A method for assessing the effectiveness of thrombolytic therapy in patients with acute coronary syndrome (medical technology). Modern problems of science and education Complications of thrombolytic therapy for acute

Keywords: acute coronary syndrome, antithrombotic agents, antiplatelet agents

INTRODUCTION AND DEFINITIONS.

Unstable angina and myocardial infarction are forms of coronary heart disease that require emergency care to prevent dangerous complications, incl. fatal. Usually, although not always, the cause of the development of these conditions is rupture of an atherosclerotic plaque or erosion of the endothelium, followed by coronary artery thrombosis and the development of acute ischemia. As numerous studies have shown, the earlier the necessary treatment is started, the greater the hope for a favorable prognosis for a particular patient. Hence, special attention is paid 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, ACS is any combination of clinical symptoms or signs that suggest myocardial infarction (MI) or unstable angina (UA). Includes MI (with or without persistent ST elevation, diagnosed by changes in enzymes or biomarkers, by late ECG signs) and UA (Fig. 1).

The term ACS was introduced in connection with:

· with the need to start treatment before a final diagnosis of the listed conditions is established;
· used to refer to patients upon first contact, and
· implies the need for their management as patients with MI or NS.

Since at the preliminary stage of diagnosis it is not always possible to differentiate between NS and MI, as well as other diseases with a similar clinical picture, it is advisable to distinguish PROBABLE ACS as a preliminary diagnosis in case of emergency hospitalization of the patient, and PRESUMED ACS as a secondary diagnosis in the case of a more probable the reason for the visit is another disease, but ACS has not yet been ruled out.

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

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

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

Sick with ACS without persistent ST elevation- 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 experience persistent or transient ST depression, inversion, flattening, or pseudonormalization of the T wave, although some patients may have a normal ECG on admission. Thrombolytic agents are not used in the treatment of such patients due to unproven effectiveness. The main objectives of treatment are to maintain the patency of the coronary artery by limiting and preventing intracoronary thrombus formation and distal thromboembolism, eliminating ischemia (conservatively or surgically - PCI). The outcome of ACS without ST elevation can be UA 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) based on clinical signs is established based on typical changes in biochemical markers of myocardial necrosis(a rise and gradual decline in troponin levels or a more rapid rise and fall in CPK-MB levels), in combination with at least one of the following:

(a) ischemic symptoms;
(b) 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).

Sustained ST elevation MI (STEMI)- “new” or presumed “new” persistent ST segment elevation in two or more contiguous 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 (STEMI)- “new” or presumably “new” ST segment depression or only T wave changes (symmetrical inversion of 0.1 mV or more) in 2 or more adjacent leads in combination with ischemic symptoms in the form of chest discomfort (pain) or clinical equivalents in the form:

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

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

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

Unstable angina unlike STEMI, ST is not accompanied by significant changes in markers of myocardial necrosis. It provides:

Angina pectoris that occurs at rest and prolonged (usually more than 20 minutes);
-new angina at a level of at least FC 3;
- progressive angina, in the form of its increase from 1 FC to at least 3 FC.

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

The goal of treatment for ACS 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 common pathogenesis of ACS, the main directions of their drug therapy should be considered:

· lysis of a thrombus obstructing a 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 secondary prevention of MI

The main groups of pharmacological agents used in the treatment of ACS are antithrombotic agents, antianginal agents, as well as drugs from other groups.

DRUGS USED IN THE TREATMENT OF ACS:

1. Antithrombotic agents:

2. Antianginal agents:

3. Other means:

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

Antithrombotic agents

Antithrombotics are intended to prevent or limit thrombosis, as well as to destroy the resulting blood clot. 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 in each group, it is necessary to briefly dwell on the main stages and mechanisms of blood coagulation.

Hemostasis is achieved 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 shed blood, but most importantly, 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 the surface and phospholipid components for the formation of enzyme-cofactor complexes in the next stage of coagulation. The interaction of plasma clotting factors leads to the completion of thrombus formation by reinforcing it with fibrin threads. A typical arterial intracoronary stenotic thrombus consists of a white head (platelet clot at the site of endothelial damage) and a red tail due to blood stasis.

Platelet hemostasis includes 2 stages: adhesion (sticking) of platelets to the exposed collagen of the vascular wall (via von Willebrand factor with the help of Ib receptors, as well as Ia receptors) and their subsequent aggregation (through the binding of IIb and IIIa platelet receptors to fibrinogen molecules and other adhesive 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 using the enzyme cyclooxygenase (inhibited by aspirin).

The “plasma” stage of coagulation can be initiated in 2 ways: by an internal mechanism, activated by the blood’s own coagulation factors upon contact with the negatively charged surface of platelets, and by an external mechanism, activated by tissue thromboplastin, which appears in the circulating blood only when the vessel is damaged.

Figure 2
MAIN POINTS OF ACTION OF THE MAIN ANTITHROMBOTIC DRUGS

What is 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 into thrombin (factor II) on the surface of platelets, which, in turn, converts fibrinogen into fibrin ( factor I) and activates fibrin-stabilizing factor (factor XIII).

In the internal coagulation pathway, factor X is activated through the sequential activation of factors XII (in the presence of high molecular weight kininogen and prekallikrein), XI and IX, under the action of a complex consisting of activated factors IX, VIII, procoagulant phospholipid and calcium ions. In the extrinsic coagulation pathway, factor X is converted to its active form by activated factor VII in combination with tissue thromboplastin.

Plasma coagulation inhibitors are: tissue factor pathway inhibitor - TFPI (inhibits Xa, as well as the VIIa + tissue thromboplastin complex), antithrombin 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 atherosclerosis of the coronary arteries is closely associated with thrombosis. It is known that thrombotic occlusion of an artery develops only in the area of ​​atherosclerotic plaque (usually due to its rupture or dissection). Therefore, antithrombotic drugs occupy a central place in the prevention and treatment of complications of coronary artery disease.

Antiplatelet agents (antiplatelet agents)

Accumulated evidence suggests 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 blood platelets are involved in the development of the atherosclerotic plaque itself by stimulating the proliferation of smooth muscle cells (platelet-derived 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 effective against damage to both the coronary and cerebral and peripheral arteries. These drugs reduce the functional activity of platelets, primarily their ability to aggregate. Blockade of aggregation can be achieved by inhibiting the effects of thromboxane A 2 (aspirin), ADP (thienopyridines) or neutralizing the IIb/IIIa glycoprotein platelet receptors themselves (absiximab, etc.).

ANTIPLATELET DRUGS (ANTIPLATELANTS):

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) adenylate cyclase stimulators
iloprost

ADP receptor blockers (thienopyridines):

Ticlopidine; clopidogrel

Antagonists of IIb/IIIa glycoprotein platelet receptors:

Abciximab; eptifibatide, tirofiban, lamifiban

In the complex treatment of ACS, only a limited list of antiplatelet drugs is actively used: these are cyclooxygenase inhibitor - acetylsalicylic acid, ADP receptor blockers thienopyridines - clopidogrel and ticlopidine, as well as antagonists of IIb / IIIa glycoprotein receptors - asciximab, eptifibatide and tirofiban.

Dipyridamole and prostacyclin analogues were ineffective in the treatment of ACS, and thromboxane blockers showed no advantage over aspirin.

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

· antiplatelet agents are the cornerstone in the treatment of acute coronary syndromes, and, therefore, an essential component of therapy;

· they should be prescribed as early as possible, with treatment starting with loading doses;

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

· antiplatelet agents are usually combined with the administration of heparin or its low molecular weight fractions;

· with conservative tactics of administering OCS, 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 consideration of the possible risk of bleeding.

Acetylsalicylic acid (Aspirin, Akuprin, 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 endothelial production of the antiplatelet agent and vasodilator prostacyclin, which serves as 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 effect of ASA begins within 5 minutes after oral administration and reaches a maximum after 30-60 minutes, remaining stable over the next 24 hours. To restore the functional state of platelets, it takes at least 72 hours after a single dose of small doses of ASA.

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. By continuing to take aspirin after stabilization of the patient's condition, a long-term preventive effect is achieved.

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

Indications: treatment of ACS; secondary prevention of MI; prevention of thrombosis and reocclusion after CABG, PCI, peripheral artery grafting; prevention of thromboembolism in the chronic form of atrial fibrillation, after heart valve replacement, in transient cerebral ischemia, and peripheral vascular diseases.

Contraindications: intolerance to ASA, severe allergies in the form of bronchospasm attacks (including bronchial asthma combined with rhinosinusopathy - “aspirin asthma”); hemophilia and thrombocytopenia; active bleeding, incl. retinal hemorrhages; erosive and ulcerative processes in the gastrointestinal tract or other sources of bleeding from the gastrointestinal tract or urinary tract; severe uncontrolled hypertension; severe renal and liver failure.

