Bastions of warfarin, or its place among oral anticoagulants

pharmachologic effect

Manufacturer: Ozone, Canon Pharma, Russia/Takeda, Denmark
Release form: tablets

Active ingredient: Warfarin

Synonyms: Warfarex, Warfarin Nycomed

Warfarin has an anticoagulant effect due to blocking the synthesis of blood coagulation factors dependent on vitamin K, reducing their content in the blood and slowing down coagulation.

The onset of action usually occurs on the second day of administration, the maximum effect occurs after about a week. After discontinuation of the vitamin-K medication, dependent factors are restored on average within five days.

Drugs with similar effects

The choice of a Warfarin substitute requires medical supervision, examination of the patient's medical history and constant monitoring of INR values. It is important to take into account contraindications, side effects, correctly evaluate the composition and calculate the dosage.

Warfarex

The anticoagulant is intended for long-term use and is indicated for deep vein thrombosis, pulmonary embolism, myocardial infarction, atrial fibrillation, and heart valve replacement. Tablets are taken once a day at an initial dose of 2.5-5 mg. Description:

1. Active ingredient: warfarin.
2. Mechanism of operation: prevents blood clotting, inhibits the synthesis of factors involved in this process, prevents the formation of blood clots and the increase in existing ones.
3. Side effects compared to the analogue: dark red color of the toes, itching, dermatitis, urticaria, nausea, vomiting, jaundice, fever, weakness, alopecia.
4. Contraindications: internal bleeding, jaundice, bacterial endocarditis, diabetes mellitus, hemorrhagic diathesis, thrombocytopenia, alcoholism, hypertension, childhood, pregnancy, lactation, gastric ulcer.
5. Price, rubles: 125 for 100 tablets.

Article on the topic: Causes and treatment of stuttering in adult patients

Marevan

The indirect-acting anticoagulant has an effect already on the 2-7th day of administration and accumulation in plasma. Its indications for use are deep vein thrombosis, prevention of myocardial infarction and thromboembolism, treatment of transient ischemic attacks and strokes. The starting dose of Marevan is 10.5 mg. Description:

1. Active ingredient: warfarin sodium.
2. Mechanism of operation: blocks the synthesis of vitamin K-dependent blood clotting factors in the liver.
3. Side effects compared to the analogue: bleeding, nausea, vomiting, hepatitis, diarrhea, priapism, vasculitis, skin necrosis, tracheal calcification.
4. Contraindications: von Willebrand disease, hemophilia, thrombocytopenia, hemorrhagic diathesis, jaundice, infective endocarditis, exudative pericarditis, diabetes mellitus, exacerbation of gastric ulcers, diverticulosis, malignant tumors, dementia, psychosis, alcoholism, 1st and 3rd trimesters of pregnancy.
5. Price, rubles: 150 per 100 pcs.

Clopidogrel

A specific active inhibitor of platelet aggregation has a coronary dilation effect. Inhibition of blood cell aggregation is observed within 2 hours after administration. The drug is indicated for the prevention of thrombotic complications. Clopidogrel is taken orally, regardless of food, 75 mg per day for 1–24 weeks. Description:

1. Active ingredient: clopidogrel.
2. Mechanism of operation: reduces the binding of adenosine triphosphate to platelet receptors, weakens their aggregation.
3. Side effects compared to the analogue: purpura, hematomas, leukopenia, agranulocytosis, hallucinations, paresthesia, vasculitis, hypotension, bronchospasm, diarrhea, dyspepsia, gastritis, colitis, arthralgia, glomerulonephritis, eczema, urticaria.
4. Contraindications: severe liver failure, acute bleeding, pregnancy, breastfeeding, age under 18 years.
5. Price, rubles: 465 for 14 tablets.

Sinkumar

The indirect anticoagulant contains an alkaloid, the peak of action of which occurs on the 1st–2nd day after administration. Sinkumar is indicated for the treatment and prevention of thrombosis and embolic strokes. The dose is prescribed individually, on the first day it is 4–8 tablets, the daily maintenance dose is 1–6 mg. Description:

1. Active ingredient: acenocoumarol.
2. Mechanism of action: antagonistic effect on vitamin K, disrupts the synthesis of prothrombin and blood clotting factors.
3. Side effects compared to the analogue: nausea, diarrhea, headache, rash, bleeding.
4. Contraindications: hemorrhagic diathesis, liver and kidney dysfunction, malignant neoplasms, physical exhaustion, hypovitaminosis K and C, diabetic retinopathy, pregnancy, lactation.
5. Price, rubles: 775 for 50 tablets.

