumental signs indicating the presence of unstable angina or myocardial infarction. The condition is manifested by chest pain lasting more than 20 minutes, which is accompanied by sweating, shortness of breath, and pallor of the skin. 15-20% of patients have atypical clinical course syndrome. For diagnostics, an analysis of cardiospecific enzymes is carried out, an ECG is recorded. Drug treatment involves the use of thrombolytics, antiplatelet agents and anticoagulants, antianginal drugs. In severe cases, surgical revascularization is indicated.

ICD-10

I20.0 I21 I24.8 I24.9

General information

Acute coronary syndrome (ACS) is a preliminary diagnosis, which is established during the first examination of the patient by a general practitioner. The term arose in connection with the need to choose treatment tactics for urgent conditions, without waiting for the final diagnosis. ACS and its complications rank first (about 48%) among all causes of mortality in the adult population. A state of emergency in men under the age of 60 is determined 3-4 times more often than in women. In the group of patients 60 years of age and older, the ratio of men to women is 1: 1.

Causes

All nosological units that make up the acute coronary syndrome have common etiological factors. The main cause of the disease is thrombosis of the coronary vessel, which occurs during erosion or rupture of an atherosclerotic plaque (atherothrombosis). Occlusion of the coronary artery by a thrombus occurs in 98% of patients with clinical picture OKS. In thrombosis, the development of coronary syndrome is associated with both mechanical blockage of the artery and the release of specific vasoconstrictor factors.

Another etiology of the acute process is extremely rare (about 2% of cases). The appearance of ACS is possible with thromboembolism or fatty embolism of the coronary artery. Even less often, a transient spasm of the coronary arteries is diagnosed - Prinzmetal's variant angina.

Risk factors

Since most episodes are associated with atherosclerotic complications, the risk factors for coronary syndrome are identical to those for atherosclerosis. Distinguish:

• Non-modifiable factors: male sex, old age, hereditary predisposition;
• Corrective factors: overweight, bad habits, physical inactivity.

The greatest danger from the prerequisites is arterial hypertension. High blood pressure contributes to an earlier onset and faster progression of atherosclerosis.

Pathogenesis

The pathophysiological underlying disease is an acute decrease in blood flow in one of the coronary vessels. As a result, the balance between the oxygen demand of muscle fibers and the supply of arterial blood... In acute coronary syndrome, transient or persistent ischemia occurs, which, with progression, causes organic changes in the myocardium (necrosis, dystrophy).

When the fibrous cover of an atherosclerotic plaque is ruptured, platelets and fibrin filaments are deposited - a thrombus is formed that blocks the lumen of the vessel. In the pathogenesis of the syndrome, an essential role is played by hemostatic disorders, which cause the formation of microthrombi in the vessels feeding the myocardium. Severe clinical symptoms are observed with a narrowing of the lumen of the coronary artery by at least 50-70%.

Classification

Complications

In the acute period of this condition, there is a high risk of sudden cardiac death: about 7% in ACS with ST segment elevation, 3-3.5% in coronary syndrome with normal ST. Early complications are detected on average in 22% of patients. The most common consequence of the disease is cardiogenic shock, which is twice as likely to be diagnosed in men. Patients over 50 years old, as a rule, develop severe rhythm and conduction disturbances.

With successful relief of an acute heart attack, 6-10% of patients remain at risk of late complications that develop 2-3 weeks after the onset of the syndrome. Due to the replacement of a section of muscle fibers connective tissue there is a possibility of developing chronic heart failure, heart aneurysm. When the body is sensitized with autolysis products, Dressler's syndrome occurs.

Diagnostics

Taking into account the typical manifestations of an acute anginal attack, a cardiologist can make a preliminary diagnosis. Physical examination is necessary to rule out non-cardiac causes of pain and cardiac abnormalities of non-ischemic origin. To differentiate different variants of coronary syndrome and the choice of treatment tactics, three main studies are carried out:

• Electrocardiography. The "gold standard" of diagnostics is ECG registration within 10 minutes from the onset of an acute attack. Coronary syndrome is characterized by ST elevation of more than 0.2-0.25 mV or depression in the chest leads. The first sign of myocardial ischemia is a pointed high T wave.
• Biochemical markers... To exclude a heart attack, the content of cardiospecific enzymes is analyzed - troponins I and T, creatine phosphokinase-MB. The earliest marker is myoglobin, which rises in the first hours of the disease.
• Coronary angiography. An invasive coronary vascular examination is used after the ST segment elevation is detected on the cardiogram. Coronary angiography is used at the stage of preparation for revascularization of an artery affected by a thrombus.

After stabilization of the condition and elimination of acute coronary syndrome, the specialist prescribes additional diagnostic methods. To assess the risk of patients with an established diagnosis of coronary artery disease, non-invasive stress tests are recommended, which show the functionality of the heart. Echocardiography is performed to measure left ventricular ejection fraction and visualize great vessels.

Acute Coronary Syndrome Treatment

Conservative therapy

Treatment of patients with ACS is carried out only in specialized cardiological hospitals, patients in grave condition hospitalized in intensive care units. Therapeutic tactics depend on the variant of the coronary syndrome. If there is ST elevation on the cardiogram, the diagnosis of acute myocardial infarction is made. In this case, intensive and thrombolytic therapy is indicated according to the standard scheme.