Application for ACS: if the patient did not take ASA before admission, the first dose of the drug (325-500 mg) should be chewed in the mouth (regular, not enteric aspirin is used). Maintenance dose - 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 were used. The advantages of enteric forms of ASA over conventional ones in terms of the frequency of hemorrhagic complications have not been proven.

There are indications that some patients may be aspirin resistant, 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 platelet glycoprotein receptors IIb/IIIa).

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

Drug interactions: weakening of the effect of antihypertensive and diuretic drugs, increased risk of bleeding when prescribed with indirect anticoagulants, other NSAIDs, potentiation of the effect of hypoglycemic drugs, etc.

Ticlopidine (Tiklid, Tiklin)

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

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

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

Pharmacokinetics: The bioavailability of ticlopidine is 80-90% (increases when taken after meals), and the maximum concentration in plasma 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 use of the drug. A stable concentration of the drug in plasma is created in the 2-3rd week of treatment. Metabolism of the drug occurs in the liver, excretion of metabolites is carried out in the urine, and part of the drug is excreted unchanged in the bile.

Indications: secondary prevention of MI; prevention of thrombosis and reocclusion after PCI, CABG; treatment of ACS; 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 indications of them in the anamnesis); severe liver failure; age under 18 years; pregnancy and breastfeeding; hypersensitivity to the drug.

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

Side effects: occur in half of the patients, these are dyspepsia (30-40%), bleeding (the drug is discontinued 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 dysfunction, hemolysis, dizziness, headache, tinnitus.

Clopidogrel (Plavix)

Pharmacodynamics: Clopidogrel, a member of the thienopyridine group, inhibits platelet aggregation by irreversibly and selectively blocking their ADP receptors.

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

According to the large CAPRIE trial, 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.

Compared to ticlopidine, the onset of action is faster and tolerability 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 ACS without ST elevation than aspirin monotherapy. 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 feces.

Indications: treatment of ACS; secondary prevention of myocardial infarction, stroke, peripheral artery 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 a patient is scheduled to undergo CABG (but not PCI), clopidogrel is not prescribed or is discontinued 5, or preferably 7, days before surgery 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 prescribed with ASA and NSAIDs

Abciximab (Abciximab, ReoPro)

Pharmacodynamics: Abciximab (AB) is a representative of the group of antagonists of glycoprotein IIb/IIIa platelet receptors. IIb/IIIa receptors (alpha IIb beta 3 integrins) are located on the surface of blood 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 the 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 receptors of platelets 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, a gradual (within 1-2 days) restoration of the aggregation ability of blood platelets occurs.

AB is a nonspecific ligand; it also blocks vitronectin receptors of endothelial cells 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 drug's ability to significantly improve the prognosis in patients undergoing PCI, primarily in patients with ACS, as well as in patients at high risk of cardiovascular complications, has been proven.

The effectiveness of AB in the conservative treatment of ACS has not been proven (unlike eptifibatide and tirofiban). The possibilities of combining the drug and other antagonists of glycoprotein IIb/IIIa receptors with thrombolytics in the treatment of ACS with ST elevation are being studied.

Pharmacokinetics: With intravenous administration, a stable concentration of AB is maintained only by continuous infusion; after its cessation, it decreases quickly within 6 hours and then slowly (over 10-14 days) due to the fraction of the drug associated with platelets. Excretion of the drug occurs 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 patients at high risk.

Contraindications: Internal bleeding; history of gastrointestinal bleeding (within the last 6 weeks); cerebrovascular accident (including 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 a low level of 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 administered after the operation. Coagulation monitoring is carried out initially, every 15-30 minutes during angioplasty and every 12 hours until the catheters are removed. Evaluated indicators: activated blood clotting time (at the level of 300-350 s), hemoglobin content, hematocrit, platelet count.

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

Eptifibatide (Integrilin)

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

The effect of Ep occurs immediately after intravenous administration at a dose of 180 mcg/kg. The suppression of aggregation is reversible. 4 hours after stopping the IV infusion at a dose of 2 mcg/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 in recommended doses is linear, and the maximum concentration is achieved quickly. The degree of protein binding is 25%. The half-life is 2.5 hours. Approximately 50% of the drug is excreted in the urine.

Indications: Prevention of thrombosis and reocclusion in connection with PCI (including stent installation); acute coronary syndrome without ST elevation (in combination with ASA, UFH or LMWH, and also 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) during antihypertensive therapy; major surgery within the last 6 weeks; history of stroke within the previous 30 days or hemorrhagic stroke; dependence on hemodialysis due to renal failure; simultaneous use of another IIb/IIIa platelet receptor inhibitor for parenteral administration; hypersensitivity to the drug.

Application for ACS: IV bolus bolus at a dose of 180 mcg/kg over 1-2 minutes, then drip administration at a dose of 2 mcg/kg/min (with serum creatinine levels 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, treatment time can be increased to a maximum of 96 hours. If PCI is planned, EP is started immediately before surgery and continued for at least 12 hours. The activated clotting time must be controlled at 200-300 s.

Side effects: mostly bleeding.

Anticoagulants

The purpose of anticoagulant therapy is to inhibit plasma clotting factors to prevent the formation or limit the spread of blood clots. These agents 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

1) Basic and clinical pharmacology / Sub. ed. B.G. Katsunga. Per. from English edited by E.E. Zwartau: In 2 volumes. - M.: Binom - St. Petersburg: Nevsky Dialect, 1998. - T.2. - P.26-43.

2) Metelitsa V.I. Handbook of clinical pharmacology of cardiovascular drugs. - 2nd ed., revised. and additional - M.: BINOM Publishing House - St. Petersburg: Nevsky Dialect, 2002. - 926 p.

3) Register of Medicines of Russia. Encyclopedia of drugs. M.: RLS, 2004. - 1497 p.

6) Ruksin V.V. Emergency cardiology. - 4th ed., revised. and additional St. Petersburg: "Nevsky Dialect", 2000. - 503 p.

7) Vidal reference book. Medicines in Russia: Directory. M.: AstraPharmServis, 2003. - 1488 p.

8) Alpert J.C. and Thygesen K., et al. Myocardial Infarction Redefined - A Consensus Document of The Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. The Joint European Society of Cardiology/American College of Cardiology Committee. // JACC. - 2000. - Vol.36, No. 3. - P.959-969.

9) Antman E.M. et al. ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction-Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction) // JACC. - 2004. - Vol. 44, No. 3. - P. 671-719.

10) Bertrand M.E. et al. Management of acute coronary syndromes in patients presenting without persistent ST segment elevation. The Task Force on Management of acute coronary syndromes of the European Society of Cardiology. // Eur Heart Journal. - 2002. - Vol.23. - P.1809-1840.

11) Braunwald E. et al. ACC/AHA Guidelines for the Management of Patients With Unstable Angina and 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.

12) Braunwald E. et al. ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction-Summary Article 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) // JACC. - 2002. -Vol. 40, no. 7. - P.1366-1374.

13) Management of acute coronary syndromes: acute coronary syndromes without persistent ST segment elevation. Recommendations of the Task Force of the European Society of Cardiology. // Eur Heart Journal. - 2000. - Vol.21. - P.1406-1432.

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 pale skin. In 15-20% of patients, an atypical clinical course of the syndrome is observed. For diagnosis, cardiac-specific enzymes are analyzed and an ECG is recorded. Drug treatment involves the use of thrombolytics, antiplatelet agents and anticoagulants, and 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 that 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 a final diagnosis. ACS and its complications rank first (about 48%) among all causes of mortality in the adult population. An emergency condition in men under 60 years of age is identified 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 included in acute coronary syndrome have common etiological factors. The main cause of the disease is coronary thrombosis, which occurs when an atherosclerotic plaque erodes or ruptures (atherothrombosis). Occlusion of the coronary artery by a thrombus occurs in 98% of patients with the identified clinical picture of ACS. With thrombosis, the development of coronary syndrome is associated both with mechanical blockage of the artery and with the release of specific vasoconstrictor factors.

Another etiology of the acute process is determined extremely rarely (about 2% of cases). The appearance of ACS is possible with thromboembolism or fat embolism of the coronary artery. Even less commonly diagnosed is transient spasm of the coronary arteries - variant Prinzmetal angina.

Risk factors

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

• Non-modifiable factors: male gender, old age, hereditary predisposition;
• Adjustable factors: excess body weight, bad habits, physical inactivity.

The greatest danger from the premises is arterial hypertension. High blood pressure contributes to earlier onset and rapid 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 need of muscle fibers for oxygen and the flow of arterial blood is disrupted. In acute coronary syndrome, transient or persistent ischemia occurs, which, as it progresses, causes organic changes in the myocardium (necrosis, dystrophy).