Lopirel

The antiplatelet drug has a coronary dilation effect, which manifests itself 2 hours after administration. Lopirel is used for the prevention of atherothrombosis after myocardial infarction or ischemic stroke. The medicine is taken regardless of food, 75 mg once a day. Course – from 7 days to six months. Description:

1. Active ingredient: clopidogrel.
2. Mechanism of operation: suppresses platelet aggregation, prevents the development of atherothrombosis.
3. Side effects compared to the analogue: headache, confusion, diarrhea, colitis, hepatitis, leukopenia, anemia, purpura, hemarthrosis, lichen planus, bullous rash, urticaria, vasculitis, bronchospasm, arthritis, glomerulonephritis, fever.
4. Contraindications: liver failure, hemorrhagic syndrome, acute bleeding, pregnancy, lactation, age under 18 years, lactase deficiency.
5. Price, rubles: 270 for 14 tablets.

Warfarin - instructions for use

Doses of Warfarin are calculated experimentally. Depending on laboratory parameters. Before prescribing therapy, the patient is measured with prothrombin time (PTT) - this is the time during which a blood clot forms in response to damage to the vessel; normally it is about 11-16 seconds. Then the international normalized ratio (INR) is calculated - equal to the ratio of the patient's PTV to the PTV of a healthy person. Normally, the INR is 0.85–1.35.

In the first four days of treatment, the patient is given 2 Warfarin tablets per day - once, at the same time. On the fifth day, the INR is determined again, which should increase to 2–3 during treatment, and 2.5–3.5 during heart valve replacement and acute myocardial infarction with complications.

Depending on the indicator, a maintenance dose is prescribed. Usually this is 1-3 tablets per day. INR monitoring is carried out every month, and the dose is adjusted if necessary.

The course of treatment with Warfarin depends on the type of disease and individual characteristics of the body and is determined by the doctor. If necessary, the drug is discontinued immediately.

If a patient is re-prescribed Warfarin, then therapy is started with twice the average dose of this particular patient in the first 2 days, then treatment is continued with the average dose. On the fifth day, the INR is also monitored and, if necessary, the dose is adjusted.

For children, the dose is selected based on body weight, functional state of the liver and INR, the level of which should be the same as in adults. The child is treated under the supervision of an experienced pediatrician. In the instructions for use of Warfarin, doses for children are described in more detail.

How to take Warfarin - before or after meals

It does not matter how you take Warfarin, before or after meals. The main thing is to take it at the same time of day, never missing a dose.

Warfarin dose selection

The most difficult and responsible stage. “Loading” initial doses of warfarin (more than 5 mg) are not recommended.

Dose selection can be carried out both with and without the use of low molecular weight heparins (Fraxiparine, Clexane), both in the hospital and on an outpatient basis. The selection period on average takes from 1 to 2 weeks, but in some cases it increases to 2 months. At this time, you will need frequent INR determinations, up to 2 - 3 times a week or daily. Each time, after receiving the next test result, your doctor will determine a change in the dose of the medication and the date of the next test.

If in several tests in a row the INR remains in the range of 2.0 - 2.5, this means that the dose of warfarin has been adjusted. Further monitoring of treatment will be much easier.

Warfarin analogues that do not require INR control

It is important to decide what to replace Warfarin with so as not to control the INR, since this brings a lot of inconvenience for the patient, frequent visits to the clinic and tests.

Warfarin analogues that do not require INR control include:

• antiplatelet agents - Plavix, Cardiomagnyl, Thrombo ACC, Aspirin Cardio;
• direct-acting anticoagulants - Pradaxa, Eliquis, Xarelto, Clexane.

Prices for Warfarin analogues can be compared in the table

Pradaxa

Manufacturer: Boehringer Ingelheim, Germany
Release form: capsules

Active ingredient: Dabigatran etexilate

Warfarin substitute Pradaxa is a German original drug, a direct-acting anticoagulant, which is converted into an active form in the body and directly and reversibly inhibits thrombin activity. Therefore, this analogue prevents the formation of blood clots.

An analogue of Pradaxa is produced in 75, 110 and 150 mg doses, the therapeutic dose is selected by the doctor. Capsules should not be opened.

The Warfarin analog Pradaxa is used for the treatment of acute thrombosis and thromboembolism and significantly reduces the risk of death from these diseases.

An INR test is not required during treatment with Pradaxa.

Sinkumar

Manufacturer: Meda Pharma, Germany
Release form: tablets

Active ingredient: Acenocoumarol

Analogue Sinkumar is an indirect anticoagulant. Like Warfarin, it is a vitamin K antagonist and inhibits the synthesis of vitamin K-dependent blood clotting factors.

The Warfarin analog Sincumar is used to treat pulmonary thromboembolism, coronary artery thrombosis and phlebothrombosis.

Treatment with Sinkumar should be accompanied by constant monitoring of coagulation parameters, namely prothrombin time and INR.