Patients who do not have persistent ST elevation are prescribed combination drug therapy without thrombolytics. To stop the attack, nitrates are used. Further treatment is aimed at eliminating ischemic processes in the myocardium, normalizing the rheological properties of blood and correcting blood pressure. For these purposes, several groups of medicines are recommended:

• Antiplatelet agents... For the prevention of thrombus formation, drugs based on acetylsalicylic acid or thienopyridine derivatives are taken. After the initial loading doses, they switch to long-term medication in medium therapeutic dosages. In the first 2-5 days, the scheme is supplemented with anticoagulants.
• Anti-ischemic drugs... To improve the blood supply to the heart and reduce the oxygen demand of the heart muscle, a number of drugs are used: calcium channel blockers, nitrates, beta-blockers. Some of these drugs have antihypertensive effects.
• Lipid-lowering drugs... All patients are prescribed statins, which lower total cholesterol and atherogenic LDL cholesterol levels in the blood. Therapy reduces the risk of recurrent development of acute coronary syndrome, significantly improves the prognosis, and prolongs the life of patients.

Surgery

Myocardial revascularization is effective in infarction and recurrent ischemia refractory to drug therapy. The method of choice is minimally invasive endovascular angioplasty, which quickly restores blood flow in the affected vessel and has a short recovery period. If it is impossible, coronary artery bypass grafting is indicated.

Forecast and prevention

Timely initiation of intensive care significantly reduces the risk of early and late complications, and reduces the mortality rate. The forecast is determined clinical option acute coronary syndrome, the presence of concomitant cardiac diseases. In 70-80% of patients, before discharge, a low or middle degree risk, which corresponds to the preserved function of the left ventricle.

Non-specific prevention of the disease includes the modification of risk factors - normalization of body weight, rejection of bad habits and fatty foods. Drug prevention of repeated episodes of ACS includes long-term (more than 12 months) antiplatelet therapy and the use of lipid-lowering drugs. Patients who have undergone acute coronary syndrome are registered with a cardiologist.

4286 0

- Anesthesia... Relief of an anginal attack is an integral part of the treatment of myocardial infarction. Pain relief should be prompt and as complete as possible.

• The drugs of choice are narcotic analgesics, which, in addition to a strong analgesic effect, also have a pronounced sedative effect.

Most often, morphine is used, which is diluted in at least 10 ml of 0.9% sodium chloride solution and injected intravenously slowly at 2-4 mg. If necessary, the appointment is repeated every 10-15 minutes at 2-6 mg until the effect is achieved or side reactions occur.

For a less intense attack, intravenous trimeperidine (promedol) is prescribed at a dose of 20 mg.

Side effects of opioids: arterial hypotension, severe bradycardia (stop with intravenous infusion of atropine 0.5-1.5 mg), nausea, vomiting (stop with phenothiazine derivatives, metoclopramide), respiratory depression. In case of respiratory failure, naloxone is prescribed intravenously at 0.1-0.2 mg, and if necessary, it is re-administered after 15 minutes.

• Sometimes neuroleptanalgesia is used - a combination of narcotic analgesics and antipsychotics (0.05 mg of fentanyl and 2.5 mg of droperidol).
• Less commonly, ataralgesia is used - a combination of narcotic analgesics and tranquilizers.
• If the anginal attack is not relieved by the above medicines, in rare cases, use means for inhalation anesthesia [dinitrogen oxide (nitrous oxide)].
• Other methods of pain relief (zpidural analgesia, electrical anesthesia) have not yet become widespread in the treatment of acute coronary syndrome with ST segment elevation.

- Thrombolytic therapy- the main pathogenetic method of treating myocardial infarction with ST segment elevation.

• Thrombolytic therapy is indicated for patients with pain or discomfort in the chest for more than 30 minutes, who do not stop after taking nitrates or at rest if the disease is less than 12 hours old and one of the following signs is present on the ECG:

Acute (or presumably acute) ST-segment elevation at point J in two or more adjacent leads, more than 0.2 mV (2 mm) in leads V1, V2, or V3, and more than 0.1 mV (1 mm) in the rest leads.

Acute left bundle branch block (or presumably acute), which complicates the analysis of the ST segment.

Depression of the ST segment in the anterior precordial leads in combination with a high R wave, suggesting the presence of a true posterior MI. In such cases, an ECG should be performed in additional precordial leads V7-V9.

• It is important to know and promptly assess the presence of contraindications to thrombolytic therapy:

Absolute:

History of hemorrhagic stroke or stroke of unknown etiology;

Ischemic stroke in the previous 6 months;

Lack of consciousness;

Dissection of the aortic wall;

Damage or neoplasms of the central nervous system;

Recent (in the previous 3 weeks) major trauma, surgery, or injury to the head;

Gastrointestinal bleeding in the previous month;

Hemorrhagic diathesis.

Relative:

Transient cerebrovascular accident in the previous month;

NACG treatment;

Pregnancy and the first week after delivery;

Function of non-compressible vessels, such as the subclavian vein;

Traumatic resuscitation measures;

Refractory severe hypertension;

Severe liver dysfunction;

Infective endocarditis;

The disease is in the acute phase.

• The maximum positive effect of thrombolytic therapy occurs in the first 3 hours from the onset of the disease, and especially during the first "golden" hour. The time from the moment of hospitalization to the start of thrombolytic therapy should not exceed 30 minutes.
• In the presence of standard indications for thrombolysis, the appointment of any of the thrombolytic drugs is indicated. The choice of a drug for thrombolysis depends on its availability and cost. The use of fibrin-specific drugs is always preferable. The scheme of administration and the main characteristics of thrombolytics are presented in table. 1.
• The main side effects of thrombolytic therapy are:

Bleeding.

Hemorrhagic stroke.

Fever.

Arterial hypotension.

Anaphylaxis.

Reperfusion arrhythmias.

• For bleeding caused by thrombolytics, fresh frozen plasma, protamine sulfate, platelet mass, cryoprecipitates are usually administered.
• It is possible to objectively judge the effectiveness of thrombolytic therapy using angiography, indirectly - on the basis of other methods.

With the help of CAG, it is possible to directly visualize the affected coronary artery and assess the degree of restoration of blood flow in it.

