Buy Coplavix tablet p/o film 100mg+75mg 100 pcs (acetylsalicylic acid+clopidogrel) at a bargain price at your nearest pharmacy. Price, instructions for medicine, drug

Coplavix tablet p/o film 100mg+75mg 100 pcs

Pharmacological group:

Antiplatelet agent.
Pharmacodynamics:
Clopidogrel is a prodrug, one of the active metabolites of which is an inhibitor of platelet aggregation. Its active metabolite irreversibly binds to platelet ADP receptors (adenosine diphosphate receptors) and selectively inhibits the binding of ADP to platelet ADP receptors and the subsequent activation of the GPIIb/IIIa complex by ADP, thereby inhibiting ADP-induced platelet aggregation. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking platelet activation by released ADP. Due to the irreversibility of clopidogrel's binding to platelet ADP receptors, platelets remain unreceptive to ADP stimulation for the remainder of their life (approximately 7-10 days), and restoration of normal platelet function occurs at a rate corresponding to the rate of platelet turnover. Since the formation of the active metabolite occurs with the help of isoenzymes of the cytochrome P450 system, some of which may differ in polymorphism or may be inhibited by other drugs, sufficient inhibition of platelet aggregation is not possible in all patients. When taking clopidogrel daily at a dose of 75 mg, from the first day of administration there is a significant suppression of ADP-induced platelet aggregation, which gradually increases over 3-7 days and then reaches a constant level (when an equilibrium state is reached). At steady state, platelet aggregation is suppressed by an average of 40–60%. After discontinuation of clopidogrel, platelet aggregation and bleeding time gradually returned to baseline levels within an average of 5 days. Acetylsalicylic acid (ASA) has a mechanism of antiplatelet action that differs from the effect of clopidogrel and complements it. ASA suppresses platelet aggregation due to irreversible inhibition of prostaglandin cyclooxygenase-1 and, as a result, a decrease in the formation of thromboxane A2, which is an inducer of platelet aggregation and vasoconstriction. This effect persists throughout the life of platelets. ASA does not alter the inhibitory effect of clopidogrel on ADP-induced platelet aggregation, while clopidogrel enhances the effect of ASA on collagen-induced platelet aggregation. Both active substances in monotherapy and when used simultaneously are capable of preventing the development of atherothrombosis in any localization of atherosclerotic vascular lesions, in particular in lesions of the cerebral, coronary or peripheral arteries. The ACTIVE-A clinical trial showed that in patients with atrial fibrillation who had at least one risk factor for vascular complications but were unable to take indirect anticoagulants, clopidogrel in combination with ASA (compared with ASA alone) reduced the incidence of combined stroke, myocardial infarction, systemic thromboembolism outside the central nervous system (CNS) vessels, or death from vascular causes, largely by reducing the risk of stroke. The advantage of taking clopidogrel in combination with ASA compared with taking ASA in combination with placebo was detected early and persisted throughout the study period (up to 5 years). The reduction in the risk of major vascular complications in the group of patients taking clopidogrel in combination with ASA was mainly due to a greater reduction in the incidence of stroke. The risk of developing stroke of any severity when taking clopidogrel in combination with ASA was reduced, and there was also a trend towards a decrease in the incidence of myocardial infarction in the group of patients taking clopidogrel in combination with ASA, but there were no differences in the incidence of thromboembolism outside the CNS vessels or death from vascular reasons. In addition, the use of clopidogrel in combination with ASA reduced the total number of days of hospitalization for cardiovascular pathology.

Pharmacokinetics:

Suction

Clopidogrel: with a single or course oral dose of 75 mg per day, clopidogrel is quickly absorbed in the intestine. Average maximum plasma concentrations of unchanged clopidogrel (approximately 2.2-2.5 ng/ml after oral administration of a single dose of 75 mg) are reached approximately 45 minutes after a single dose. According to the excretion of clopidogrel metabolites by the kidneys, its absorption is approximately 50%.

ASA: after absorption, ASA undergoes hydrolysis to form salicylic acid, the maximum concentrations of which in the blood plasma are reached 1 hour after taking ASA. Due to rapid hydrolysis, 1.5-3 hours after oral administration of the drug Coplavix, ASA is practically not detected in the blood plasma

Distribution

Clopidogrel: In vitro, clopidogrel and its main circulating inactive metabolite are reversibly bound to plasma proteins (98% and 94%, respectively) and this binding in vitro is unsaturated up to a concentration of 100 mg/l.

ASA: ASA weakly binds to plasma proteins and has a small volume of distribution (10 L). Its metabolite, salicylic acid, binds well to plasma proteins, but its binding to plasma proteins depends on its concentration in the blood plasma (nonlinear relationship). At low concentrations (

Metabolism

Clopidogrel: Clopidogrel is extensively metabolized in the liver. In vitro and in vivo, clopidogrel is metabolized via two metabolic pathways. The first way: metabolism is carried out with the help of enzymes (esterases), which leads to hydrolysis with the formation of an inactive metabolite - a derivative of carboxylic acid (accounts for 85% of the metabolites circulating in the systemic circulation). The second pathway: metabolism via several isoenzymes of the cytochrome P450 system. In this case, clopidogrel is first metabolized to 2-oxo-clopidogrel, which is an intermediate metabolite. Subsequent metabolism of 2-oxo-clopidogrel leads to the formation of the active metabolite of clopidogrel, the thiol derivative of clopidogrel. The active metabolite is formed primarily by CYP2C19 with the participation of several other isoenzymes, including CYP1A2, CYP2B6 and CYP3A4. The active thiol metabolite of clopidogrel, which was isolated in in vitro studies, binds rapidly and irreversibly to platelet receptors, inhibiting platelet aggregation. After taking a loading dose of clopidogrel 300 mg, the maximum concentration (Cmax) of the active metabolite is 2 times higher than that after taking a maintenance dose of clopidogrel 75 mg for 4 days, while its Cmax is reached approximately 30-60 minutes after taking clopidogrel.