Clexane

Manufacturer: Sanofi, France
Release form: injection solution

Active ingredient: Enoxaparin sodium

Synonyms: Enixum, Anfibra, Gemapaksan

The Clexane analogue is a direct anticoagulant that acts by inhibiting the function of the thrombokinase enzyme, a blood clotting factor.

Clexane is a low molecular weight heparin, an injection solution with various concentrations of the active substance.

The drug is administered subcutaneously or intravenously; it cannot be used intramuscularly. Treatment is often carried out in a hospital setting for patients on bed rest.

No additional monitoring of blood parameters is required.

Comparison with Xarleto

Xarleto is an anticoagulant based on rivaroxaban. It is usually produced in the form of tablets, but there are also injection solutions in ampoules. The following mechanisms of action are distinguished:

• activation of Factor Xa;
• suppression of the conversion of prothrombin to thrombin;
• decreased fibrin thrombus formation, platelet activation.

The effect on the coagulation system depends on the dose of the drug. The higher it is, the stronger the effect. The drug is different in that the doctor does not need to periodically monitor the INR. This indicator is calibrated for the drug.

The drug increases APTT, but the doctor does not need to periodically measure this parameter; this is the main difference between the drug and warfarin-based drugs.

When taking tablets, absorption occurs in the gastrointestinal tract. If you use an injection, the active substance directly enters the bloodstream. The connection with blood plasma proteins is high. Metabolism occurs in the liver and excretion occurs through urine and feces. Both metabolites and stored active components are removed. Indications for use:

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• prevention, treatment of stroke, thromboembolism, fibrillation;
• treatment of deep vein thrombosis, prevention of relapses.

Xarleto is recommended by phlebolologists and cardiologists due to good clinical trial results. However, it has a number of negative consequences, which are taken into account when prescribing for patients of a certain age and condition of internal organs.

Side effects and contraindications

Despite the absence of the need to check the coagulation system during treatment, the drug has a number of negative reactions on the body. It is prohibited to be used in combination with other anticoagulants. Bleeding will inevitably occur. It is contraindicated in the following conditions:

• bleeding of external and internal organs;
• peptic ulcer of the stomach and duodenum, malignant tumors, injuries of the brain and spinal cord, recent operations;
• pathologies of the venous system (varicose veins, thrombophlebitis);
• inflammatory liver diseases accompanied by coagulation disorders;
• severe kidney pathologies;
• pregnancy, breastfeeding, minor age.

The drug can be used, but with caution if there is a low risk of bleeding during inflammation of internal organs, mild or moderate kidney damage. It has the following side effects:

• reduction of blood sprouts;
• dizziness, headache;
• hemorrhage, bleeding gums and nasal passages;
• decreased liver and kidney function;
• fever.

If any adverse reactions occur, the drug should be discontinued immediately. Before prescribing therapy, tell the doctor about all the medications the patient is taking to avoid cross-interactions. This is especially true for non-steroidal anti-inflammatory drugs.

Warfarin or Aspirin Cardio – which is better?

Manufacturer: Bayer, Germany
Release form: film-coated tablets

Active ingredient: Acetylsalicylic acid

Synonyms: Thrombo ACC, Thrombopol, CardiASK, ASC Cardio

Warfarin analogue Aspirin Cardio is an original German drug that has an antiplatelet effect by blocking the enzyme cyclooxygenase-1, and thus preventing platelet aggregation.

The analogue of Aspirin Cardio is used mainly for prophylactic purposes to prevent cerebrovascular accidents, stroke, acute myocardial infarction, and complications after vascular surgery.

One of the indications for the use of the Aspirin Cardio analogue is stable and unstable angina.

The active ingredient Acetylsalicylic acid in doses of 500 mg has an analgesic, antipyretic and anti-inflammatory effect.

Characteristics of Pradaksa

Pradaxa is an anticoagulant based on dabigatran etexilate. It is used orally, intravenously. It refers to drugs that inhibit thrombin. The following pharmacological actions are distinguished:

• suppression of thrombin formation;
• inhibition of the transition of fibrinogen to fibrin;
• elimination of platelet aggregation.

The more active substance is in the blood plasma, the higher its effectiveness. The medicine prolongs the APTT, but does not affect the INR. Therefore, coagulation measurements are not required during therapy. This is the main difference from warfarin-based drugs. The product has the following indications for use:

• venous thromboembolism after surgery;
• risk of stroke, atrial fibrillation;
• deep vein thrombosis, pulmonary embolism.

The medicine is strictly prohibited during pregnancy and lactation. During this period, the ratio of clotting factors changes, which can lead to DIC syndrome during childbirth. This is a condition for which therapy with such agents is not recommended.