When the fibrous cover of an atherosclerotic plaque ruptures, platelets and fibrin threads are deposited - a blood clot is formed that blocks the lumen of the vessel. In the pathogenesis of the syndrome, a significant role is played by hemostatic disorders, which cause the formation of microthrombi in the vessels supplying the myocardium. Severe clinical symptoms are observed when the lumen of the coronary artery is narrowed by no less than 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 diagnosed twice as often in men. Patients over 50 years of age usually 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 manifestation of the syndrome. Due to the replacement of a section of muscle fibers with connective tissue, there is a possibility of developing chronic heart failure and cardiac aneurysm. When the body is sensitized by autolysis products, Dressler 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 exclude noncardiac causes of pain and cardiac pathologies of non-ischemic origin. To differentiate different variants of coronary syndrome and select treatment tactics, three main studies are carried out:

• Electrocardiography. The “gold standard” for diagnosis is considered to be recording an ECG within 10 minutes of the onset of an acute attack. Coronary syndrome is characterized by ST elevation of more than 0.2-0.25 mV or its depression in the precordial leads. The first sign of myocardial ischemia is a pointed, tall T wave.
• Biochemical markers. To exclude a heart attack, the content of cardiac-specific enzymes - troponins I and T, creatine phosphokinase-MB - is analyzed. The earliest marker is myoglobin, which increases already in the first hours of the disease.
• Coronary angiography. An invasive method for studying the coronary vessels is used after identifying ST segment elevation on the cardiogram. Coronary angiography is used in 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 diagnosed with 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 the great vessels.

Treatment of acute coronary syndrome

Conservative therapy

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

Patients who do not have persistent ST elevation are prescribed combination drug therapy without thrombolytics. Nitrates are used to stop an attack. 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 drugs are recommended:

• Antiplatelet agents. To prevent thrombosis, take drugs based on acetylsalicylic acid or thienopyridine derivatives. After the initial loading doses, they switch to long-term medication in average therapeutic dosages. In the first 2-5 days, the regimen is supplemented with anticoagulants.
• Anti-ischemic drugs. To improve 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 reduce the level of total cholesterol and atherogenic LDL in the blood. Therapy reduces the risk of recurrent acute coronary syndrome, significantly improves the prognosis, and prolongs the life of patients.

Surgery

Myocardial revascularization is effective for 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 bypass surgery is indicated.

Prognosis and prevention

Timely initiation of intensive therapy significantly reduces the risk of early and late complications and reduces the mortality rate. The prognosis is determined by the clinical variant of acute coronary syndrome and the presence of concomitant cardiac diseases. In 70-80% of patients, a low or medium risk level is established before discharge, which corresponds to preserved left ventricular function.

Nonspecific prevention of the disease includes modification of risk factors - normalization of body weight, abandonment of bad habits and fatty foods. Drug prevention of recurrent episodes of ACS includes long-term (more than 12 months) antiplatelet therapy and lipid-lowering drugs. Patients who have suffered acute coronary syndrome are monitored by a cardiologist.

Owing to adverse influences of factors of environment at world level are widespread neurotouch relative deafness. In this connection topical issues of their early identification and carrying out preventive actions.

Key words: environment, neurotouch relative deafness, prevention

UDC 616.127.005.8-085

THROMBOLYTIC THERAPY IN PATIENTS WITH ACUTE CORONARY SYNDROME WITH ST Elevation

G.K. Asanova

South Kazakhstan State Pharmaceutical Academy, Shymkent

The most important treatment strategy for patients with acute coronary syndrome with ST elevation is pharmacological reperfusion using thrombolytic drugs. Thrombolytic therapy should be aimed at quickly restoring the patency of the infarct-related artery, as well as combating coronary artery reocclusion.

Key words: acute coronary syndrome, pharmacological reperfusion, thrombolytic therapy, alteplase

Acute coronary syndrome (ACS) is a period of exacerbation of coronary heart disease (CHD). As is known, the course of atherosclerotic arterial lesions is characterized by alternating stable and unstable phases. The term was introduced into clinical practice due to the need for emergency interventions at an early stage of an acute disease, before an accurate diagnosis has been established, the presence or absence of myocardial infarction. The term “acute coronary syndrome” was introduced into medical practice by the New Zealand clinician Harvey White in 1996-1997. . According to the definition of experts from the European Society of Cardiology (ESC) and the American College of Cardiology, acute coronary syndrome is a combination of clinical signs or symptoms suggestive of acute myocardial infarction (AMI) or unstable angina.

The common pathophysiological substrate of acute coronary syndrome, which is based on myocardial ischemia, is the destruction of unstable plaques. The determining factor in the development of one or another variant of ACS is the quantitative characteristics of the thrombus formation process - the degree and

duration of coronary artery occlusion. The process of development of atherosclerotic plaque is initiated by endothelial dysfunction, which promotes the migration of monocytes into the vascular intima; monocytes that penetrate the vascular intima are transformed into macrophages, which, with the help of receptors, absorb lipoproteins. Macrophages overloaded with lipids turn into foam cells. Foam cells for the most part remain in the intima of the arteries and die, undergoing apoptosis - programmed cell death and destruction of the cell membrane. In this case, the cholesterol esters, non-esterified cholesterol and cholesterol monohydrate crystals accumulated in the foam cells are released. These processes lead to focal accumulations of cholesterol in the intima of the arteries and create the preconditions for the development of lipid spots, then lipid streaks and subsequently atherosclerotic plaques. In addition to macrophages, high-density lipoproteins, which provide reverse cholesterol transport, participate in the removal of cholesterol from the affected intima. If the intake of lipoproteins into the intima prevails over the excretion, the lipids accumulate and form the lipid core of the atherosclerotic plaque. The further development of atherosclerotic lesions is characterized by the migration of smooth muscle cells into the intima and their proliferation, the proliferation of connective tissue and the formation of fibroatheroma. An atherosclerotic plaque at this stage has a lipid core and a fibrous membrane. As the atherosclerotic lesion progresses, microvessels begin to grow into the plaque, forming a vascular network. The microvascular network can contribute to the development of various complications; vessels can easily rupture, leading to hemorrhage and blood clots. Thrombosis is preceded by cracks, tears, ruptures of the fibrous cap and a complicated atherosclerotic plaque becomes a source of embolism in various arteries. According to the clinical course and dynamics of changes in the ECG, acute coronary syndrome is divided into ACS with ST elevation (ACSpST) when ST segment elevation is detected in at least two consecutive leads and ACS without ST elevation in the absence of ST segment elevation. ACS with persistent ST segment elevation (more than 20 minutes) or “new” (new left bundle branch block) on the ECG in patients with anginal pain or discomfort in the chest reflects the presence of acute complete occlusion of the coronary artery and in most cases leads to development of myocardial infarction with ST elevation. In this case, the goal of treatment is to achieve complete and sustained myocardial reperfusion through primary coronary intervention or fibrinolytic therapy.

Thrombolytic therapy (TLT) is an important part of restoring coronary blood flow, especially in cases where primary percutaneous coronary intervention (PCI) is not possible. In the development of thrombolytic therapy

Occupational hygiene and medical ecology. №2 (47), 2015

PPI for myocardial infarction was made by scientists of the Soviet school E.I. Chazov, G.V. Andreenko, V.M. Panchenko.

Studies by DeWood et al. in 1980, Rentrop et al. in 1979. with the widespread use of coronary angiography, as well as the morphological work of Falk and Davies in 1983. , which convincingly showed that the cause of developing myocardial infarction (MI) is intracoronary thrombosis, which usually occurs at the site of an existing atherosclerotic plaque with a damaged surface during AMI, played a decisive role in the development of TLT. Based on the results of these works, two large multicenter studies were carried out, which became classic, since it was with their help that it was proven

effectiveness of TLT to reduce mortality in MI. One of them is GISSI___1

(Gruppo Italiano per lo Studio della Streptochinasi ne nell’Infarto miocardico) - was performed in Italy and published in 1986; the second - ISIS-2 (Second International Study of Infarct Survival) - was international, and its results became available in 1988. .

The opinions of scientists on the question of which method of emergency care for ACS is better: invasive or drug-based, differ; percutaneous coronary angioplasty followed by stenting when urgently performing these manipulations is considered the most effective way to help with MI.

The possibilities of modern pharmacotherapy for MI have been studied quite well, since this problem is very relevant. A significant reduction in mortality during prehospital TLT in the first 2 hours was shown by meta-analyses of previous studies, confirmed by data from registries conducted in European countries and analyzes of several recent randomized trials. With an adequate choice of components of thrombolytic therapy, the effectiveness of drug treatment is not inferior to the effectiveness of coronary interventions. Thrombolytic therapy is recommended for patients with ST elevation ACS without contraindications within 12 hours of symptom onset if primary PCI cannot be performed within 120 minutes of first medical contact. The timing of treatment initiation is a decisive factor in the effectiveness of thrombolysis. When performing TLT in the early stages, the best effect of restoring coronary circulation is achieved, which justifies the need and advantage of TLT on the prehospital effect.