ASA: ASA, when taken in combination with clopidogrel, is rapidly hydrolyzed in the blood plasma to salicylic acid with a half-life of 0.3 - 0.4 hours for ASA doses of 75-100 mg. Salicylic acid is mainly conjugated in the liver to form salicyluric acid, phenolic glucuronide and acyl glucuronide, as well as a large number of minor metabolites.

Removal

Clopidogrel: Within 120 hours of human ingestion of 14C-labeled clopidogrel, approximately 50% of the radioactivity is excreted by the kidneys and approximately 46% of the radioactivity is excreted through the intestines. After a single oral dose of 75 mg, the half-life of clopidogrel is approximately 6 hours. After a single and course dose of clopidogrel, the half-life of the main inactive metabolite circulating in the blood is 8 hours.

ASA: When administered with Coplavix, salicylic acid has a plasma half-life of approximately 2 hours. The metabolism of salicylate is saturable and total clearance is reduced at higher serum concentrations due to the limited ability of the liver to form salicyluric acid and phenolic glucuronide. After taking toxic doses of ASA (10-20 g), the plasma half-life can increase to 20 hours. At high doses of ASA, the elimination of salicylic acid corresponds to zero-order kinetics (that is, the rate of elimination depends on the concentration in the blood plasma) with a half-life of 6 h or more. Renal excretion of unchanged active substance depends on urine pH. When the pH increases above 6.5, the renal clearance of free salicylate increases from 80%. After taking therapeutic doses, approximately 10% of the dose is found in the urine as salicylic acid, 75% of the dose as salicyluric acid, 10% of the dose as phenolic glucuronides and 5% of the dose as acyl glucuronides.

Pharmacogenetics: with the help of the CYP2C19 isoenzyme, both the active metabolite and the intermediate metabolite, 2-oxo-clopidogrel, are formed. The pharmacokinetics and antiplatelet effect of the active metabolite of clopidogrel in an ex vivo platelet aggregation study (in vitro study of platelet aggregation in blood taken from a patient who took clopidogrel orally, that is, after the metabolism of clopidogrel in the body) varies depending on the genotype of the CYP2C19 isoenzyme. The allele of the CYP2C19*1 isoenzyme gene corresponds to fully functional metabolism, while the alleles of the CYP2C19*2 and CYP2C19*3 isoenzyme genes are non-functional. Alleles of the CYP2C19*2 and CYP2C19*3 isoenzyme genes cause a decrease in metabolism in the majority of representatives of the Caucasian (85%) and Mongoloid races (99%). Other alleles associated with absent or decreased metabolism are less common and include, but are not limited to, alleles for the CYP2C19*4, *5, *6, *7, and *8 genes. A patient with low CYP2C19 activity will have two of the above loss-of-function gene alleles. Published frequencies in general populations of people with the low CYP2C19 phenotype are: Caucasians 2%, Blacks 4% and Chinese 14%. To determine the patient's genotype of the CYP2C19 isoenzyme, there are appropriate tests. According to a crossover study (40 healthy volunteers) and a meta-analysis of six studies (335 volunteers taking clopidogrel) that included healthy volunteers with very high, high, intermediate and low CYP2C19 isoenzyme activity, there were no significant differences in exposure no active metabolite was detected in the average values of inhibition of platelet aggregation (IAT) (induced by ADP) in healthy volunteers with very high, high and intermediate activity of the CYP2C19 isoenzyme. In healthy volunteers with low CYP2C19 isoenzyme activity, compared with healthy volunteers with high CYP2C19 isoenzyme activity, exposure to the active metabolite was reduced. When volunteers with low CYP2C19 isoenzyme activity took clopidogrel according to the regimen: 600 mg loading dose/150 mg maintenance dose (600 mg/150 mg), exposure to the active metabolite was higher than when taking clopidogrel according to the regimen: 300 mg/75 mg. In addition, the IAT was similar to that in groups of patients with a higher rate of metabolism via the CYP2C19 isoenzyme who took clopidogrel according to the regimen: 300 mg/75 mg. However, in studies taking into account clinical outcomes, the dosage regimen of clopidogrel for patients in this group (patients with low CYP2C19 isoenzyme activity) has not yet been established. This is due to the fact that clinical studies conducted to date have not had a sufficient sample size to detect differences in clinical outcome in patients with low CYP2C19 activity.

Selected patient groups

The pharmacokinetics of the active metabolite of clopidogrel in certain groups of patients has not been studied.

Elderly: In elderly volunteers (over 75 years of age), when compared with young volunteers, there were no differences in platelet aggregation and bleeding time. No dose adjustment is required for the elderly.

Children and adolescents: no data available.

Patients with impaired renal function: after repeated doses of clopidogrel at a dose of 75 mg/day in patients with severe impaired renal function (creatinine clearance from 5 to 15 ml/min), the inhibition of ADP-induced platelet aggregation was lower (by 25%) compared with 9 However, the prolongation of bleeding time was similar to that in healthy volunteers receiving clopidogrel 75 mg daily.

Patients with impaired liver function: after daily administration of clopidogrel at a daily dose of 75 mg for 10 days in patients with severely impaired liver function (Child-Pugh score greater than 9), the inhibition of ADP-induced platelet aggregation was similar to that in healthy volunteers. The mean bleeding time was also comparable in both groups

Ethnicity: the prevalence of alleles of the CYP2C19 isoenzyme genes responsible for intermediate and reduced metabolism varies among representatives of different ethnic groups. There are limited literature data on their prevalence among representatives of the Mongoloid race, which does not allow us to assess the clinical significance of the influence of CYP2C19 isoenzyme genotypes on clinical outcomes.