Side effects and contraindications

Negative consequences arise from individual intolerance. They often form if the patient carries out therapy independently. The following types of side effects are distinguished:

• decrease in red blood cells and platelets;
• local, systemic allergy;
• bleeding, hemoptysis, hemorrhage into internal organs;
• dyspepsia, nausea, inflammation of various parts of the gastrointestinal tract;
• liver dysfunction, jaundice.

There are quite a lot of contraindications. Therefore, before prescribing the drug, doctors collect the patient’s medical history and be sure to identify the drugs that he uses. Contraindications for use:

• increased sensitivity to the product;
• severe diseases of the liver, kidneys, gastrointestinal tract;
• hemorrhagic diathesis, reduced number of platelets and clotting factors, periodic bleeding;
• malignant neoplasms, brain damage, ophthalmological operations, increased intracranial pressure, varicose veins;
• use of any types of anticoagulants;
• minor age, pregnancy, lactation.

There are diseases for which the drug is used, but with caution. Then it is recommended to carry out a detailed coagulogram and constantly calculate the number of platelets and clotting factors. If a side effect occurs, the drug is immediately discontinued.

Warfarin or Thrombo ACC – which is better?

Manufacturer: Lannacher, Austria
Release form: film-coated tablets

Active ingredient: Acetylsalicylic acid

Synonyms: Aspirin Cardio, Thrombopol, CardiASK

To thin the blood, Warfarin can be replaced with the Austrian drug Trombo ACC, which contains acetylsalicylic acid in 50 and 100 mg doses. In these tiny doses it has antiplatelet properties.

An analogue of Thrombo ACC can be freely purchased without a doctor’s prescription and taken 1 tablet daily for the prevention of heart attack, stroke, and other diseases accompanied by increased thrombus formation.

An analogue of Thrombo ACC is also prescribed after vascular surgery.

To prevent the negative effects of acid on the stomach, Trombo ACC tablets are coated with a special enteric coating. Therefore, they should not be chewed or divided in half.

Warfarin and pregnancy

During pregnancy, taking warfarin is contraindicated. In the event of pregnancy, indirect anticoagulants are immediately discontinued; if further prevention of thrombosis is necessary, heparins are usually used. Therefore, if you suspect pregnancy, refrain from taking the drug until you consult your doctor.

It is possible to use warfarin during breastfeeding. Warfarin is excreted in breast milk in extremely small quantities and does not affect the baby's blood clotting processes, but for complete safety it is recommended to refrain from breastfeeding during the first three days of the mother's treatment with the drug.

Warfarin or Cardiomagnyl - which is better?

Manufacturer: Takeda, Germany
Release form: film-coated tablets

Active ingredient: Acetylsalicylic acid + Magnesium hydroxide

Synonyms: Fasostabil, TromboMag, Trombital

A substitute for Warfarin without INR control, Cardiomagnyl is an over-the-counter complex drug consisting of acetylsalicylic acid and magnesium hydroxide, which is needed to protect the gastric mucosa from the damaging effects of acid. If acetylsalicylic acid is used for a long time without protecting the stomach, it can lead to ulcers or gastritis.

The antiplatelet drug Cardiomagnyl is used for the prevention of cardiovascular diseases characterized by increased thrombus formation, including stroke or heart attack.

For preventive purposes, the Cardiomagnyl analogue is taken 150 mg on the first day, then 75 mg once a day on an ongoing basis.

If there have already been cases of heart attack or stroke, the drug is prescribed 150 mg daily.

Why is this necessary?

If you have suffered deep vein thrombosis of the lower or upper extremities, your doctor will most likely prescribe you indirect anticoagulants.
The main drug in this group today, both here and abroad, is warfarin. In our country, another drug of this group is used quite widely - phenylin. Other coumarin drugs (acenocoumarol, marcumar, marivan) can be used. The recommendations given are mostly applicable to any anticoagulant. The purpose of this medication is to prevent blood clots from recurring, which could cause your condition to worsen or cause life-threatening complications. The risk of recurrence of thrombosis is quite high during the first year after the first episode of the disease, therefore, taking into account various factors, warfarin is prescribed for a period of 2 to 12 months. In rare cases, longer therapy is performed. Indirect anticoagulants have no effect on an already formed blood clot.

To determine the duration of treatment, special (including genetic) blood tests are sometimes required to identify an increased tendency to blood clots.

A very large number of patients around the world receive the treatment you have prescribed. It is used not only in phlebology, but also in such areas of medicine as vascular surgery. In addition to deep vein thrombosis, the basis for prescribing anticoagulant therapy is often previous heart attacks, cardiac arrhythmias, valve and peripheral vessel replacement, and much more.

Warfarin or Xarelto - which is better for thrombosis and atrial fibrillation

Manufacturer: Bayer, Germany
Release form: film-coated tablets

Active ingredient: Rivaroxaban

The imported analogue of Xarelto is an original German drug that has no synonyms. This is a direct-acting anticoagulant, selectively suppresses factor Xa, as a result prevents the formation of blood clots and does not require regular blood tests to determine PTT and INR.