Since the early 90s, TLT has been included in the list of mandatory measures for AMI. To dissolve a thrombus occluding an artery, fibrinolytic drugs are used, to maintain the patency of the coronary artery, various classes of antithrombotic agents are used: drugs that inhibit platelet function, as well as the formation and inactivation of the key coagulation enzyme - thrombin.

Occupational hygiene and medical ecology. №2 (47), 2015

Modern thrombolytic drugs are plasminogen activators that promote the transition of plasminogen to plasmin, an active protease that can break down fibrin into small fragments that are excreted from the body by the organs of the reticuloendothelial system. It has now been established that the effectiveness of thrombolysis depends on the speed of its implementation in relation to the onset of MI symptoms. The advantages of early thrombolysis are unconditional, as it helps reduce mortality, and in 40% it interrupts the development of MI. Early thrombolysis prevents irreversible damage, the development of myocardial dysfunction and sudden death, most of which occur in the first hours of myocardial infarction. Therefore, the first hour from the onset of MI symptoms is called the “golden” hour for thrombolysis.

The effectiveness of thrombolysis is greater in the most severe patients with MI and increases in proportion to the increase in the risk of death. With the undoubted advantage of early thrombolysis, late thrombolysis performed with streptokinase in the first 12-24 hours from the onset of MI symptoms can also reduce mortality over 5 weeks of observation by 19% (ISIS-2). According to the LATE (Late Assessment of Thrombolytic Efficacy) study, late thrombolysis with tissue plasminogen activator (tPA) reduced mortality by 27% at 35 days of follow-up. Among the possible mechanisms of the positive effect of late thrombolysis, the impact on the electrical stability of the myocardium, the mechanisms of left ventricular remodeling and the occurrence of arrhythmias are considered.

A serious problem of thrombolytic therapy is hemorrhagic complications - their frequency averages about 0.7%, with 0.4% accounting for the most serious complications - hemorrhagic strokes. Age over 65 years, body weight less than 70 kg, systolic and diastolic arterial hypertension, and a history of cerebral vascular pathology are reliable risk factors for hemorrhagic stroke. Contraindications to thrombolysis are divided into absolute and relative. Absolute cases include stroke, bleeding from the gastrointestinal tract in the previous month, episodes of hemorrhagic diathesis in history, trauma or major surgery undergone in the previous 3 weeks, puncture of large non-compressible vessels, dissecting aortic aneurysm. Relative ones include transient cerebrovascular accident in the previous 6 months, therapy with indirect anticoagulants, pregnancy, trauma after resuscitation, refractory arterial hypertension (systolic blood pressure above 180 mm Hg), progressive liver disease and infective endocarditis.

The most studied and used thrombolytics are streptokinase and al-teplase, tissue plasminogen activator. Streptokinase, due to its antigenic properties, can cause anaphylactic reactions, the frequency of which is up to

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0.1%. In the GISSI-1 and ISIS-2 studies, it was found that intravenous administration of 1.5 million units. Streptokinase within 60 minutes improves the prognosis for MI. In patients in the first 12 hours of MI, a reduction in mortality was found by 18%, and in patients with thrombolysis performed in the first hour from the onset of MI, by 47%. The effectiveness of thrombolysis was maintained during 1 year of observation and was proven for patients with major MI, as well as for people over 65 years of age. In the first 24 hours of MI, the reduction in mortality in the group of patients who received streptokinase was 23%.

Alteplase, commercial name Actilyse, tissue plasminogen activator is an enzyme synthesized by the endothelium and capable of converting plasminogen into plasmin in the presence of fibrin. The activity of tPA is fibrin dependent, has a short plasma half-life, and is regulated by a specific inhibitor, ITAP-1. Activation of tPA occurs on the surface of fibrin, while the resulting plasmin is protected from the action of a specific antiplasmin inhibitor. Unlike streptokinase, alteplase is a fibrin-selective drug, has the ability to dissolve blood clots resistant to lysis and does not cause a sharp decrease in plasminogen. Alteplase is a physiological plasminogen activator and does not have allergenic properties. Its administration does not produce antibodies, so it can be administered repeatedly and, unlike streptokinase, is less likely to cause hypotension and shock.

A reduction in mortality with the use of alteplase was first shown in the ASSET (AngloScandinavian Study of Early Thrombolysis) study. Subsequently, in the GUSTO_I (Global Utilization of Streptokinase and t-PA for Occluded coronary arteries_I) study, alteplase compared with streptokinase showed the greatest benefits in terms of mortality in anterior myocardial infarction, in persons over 75 years of age.

An important criterion for the effectiveness of a thrombolytic drug, in addition to the effect on mortality, is the degree of restoration of coronary blood flow in the infarct-related artery (ISA).

To increase the effectiveness of thrombolytic therapy, it is promising to search for new thrombolytic agents, as it is known that in 10-15% of patients with MI, blood clots in the coronary arteries are resistant to the action of thrombolytics. After studying the structure of the alteplase molecule and the function of its various domains, the search for new drugs was associated with the creation of recombinant molecules lacking certain domains or with the creation of mutant molecules. Unlike alteplase, recombinant plasminogen activator (reteplase) is distinguished by the absence of three domains in the molecule, which reduces the affinity for fibrin on the surface of the blood clot and a greater ability to penetrate into the blood clot. Reteplase has a longer half-life than alteplase, allowing the drug to be administered more quickly and at a lower dosage.

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The GUSTO_III (The Global Use of Strategies to Open Occluded coronary arteries_III) study compared the effectiveness of alteplase and reteplase. In this study, reteplase showed no advantage over alteplase in terms of mortality. The only advantage of reteplase was the method of its administration in the form of two intravenous boluses.

The effectiveness of tenecteplase, a mutant form of alteplase, was compared with the gold standard thrombolytic therapy, alteplase, in patients with myocardial infarction in the ASSENT-2 study (The Assessment of the Safety and Efficacy of a New Thrombolytic-2).

In terms of the incidence of death and survival in the groups receiving tenecteplase and alteplase, the indicators were completely identical, and in the case of tenecteplase, the advantage over alteplase was the ease of administration of the drug. Alteplase is by far the most widely used thrombolytic and has certain advantages over streptokinase, including fibrin specificity, faster restoration of ISA patency, lack of allergenic properties, the ability to reuse the drug, and greater effectiveness in reducing mortality.

Thus, thrombolytic therapy is included in the list of standard interventions for ACS with ST elevation. It has been established that when used in the first 6 hours from the onset of MI, it saves potentially necrotic myocardium, improves left ventricular function and, most importantly, reduces mortality rates.

The main strategies for the treatment of ACS with ST elevation are thrombolytic therapy and percutaneous coronary intervention. With PCI, recovery is achieved in 90-95% of cases, with TLT - in 60-70% of cases. The advantages of PCI are the less frequent development of restenosis in the ISA, post-infarction angina and recurrent AMI, as well as the possibility of performing it in cases of relative and absolute contraindications to TLT. Primary coronary intervention avoids the risk of bleeding due to fibrinolytic therapy, increases left ventricular ejection fraction and improves long-term outcomes. Primary coronary intervention - emergency PCI for ST-elevation ACS, without prior fibrinolytic therapy, is the preferred reperfusion strategy, provided it is performed within the established time frame. But the existing economic and organizational difficulties in implementing PCI limit the provision of this type of care to patients with acute coronary syndrome. Pharmacological reperfusion makes it possible to restore the ISA at an earlier stage, even at the emergency stage, and also has the advantages of performing prostate cancer and lower cost compared to PCI.

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ST-nің zhogarylauymen zhuretіn otkіr koronarlyk syndromes bar naukas-tardy emdeudіn en manyzdy strategies - thrombolytics drug tardy qol-danu arkyly pharmacological reperfusion. Thrombolytic therapy infarction-bylanysty arteries otіmdіligіn tez arada kalpyna keltiruge, sonday-ak tazh arteries son reocclusion son bagyttaluy tis.

Tuyindi sozder: atkir coronary syndrome, pharmacological reperfusion, thrombolytic therapy, alteplase

The most important treatment strategy for patients with acute coronary syndrome with ST-elevation pharmacological reperfusion with use of thrombolytic agents. Thrombolytic therapy should be directed to the early restoration of patency of the infarct-related artery, as well as the fight against coronary arteryreocclusion.