Based on the pharmacokinetics and metabolic characteristics of both active substances of Coplavix, no clinically significant pharmacokinetic interactions are expected between them.

Coplavix

The following are clinically significant adverse effects observed in five large clinical studies and post-marketing use of the combination of clopidogrel + ASA, clopidogrel as monotherapy and ASA as monotherapy.

The incidence of side effects was determined according to the WHO classification: very often (≥10%), often (≥1% and

Legend

1 Adverse effects that were observed when using a combination of clopidogrel and ASA.

2 Adverse effects that were observed with the use of clopidogrel.

3 Adverse effects that were observed with the use of ASA.

Hematological disorders (purpura/bruising; nosebleeds; hematuria; hemorrhages in skin tissue, bones and muscles; hematomas; hemorrhages in the joint cavity [hemarthrosis], in the conjunctiva, in the internal media and retina of the eye; bleeding from the respiratory tract, hemoptysis; bleeding from a surgical wound; intracranial hemorrhages (hemorrhagic strokes); bleeding from the gastrointestinal tract, retroperitoneal hemorrhages, etc.)

Bleeding and hemorrhage were the most frequently observed adverse events in clinical studies and post-marketing use of the drug, mainly occurring during the first month of treatment.

Often - major bleeding1: life-threatening bleeding requiring transfusion of 4 or more units of blood; other major bleeding requiring 2-3 units of blood transfusion; non-life-threatening major bleeding (in the COMMIT study, the incidence of major non-cerebral bleeding and intracranial hemorrhage was “infrequent”)1; minor bleeding (according to the ACTIVE-A study, the incidence of minor bleeding was “very common”)1; bleeding at the site of vascular puncture1,2; bruising2; hematomas2.

The incidence of major bleeding when using the combination of clopidogrel + ASA depended on the dose of ASA, as well as their frequency when using ASA alone.

Patients who stopped treatment more than 5 days before coronary artery bypass grafting did not experience an increase in major bleeding within 7 days after this procedure. In patients who remained on antiplatelet therapy in the last 5 days before coronary artery bypass surgery, the incidence of these bleedings after surgery was 9.6% (clopidogrel + ASA) and 6.3% (ASA alone).

Uncommon - fatal bleeding1: life-threatening bleeding: bleeding with a decrease in blood hemoglobin by more than 5 g/dl (according to the CLARITY clinical trial, the frequency of their development was “common”)1; bleeding requiring surgery1; intracranial hemorrhages (hemorrhagic strokes) (according to the CLARITY clinical trial, the incidence of their development was “common”)1; bleeding requiring the administration of inotropic drugs1; severe bleeding: purpura and nosebleeds were most often observed; Hematuria and intraocular hemorrhages, mainly conjunctival, were less common2.

Rarely - intraocular hemorrhages with significant visual impairment1, retroperitoneal hemorrhages1.

Unknown frequency (post-marketing experience) - serious cases of bleeding2, mainly hemorrhage in the skin tissue2, in the bones, muscles and joint cavity (hemarthrosis)2, in the eye tissue (conjunctival, in the internal media and retina of the eye)2, bleeding from respiratory tract2, hemoptysis2, nosebleeds2, hematuria2, bleeding from the surgical wound2; intracranial hemorrhage3, including fatal cases3, especially in elderly patients; other cases of fatal bleeding (in particular, bleeding from the gastrointestinal tract and retroperitoneal hemorrhage)2.

From the hematopoietic system: infrequently - a decrease in the number of platelets in the peripheral blood1, severe thrombocytopenia with a platelet count in the peripheral blood of 80,000/μl, but >30,000/μl1, leukopenia1, a decrease in the number of neutrophils in the peripheral blood1, eosinophilia1, prolongation of bleeding time1; rarely - neutropenia1, including severe neutropenia (

From the central and peripheral system: infrequently - headache1, dizziness1 and paresthesia1; rarely - vertigo1; unknown frequency (post-marketing experience of use) - change in taste sensations2.

From the digestive system: often - gastrointestinal bleeding1, dyspepsia1, abdominal pain1, diarrhea1; uncommon - nausea1, gastritis1, flatulence1, constipation1, vomiting1, gastric ulcer1 and duodenal ulcer1; unknown frequency (post-marketing experience) - colitis (including ulcerative or lymphocytic colitis)2, pancreatitis2, stomatitis2, esophagitis3, ulceration, esophageal perforation3, erosive gastritis3, erosive duodenitis3, ulcer or ulcerative perforation of the stomach and/or duodenum3, symptoms of upper tract lesions gastrointestinal tract, such as gastralgia3, ulcers of the small intestine (jejunum and ileum)3 and large intestine (colon and rectum)3, colitis and intestinal perforation3 (these reactions may or may not be accompanied by bleeding, and can occur with any dose of ASA, as well as in patients with and without warning symptoms and a history of serious gastrointestinal complications).

From the liver and biliary tract: unknown frequency (post-marketing experience of use) - hepatitis (infectious etiology)2, acute liver failure2, increased activity of liver enzymes3, deviations from the norm in indicators of the functional state of the liver2, liver damage, mainly hepatocellular3.

Dermatological reactions: uncommon - skin rash1, itching1; unknown frequency (post-marketing experience with use) - maculopapular, erythematous or exfoliative rash2, urticaria2, pruritus2, angioedema2, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis)2, drug hypersensitivity syndrome, drug rash with eosinophilia and systemic manifestations (DRESS syndrome)2, eczema2, lichen planus2.

Allergic reactions: unknown frequency (post-marketing experience) - anaphylactoid reactions2, serum sickness2, cross-hypersensitivity reactions with other thienopyridines (such as ticlopidine, prasugrel)2, anaphylactic shock3, increased symptoms of food allergy3.