The most common and available indirect method is to assess the dynamics of the ST segment on an ECG. When coronary blood flow is restored, observe rapid decline the ST segment in the leads in which it was elevated. ECG is recorded 90 and 180 minutes after the start of thrombolytic therapy. A decrease in the ST segment by more than 50% from the initial level in the lead, where its rise was maximal, is considered a sign of reperfusion. If the ST segment decreases by the indicated amount before the initiation of thrombolytic therapy, spontaneous reperfusion can be assumed.

Others indirect sign reperfusion, there is a rapid dynamics of markers of myocardial necrosis.

Table 1

Comparative characteristics of thrombolytic drugs

- Anticoagulants.

UFH is prescribed when using fibrin-specific thrombolytics (alteplase, reteplase, tenecteplase). When using streptokinase, anticoagulants are not indicated. In addition, UFH is prescribed if thrombolytic therapy is not administered. The duration of therapy with this anticoagulant in these cases is 1-2 days. UFH is also used as an accompanying therapy in PTCA.

There are additional indications for the appointment of UFH: intracardiac thrombosis, severe heart failure, venous thrombosis, PE. In such cases, the duration of anticoagulant therapy can be increased.

UFH is used at a dose of 70 U / kg body weight intravenously as a bolus (but not more than 5000 U), then by intravenous infusion at a rate of 12-18 U / kg body weight per hour with maintaining APTT at a level of 50-70 s (at 1.5 -2 times the norm). When administered together with blockers of glycoprotein IIb / IIIa receptors, UFH is administered as a bolus at a dose of 60 U / kg of body weight, but not more than 4000 U, and the subsequent infusion is not performed.

• NMH. LMWH can be used as an alternative to UFH for MI. The efficacy and safety of two drugs from this group in the treatment of patients with acute coronary syndrome with ST-segment elevation has been proven.

Enoxaparin sodium is administered subcutaneously at a dose of 1 mg / kg of body weight every 12 hours. The duration of therapy is 3-5 days. In all patients receiving enoxaparin, renal function should be examined, and if signs of renal failure are detected, the dose of the drug should be reduced.

Reviparin sodium is prescribed subcutaneously 2 times a day for 7 days at 3436 IU for patients weighing less than 50 kg, 5153 IU for patients weighing 50-75 kg and 6871 IU for patients weighing more than 75 kg.

• Based on comparable clinical efficacy, it is preferable to use LMWH due to the simplified route of administration and the absence of the need for laboratory control. However, due to the higher risk of bleeding, LMWH is not recommended for patients over 75 years of age. With severe renal failure (the concentration of creatinine in the blood is more than 221 μmol / L in men and more than 177 μmol / L in women), it is better to refrain from prescribing LMWH.
• With anticoagulant therapy for more than 48 hours, platelet counts should be monitored daily due to the risk of thrombocytopenia.
• In patients with severe varicose veins of the lower extremities, a history of thrombophlebitis, severe heart failure, prolonged bed rest, prevent venous thrombosis and embolism:

UFH at 7500-12500 IU subcutaneously 2 times a day.

Enoxaparin sodium 40 mg subcutaneously 1 time per day or dalteparin sodium 5,000 IU subcutaneously 1 time per day.

• NACG.

NACT is prescribed in cases of need for long-term anticoagulant therapy.

LV thrombosis;

Constant atrial fibrillation;

CHF with an ejection fraction of less than 30%;

History of thromboembolism.

Usually, warfarin is given with an INR of 2 to 3 (target of 2.5). If patients receive acetylsalicylic acid and / or clopidogrel in the absence of these additional indications, NACG is usually not prescribed. There is evidence that prescribing warfarin to patients with ST-segment elevation acute coronary syndrome under 75 years of age in addition to acetylsalicylic acid or as monotherapy leads to a decrease in mortality and the incidence of strokes. However, due to the risk of bleeding, the need for constant laboratory monitoring, warfarin is rarely prescribed without special indications. In the presence of contraindications or intolerance to antiplatelet agents, NACG is indicated according to the usual scheme.

- Disaggregants.

• Acetylsalicylic acid (aspirin) is indicated for all patients with acute coronary syndrome with ST elevation in the absence of contraindications. Prescribing the drug is accompanied by a significant improvement in prognosis, a decrease in mortality and the risk of re-infarction. The initial dose is 250-500 mg, if the drug was not prescribed earlier. To accelerate the onset of action, as well as with severe nausea, diseases of the esophagus, stomach, it is possible to administer the drug intravenously at 300-500 mg or in the form of suppositories. The maintenance dose is 75-150 mg / day. Usually, an enteric-coated drug or "soft" form is used. After ulcerative bleeding, acetylsalicylic acid can be prescribed no earlier than 8 weeks later. If there is a history of peptic ulcer disease, proton pump inhibitors (omeprazole) are additionally indicated. There is no generally accepted point of view regarding the advisability of monitoring the effectiveness of acetylsalicylic acid therapy using aggregatometry.
• Clopidogrel is a thienopyridine that irreversibly inhibits platelet aggregation induced by ADP. The drug is indicated for all patients with ST-segment elevation acute coronary syndrome. Usually the loading dose is 300 mg orally, but if PTCA is planned in the next 2 hours, the dose is increased to 600 mg. The maintenance dose is 75 mg / day. Contraindications for the appointment of clopidogrel include confirmed hypersensitivity, active bleeding, exacerbation peptic ulcer and cerebral hemorrhage. Currently, the effectiveness of the use of clopidogrel during the period of hospitalization for acute coronary syndrome with ST segment elevation has been proven. If PTCA with stenting has been performed, especially with implantation of drug-eluting stents, clopidogrel should be taken for a year.
• Blockers of glycoprotein IIb / IIIa receptors (abciximab, tirofiban and others) were ineffective when used together with thrombolytics. Indications for use are limited to the planned TBCA in the case when clopidogrel is not prescribed or did not have time to act.