Key words: acute coronary syndrome, pharmacological reperfusion, thrombolysis, alteplase

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For quotation: Novikova N.A., Gilyarov M.Yu. Antithrombotic therapy for acute coronary syndrome with ST segment elevation // Breast cancer. 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 agents
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 demonstrated the benefit of this treatment approach in a large number of patients.
TLT drugs currently used do not directly destroy the fibrin clot, but act on it through the physiological fibrinolysis system (Fig. 1). This system breaks down insoluble fibrin strands into soluble fragments, resulting in thrombus lysis. The physiological process of fibrinolysis is initiated by tissue plasminogen activators, which are secreted by endothelial cells. Plasminogen activators convert plasminogen into plasmin, a protein that directly destroys 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, as well as prothrombin. Therefore, increasing the level of plasmin not only lyses the thrombus, but also slows down thrombus formation.
Thrombolytic drugs affect the fibrinolytic system through various mechanisms. Thus, streptokinase forms a complex with plasminogen, as a result of which its active site opens. This region promotes the transition of other plasminogen molecules to plasmin. This leads to the appearance of streptokinase-plasmin complexes, which are resistant to the neutralizing effects of a2-antiplasmin and cause a fibrinolytic effect. In this case, the streptokinase-plasminogen complex activates both fibrin thrombus-bound and free plasminogen molecules circulating in the blood to approximately the same extent.
Unlike streptokinase, recombinant tissue plasminogen activators are fibrin-specific agents, i.e., they directly promote the transition of fibrin-bound plasminogen to plasmin due to cleavage of 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. This is a single-chain polypeptide that does not contain carbohydrates, with a molecular weight of 47,000 D, which is produced from the culture of b-hemolytic streptococcus group C.
The half-life of streptokinase is 15-25 minutes. Streptokinase is obtained from a bacterial culture, as a result of which it has antigenic properties. Antibodies against streptokinase are always detected in human blood, which is associated with the high prevalence of streptococcal infections in the general population. Antistreptokinase antibody titers increase rapidly within a few days after its administration and reach a peak after a few weeks. This peak can be 1000 times higher than the initial titers of anti-streptokinase antibodies. 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 repeated administration of the drug, as well as allergic reactions. reactions.
In the treatment of acute MI, streptokinase is usually prescribed in a dose of 1,500,000 units, which is diluted in 100 ml of isotonic sodium chloride solution or 5% glucose solution and administered over 60 minutes. With faster administration of 1,500,000 units of the drug (in 30 minutes), the effectiveness of thrombolytic therapy, assessed by the rate of patency of the infarct-related coronary artery, increases, but the risk of developing hypotension increases significantly.
The effectiveness of streptokinase has been proven in several randomized studies (GISSI-1, ISAM, ISIS-2 and EMERAS). According to a meta-analysis of the Fibrinolytic Therapy Trialists Collaborative Group, the use of streptokinase in the first 6 hours from the onset of MI saves 30 lives per 1000 patients, and when the drug is administered within 7 to 12 hours, it saves 20 lives per 1000 patients.
Prourokinase
Prourokinase, or single-chain urokinase-type plasminogen activator, has high specificity for fibrin-bound plasminogen (compared to strepto- and urokinase), as well as a longer half-life. Pro-urokinase preferentially 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 subsequent years, a number of large clinical studies were carried out with a drug obtained by genetic engineering using the native molecule of prourokinase - saruplase (PASS, SESAM, COMPASS), which showed comparable with r- tPA effectiveness.
Alteplase
Tissue plasminogen activator (tPA), alteplase is a serine protease with a molecular weight of 72,000 D, which is synthesized primarily by vascular endothelial cells. TPA is secreted into the bloodstream as a single-chain molecule (molecular weight 70,000 D), which is converted into a double-chain molecule under the influence of plasmin, trypsin, kallikrein or factor Xa of the blood coagulation system. A unique property of tPA is its very high selectivity for fibrin-bound plasminogen, which ensures its preferential activation on the surface of the fibrin thrombus. However, this selectivity is largely lost when tPA is used in therapeutic doses.
tPA does not have antigenic properties and does not have a significant effect on hemodynamics; pyrogenic and allergic reactions in response to tPA administration are rare. For clinical use, tPA is obtained by the 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 administered as a bolus over 2 minutes. Because alteplase at a total dose of 150 mg often caused hemorrhagic complications, and a 3-hour infusion led too late to recanalization of the infarct-related coronary artery, two new regimens for administering recombinant tPA have been proposed in recent years.
K. Neuhaus et al. (1989) proposed a scheme for “accelerated” administration of recombinant tPA: 100 mg over 90 minutes, with the first 15 mg of the drug administered as a bolus, then the infusion begins (50 mg over 30 minutes and 35 mg over the remaining 60 minutes) .
Another scheme for administering alteplase in the acute period of myocardial infarction was proposed by J. Puruis et al. (1994): the drug is administered in the form of two boluses of 50 mg with an interval of 30 minutes between boluses. With a two-bolus regimen of recombinant tPA, 90-minute patency of the infarct-related coronary artery was observed in 78 of 84 (93%) patients, with complete patency in 88% of cases.
In a comparative assessment of 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, 30-day mortality was lower by 14% with a slightly higher incidence of hemorrhagic strokes.
Tenecteplase
The drug tenecteplase, obtained using recombinant DNA technology, is the most successful attempt by scientists to improve natural human TPA due to changes in the structure of various parts of the complementary DNA molecule. Structural modifications resulted in a molecule with a longer plasma half-life, increased fibrin specificity, and greater resistance to plasminogen activator inhibitor type 1 (PAI-1) compared to natural tPA.
The results of the multicenter randomized trials ASSENT-I and ASSENT-II, published in 1999, showed that both of these thrombolytic agents were 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 initiation. The expansion of the necrosis zone during MI increases like an avalanche, which is why the saying is true: “Time is the myocardium.” The greatest number of lives can be saved when TLT is started within 1 hour from the onset of MI symptoms, which makes thrombolysis at the prehospital stage particularly relevant.
Acetylsalicylic acid
and clopidogrel
Acetylsalicylic acid (ASA) inhibits platelet aggregation by inhibiting cyclooxygenase and reducing the synthesis of thromboxane A2. To date, the effectiveness of ASA in patients with ST-segment elevation ACS is beyond doubt. According to the ISIS-2 study, the administration of ASA reduced the relative risk of death by 23%, and in combination with thrombolytic therapy with streptokinase - by 42%. It should be noted that ASA demonstrated the same effectiveness as streptokinase when administered separately (Fig. 2).
According to a meta-analysis by Roux S. et al., the administration of 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 MI, stroke and cardiovascular death by 25%.
Currently, 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 no contraindications. It is recommended to chew ASA in a dose of 160-325 mg. Subsequently, the drug is prescribed at a dose of 75-325 mg/day. .
Clopidogrel selectively and irreversibly blocks the binding of ADP to platelet receptors, suppresses their activation, reduces the number of functioning ADP receptors (without damage), prevents the sorption of fibrinogen and inhibits platelet aggregation. Clopidogrel is a prodrug, bio-transformed in the liver to form an active metabolite.
In the recommendations for the diagnosis and treatment of ST-segment elevation ACS, the prescription of clopidogrel was considered as an alternative to ASA in case of its intolerance. However, since the publication of these guidelines, two large studies have been conducted: COMMIT-CCS-2 and CLARITY-TIMI-28, which assessed the effectiveness of dual antithrombotic therapy (ASA + clopidogrel) in patients with ST-segment elevation ACS.
The COMMIT-CCS-2 study included 45,852 patients who received ASA 162 mg/day in addition to basic therapy. 75 mg clopidogrel (without loading dose) for an average of 14.9 days. The incidence of the composite endpoint of death, recurrent myocardial infarction and stroke was 10.1% in the placebo group and 9.2% in the clopidogrel group (HR 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 clopidogrel administration was observed regardless of thrombolytic therapy.
The CLARITY-TIMI-28 study included 3491 patients. Clopidogrel was prescribed as a single dose of 300 mg followed by 75 mg/day. The primary endpoint included occlusion of the infarct-related artery according to coronary angiography, death, and recurrent MI. In the clopidogrel group, the incidence 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. .
Data from these studies required changes to existing recommendations for the diagnosis and treatment of patients with ST-segment elevation ACS, and additions to them were published in 2007.
Currently, clopidogrel is prescribed 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 administered (Class I, Level A). For patients under 75 years of age, regardless of thrombolytic therapy, a loading dose of clopidogrel of 300 mg is recommended (Class IIa, Level C). Long-term therapy with clopidogrel (for a year) is advisable in patients with ST-segment elevation ACS, regardless of reperfusion therapy (class IIa, level C).
Warfarin
The history of the use of warfarin for myocardial infarction goes back more than 50 years. Back in 1956, this drug was prescribed to US President D. Eisenhower.
However, today the indications for long-term use of warfarin in patients who have undergone ST-segment elevation ACS remain controversial.
Use of combination therapy with low doses of 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 receiving ASA at a dose of 75 mg/day included 1641 patients. The follow-up period was 5 years. And in this study, the addition of low-dose warfarin did not reduce 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 and intense anticoagulation. In the APRICOT II study, when warfarin was prescribed to achieve an INR of 2.0-3.0 in combination with 80 mg ASA compared with 80 mg ASA, a lower rate of reocclusion was observed (15 vs. 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 receiving warfarin up to an INR of 2.8-4.2, warfarin up to an INR of 2.0-2.5 + ASA 75 mg and ASA 160 mg. The follow-up period was 4 years. Compared with ASA, patients in group 1 experienced a reduction 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). There were no differences in survival, and the benefit was achieved by reducing the incidence of MI and stroke. In addition, a higher incidence of bleeding was observed in the warfarin group and about 35% of patients discontinued warfarin.
The ASPECT trial followed a similar design and found comparable results. The incidence of the combined endpoint (death, MI, stroke) in the high-intensity anticoagulation group (INR 3.0-4.0) was 5%, in the combination therapy group (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 (the incidence of major bleeding did not differ between groups). However, 20% of patients stopped taking warfarin and only 40% had the 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 incidence of bleeding. In addition, the results were obtained among patients less than 75 years of age. Another concern was the high rate of warfarin discontinuation and difficulty achieving INR targets.
Currently, the prescription of warfarin for acute MI is considered appropriate only in patients with a high risk of thromboembolic complications: with large anterior infarctions, the presence of intracardiac thrombosis, episodes of thromboembolism in the systemic and pulmonary circulation, in the presence of atrial fibrillation and in patients with deep vein thrombosis of the lower veins. limbs. Patients with these risk factors after heparin therapy are recommended to continue treatment with warfarin during their hospital stay. In the presence of an intracardiac thrombus, warfarin therapy is recommended to be continued for at least 3 months. For persistent atrial fibrillation, warfarin must be taken continuously. It is recommended to maintain the INR between 2.0 and 3.0.
Unfractionated heparin
Thrombosis on the surface of an unstable plaque plays a key role in the pathogenesis of ACS. Thrombolytic therapy eliminates arterial occlusion by dissolving the thrombus, but it does not affect recurrent thrombus formation and, therefore, despite successful thrombolysis, there remains a high chance of reocclusion of the target vessel.
Unfractionated heparin (UFH) has been used in the treatment of MI for more than 40 years. In patients receiving thrombolytic therapy, the administration of UFH depends on the type of drug used. Nonspecific thrombolytic drugs (streptokinase, antistreplase and urokinase) reduce coagulation potential by reducing the concentration of factors V and VIII and the formation of large quantities of fibrin degradation products. Because of this, the need for additional prescription of anticoagulants during their use is not so obvious.
These theoretical positions are confirmed by data from studies in which no significant benefit was obtained from the additional administration of UFH. According to a meta-analysis by Collins et al. the administration of heparin after systemic thrombolysis with streptokinase allows saving 5 lives per 1000 treated patients at the cost of 3 bleedings per 1000 patients. Although the difference was statistically significant, the overall effect was small. Therefore, in current recommendations, the administration of UFH after thrombolysis with streptokinase is indicated only for 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 much less pronounced effect on systemic coagulation, and after their use the prescription 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 original value (up to approximately 50-70 s). The duration of the infusion is at least 48 hours.
As an alternative, in case of heparin intolerance or in case of heparin-induced thrombocytopenia, bivalirudin can be used, 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 quite inconvenient. Low molecular weight heparins (LMWHs) do not have these disadvantages. Currently, reviparin and enoxaparin or the synthetic Factor Xa inhibitor fondaparinux are proposed as alternatives to UFH. The last two drugs are available in our country. Data on the effectiveness and safety of the drugs are presented in Table 1.
Enoxaparin after thrombolysis was prescribed taking into account the patient's age and creatinine clearance. For patients less than 75 years old, 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 of age, the drug was administered only subcutaneously and at a reduced dose (0.75 mg/kg) 2 times a day. When creatinine clearance decreased, enoxaparin was prescribed at a dose of 1 mg/kg once a day. Patients with elevated creatinine levels (men more than 2.5 mg% and women more than 2.0 mg%) are not prescribed enoxaparin.
Fondaparinux is prescribed to 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 daily. The duration of therapy with enoxaparin and fondaparinux ranges from 2 to 8 days. Both drugs are recommended for use in the latest revision of the ACC/AHA guidelines, with the highest class and level of evidence (IA).
Both drugs are indicated for patients with ST-segment elevation ACS in the absence of thrombolytic therapy.
IIb/IIIa receptor inhibitors
platelets
This group of drugs, as has been 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 combination therapy in the form of a half dose of reteplase and a full dose of abciximab during the first 6 hours from the onset of MI. Mortality did not differ significantly in both subgroups (5.6 and 5.9%, respectively), but the combination therapy group had a lower incidence of recurrent infarction and complications of myocardial infarction. However, the incidence of bleeding increased significantly when using combination therapy (4.6 vs. 2.3%; p = 0.001), especially in the group of patients over 75 years of age. In the same age group, the incidence of intracranial hemorrhage also increased. Similar results were obtained with the combination of ab-ciximab with half the dose of tenecteplase in the ASSENT-3 study. Thus, such an approach has the right to exist in people under 75 years of age, 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 RKNPK specialists. Currently, there is no data on the combined use of monofram and thrombolytics, but it is known that the drug has demonstrated high effectiveness during 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, LMWHs, and fondaparinux have been introduced into current clinical practice as mandatory thrombolytic agents. The number of intracoronary interventions is growing, which requires special antithrombotic treatment regimens. At the same time, in our country, thrombolytic therapy is still insufficiently used, which in the early period of MI is comparable in effectiveness to angioplasty.
The appearance on the market of new drugs that affect hemostasis is not far off - prasugrel, Indraparinux and, possibly, direct thrombin inhibitors, in particular dabigatran. It is also possible that oral factor Xa inhibitors - rivaroxaban and apixaban - will be introduced into practice. Their effectiveness and safety are the subject of evaluation in upcoming clinical trials.