Mental disorders: unknown frequency (post-marketing experience) - confusion2, hallucinations2.

From the cardiovascular system: unknown frequency (post-marketing experience) - vasculitis2, decreased blood pressure2.

From the respiratory system: unknown frequency (post-marketing experience of use) - bronchospasm2, interstitial pneumonitis2, eosinophilic pneumonia2, non-cardiogenic pulmonary edema with constant use of the drug associated with a hypersensitivity reaction3.

From the musculoskeletal system: unknown frequency (post-marketing experience) - arthralgia2, arthritis2, myalgia2.

From the urinary system: unknown frequency (post-marketing experience of use) - glomerulopathy, including glomerulonephritis2, acute renal dysfunction (especially in patients with pre-existing renal failure, decompensated chronic heart failure, nephritic syndrome or in patients simultaneously taking diuretics)3.

General disorders: unknown frequency (post-marketing experience) - fever2.

Laboratory and instrumental data: unknown frequency (post-marketing experience of use) - deviation from the norm in indicators of the functional state of the liver2, increased concentration of creatinine in the blood2.

From the metabolic side: unknown frequency (post-marketing experience of use) - hypoglycemia3, gout3.

On the part of the hearing organ: unknown frequency (post-marketing experience of use) - hearing loss3, tinnitus3.

There are no data regarding overdose.

An overdose of clopidogrel can lead to an increase in bleeding time with subsequent complications in the form of bleeding. If bleeding occurs, appropriate treatment is required. No antidote for clopidogrel has been established. If rapid correction of prolonged bleeding time is necessary, platelet transfusion is recommended.

Symptoms of a moderate overdose of ASA: dizziness, ringing in the ears, headache, confusion and gastrointestinal symptoms (nausea, vomiting and stomach pain).

Severe overdose of ASA: severe disturbances in acid-base balance occur. Initially, the resulting hyperventilation leads to the development of respiratory alkalosis, then respiratory acidosis develops as a consequence of the inhibitory effect of respiratory alkalosis on the respiratory center. Also, due to the presence of salicylates in the blood, metabolic acidosis develops. In addition, the following symptoms appear: hyperthermia and profuse sweating, leading to dehydration, restlessness, convulsions, hallucinations and the development of hypoglycemia. Suppression of the nervous system can lead to the development of coma, collapse and respiratory arrest. The lethal dose of ASA is 25-30 g. A plasma concentration of salicylate over 300 mg/l (1.67 mmol/l) confirms the presence of intoxication. In acute and chronic overdose of ASA, non-cardiogenic pulmonary edema may develop.

If symptoms of a severe overdose of acetylsalicylic acid are detected, hospitalization is required. In case of moderate intoxication, you can try to artificially induce vomiting; if unsuccessful, gastric lavage is indicated. After this, activated charcoal and a saline laxative should be taken orally (if the patient can swallow) or administered into the stomach through a tube. In order to force the alkalinization of urine to accelerate the excretion of salicylates, intravenous drip administration of 250 mmol of sodium bicarbonate is indicated for 3 hours under the control of urine pH and acid-base balance. The preferred treatment for severe overdose is hemodialysis or peritoneal dialysis. If necessary, symptomatic treatment of other manifestations of intoxication is used.

Coplavix®

Medicines whose use is associated with a risk of bleeding

There is an increased risk of bleeding due to their potential additive effects with clopidogrel. Treatment should be carried out with caution.

Nikorandil

Patients concomitantly taking nicorandil and NSAIDs, including ASA and lysine acetylsalicylate, have an increased risk of developing severe complications, such as the formation of ulcers and perforations in the gastrointestinal tract and gastrointestinal bleeding (see section "Special Instructions").

Thrombolytics

The safety of concomitant use of clopidogrel, fibrin-specific or non-fibrin-specific thrombolytic agents and heparin was analyzed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed with the simultaneous use of thrombolytic agents and heparin with ASA. Due to the lack of clinical data on the simultaneous use of clopidogrel and thrombolytic agents, caution should be exercised when using them simultaneously (see section "Special Instructions").

Glycoprotein IIb/IIIa inhibitors

Between glycoprotein IIb/IIIa inhibitors, which requires caution when using them simultaneously.

Heparin

According to a clinical study conducted with healthy volunteers, when taking clopidogrel, no change in the dose of heparin was required, and its anticoagulant effect did not change. Concomitant use of heparin did not change the inhibitory effect of clopidogrel on platelet aggregation. There may be a pharmacodynamic interaction between clopidogrel and heparin, which may increase the risk of bleeding, and therefore their simultaneous use requires caution (see section "Special Instructions").

Indirect anticoagulants

The simultaneous use of clopidogrel and oral anticoagulants (warfarin) may increase the intensity of bleeding, and therefore the use of this combination is not recommended.

Clopidogrel at a dose of 75 mg does not affect the pharmacokinetics of warfarin and does not change the International Normalized Ratio (INR) value in patients taking warfarin for a long time. However, concomitant use of warfarin with clopidogrel may increase the risk of bleeding due to the independent effects of these drugs on hemostasis.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

In a clinical study conducted in healthy volunteers, concomitant use of clopidogrel and naproxen increased occult gastrointestinal blood loss. Therefore, the use of NSAIDs, including cyclooxygenase-2 (COX-2) inhibitors, in combination with clopidogrel is not recommended (see section "Special Instructions").

Experimental evidence suggests that ibuprofen (given as a single 400 mg dose between 8 hours before and 30 minutes after immediate administration of 81 mg immediate-release ASA) may inhibit the effect of low-dose ASA on platelet aggregation. However, if ibuprofen is not taken regularly, no clinically significant effects on the antiplatelet effect of ASA are expected.

Selective serotonin reuptake inhibitors (SSRIs)

Since SSRIs impair platelet activation and increase the risk of bleeding, concomitant use of SSRIs with clopidogrel should be done with caution.