- Nitroglycerin.

• In patients with uncomplicated myocardial infarction, nitroglycerin therapy is not accompanied by an improvement in prognosis. However, it is customary to carry out infusion therapy with nitroglycerin for 12-24 hours in all patients with MI. Exists clinical indications, in which the appointment of nitrates is necessary: ​​persistent anginal attack, signs of heart failure, uncontrolled hypertension.
• With infusions longer than 24 hours, the likelihood of developing nitrate tolerance is high. To prevent it, they are prescribed intermittently in order to excrete during the day a period of time when nitrates do not work. The duration of such a period should be at least 10-12 hours.
• Basic by-effect- arterial hypotension, which usually goes away quickly after stopping the infusion. Quite often, a severe headache is noted, sometimes preventing the continuation of therapy.
• The initial nitroglycerin infusion rate should be 10 μg / min. Then the rate is increased by 10 μg / min every 3-5 minutes until blood pressure decreases or symptoms improve. Blood pressure should not be reduced below 100 mm Hg. in individuals with normal blood pressure or more than 25% of the baseline in patients with hypertension. Maximum dose(injection rate) of nitroglycerin is 200 μg / min.
• Do not use nitrates for RV MI.

- β-blockers.

- β-blockers are among the main drugs used in the treatment of acute coronary syndrome with ST segment elevation. It has been proven that they prevent dangerous rhythm disturbances, reduce the risk of MI recurrence, and have an anti-ischemic effect. The data on the effect on mortality in patients with acute coronary syndrome with ST-segment elevation are contradictory.

In the absence of contraindications, the appointment of β-blockers without intrinsic sympathomimetic activity is indicated for all patients with MI from the first hours of the disease. In patients with extensive myocardial infarction or with signs of heart failure, treatment with this group of drugs begins with intravenous administration... Usually propranolol, esmolol, metoprolol or atenolol are used for this purpose. If β-blockers cannot be prescribed on the first day of myocardial infarction, the possibility of their use in the future should be constantly evaluated.

• Propranolol is administered intravenously at 1 mg every 5-10 minutes, in a total dose of up to 6-10 mg (0.1 mg / kg of body weight). With good tolerance, after 1 hour, the drug is prescribed orally at 10-20 mg every 4 hours. daily dose reaches 480 mg.
• Metoprolol is administered intravenously at 5 mg with the possibility of re-administration after 5-10 minutes to a total dose of 15-20 mg. After 1 hour, the drug can be given orally at 25-50 mg every 6-8 hours. The maximum daily dose is up to 300 mg.
• Atenolol is prescribed intravenously at a dose of 5 mg with the possibility of re-administration after 5-10 minutes to a total dose of 15-20 mg. After 1 hour after taking the drug, they switch to taking the drug inside at 12.5-25 mg every 8-12 hours. The maximum daily dose should not exceed 200 mg.
• Esmolol is used as an intravenous infusion at a dose of 0.1 mg / kg of body weight per minute with an increase of 0.05 mg / kg of body weight per minute every 10-15 minutes until the desired therapeutic effect is achieved. The maximum dose is 0.3 mg / kg body weight per minute. Esmolol is referred to as ultra-short-acting drugs, and after the termination of the infusion, after a few minutes, its effect ceases. With unstable hemodynamics, esmolol is considered the drug of choice.

The principle of dosing β-blockers consists in the initial appointment of small doses followed by titration until the target heart rate at rest from 50 to 60 per minute is achieved. With a heart rate of less than 45 per minute, the dose of a β-blocker should be reduced.

In patients with heart failure and reduced LV ejection fraction, it is recommended to use the selective β-blocker bisoprolol (at a dose of 2.5-10 mg / day once) and carvedilol, which blocks α and β-adrenergic receptors (at a dose of 1.25-5 mg / day). once).

- β-blockers are contraindicated in severe bronchial asthma, allergic diseases, AV blockade II-III degree, sino-atrial blockade, sinus bradycardia, SBP less than 100 mm Hg, moderate and severe heart failure, P-Q interval more than 0.24 s, obstructive pulmonary diseases.

- ACE inhibitors are shown to all patients with acute coronary syndrome with ST segment elevation with anterior myocardial infarction, a pronounced decrease in LV contractile function (ejection fraction less than 40%), signs of heart failure, hypertension, diabetes mellitus, repeated heart attack.

- Long-term therapy with ACE inhibitors in such patients, it leads to a significant reduction in mortality, the risk of recurrent myocardial infarction, and cardiac decompensation. Most experts consider it advisable to prescribe ACE inhibitors to all patients with acute coronary syndrome with ST-segment elevation in the absence of contraindications, at least during the period of hospitalization.

• Start therapy with short-acting drugs (captopril 6-12 mg 3-4 times a day) or prescribe prolonged drugs (ramipril, lisinopril, zofenopril). To obtain the optimal therapeutic effect, the dose is gradually increased to the maximum tolerated.
• Contraindications for therapy with ACE inhibitors are arterial hypotension (SBP less than 100 mm Hg), severe renal failure, bilateral renal artery stenosis, individual intolerance. The most common side effects of ACE inhibitor therapy are hypotension and dry cough.

- Angiotensin II receptor blockers- an alternative to ACE inhibitors: they are prescribed for intolerance to ACE inhibitors (usually due to cough). The indications are the same as for ACE inhibitors.

- Aldosterone receptor blockers.