Literature
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3. The GUSTO Investigators. An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction N. Engl. J. Med., 1993; 329: 673-682.
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This review presents a variety of clinical scenarios that require a combination of clinician intuition, experience and knowledge of the latest expert recommendations in the management of patients with acute coronary syndrome (ACS) to make informed and effective decisions regarding diagnostic and therapeutic tactics. The emphasis is on the choice of antiplatelet, anticoagulant and thrombolytic therapy, their combination for different variants of the course of the disease, taking into account multiple factors that determine the balance of thrombotic and hemorrhagic risks.

Scenario #1

Patient M., 70 years old. Myocardial infarction (MI) with ST segment elevation (STEMI). Delivered 4 hours after the onset of pain. History: acute cerebrovascular accident suffered 1 year ago, arterial hypertension (AH), diabetes mellitus (DM) type 2. Creatinine determined 4 months ago – 171 µmol/l; creatinine clearance (CC) – 45 ml/min. At the prehospital stage, the patient received clopidogrel at a dose of 300 mg, heparin at 5000 U IV, acetylsalicylic acid (ASA) at 300 mg, and morphine. Primary percutaneous coronary intervention (PCI) is planned.

What should be the tactics of antithrombotic therapy before, during and after PCI?

In the PCI strategy, dual antiplatelet therapy (DAPT) is recommended to begin as early as possible, before or during coronary angiography, with loading doses of ASA and ticagrelor. To speed up the effect, you can ask the patient to chew the tablets. If loading doses of ASA and ticagrelor were taken by the patient at the prehospital stage, then after PCI the use should be continued in maintenance doses. Otherwise, the loading dose is given to the patient directly during the revascularization procedure, then maintenance treatment continues. Prescribing clopidogrel at the prehospital stage is not in most cases a limitation for transferring the patient to subsequent administration of ticagrelor (in the absence of contraindications to its administration). For the purpose of anticoagulant therapy (ACT) during intervention, the priority is the use of unfractionated heparin (UFH) (grade of recommendation I, level of evidence C), enoxaparin (IIa, A) or bivalirudin (IIa, A). UFH is administered intravenously (i.v.) as a bolus at a rate of 70-100 U/kg body weight (50-70 U/kg body weight when used together with GPIIb/IIIa receptor blockers) ( table 1).

The possibility of using enoxaparin during intervention in patients with STEMI was proven in the ATOLL study (n=910), in which its administration at a dose of 0.5 mg/kg body weight IV bolus compared with the indicated doses of UFH was not accompanied by a significant decrease incidence of the primary endpoint (death/MI/PCI failure/major bleeding—relative risk reduction [RRR] 17%; p=0.063), but led to a significant reduction in the incidence of secondary endpoint events (death/MI/unstable angina/urgency revascularization – RRR 41%; p=0.01). However, the probability of bleeding in the two groups did not differ significantly.