Other combination therapy with clopidogrel

Potent and moderate inhibitors of the CYP2C19 isoenzyme

Since clopidogrel is metabolized to its active metabolite in part by the CYP2C19 isoenzyme, it is expected that the use of drugs that inhibit the activity of this isoenzyme may lead to a decrease in the concentration of the active metabolite of clopidogrel. The clinical significance of this interaction is unknown. As a precaution, concomitant use of clopidogrel and strong or moderate inhibitors of the CYP2C9 isoenzyme should be avoided.

Potent and moderate inhibitors of the CYP2C9 isoenzyme are omeprazole, esomeprazole, fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, chloramphenicol.

Concomitant use with clopidogrel of proton pump inhibitors that are strong or moderate inhibitors of the CYP2C19 isoenzyme (for example, omeprazole, esomeprazole) is not recommended. If the patient still needs to use a proton pump inhibitor while taking clopidogrel, then a proton pump inhibitor with a minor effect on the activity of the CYP2C19 isoenzyme, such as pantoprazole or lansoprazole, should be used.

Medicines that are substrates of the CYP2C8 isoenzyme

Clopidogrel increased the systemic exposure of repaglinide in healthy volunteers. In vitro studies

showed that the increase in systemic exposure of repaglinin is a consequence of inhibition of the CYP2C8 isoenzyme by the glucuronide metabolite of clopidogrel. Caution should be exercised during the simultaneous use of clopidogrel and drugs that are predominantly eliminated from the body by metabolism via the CYP2C8 isoenzyme (for example, repaglinide, paclitaxel).

A number of clinical studies have been conducted with clopidogrel and other concomitantly administered drugs to examine possible pharmacodynamic and pharmacokinetic interactions, which have shown that:

- when clopidogrel was used simultaneously with atenolol, nifedipine, or with both of these drugs taken simultaneously, no clinically significant pharmacodynamic interaction was observed;

- simultaneous use of phenobarbital, cimetidine and estrogens did not have a significant effect on the pharmacodynamics of clopidogrel;

— the pharmacokinetic parameters of digoxin and theophylline did not change when they were used simultaneously with clopidogrel;

- antacid drugs did not reduce the absorption of clopidogrel;

- Phenytoin and tolbutamide can be safely used concomitantly with clopidogrel (CAPRIE study), although data obtained from studies with human liver microsomes indicate that the carboxyl metabolite of clopidogrel may inhibit the activity of the CYP2C9 isoenzyme, which may lead to increased plasma concentrations of some drugs, for example, phenytoin, tolbutamide and some NSAIDs, which are metabolized by the CYP2C9 isoenzyme.

Other combination therapy with ASA

ASA has been reported to interact with the following drugs:

— uricosurics (medicines that promote the removal of uric acid) (benzbromarone, probenecid, sulfinpyrazone)

: Caution is required, since ASA can suppress their uricosuric effect due to competition with uric acid at the excretion level;

— methotrexate

: Methotrexate taken in doses greater than 20 mg/week should be used with caution when combined with clopidogrel (due to the presence of ASA in Coplavix®), since ASA may reduce the renal clearance of methotrexate, which in turn may increase its myelotoxic effect (see section “With caution”);

— metamizole

: Metamizole, when used simultaneously with ASA, may reduce the effect of ASA on platelet aggregation. Therefore, this combination should be used with caution in patients taking low-dose ASA for cardioprotection;

— acetazolamide

: Caution is recommended when using salicylates and acetazolamide simultaneously due to an increased risk of developing metabolic acidosis;

Some aspects of the use of acetylsalicylic acid and clopidogrel in cardiac patients

The recognition of atherothrombosis as the basis for the pathogenesis of most cardiovascular diseases (CVDs) and advances in the study of the molecular mechanisms of thrombosis have influenced the development of antiplatelet therapy and contributed to the emergence of new drugs [1]. The most studied and widely used antiplatelet drugs in clinical practice are currently acetylsalicylic acid (ASA) and clopidogrel.

ASA has been known as a medicine since 1899. Despite more than 100 years of experience in use and the emergence of new antiplatelet agents in recent years, ASA has managed to retain its position as the “gold” standard of antiplatelet therapy. The antiplatelet effect of ASA is based on its ability to irreversibly inhibit the enzyme cyclooxygenase (COX) of platelets, as a result of which the formation of thromboxane A2, a powerful stimulator of platelet aggregation and vasoconstrictor, is reduced. Cyclooxygenase has two isoforms: COX-1 and COX-2. Despite the fact that ASA blocks both isoforms, its activity against COX-1 in platelets is 50–100 times higher than its effect on COX-2 in monocytes and other inflammatory cells. Since platelets do not have a nucleus and therefore are not able to synthesize proteins, irreversible inhibition of COX-1 leads to the fact that the blockade of thromboxane A2 synthesis by ASA persists throughout the entire period of platelet life (for 7–10 days). It is the ability to irreversibly block COX-1 that determines the stable and long-lasting antiplatelet effect of ASA [2].

Clopidogrel's chemical structure is a thienopyridine. The mechanism of the antiplatelet action of clopidogrel differs from that of ASA and consists of selective and irreversible inhibition of platelet P2Y12 receptors, which, in turn, leads to inhibition of stimulation of the adenylate cyclase mechanism and blocking of the associated signal aimed at enhancing platelet aggregation [3]. Clopidogrel is a prodrug and is metabolized in the liver to its active metabolite by several cytochrome P450 (CYP) isoenzymes. Recent studies have shown that there are gene polymorphisms, the carriage of which is associated with a decrease in the activity of enzymes involved in the conversion of clopidogrel into the active metabolite [4]. Thus, carriage of the CYP2C19*1 allele ensures fully functioning metabolism, while carriage of the CYP2C19*2 and CYP2C19*3 alleles reduces the functional activity of enzymes that metabolize clopidogrel. It has been established that carriage of various CYP2C19 alleles determines not only the pharmacokinetics of the active metabolite of clopidogrel, but also the antiplatelet effect. According to several studies [5–10], carriage of the CYP2C19*2 and CYP2C19*3 alleles is associated with less suppression of platelet aggregation and a higher incidence of adverse cardiovascular events (including intracoronary stent thrombosis) in patients receiving standard dosage clopidogrel (75 mg/day).