Doses of the Xarelto analog range from 2.5 to 15 mg. The doctor decides which one to use for certain indications.

Doses of up to 10 mg of Xarelto are prescribed for prophylaxis once a day, 20–30 mg per day is required for the treatment of thromboembolism, atrial fibrillation, and venous thrombosis.

It is important

Always tell any health care professional you see that you are taking anticoagulants. It is advisable to carry your “account” book or treatment diary with you.

Most dental procedures (except tooth extraction) can be performed without changing your treatment regimen. When removing a tooth, it is usually sufficient to use a tampon with a local hemostatic agent (aminocaproic acid, thrombin sponge).

If you have problems with blood pressure, you need to regularly monitor it and maintain it at a level not higher than 130/80 mmHg.

Warfarin or Eliquis – which is better?

Manufacturer: Pfizer, USA
Release form: film-coated tablets

Active ingredient: Apixaban

Eliquis is an analogue of Warfarin that does not require INR control; it is a direct anticoagulant.

The drug blocks factor Xa, which stimulates blood clotting, and prevents blood clots.

The American analogue Eliquis is taken to prevent thrombosis during endoprosthetics, stroke and thrombosis in patients with atrial fibrillation.

The Warfarin analog Eliquis is available in the form of tablets of 2.5 and 5 mg. The usual dosage regimen is 2 tablets per day, 2.5 mg for prevention, and 5–10 mg for the treatment of venous thrombosis and pulmonary embolism.

Reviews from patients indicate that the medication is well tolerated.

Monitoring the dose of warfarin

If the dose of the drug is selected, less frequent monitoring is sufficient - first once every 2 weeks, then once a month. The frequency of additional studies is determined separately. The need for an extraordinary determination of the INR may arise in a number of cases, which we will discuss below. If in any doubt, ask your doctor for advice.

Currently, there are portable devices for self-determination of INR (similar to systems for monitoring blood sugar levels in patients with diabetes), but their cost is very high and, in most cases of deep vein thrombosis, purchasing them is impractical.

Warfarin or Phenilin

, Ukraine
Release form: tablets

Active ingredient: Phenindione

Warfarin analog Phenilin is an indirect anticoagulant that blocks the enzyme K-vitamin reductase. It is used for the treatment and prevention of thrombosis and embolism, for prosthetic heart valves.

Doses are selected based on laboratory tests.

The disadvantage of the Phenilin analogue is the requirement for constant monitoring of not only prothrombin time and INR, but also regular analysis of coagulograms, thromboelastograms and platelet counts.

Characteristics of Warfarin

Warfarin is an indirect anticoagulant. Based on the active ingredient of the same name. The medicine is produced in different forms. It is used orally, intravenously. The latter action is more effective, since the active component minutes physiological barriers, immediately entering the systemic bloodstream.

The synthesis of vitamin K and clotting factors stops, so blood clots stop forming.

Absorption after oral administration occurs in the gastrointestinal tract. The binding of blood plasma proteins is high. Metabolism occurs in the liver, excretion occurs in bile and urine. If you take the medicine for a long time, follow a diet. Nutrition is prescribed by a phlebologist and nutritionist.

The product is indicated for use in the treatment and prevention of the following diseases:

• thrombosis;
• thromboembolism;
• heart attack caused by blockage by a blood clot;
• ischemic attacks, stroke.

The product is used only according to the instructions from the doctor; self-medication should not be carried out. This is due to the fact that it causes many negative reactions, even death, if used incorrectly.

When intestinal function decreases and abdominal pain occurs, drugs that have a complex effect are used - Neobutin, Trimedat, Duspatalin. All 3 drugs have analogues if the patient has contraindications or side effects. Read more in the article: “Which is better neobutin, trimedat or duspatalin.”

Side effects, contraindications for use

Negative actions occur frequently, especially in patients with individual intolerance. Therefore, before prescribing the drug, the patient is completely examined, conducting a detailed coagulogram. The following side effects are possible:

• increased bleeding;
• dyspepsia, impaired stool formation, discharge of blood in feces;
• inflammation of blood vessels, necrosis of skin areas;
• local and systemic allergic reactions;
• increased liver enzymes, jaundice;
• nose bleed.

The medicine is strictly contraindicated in cases of bleeding, severe kidney and liver diseases, disseminated intravascular coagulation syndrome, and a decrease in platelet count. It is not recommended to use it for inflammatory diseases, damage to veins and arteries. Not compatible with alcohol. Severe defects may occur with gastric and duodenal ulcers, endocarditis, arterial hypertension, a tendency to strokes and intracranial hemorrhages.