Enoxaparin had advantages over UFH and according to the results of a meta-analysis by J. Silvain et al. (34% reduction in mortality compared with UFH), while the improvement in patient survival was supported by a simultaneous reduction in the incidence of both ischemic and major hemorrhagic events.

This scenario presents a patient with very high ischemic (ACS, concomitant diabetes, renal dysfunction, age) and hemorrhagic (concomitant diabetes, renal dysfunction, age, hypertension) risks. At the prehospital stage, the patient received loading doses of DAPT (ASA and clopidogrel) and an anticoagulant. Since there is no clear indication of the type of stroke suffered, it is rational to continue to manage the patient on clopidogrel, since this drug has been well studied in a variety of patient subgroups, including those with acute cerebrovascular accidents. At the same time, a previous ischemic stroke confirmed by imaging methods is not a contraindication for the use of ticagrelor. Considering the high risk of ischemic events in this patient, in case of objective confirmation of the ischemic nature of the stroke (discharge, neuroimaging data), he should be transferred to ticagrelor (loading dose - 180 mg and then 90 mg every 12 hours). After the revascularization procedure, the patient must take DAPT for at least 1 year.

After PCI, it is necessary to continue ACT in prophylactic doses - 0.4 ml of enoxaparin (4000 anti-Xa IU) once a day or 2.5 mg/day of fondaparinux) to prevent the development of venous thromboembolic complications during the period of immobilization of the patient. In the future, anticoagulants can be discontinued in the absence of other indications for their use (ongoing active myocardial ischemia, thrombi in the cavities of the heart, atrial fibrillation [AF], mechanical valves).

Scenario #2

Patient M., 62 years old, 85 kg. Smoker. STEMI. Delivered 10 hours after the onset of pain. At the prehospital stage, thrombolytic therapy (TLT) with tenecteplase at a dose of 9000 IU was performed 3 hours ago. The patient also received 300 mg of clopidogrel, 300 mg of ASA, 30 mg of enoxaparin IV bolus and 80 mg subcutaneously. At the time of examination, the pain was relieved, the ST segment decreased by more than 50%.

Should PCI be performed and when? What should be the tactics of further antithrombotic therapy?

In this case, relief of pain and a decrease in the ST segment by more than 50% indicate successful TLT. But there should be no doubt that the patient needs angiography. Since thrombolysis was successful, the time window recommended for angiography ranges from 2 to 24 hours after the start of reperfusion. Regarding the second question, according to the ESC recommendations (2017), patients after TLT should then be treated with DAPT with clopidogrel (75 mg/day). At the same time, it is allowed to transfer patients who underwent PPCI after TLT from clopidogrel to new platelet P2Y12 receptor inhibitors (prasugrel or ticagrelor) 48 hours after administration of the fibrinolytic to reduce the likelihood of developing thrombotic complications ( rice. 1).

Scenario #3

Patient D., 65 years old. Angina pectoris II functional class (FC). Three years ago, she suffered a Q-MI in the posterior wall of the left ventricle (LV). History of dyslipidemia. Takes ASA, atorvastatin, bisoprolol. Coronary ventriculography (CVG) was not performed. She was admitted due to the development of anginal pain lasting up to 15 minutes at rest. Over the course of two days, progression of angina pectoris and the appearance of angina at rest were observed. Against the background of pain, the electrocardiogram (ECG) shows depression of the ST segment up to 1.5 mm in leads I, aVL, V3-V6. There is no pain upon admission. Blood pressure (BP) –​128/70 mm Hg. Art., heart rate (HR) – 82 beats/min, no signs of heart failure (HF). Creatinine–​105 µmol/l. She was admitted to the center without the possibility of angiography.

What is the management strategy for the patient?

Based on the totality of clinical manifestations and ECG graphics, this condition should be regarded as ACS without ST segment elevation. In accordance with the ESC recommendations (2015), the management tactics for this category of patients are determined by the degree of risk of complications. There are four risk categories ( table 3).

The presence of one of the listed factors is sufficient to classify the patient into one or another risk group. The most accurate risk stratification is provided by the GRACE (Global Registry of Acute Coronary Events) scale. On this scale, the patient scores 157 points, that is, she belongs to the category of high risk of developing complications. Also in this case, it is rational to do a troponin test, which will most likely confirm a high risk. Thus, the patient should be transferred to a center with the ability to conduct interventional interventions, where a CVG will be performed within 24 hours.

As for antiplatelet therapy, ticagrelor (loading dose 180 mg, then 90 mg twice daily) in addition to ASA is recommended in addition to ASA, regardless of the further strategy, in patients with ACS without ST segment elevation with a moderate to high thrombotic risk in the absence of contraindications. treatment, including in patients who have already received clopidogrel (in which case it should be discontinued) (class of recommendation I, level of evidence B). Clopidogrel remains the drug of choice for patients taking oral anticoagulants (OCs) (I, B).

Fondaparinux is recommended for ACT in patients with ACS without ST-segment elevation, regardless of strategy (I, B). If the patient undergoes PCI, then an additional bolus of UFH is administered at a dose of 70-85 IU/kg (I, B).

Scenario #4

Patient O., 65 years old. STEMI. PCI is planned. Cholesterol levels are unknown.

Is it necessary to prescribe statins? What is the drug, dose, time to start therapy?

The advisability of using statins in ACS for secondary prevention of cardiovascular events is no longer discussed. Their benefits have been convincingly proven in a number of controlled clinical studies. According to European recommendations, a patient with ACS with ST segment elevation should begin intensive lipid-lowering therapy as early as possible, regardless of cholesterol level, and maintain it for a long time (Table 4).

The optimal timing of initiation of therapy has not been determined. Most studies using statins for ACS started within the first 10 days. Not all of them confirmed that statins reduce the incidence of recurrent major cardiovascular events after ACS. Direct evidence was obtained for atorvastatin 80 mg/day to improve long-term outcomes in the MIRACL (compared with placebo) and PROVE-IT (compared with pravastatin 40 mg) trials. A meta-analysis of 26 randomized trials involving 170 thousand patients demonstrated convincing benefits of an intensive statin therapy strategy in reducing the risk of cardiovascular death, non-fatal MI, stroke and the need for coronary revascularization (Cholesterol Treatment Trialists’ Collaboration, Lancet, 2010). If the patient was already taking a statin before developing ACS, but the therapy was of low or moderate intensity, it should be increased to the maximum dose - increase the dose or switch to drugs with maximum potential (atorvastatin or rosuvastatin), provided that there is no history of intolerance to high doses .

The appropriateness of a loading dose of a statin before PCI remains open due to the neutral result of the recently completed SECURE-PCI trial (Berwanger et al., JAMA, 2018), which showed no effect on 30-day cardiovascular event rates. However, given the proven non-lipid effects of statins, which contribute to the stabilization of atherosclerotic plaques after injury, the implementation of the antiplatelet properties of these drugs (Ostadal, 2012; Zamani et al., 2016), as well as data on the prevention of contrast-induced nephropathy and periprocedural myocardial damage after coronary intervention against the background of a loading dose of atorvastatin (Liu et al., 2016; Lee et al., 2016), there is every reason to expect benefit from early (before angiography) initiation of statin therapy in the acute phase of ACS.

Thus, a patient in a clinical scenario should be prescribed atorvastatin 80 mg or rosuvastatin 40 mg as quickly as possible, without waiting for laboratory results. However, a lipid profile is still necessary to further assess the effectiveness of statin therapy. A lipid profile should be re-evaluated 4–6 weeks after statin initiation to ensure that target LDL cholesterol levels have been achieved and to assess the safety of therapy.

Scenario #5

Patient M., 56 years old. STEMI in the posterior wall of the LV. Upon admission, there was a paroxysm of AF with a heart rate of 95 beats/min, which developed for the first time in life. There are no signs of ALV. History of hypertension. Two years ago, planned stenting of the anterior interventricular branch (LAD) of the left coronary artery (LCA) was performed. The patient was admitted for PCI.

What should be the treatment tactics?

The European recommendations for the management of patients with STEMI have a section devoted to the peculiarities of treatment tactics for the development of supraventricular arrhythmias in the acute period. Recommendations are divided into heart rate control and rhythm restoration (cardioversion) ( table 5).

In the patient's clinical scenario, in the absence of signs of AHF and hypotension, a rapid-acting β-blocker (eg, metoprolol) is clearly indicated for heart rate control. Priority is given to the use of intravenous β-blockers, which allows the desired effect to be achieved more quickly and makes therapy more manageable. As for oral ACT, which is indicated for patients with AF and a score of ≥2 points on the CHA2DS2-VASc scale for the prevention of cardioembolic stroke, in this case there is no need to start it in the acute period. Posterior MI is often complicated by rhythm and conduction disturbances. The paroxysmal arrhythmia in this patient is probably associated with local ischemia and can be relieved by successful PCI. In preparation for PCI, the patient should receive an anticoagulant parenterally, as well as DAPT in loading doses (mainly with ticagrelor). Within 3-4 days after the procedure, it is necessary to carry out restratification according to CHA2DS2-VASC. If there is a high risk or recurrence of paroxysmal AF, it is necessary to decide on oral ACT. Moreover, if the patient was taking ticagrelor, then he must be switched to clopidogrel, since ticagrelor is not recommended for use in combination with OAC ( rice. 2).