• Aldosterone receptor blockers are indicated for patients with severe systolic dysfunction(ejection fraction less than 40%), in need of constant therapy with diuretic drugs. Spironolactone is used (at a dose of 25-100 mg / day).
• Aldosterone receptor blockers are contraindicated in severe renal failure, hyperkalemia (more than 5 mmol / l). During treatment, there is a threat of hyperkalemia, therefore, careful monitoring of the concentration of this electrolyte in the blood is necessary.

- Statins. Patients with ST-segment elevation acute coronary syndrome are prescribed lipid-lowering therapy with statins during hospitalization. For the initial values ​​of the lipid content in the blood, the indicators obtained on the first day of the disease are taken, since in the following days the concentration of cholesterol may decrease due to the developed MI. The target content of total cholesterol is well below 4 mmol / l (160 mg / dl), and LDL - 2.6 mmol / l (100 mg / dl). It has been shown that a decrease in LDL concentration to 1.8 mmol / L (70 mg / dL) is accompanied by an additional improvement in prognosis. According to a large study, the administration of high doses of atorvastatin (80 mg / day) resulted in a 16% reduction in cardiovascular risk compared to the administration of standard doses (40 mg of pravastatin).

Shakhnovich R.M.

Acute coronary syndrome

For citation: Novikova N.A., Gilyarov M.Yu. Antithrombotic therapy in acute coronary syndrome with ST segment elevation // BC. 2008. No. 11. S. 1616

Currently, the occurrence of acute coronary syndrome (ACS) is usually considered within the framework of the concept of atherothrombosis. The pathogenesis of this condition is associated with the formation of an unstable atherosclerotic plaque, its subsequent rupture and the formation of a thrombus on the ulcerated surface, occluding the lumen of the vessel. According to coronary angiography, arterial thrombosis is detected in more than 90% of cases of ACS with ST segment elevation. These data determine the important role of agents affecting the hemostatic system in the treatment of patients with myocardial infarction.