Candidiasis is a common pathology of the mucous membranes. The disease occurs when yeast-like fungi appear. Features of the drug The body of an adult is able to deal with the disease on its own. Read more in the article: “how to take flucostat for thrush.”

INR control

INR (international normalized ratio) is a blood test in a detailed coagulogram, recognized to show the quality of the coagulation system. If the value is above the average acceptable level, there is a risk of bleeding, especially with the use of certain categories of anticoagulants, which include Warfarin.

The drug greatly affects the number of clotting factors and the number of platelets. It prevents blood clotting by changing the INR level. The risk group includes patients with the following diseases:

• increased intracranial pressure;
• arterial hypertension;
• tendency to strokes and heart attacks.

Patients at risk are recommended to use the drug only in a hospital setting. When using it, blood is constantly donated for a coagulogram to determine the INR. This is inconvenient for the attending physician, so many of them prefer anticoagulants without affecting this indicator.

Answers on questions

How to replace Warfarin for atrial fibrillation

With atrial fibrillation or atrial fibrillation, the risk of blood clots increases; to prevent this phenomenon, Warfarin analogues and substitutes are prescribed - direct or indirect anticoagulants.

When is it better to take Warfarin - morning or evening?

The time of day does not matter when taking Warfarin. It is important to take regularly, at the same time.

Warfarin - direct or indirect anticoagulant

The drug belongs to the group of indirect anticoagulants, since it does not act directly on thrombin, but as a vitamin K antagonist.

What may affect treatment

• Any concomitant diseases (including “colds” or exacerbation of chronic diseases)
• The use of drugs that affect the blood coagulation system. This is especially true for a large class of drugs that includes aspirin. It also includes many drugs prescribed as anti-inflammatory and painkillers (diclofenac, ibuprofen, ketoprofen, etc.). As a mild analgesic during treatment with warfarin, it is better to use paracetamol in normal dosages. In any case, the need for a new medication and the duration of its use must be agreed with the attending physician. When warfarin and aspirin are prescribed simultaneously, the INR is maintained in the range of 2.0 - 2.5.
• The use of drugs that affect the absorption, excretion and metabolism of warfarin. Most often, it is necessary to take into account the prescription of broad-spectrum antibiotics and oral antidiabetic agents. However, taking any new medicine may change how warfarin works. If concomitant treatment is necessary, additional INR analysis is usually prescribed at the beginning and end of therapy.
• Diet changes.

Warfarin acts on blood clotting through vitamin K, which is found in varying amounts in food.

There is no need to avoid foods high in vitamin K! Nutrition should be complete. You just need to make sure that there is no significant change in their proportion in the diet, for example, depending on the season. If you significantly increase your intake of foods rich in vitamin K while on a stable dose of warfarin, this may greatly weaken its effect and lead to thromboembolic complications.

The maximum amount of vitamin K (3000 - 6000 mcg/kg) is found in dark green leafy vegetables and herbs (spinach, parsley, green cabbage), and in green tea up to 7000 mcg/kg; intermediate amounts (1000 - 2000 mcg/kg) - in plants with paler leaves (white cabbage, lettuce, broccoli, Brussels sprouts). A significant amount of the vitamin is found in legumes, mayonnaise (due to vegetable oils), and green tea. Fats and oils contain varying amounts of vitamin K (300 - 1000 mcg/kg), more of it in soybean, rapeseed, and olive oils. The content of vitamin K in dairy, meat, bakery products, mushrooms, vegetables and fruits, black tea, coffee is low (no more than 100 mcg/kg). Regular consumption of berries and cranberry juice may increase the effect of warfarin.

Small doses of alcohol with normal liver function do not affect anticoagulant therapy, but alcohol consumption must be treated with caution.

Taking multivitamins that contain vitamin K may reduce the effect of warfarin.

Bastions of warfarin, or its place among oral anticoagulants

Cardiology: news, opinions, training. 2015. No. 3. P. 76-80.

Drugs that block thrombus formation processes are widely used in all areas of modern medicine. Indications for their use are the treatment of thrombosis and systemic thromboembolic complications (TEC), as well as their prevention in situations accompanied by hyperactivation of the hemostatic system. One of the first anticoagulants, used for more than 60 years, are vitamin K antagonists (VKAs). Their mechanism of action is the blockade of vitamin K, the active form of which is involved in the final stages of the synthesis of blood coagulation factors II, VII, IX and X, as well as the natural anticoagulants protein C (PrC) and protein S (PrS). VKAs block the enzyme vitamin K reductase, which reduces the oxidized form of vitamin K to its active form. Violation of vitamin K activation is accompanied by the synthesis of inactive forms of vitamin K-dependent blood coagulation factors, the ability of which to coagulate reactions is significantly reduced (PIVKA proteins - Proteins, Induced Vitamin KAbsence). A hypocoagulable state develops, preventing the formation of thrombin, the formation of a fibrin clot and, consequently, the development and progression of thrombus formation.