Thus, if there is an indication for oral ACT, the patient will receive triple therapy: ASA, clopidogrel and an anticoagulant. In this case, it is preferable to use direct non-VKA-dependent drugs as an anticoagulant in the minimum proven doses (2.5 mg 2 times a day for apixaban, 110 mg 2 times a day for dabigatran and 15 mg/day for rivaroxaban). Rivaroxaban at a dose of 15 mg/day, according to the results of the PIONER study, can also be used in combination with clopidogrel monotherapy (75 mg/day). This dual combination (anticoagulant and clopidogrel) is recommended in patients with a high risk of bleeding and a low risk of ischemic events.

Scenario #6

Patient N., 72 years old. STEMI anterior localization. Delivered 2 hours after the onset of symptoms. Transportation from the district center to the catheter laboratory has been agreed upon, which will approximately take about 2 hours.

How to manage a patient before transfer to a reperfusion center? What is not recommended in this case?

Since 2 hours have already passed since the onset of symptoms and the same amount (and perhaps even more) will pass before the patient crosses the threshold of the catheter laboratory, in this case it is worth considering thrombolysis. The effectiveness of the strategy of performing primary TLT and subsequent delivery to a reperfusion center was convincingly proven in the STREAM study for patients admitted to the clinic without the possibility of angiography in the first 3 hours from the onset of symptoms. According to ESC recommendations, the decision to conduct TLT in this situation is left to the discretion of the doctor and depends on local conditions, including the real time of delivery to the regional center from the area. In such cases, it is not recommended to initiate anticoagulant therapy with fondaparinux, since a bolus of heparin will be administered in the catheter laboratory before coronary angiography. For TLT, a fibrin-specific thrombolytic (tenecteplase, alteplase) should be used.

The composition of the DAT depends on the decision made. If TLT is performed, then ASA, a loading dose of clopidogrel (300 mg) and enoxaparin are prescribed (in patients under 75 years of age - IV bolus 30 mg and subcutaneous administration at a dose of 1 mg/kg body weight 15 minutes after the bolus and then every 12 hours). If a decision is made not to perform thrombolysis, then ticagrelor becomes the preferred antiplatelet agent.

Scenario #7

Patient T., 63 years old. Acute non-Q-MI. On the second day of the disease, stenting of the right coronary artery (RCA) (one metal stent) and the circumflex branch of the LMCA (one drug-eluting stent) was performed; residual stenosis of 60% RCA. He takes ticagrelor at a dose of 90 mg twice a day, ASA 100 mg/day, fondaparinux 2.5 mg/day. On the fourth day of the disease, the patient began to complain of weakness. BP –​100/70 mm Hg. Art., heart rate – 92 beats/min. Vomiting of coffee grounds, melena. Initial Hb is 128 g/l, Hb upon development of symptoms is 96 g/l.

How to stop bleeding and what to do with antithrombotic therapy?

It is obvious that antithrombotic therapy provoked gastrointestinal bleeding, which was regarded as clinically significant, since it led to a decrease in Hb level by more than 30 g/l. At the same time, the patient has a very high thrombotic risk due to three-vessel coronary disease and the placement of two types of stents—drug-eluting and non-drug-eluting. Therefore, complete withdrawal of antithrombotic therapy is extremely undesirable. The complexity of such cases lies in the fact that it is necessary to stop the bleeding, protecting the patient as much as possible from possible repeated thrombotic events.

Of the entire list of drugs, it is rational to cancel ASA first. Ticagrelor can be interrupted until stable hemostasis is achieved, but should then be resumed.

The patient is indicated for urgent gastroscopy using local methods to stop bleeding. However, the use of tranexamic acid is not recommended, as it may increase the risk of thrombosis. To replenish blood loss, it is rational to use cryoplasma. Recommendations are given at Figure 3.

Continuation of the scenario. The next morning: melena, blood pressure – 100/70 mm Hg. Art., heart rate – 84 beats/min. Anginal pain does not bother me. Hb–​81 g/l.

Is a blood transfusion necessary?

The patient's hemodynamics are stable, but the Hb level continues to decrease, which may be due to the effect of hemodilution. At this time, blood transfusion is not indicated. Within 24 hours, you should ensure the stability of hemostasis and make a decision on further adjustment of antithrombotic therapy.

Scenario #8

Patient S., 58 years old.

History: hypertension, type 2 diabetes, dyslipidemia. A year ago I suffered a Q-MI in the anterior wall of the LV. Stented during the acute period of the disease: two drug-eluting stents (3×24 mm, 2.5×24 mm) were installed in the LAD; residual stenosis of 50% of the circumflex branch of the LMCA. There is no angina pectoris, signs of heart failure in the form of shortness of breath, NYHA class II.

According to echocardiography: LV end-diastolic volume is 160 ml, EF is 42%. He constantly takes ASA at a dose of 100 mg, ticagrelor 90 mg twice a day, carvedilol, ramipril, eplerenone and rosuvastatin.

This scenario assumes that 12 months have passed since the MI and revascularization, which is the minimum period for mandatory DAPT with proven effectiveness in preventing stent thrombosis and recurrent coronary events. The question of continuing or canceling DAT at this stage requires a reassessment of risks.

Practical recommendations for the management of patients who develop bleeding during DAPT with or without OAC

Major bleeding is any bleeding requiring hospitalization, associated with severe blood loss (decrease in Hb level >5 g/dL), hemodynamically stable and slowly progressive.

• consider discontinuation of DAPT and continuation of monotherapy, preferably a P2Y12 inhibitor, especially in cases of upper gastrointestinal bleeding;
• if bleeding continues despite therapy, or treatment is not possible, consider discontinuing all antithrombotic drugs;
• Once bleeding has stopped, re-evaluate the need for DAPT or monotherapy, preferably a P2Y12 inhibitor, especially in cases of upper gastrointestinal bleeding;
• When resuming DAPT, consider reducing its duration or replacing it with a less potent P2Y12 inhibitor (for example, replacing ticagrelor or prasugrel with clopidogrel), especially if bleeding recurs.

Note: Adapted from Ibanez, 2017.

As recommended, the DAPT scale should be used for this purpose. This technique was developed on the basis of a mathematical model for assessing the ratio of the risk of ischemic and hemorrhagic events against the background of DAPT, based on the results of the DAPT study of the same name (2014). The trial examined whether extending DAPT to 30 months provided additional benefit.

As a result, it was found that when assessed on a scale<2 баллов пользы от продления ДАТ нет, а риск кровотечений увеличивается. У пациентов с оценкой >2 points, a clear significant reduction in the incidence of MI and stent thrombosis was obtained with a lower risk of bleeding.

Thus, the DAPT scale allows for maximum individualization of the decision to extend or discontinue DAPT. In this case, the patient scores 5 points ( table 6), which corresponds to a very high risk of recurrent thrombosis and argues in favor of prolonging DAPT.

However, the DAPT score was developed from a study using thienopyridines (clopidogrel and prasugrel) and has not been tested in patients taking ticagrelor. On the other hand, we have data from the PEGASUS study, which examined the issue of prolonging ticagrelor therapy after 12 months from the onset of MI in patients with characteristics similar to those of our patient (DM, recurrent MI, renal dysfunction, multivessel coronary artery disease).

Based on the results of the DAPT and PEGASUS studies, the most appropriate solution in our case would be to continue therapy with ticagrelor, but at a dose of 60 mg twice daily (PEGASUS). Apparently, in some patients (with a high risk of bleeding), in such cases it is possible to switch to maintenance doses of clopidogrel for prolonged therapy. However, this issue requires further clarification in clinical studies.

Scenario #9

Patient S., 77 years old, 90 kg. ACS with ST segment elevation. Delivered 3 hours after the onset of pain. A decision was made to perform TLT with tenecteplase.

How to dose a thrombolytic? What should be the concomitant antithrombotic therapy?

Features of TLT in patients of the older age group are described in the corresponding section of the European recommendations (Table 7).

Taking into account the patient's age, half the dose of tenecteplase should be administered, which will reduce the risk of intracranial hemorrhage in the first place. As for antiplatelet therapy, before undergoing TLT the patient should receive ASA and clopidogrel (in this case, the loading dose is 75 rather than 300 mg). In addition, a bolus of enoxaparin is not administered, but subcutaneous injections are started immediately at a reduced dose of 0.75 mg/kg body weight twice daily.