Thrombolytic drugs
The experience of using thrombolytic therapy (TLT) for myocardial infarction (MI) goes back almost half a century. In 1958 A. P. Fletcher was the first to successfully administer streptokinase to a patient with MI. Further studies have demonstrated the benefits of this therapeutic approach in a large number of patients.
Drugs for TLT used at present do not directly destroy the fibrin clot, but act on it through the physiological system of fibrinolysis (Fig. 1). This system breaks down the strands of insoluble fibrin to soluble fragments, which leads to lysis of the thrombus. The physiological process of fibrinolysis is initiated by tissue plasminogen activators, which are secreted by endothelial cells. Plasminogen activators convert plasminogen to plasmin, a protein that directly degrades fibrin by hydrolysis. In addition to fibrin, plasmin is capable of destroying other components of the blood coagulation system, such as fibrinogen, factors V, VIII and XII, and prothrombin. Therefore, an increase in the level of plasmin not only lyses a thrombus, but also slows down thrombus formation.
Thrombolytic drugs affect the fibrinolysis system through various mechanisms. So, streptokinase forms a complex with plasminogen, as a result of which its active site opens. This site facilitates the transfer of other plasminogen molecules to plasmin. This leads to the appearance of streptokinase-plasmin complexes, which are resistant to the neutralizing effect of a2-antiplasmin and cause a fibrinolytic effect. In this case, the streptokinase-plasminogen complex approximately equally activates both the fibrin thrombus-bound and free plasminogen molecules circulating in the blood.
In contrast to streptokinase, recombinant tissue plasminogen activators are fibrin-specific agents, i.e., they directly promote the transition of fibrin-bound plasminogen to plasmin by cleaving the peptide bond.
Currently, four thrombolytic drugs are available on the domestic market: streptokinase, prourokinase, alteplase and tenecteplase.
Streptokinase
Streptokinase is a direct plasminogen activator. It is a single-chain polypeptide that does not contain carbohydrates, with a molecular weight of 47,000 D, which is produced from a culture of b-hemolytic group C streptococcus.
The half-life of streptokinase is 15-25 minutes. Streptokinase is obtained from the culture of bacteria, as a result of which it has antigenic properties. Antibodies against streptokinase are always found in human blood, which is associated with the high prevalence of streptococcal infections in the general population. Antistreptokinase antibody titers rise rapidly within a few days after administration and reach a peak within a few weeks. This peak can be 1000 times the baseline anti-streptokinase antibody titers. In some patients, the titers of antistreptokinase antibodies return to the initial level (before its administration) after 6 months, however, in many cases, the titers of these antibodies remain elevated in patients who received streptokinase 2-4 years ago, causing resistance to re-introduction drug, as well as allergic reactions.
In the treatment of acute myocardial infarction, streptokinase is usually prescribed in a dose of 1,500,000 U, which is diluted in 100 ml of isotonic sodium chloride solution or 5% glucose solution and injected over 60 minutes. With a more rapid introduction of 1,500,000 IU of the drug (in 30 minutes), the effectiveness of thrombolytic therapy, assessed by the frequency of patency of the infarction-associated coronary artery, increases, but the risk of hypotension increases significantly.
The effectiveness of streptokinase has been proven in several randomized trials (GISSI-1, ISAM, ISIS-2 and EMERAS). According to the meta-analysis of the Fibrinolytic Therapy Trialists Collaborative Group, the use of streptokinase in the first 6 hours after the onset of myocardial infarction saves 30 lives per 1000 patients, and if the drug is administered within 7 to 12 hours - 20 lives per 1000 patients.
Prourokinase
Prourokinase, or urokinase-type single-chain plasminogen activator, has a high specificity for fibrin-bound plasminogen (compared to strepto- and urokinase), as well as a longer half-life. Pro-urokinase predominantly activates fibrin-bound plasminogen, which has a different conformation compared to circulating plasminogen.
The first report on the use of prourokinase in humans was made by Van de Werf in 1986. In the following years, a number of large clinical studies were carried out with a drug obtained by genetic engineering methods using a native prourokinase molecule - saruplase (PASS, SESAM, COMPASS), which showed comparable to r- tPA efficiency.
Alteplaza
Tissue plasminogen activator (TAP), alteplase, is a serine protease with a molecular weight of 72,000 D, which is synthesized mainly by vascular endothelial cells. TAP is secreted into the bloodstream as a single-stranded molecule (molecular weight 70,000 D), which is converted into a double-stranded molecule under the action of plasmin, trypsin, kallikrein or factor Xa of the blood coagulation system. A unique property of TAP is its very high selectivity in relation to fibrin-bound plasminogen, which ensures its preferential activation on the surface of a fibrin thrombus. True, this selectivity is largely lost when TAP is used in therapeutic doses.
TAP does not possess antigenic properties and does not significantly affect hemodynamics; pyrogenic and allergic reactions in response to TAP administration are rare. For clinical use TAP is produced by DNA recombinant method.
For the treatment of acute MI, alteplase is usually prescribed in a total dose of 100-150 mg over 3 hours, with the first 6-10 mg of the drug being administered as a bolus over 2 minutes. Due to the fact that alteplase in a total dose of 150 mg often caused hemorrhagic complications, and 3-hour infusion too late led to recanalization of the infarction-associated coronary artery, in recent years, two new regimens for the administration of recombinant TAP have been proposed.
K. Neuhaus et al. (1989) proposed a scheme of "accelerated" administration of recombinant TAP: 100 mg for 90 minutes, with the first 15 mg of the drug being administered as a bolus, then starting the infusion (50 mg for 30 minutes and 35 mg for the remaining 60 minutes) ...
Another scheme for the administration of alteplase in the acute period of myocardial infarction was proposed by J. Puruis et al. (1994): the drug is administered as two 50 mg boluses with an interval of 30 minutes between boluses. With a bipolar regimen of recombinant TAP administration, 90-minute patency of the infarct-associated coronary artery was observed in 78 of 84 (93%) patients, with complete patency in 88% of cases.
At comparative assessment the effectiveness of streptokinase and alteplase in the GUSTO-I study, which involved more than 41 thousand patients, it was shown that with the use of alteplase, the 30-day mortality rate was 14% lower with a slightly higher incidence of hemorrhagic strokes.
Tenekteplaza
The drug tenecteplase, obtained using recombinant DNA technology, is the most successful attempt by scientists to improve natural human TAP by changing the structure of various regions of the complementary DNA molecule. As a result of structural modifications, a molecule with a longer plasma half-life, increased specificity for fibrin, and greater resistance to the first type of plasminogen activator inhibitor (PAI-1) compared to natural TAP was obtained.
The results of the multicenter randomized trials ASSENT-I and ASSENT-II, published in 1999, showed that both of these thrombolytic agents are equivalently highly effective when used in patients with myocardial infarction (MI). The undoubted advantage of tenecteplase when used in this category of patients is the improved safety profile of the drug and the possibility of its single bolus administration.