The use of drugs in this group requires the practitioner to understand some of the nuances of their mechanism of action. Thus, the rate of decrease in the activity of blood coagulation factors under the influence of VKA is not the same. The activity of F VII decreases first, T1/2 of which in plasma is 4-6 hours; then - F IX and FX, whose T1/2 is 48 hours; the latter decreases the activity of F II - approximately 3-4 days from the start of taking the drug. Factor levels are restored in the same order after VKA withdrawal: F VII quickly returns to normal, later F IX and FX return to normal, and only after a few days F II returns to normal. It has now been established that in order to obtain a pronounced antithrombotic effect, a decrease in plasma levels of F II is of paramount importance. Therefore, when transferring a patient from heparins to VKA therapy, it is important to prescribe the latter 4-5 days before discontinuing heparin. Otherwise, a period of time occurs during which the patient remains without anticoagulant protection, which is accompanied by an increase in thrombus formation.

Also, when prescribing VKA, it is important to remember that already on the first day of treatment, a pronounced decrease in the activity of natural physiological anticoagulants—PrC and its cofactor PrS—develops, which enhances the hypercoagulable state at the beginning of treatment with VKA. Then there is a stabilization of their activity and even some restoration of its level, while the depression of blood coagulation factors persists. Therefore, it is advisable to avoid prescribing VKA for thrombophilias caused by a deficiency of these anticoagulants, as well as for DIC syndrome, when PrC activity sometimes decreases to a critical level.

The main representative of VKA, warfarin, was registered in Russia in 2001. Since then, the drug has been actively used in various fields of clinical medicine. Indications for its use are currently quite wide. They include the treatment and prevention of thrombosis and embolism of blood vessels in various clinical situations (acute and recurrent venous thrombosis, pulmonary embolism, transient ischemic attacks and strokes, secondary prevention of myocardial infarction and TEC after myocardial infarction, prevention of TEC in patients with atrial fibrillation (AF) ), lesions of the heart valves or with prosthetic heart valves, prevention of postoperative thrombosis).

However, the successful use of warfarin is based on compliance with certain requirements. Thus, an adequate therapeutic dose of the drug should be selected based on the level of prothrombin time (PT) in the interpretation of the international normalized ratio (INR), which requires competent organization of laboratory monitoring. Practitioners who use warfarin in their practice should remember that the inability to determine the INR is a contraindication to the use of warfarin, since it is the INR that allows diagnosing the state of the blood coagulation system. An increase in INR level >3.0 is dangerous for the development of hemorrhagic complications; a decrease <2.0 indicates a threat of thrombus formation [1, 2].

Before prescribing warfarin, the patient's medical history should be carefully collected, since hemorrhagic complications often develop not due to relatively high doses of VKA, but due to underestimation of the prognostic importance of previous bleeding episodes or concomitant diseases. It is possible to prevent hemorrhagic complications only with a correct assessment of bleeding risk factors using the HAS-BLED scale and timely laboratory monitoring of therapy using the INR level [3, 4].

The size of the maintenance dose of warfarin and the stability of its hypocoagulation effect depend on a number of congenital and acquired factors: nutritional characteristics and diet, concomitant somatic pathology (primarily liver and kidney diseases), taking other medications, the patient’s age, polymorphisms of the cytochrome P 450 CYP2C9 and vitamin K-epoxide reductase (VKORC 1), which determine increased or decreased sensitivity to warfarin, regularity of drug administration, and adequacy of laboratory monitoring.

The need to control all of the above factors often limits the use of warfarin in clinical practice. According to several prospective studies conducted among patients with AF in the USA and Europe, the frequency of warfarin prescription by practitioners is 55-67% of the required [5-7], while only 44% of patients achieve target INR values ​​[8-10 ]. According to our data, at the outpatient stage in this clinical situation, only 28.7% of patients take warfarin, of which only 43.5% have INR values ​​within the therapeutic range.

Currently, doctors have a real alternative to warfarin - new oral anticoagulants (NOACs): dabigatran ethoxylate, rivaroxaban, apixaban, edoxaban (registered in the USA in 2015).

Indications for their use are the prevention of systemic TEC in patients with non-valvular AF (dabigatran ethoxylate, rivaroxaban, apixaban), as well as the treatment of deep vein thrombosis and pulmonary embolism and the prevention of their relapse (dabigatran ethoxylate, rivaroxaban). Only rivaroxaban has a registered indication for use, such as the prevention of death due to cardiovascular causes and myocardial infarction in patients after acute coronary syndrome, which occurred with an increase in cardiac-specific biomarkers. Edoxaban is currently not registered in Russia.