It is important to note that with simultaneous use of ASA and clopidogrel, the antiplatelet effect is enhanced. This is believed to be due to the synergism between the two drugs in suppressing collagen-induced platelet aggregation [3, 11].

Acetylsalicylic acid is certainly a more studied drug than clopidogrel, so it is not surprising that the range of its use in cardiology is much wider. Prescribing ASA can reduce the incidence of adverse outcomes in patients with stable and unstable angina, myocardial infarction with and without the presence of a Q wave on the ECG, after percutaneous coronary interventions and coronary artery bypass surgery, with cerebrovascular disease, as well as in patients with intermittent claudication of atherosclerotic origin. According to the recommendations of the European, American and Russian medical communities, for all of the above diseases and conditions, unlimited long-term (lifelong) use of ASA is recommended. Different recommendations for the same disease prescribe the use of different doses of ASA (for example, in Europe, the maintenance dose of ASA is usually 75–100 mg/day, and in the USA - 81 mg/day), but low doses are still preferable ASA as minimally effective.

Clopidogrel is recommended for use primarily in combination with ASA (so-called dual antiplatelet therapy) for myocardial infarction and unstable angina, as well as in patients undergoing percutaneous coronary intervention, since, as has been shown in numerous large studies, the addition of clopidogrel to ASA in these situations superior in effectiveness to ASA monotherapy. Clopidogrel monotherapy as an alternative to ASA monotherapy can be recommended only for atherosclerotic lesions of the arteries of the lower extremities [12–14] and as a means of secondary prevention in patients who have suffered acute cerebrovascular accident [15–17]. In all other cases, monotherapy with clopidogrel is possible only if ASA is intolerant.

Let us consider in more detail some aspects of the use of ASA and clopidogrel in cardiological practice.

Primary prevention of CVD

Acetylsalicylic acid is the only antiplatelet drug recommended for the primary prevention of CVD. At different times, randomized controlled trials on primary prevention of CVD were carried out: British Doctors' Study (BDT), US Physicians' Health Study (PHS), Thrombosis Prevention Trial (TPT), Hypertension Optimal Treatment Trial (HOT), Primary Prevention Project (PPP) ) and Women's Health Study (WHS). In 2009, the results of a meta-analysis were published [18], combining all 6 studies, which included 95,000 people, 660,000 patient-years, 3,554 adverse cardiovascular events (Table). Overall, the reduction in the risk of adverse cardiovascular events in ASA users was 12% (p = 0.0001) and was achieved mainly due to a reduction in the risk of nonfatal myocardial infarction. ASA therapy had virtually no effect on the total number of strokes, but reduced the risk of ischemic stroke by 14% (p = 0.05). Cardiovascular mortality did not differ between those receiving ASA and placebo, both in men and women. The incidence of major (mainly gastrointestinal) bleeding was higher in those receiving ASA (0.1% per year for ASA vs. 0.07% per year for placebo, p < 0.0001). A meta-analysis showed that taking ASA prevents about 8 cases of myocardial infarction for every 1,000 men and about 2 ischemic strokes for every 1,000 women. It was also noted that the administration of ASA for the purpose of primary prevention can prevent the development of 5 non-fatal adverse cardiovascular events with a risk of 3 gastrointestinal and 1 intracranial bleeding per 10,000 patients per year.

In addition, the HOT study [19] demonstrated the benefit of administering low doses of ASA (75 mg/day) to patients with arterial hypertension with well-chosen antihypertensive therapy. Thus, while taking ASA, the reduction in the risk of myocardial infarction was 36% (p = 0.002), and any cardiovascular complications - 15% (p = 0.003). Subgroup analysis showed that in some categories of patients the benefits of ASA use exceeded the risk of hemorrhagic complications. The risk of any adverse cardiovascular events was lower by 45% in patients with arterial hypertension with a serum creatinine level ≥ 115 μmol/l, by 20% in patients with initial systolic blood pressure ≥ 180 mm Hg. Art., by 29% - with initial diastolic blood pressure ≥ 107 mm Hg. Art., by 22% - in patients with a CVD risk level ≥ 10% on the SCORE scale. At the same time, the greatest effect of ASA therapy was observed in patients with a high and very high level of CVD risk. The results obtained allowed experts to recommend low doses of ASA (75–150 mg/day) in patients with arterial hypertension with a moderate increase in serum creatinine or at a very high risk of cardiovascular complications, even in the absence of other CVD [20, 21].

Currently, there are no data on the effectiveness and safety of clopidogrel monotherapy in the primary prevention of CVD.