The effectiveness of TLT strongly depends on the time of its onset. The expansion of the zone of necrosis in myocardial infarction grows like an avalanche, therefore the statement is so true: "Time is the myocardium." The greatest number of lives can be saved at the onset of TLT within 1 hour from the onset of MI symptoms, which makes it especially important to conduct thrombolysis at the prehospital stage.
Acetylsalicylic acid
and clopidogrel
Acetylsalicylic acid (ASA) inhibits platelet aggregation by inhibiting cyclooxygenase and reducing the synthesis of thromboxane A2. Today, the effectiveness of ASA in patients with ACS with ST-segment elevation is beyond doubt. According to the ISIS-2 study, ASA administration reduced the relative risk of death by 23%, and in combination with thrombolytic therapy with streptokinase - by 42%. It should be noted that ASA showed the same efficacy as streptokinase when administered separately (Fig. 2).
According to a meta-analysis by Roux S. et al., Prescribing ASA after thrombolytic therapy reduces the risk of reocclusion (11% in the ASA group and 25% without it, p<0,001), частоту повторных эпизодов ишемии (25 и 41% соответственно, р<0,001). Эффект АСК был одинаковым как при проведении тромболитической терапии стрептокиназой, так и альтеплазой .
Another meta-analysis showed that the use of ASA as a means of secondary prevention can reduce the risk of recurrent myocardial infarction, stroke and cardiovascular death by 25%.
At present, it can be considered proven (and this is reflected in the recommendations for the treatment of ACS) that ASA should be prescribed to all patients with MI and who have no contraindications. It is recommended to chew ASA at a dose of 160-325 mg. In the future, the drug is prescribed at a dose of 75-325 mg / day. ...
Clopidogrel selectively and irreversibly blocks the binding of ADP to platelet receptors, inhibits their activation, reduces the number of functioning ADP receptors (without damage), prevents fibrinogen sorption and inhibits platelet aggregation. Clopidogrel is a prodrug, bio-trans-formed in the liver with the formation of an active metabolite.
In the recommendations for the diagnosis and treatment of ST-segment elevation ACS, the appointment of clopidogrel was considered as an alternative to ASA in case of its intolerance. However, since the publication of these recommendations, two large studies have been conducted: COMMIT-CCS-2 and CLARITY-TIMI-28, which evaluated the efficacy of dual antithrombotic therapy (ASA + clopidogrel) in patients with ST-segment elevation ACS.
The COMMIT-CCS-2 study included 45852 patients who received ASA 162 mg / day in addition to basic therapy. 75 mg of clopidogrel (no loading dose) for an average of 14.9 days. The incidence of the combined endpoint of death, recurrent MI, and stroke was 10.1% in the placebo group and 9.2% in the clopidogrel group (RR 0.91; 95% CI 0.86-0.97; p = 0.002). In the clopidogrel group, a decrease in overall mortality was also observed (7.5% and 8.1%, respectively, p = 0.03). The incidence of intracranial hemorrhage and bleeding did not differ significantly (0.55% in the placebo group and 0.58% in the clopidogrel group; p = 0.59). The effect of the appointment of clopidogrel was observed regardless of the conduct of thrombolytic therapy.
The CLARITY-TIMI-28 study included 3491 patients. Clopidogrel was administered once at a dose of 300 mg, followed by a dose of 75 mg / day. The primary endpoint included CAG occlusion of an infarct-associated artery, death, and recurrent myocardial infarction. In the clopidogrel group, the frequency of the primary endpoint was 15%, in the placebo group - 21.7% (OR 0.64; 95% CI 0.53-0.76; p<0,001). Следует отметить, что в исследование не включались пациенты, получившие дозу гепарина более 4000 ед. .
The data from these studies required a change in the existing recommendations for the diagnosis and treatment of patients with ACS with ST-segment elevation, and amendments to them were published in 2007.
Currently, the appointment of clopidogrel at a dose of 75 mg / day. recommended for all patients with ST-segment elevation ACS for at least 14 days, regardless of whether or not thrombolytic therapy was carried out (class I, level A). For patients under 75 years of age, regardless of thrombolytic therapy, it is recommended to prescribe a loading dose of clopidogrel 300 mg (class IIa, level C). Long-term therapy with clopidogrel (within a year) is advisable in patients with ACS with ST-segment elevation, regardless of reperfusion therapy (class IIa, level C).
Warfarin
The history of the use of warfarin in myocardial infarction has more than 50 years. Back in 1956, this drug was prescribed to US President D. Eisenhower.
Nevertheless, even today, the indications for long-term prescription of warfarin in patients after ACS with ST-segment elevation remain controversial.
Use of combination therapy with low-dose warfarin (INR<2,0) и низкими дозами АСК не влияло на частоту комбинированной конечной точки (смерть, повторный ИМ, инсульт). В исследование CARS было включено 8803 пациента, которые были раз-де-лены на 3 группы: получавшие 160 мг/сутки АСК, раз-лучавшие 3 мг/сут. варфарина + 80 мг/сутки АСК и получавшие 1 мг/сут. варфарина + 80 мг/сутки АСК. Средний срок наблюдения составил 14 месяцев. По результатам исследования не было получено преимуществ от добавления фиксированных низких доз варфарина к стандартной терапии АСК. Частота первичной конечной точ-ки составила 8,6, 8,4 и 8,8% соответственно .
In the LoWASA study, 1659 patients received 1.25 mg warfarin / day + 75 mg ASA. The control group, which received ASA at a dose of 75 mg / day, included 1641 patients. The observation period was 5 years. And in this study, the addition of low doses of warfarin did not lead to a decrease in the incidence of the combined endpoint (death, recurrent myocardial infarction, stroke), which was 28.1% and 28.8%, respectively.
Much more encouraging results were observed with moderate to intense anticoagulation. In the APRICOT II study, when warfarin was prescribed until an INR of 2.0-3.0 in combination with 80 mg of ASA compared with 80 mg of ASA, a lower incidence of reocclusions was observed (15 versus 28%, p<0,02) и на 23% (р<0,01) снижение относительного риска возникновения комбинированной конечной точки, включавшей смерть, ИМ и реваскуляризацию в группе пациентов, получавших комбинированную терапию .
The WARIS II study included 3630 patients who were divided into 3 groups: those who received warfarin until an INR of 2.8-4.2, warfarin up to an INR of 2.0-2.5 + ASA 75 mg and 160 mg ASA. The observation period was 4 years. Compared to ASA, patients in group 1 showed a decrease in the relative risk of a combined endpoint that included death, MI, and embolic stroke by 19% (p = 0.001), and in patients of group 2 - by 29% (p = 0 , 03). At the same time, there were no differences in survival, and the advantage was achieved due to a decrease in the frequency of MI and strokes. In addition, the warfarin group had a higher incidence of bleeding and about 35% of patients stopped taking warfarin.
The ASPECT study had a similar design and comparable results. The frequency of the combined endpoint (death, MI, stroke) in the group of high-intensity anticoagulation (INR 3.0-4.0) was 5%, in the group of combination therapy (INR 2.0-2.5 + ASA 81 mg) - 5% and in the ASA 81 mg group, 9%. But the combination therapy group had the highest incidence of minor bleeding (incidence of major bleeding did not differ between groups). At the same time, 20% of patients stopped taking warfarin and only 40% had a target level of anticoagulation.
Although in the above studies, moderate-intensity anticoagulation with warfarin in combination with ASA proved to be effective in reducing the risk of recurrent myocardial infarction and stroke, this was achieved with an increase in the frequency of bleeding. In addition, results were obtained among patients less than 75 years old. Another problem was the high withdrawal rate of warfarin and the difficulty in reaching the INR target values.
Currently, the appointment of warfarin in acute myocardial infarction is considered appropriate only in patients with a high risk of thromboembolic complications: with large anterior heart attacks, the presence of intracardiac thrombosis, episodes of thromboembolism in the pulmonary and pulmonary circulation, in the presence of atrial fibrillation and in patients with deep vein thrombosis of the lower limbs. Patients with these risk factors after heparin therapy are recommended to continue treatment with warfarin for the duration of their hospital stay. In the presence of an intracardiac thrombus, warfarin therapy is recommended to be continued for at least 3 months. With persistent atrial fibrillation, warfarin must be taken continuously. It is recommended to maintain the INR at a level of 2.0 to 3.0.
Unfractionated heparin
Thrombus formation on the surface of an unstable plaque plays a key role in the pathogenesis of ACS. Thrombolytic therapy removes the occlusion of the artery by dissolving the thrombus, however, it does not affect re-thrombus formation and, therefore, despite successful thrombolysis, there is a high chance of re-occlusion of the target vessel.
Unfractionated heparin (UFH) has been used in the treatment of MI for over 40 years. In patients receiving thrombolytic therapy, the use of UFH depends on the type of drug used. Nonspecific thrombolytic drugs (streptokinase, antistreplase and urokinase) reduce the coagulation potential by reducing the concentration of factors V and VIII and the formation of large amounts of fibrin degradation products. Because of this, the need for additional prescription of anticoagulants during their use is not so obvious.
These theoretical considerations are supported by evidence from studies that have not shown significant benefit from the addition of UFH. According to a meta-analysis by Collins et al. prescribing heparin after systemic thrombolysis with streptokinase saves 5 lives per 1000 treated patients at the cost of 3 bleeding per 1000 patients. Although the difference was statistically significant, the net effect was small. Therefore, in the current recommendations, the appointment of UFH after thrombolysis with streptokinase is indicated only in patients with a high risk of thromboembolic complications (with extensive anterior MI, atrial fibrillation, a history of thromboembolism, or the presence of an intracardiac thrombus).
Unlike streptokinase, fibrin-specific drugs (alteplase and tenecteplase) have a once-to-less pronounced effect on systemic coagulation, and after their use, the appointment of anticoagulants is required. UFH therapy begins with a bolus of 60 units / kg (but not more than 4000 units) followed by an infusion of 12 units / kg / hour (but not more than 1000 units / hour) until the activated partial thromboplastin time (APTT) increases by 1 , 5-2 times from the initial value (up to about 50-70 s). The duration of the infusion is at least 48 hours.
Bivalirudin can be used as an alternative if heparin is intolerant or if heparin-induced thrombocytopenia develops, but this drug is very expensive and is not available in our country.
Low molecular weight heparins
and fondaparinux
The need for long-term intravenous infusion and frequent monitoring of APTT makes the use of UFH rather inconvenient. Low molecular weight heparins (LMWH) are devoid of these disadvantages. Currently, as an alternative to UFH, it is proposed to use reviparin and enoxaparin or the synthetic inhibitor of factor Xa fondaparinux. The last two drugs are available in our country. Data on the effectiveness and safety of drugs are presented in Table 1.
After thrombolysis, enoxaparin was prescribed taking into account the patient's age and creatinine clearance. Pa-tsi-en-tam for less than 75 years, the drug was prescribed as an intravenous bolus of 30 mg, followed by subcutaneous administration of 1 mg / kg (no more than 120 mg) 2 times a day. In persons over 75 years old, the drug was prescribed only subcutaneously and in a reduced dose (0.75 mg / kg) 2 times a day. With a decrease in creatinine clearance, enoxaparin was administered at a dose of 1 mg / kg once a day. Patients with elevated creatinine levels (men over 2.5 mg% and women over 2.0 mg%) are not prescribed enoxaparin.
Fondaparinux is prescribed for patients with creatinine levels below 3.0 mg% at a dose of 2.5 mg IV followed by subcutaneous administration of 2.5 mg once a day. The duration of therapy with enoxaparin and fondaparinux is 2 to 8 days. Both drugs are recommended for use in the latest revision of the ACC / AHA guidelines, with the highest grade and level of evidence (IA).
Both drugs are indicated for patients with ACS with ST-segment elevation and in the absence of thrombolytic therapy.
Inhibitors of IIb / IIIa receptors
platelets
This group of drugs, as shown in a number of studies, does not have reperfusion activity. But they can be used in combination with fibrin-specific thrombolytics, and the latter are used in half the dose. Thus, the GUSTO-V study compared the use of a full dose of reteplase and a combination therapy in the form of a half dose of reteplase and a full dose of abciximab during the first 6 hours from the development of MI. Mortality did not differ significantly in both subgroups (5.6% and 5.9%, respectively), but in the combination therapy group there was a lower incidence of recurrent heart attacks and complications of myocardial infarction. At the same time, the frequency of bleeding increased significantly with the use of combination therapy (4.6 versus 2.3%; p = 0.001), especially in the group of patients over 75 years old. In the same age group, the frequency of intracranial hemorrhages also increased. Similar results were obtained with the combination of ab-cic-simab with a half-dose of tenecteplase in the ASSENT-3 study. Thus, such an approach has the right to exist in people less than 75 years old, especially in those who are planning to undergo percutaneous coronary intervention.
In our country, there are no foreign inhibitors of IIb / IIIa receptors, but there is a domestic drug from this group - monofram, developed by specialists from the RKNPK. Currently, there is no data on the combined use of monofram and thrombolytics, but it is known that the drug has demonstrated high efficiency in performing percutaneous interventions on the coronary arteries in high-risk patients.
Conclusion
In recent years, antithrombotic therapy in patients with ST-segment elevation ACS has become increasingly aggressive. Thienopyridines, LMWH, fondaparinux have been introduced into current clinical practice as mandatory thrombolytic agents. The number of intracoronary interventions is growing, which requires special regimens of antithrombotic therapy. At the same time, thrombolytic therapy is still insufficiently used in our country, which in the early period of myocardial infarction is comparable in efficiency with angioplasty.
Not far off is the appearance on the market of new agents affecting hemostasis - prasugrel, indraparinux and, possibly, direct thrombin inhibitors, in particular dabigatran. The introduction into practice of oral factor Xa inhibitors - rivaroxaban and apixaban - is also possible. Their efficacy and safety are subject to evaluation in forthcoming clinical trials.

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