The use of a combination of ASA and clopidogrel for the purpose of primary prevention of CVD in people at high risk is also inappropriate. This was demonstrated by subgroup analysis in the CHARISMA study [22]. The aim of this multicenter, randomized, placebo-controlled clinical trial was to compare clopidogrel (75 mg/day) and placebo in patients receiving low-dose ASA (75–162 mg/day) for both primary and secondary prevention of cardiovascular events. It included 15,603 patients aged 45 years and older (mean age 64 years; 70% men) with documented symptomatic CVD (coronary heart disease - about 50% of participants; cerebrovascular disease - about 35%; atherosclerotic lesions of the arteries of the lower extremities - about 23%), as well as with multiple risk factors for atherothrombosis. Half of the patients (n = 7,802) received clopidogrel and ASA (intervention group), the remaining participants (n = 7,801) received placebo and ASA (control group), however, 20.4% and 18.2% of patients stopped taking the drugs early, respectively (p < 0.001), including 4.8% and 4.9% due to the development of side effects. The average follow-up period was 28 months. The incidence of the primary endpoint (myocardial infarction + stroke + cardiovascular death) in the clopidogrel and placebo groups was 6.8% and 7.3%, respectively (relative risk (RR) 0.93; 95% confidence interval (CI) 0 .83–1.05; p = 0.22). There were no statistically significant differences in the incidence of major bleeding between the clopidogrel and placebo groups (1.7% vs 1.3%, respectively; RR 1.25; 95% CI 0.97–1.61; p = 0.09), although there was a trend in favor of placebo. Thus, in general, for the studied sample of patients, combination therapy with clopidogrel and ASA did not show any advantages over ASA monotherapy.

Subgroup analysis showed that among 3,284 subjects with multiple CVD risk factors, the incidence of the primary endpoint in the clopidogrel group was higher than in the placebo group (6.6% versus 5.5%, respectively), which was accompanied by a 20% increase in the risk of adverse vascular events. % (RR 1.20; 95% CI 0.91–1.59; p = 0.20), which, however, did not reach the level of statistical significance. However, there was a significant increase in mortality from both all causes (5.4% versus 3.8% in the placebo group; p = 0.04) and cardiovascular mortality (3.9% versus 2.2% in the placebo group; p = 0.01). The results of this particular fragment of the study allowed us to conclude that the use of clopidogrel monotherapy for the purpose of primary prevention of CVD is inappropriate.

In contrast, the use of clopidogrel for secondary prevention of CVD was more effective in the same study. This is indicated by a subgroup analysis that included 12,153 symptomatic patients with confirmed CVD. In this category of patients, the incidence of the primary endpoint in the clopidogrel group was lower than in the placebo group (6.9% versus 7.9%, respectively), which was accompanied by a 12% reduction in the risk of adverse events (RR 0.88; 95% CI 0 .77–0.998; p = 0.046) without any effect on the risk of cardiovascular death. There was no difference in the incidence of major bleeding between those taking clopidogrel and placebo, but the incidence of minor bleeding was significantly higher in the clopidogrel group (2.1% vs. 1.3% in the placebo group; p < 0.001).

Antiplatelet therapy in patients with stable manifestations of atherothrombosis

A direct comparison of ASA monotherapy with clopidogrel monotherapy in high-risk patients who had recently suffered a myocardial infarction, stroke, or had clinical manifestations of atherosclerosis of the arteries of the lower extremities was performed in the randomized controlled trial CAPRIE [23], the results of which were published in 1996. The study was multicenter (384 hospitals from 16 countries) and included 19,185 patients. The reason for inclusion was the presence in the patient of one of the clinical manifestations of atherosclerosis: 1) myocardial infarction with the formation of pathological Q waves on the ECG and/or an increase in the level of cardiac-specific enzymes by more than 2 times the upper limit of normal for a period ranging from several days to 35 days; 2) ischemic stroke (including lacunar) from 1 week to 6 months ago; 3) symptoms of atherosclerosis of the peripheral arteries (intermittent claudication of presumably atherosclerotic origin in combination with a reduced ankle-brachial index or a history of surgical interventions due to intermittent claudication). The presence of one of these diseases is the main criterion for inclusion in the study, according to which patients were divided into three subgroups. However, in many patients, the manifestations of atherosclerosis were not limited to one vascular region; there was often a combined lesion (for example, some patients with ischemic stroke had previously suffered a myocardial infarction or had concomitant intermittent claudication), so the distribution into subgroups according to the main inclusion criterion is quite arbitrary. All patients were randomized to receive either ASA (325 mg/day) or clopidogrel (75 mg/day) for 1–3 years (mean duration of antiplatelet therapy was 1.91 years).

The total incidence of adverse events (myocardial infarction, ischemic stroke and cardiovascular death) was slightly lower in the clopidogrel group (5.32% per year for clopidogrel versus 5.83% per year for ASA), which corresponded to a decrease in RR by 8.7 % (95% CI 0.3–16.5; p = 0.043). Overall, the use of clopidogrel prevented an additional 5 adverse outcomes for every 1,000 patients treated per year. Based on the results obtained, a point of view has been formed that even if clopidogrel has some advantage over ASA, it is not so pronounced and obvious as to justify a large-scale replacement of the widely available and cheap ASA with the more expensive clopidogrel.

When analyzing subgroups, it turned out that if the basis for inclusion in the study was a recent myocardial infarction or ischemic stroke, then the effectiveness of ASA and clopidogrel was almost the same. If patients were included due to clinically significant atherosclerosis of the arteries of the lower extremities, the advantage of clopidogrel was more significant than in the study as a whole. Among 6,452 patients with atherosclerosis of the arteries of the lower extremities, 3,198 were randomized to the ASA group, 3,233 to the clopidogrel group. The frequency of adverse cardiovascular events in these patients is presented in Fig. 1. The reduction in the risk of any adverse events while taking clopidogrel was 23.8% per year, which corresponded to the prevention of 11 adverse outcomes per 1,000 patients treated.

Clopidogrel was also superior to ASA in its ability to prevent fairly extensive myocardial infarction (with the formation of pathological Q waves on the ECG and/or an increase in the level of cardiac-specific enzymes by more than 2 times the upper limit of normal). In those taking clopidogrel, the RR of this complication over the entire observation period (1–3 years) was lower by 19.2% (p = 0.008) [24].

A further retrospective analysis of the CARPIE study database found that the effectiveness of clopidogrel was higher in patients who had previously undergone coronary artery bypass surgery, had several complications of atherosclerosis in their history, and had diabetes mellitus, especially insulin-dependent diabetes.

Thus, the results of the CAPRIE study indicate that, in general, clopidogrel monotherapy is at least as effective as ASA monotherapy in the prevention of cardiovascular complications in patients with clinically significant manifestations of atherosclerosis. It cannot be excluded that in the presence of atherosclerotic disease, clopidogrel may be better than ASA in preventing myocardial infarction, especially in patients with an initially high risk of this particular unfavorable outcome. However, since these data were obtained from a subgroup analysis (mostly retrospective), it is not possible to confidently state the presence of such patterns and, accordingly, draw a conclusion about the advantage of clopidogrel over ASA in these categories of patients.

The previously mentioned CHARISMA study showed that in patients with stable manifestations of atherosclerosis (coronary heart disease, cerebrovascular disease and atherosclerosis of the arteries of the lower extremities), the use of a combination of ASA and clopidogrel can significantly reduce the risk of adverse outcomes without a significant increase in the incidence of major bleeding. However, this pattern was identified in a retrospective subgroup analysis of a study that demonstrated an overall negative result, so the data obtained need to be confirmed in prospective studies and cannot serve as the basis for a confident judgment about the preferability of such a treatment strategy.

Safety of antiplatelet therapy

The main side effect of antiplatelet therapy is considered to be an adverse effect on the mucous membrane of the gastrointestinal tract (GIT), ranging from symptoms of dyspepsia to gastrointestinal bleeding, which in some cases is fatal. Despite the differences in the mechanisms of antiplatelet action, both ASA and clopidogrel have an adverse effect on the gastrointestinal tract. However, it cannot be said that the latter is safer in this regard than ASA. Clopidogrel does not have a significant effect on the gastric mucosa only with short-term use [25]. However, since platelets are a source of growth factors that stimulate angiogenesis in the stomach wall, by irreversibly suppressing platelet function, clopidogrel prevents the healing of ulcers and erosions [26]. According to experts, the use of clopidogrel instead of ASA to prevent gastric bleeding is inappropriate [26, 27].

The results of many studies indicate that, despite the absence of direct irritant effects on the mucous membrane, the risk of bleeding from the upper gastrointestinal tract during clopidogrel monotherapy is quite high. In the CAPRIE study [28], on the contrary, the incidence of gastrointestinal bleeding in the clopidogrel group was lower than in the ASA group (0.52% versus 0.72%, respectively). However, in this work they used a dose of ASA that was too high by modern standards (325 mg/day). The currently recommended doses of ASA for long-term use are much lower and in most cases are 75–150 mg/day. It is also known that the adverse effects of ASA on the gastrointestinal mucosa and the risk of bleeding are dose dependent (Fig. 2) and are minimal when used in doses up to 100 mg/day [29–31]. As shown by the results of a large meta-analysis [31], which included 338,191 patients, the risk of gastrointestinal bleeding during treatment with ASA in doses exceeding 325 mg/day and clopidogrel is significantly higher than with therapy with low doses of ASA and dipyridamole (Fig. 2) . In another epidemiological case-control study involving 8,309 patients, the risk of gastrointestinal bleeding increased equally with clopidogrel and ASA (100 mg/day) [32].

In patients at high risk of developing gastrointestinal bleeding, the use of proton pump inhibitors (PPIs), such as omeprazole, is recommended to increase the safety of long-term treatment with clopidogrel [1]. However, in recent years, doubts have arisen regarding the advisability of using PPIs and clopidogrel together. The results of some studies have suggested an interaction between clopidogrel and PPIs, which reduces the antiplatelet effect of clopidogrel when used simultaneously with PPIs. There are several possible explanations for this phenomenon. First, some PPIs may interfere with the conversion of clopidogrel to its biologically active form, thereby reducing its effectiveness and increasing the risk of adverse outcomes due to activation of blood clotting. Secondly, the metabolism of PPIs and clopidogrel is controlled by the same gene, CYP2C19. It is possible that there are other mechanisms by which PPIs influence the effectiveness of clopidogrel. However, data on the presence of interactions between clopidogrel and PPIs are contradictory and relate mainly to one representative of this group - omeprazole. Some studies have shown that clopidogrel does not interact with other PPIs, in particular pantoprazole. The clinical significance of the interaction between clopidogrel and PPIs has not been fully determined. Experts agree that doctors should use caution and only prescribe PPIs if a patient has obvious gastrointestinal problems that are not controlled by taking H2 blockers. If the use of a PPI is still necessary and justified, then omeprazole should probably be avoided and other PPIs, such as pantoprazole, should be preferred.

In order to improve the tolerability of treatment, protect the gastric mucosa and reduce the likelihood of side effects from the gastrointestinal tract with long-term use, “protected” dosage forms of ASA should be used - enteric or buffered. There is evidence [33, 34] that the subjective tolerability and safety profile of buffer forms of ASA are better than enteric forms. An example of a buffer form of ASA is the drug Cardiomagnyl, which, along with ASA, contains an acid buffer - a non-absorbable antacid, magnesium hydroxide. The addition of magnesium hydroxide helps protect the gastric mucosa from the adverse effects of ASA without reducing its antiplatelet effect [35].

Thus, both ASA and clopidogrel are effective antiplatelet drugs that have been successfully used in cardiological practice for a long time. Despite the emergence of new antiplatelet agents in recent years, ASA still remains the most popular antiplatelet drug and retains its position as the “gold” standard. Clopidogrel, although slightly more effective than ASA in reducing the incidence of cardiovascular events in high-risk patients in the CAPRIE study, is nevertheless rarely used as monotherapy.

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N. M. Vorobyova, Doctor of Medical Sciences

FSBI RKNPK Ministry of Health of the Russian Federation, Moscow

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