NOACs by their mechanism of action are fundamentally different from warfarin: each of them selectively inhibits only one blood coagulation factor: dabigatran - F IIa (thrombin), rivaroxaban, apixaban, edoxaban - F Xa. At the same time, the PLA are direct

inhibitors of F IIa and FXa, i.e., unlike heparins and fondaparinux, they do not need to form a complex with antithrombin to exhibit an anticoagulant effect. The small size of the molecules of direct inhibitors of factors Xa and IIa makes it possible to inactivate not only F IIa and FXa circulating in the blood, but also the molecules of these factors located on the surface of the blood clot, and thereby limit the growth of the latter. In addition, dabigatran, rivaroxaban, apixaban and edoxaban, unlike heparins, do not bind to platelet factor 4, are not antigens and do not cause immune thrombocytopenia.

According to the results of randomized clinical trials (RCTs) conducted among patients with non-valvular AF [11–13], NOACs showed at least comparable effectiveness to warfarin in the prevention of cardioembolic stroke and systemic embolism. At the same time, dabigatran at a dose of 150 mg 2 times a day significantly exceeded the effectiveness of warfarin. According to published data, NOACs have shown advantages over warfarin in terms of the safety of their use - a significantly lower incidence of intracranial and life-threatening bleeding. In the population of patients with venous thrombosis and TEC in general, NOACs are comparable in effectiveness and safety to warfarin, and they are easier to use, which improves the quality of life of patients.

When deciding whether to prescribe NOACs in patients with AF, practitioners should clearly understand the difference between the concepts of valvular and non-valvular AF.

For example, a survey conducted among 500 Italian doctors showed that only 57.1% of cardiologists and 67.9% of internists believe that the definition of these terms in modern medical literature is sufficiently clear and precise [14]. However, according to current clinical guidelines, the concept of “valvular” refers to atrial fibrillation that develops in patients with implanted heart valves (ICS) or suffering from mitral stenosis [3, 15].

The separation of such patients into a special group is due to the presence of proven differences in the mechanisms of thrombus formation in the cavities of the heart in comparison with other forms of AF. Mitral stenosis, even occurring in sinus rhythm, is associated with an increased risk of thromboembolic events. At the same time, the risk of thrombosis increases significantly with the addition of AF [16]. Thus, before the use of anticoagulants in the treatment of such patients, 25% of patients with mitral stenosis died from systemic TEC [17, 18]. According to KH Olesen [19], with the addition of AF, 1/3 of cases of TEC in patients with mitral stenosis develop within the first month from the moment of its onset, and another 2/3 - within the first year.

At the same time, other forms of mitral valve damage (myxomatous mitral valve degeneration, Barlow’s disease), manifested by mitral regurgitation, are not accompanied by an increased risk of thrombus formation, which in such situations is comparable to the incidence of TEC due to isolated AF [20, 21].

Patients with ICS require long-term (lifelong) use of anticoagulants even in sinus rhythm [22]. The presence of a foreign surface promotes the activation of platelets and blood coagulation factors with the subsequent formation of a fibrin network and the formation of thrombotic masses on the surface of the artificial valve [23]. In the absence of anticoagulant therapy, the average incidence of TEC is 4% per year. The risk of TEC in patients with ICS in the mitral position is approximately 2 times higher than in patients with ICS in the aortic position [24]. During VKA therapy, the incidence of systemic TEC, primarily strokes, decreases to 0.7-1.0% and to 2.2% when using aspirin [24, 25].

Given the different mechanisms of thrombus formation, the presence of mitral stenosis or ICS was an exclusion criterion for RCTs with new oral anticoagulants. However, after obtaining encouraging results for the prevention of TEC in patients with non-valvular AF in the RE-LY study, the RE-ALIGN RCT was initiated, which included 252 patients undergoing ICS implantation in the mitral or aortic position.

Target

This study is to compare the effectiveness and safety of anticoagulant prophylaxis with dabigatran ethoxylate and warfarin. 168 patients were randomized to receive dabigatran and 84 to warfarin. The groups were comparable in terms of basic baseline characteristics. The choice of dose of dabigatran ethoxylate (150, 220 or 300 mg/day) was based on renal function [15]. The initial dose of dabigatran was 150 mg in 15% of patients, 220 mg in 54%, and 300 mg in 31%. In 24% of patients, the dose was subsequently increased, in 8% the drug was discontinued due to failure to achieve the required concentration at the maximum dose.

The RE-ALIGN study was stopped early because the incidence of thromboembolic and hemorrhagic complications was significantly higher in the dabigatran ethoxylate group. Thus, ischemic episodes were noted in 5% of patients taking NOACs and in no patients in the warfarin group; Major bleeding was reported in 4% and 2% of patients, respectively [15]. Most likely, the reason for these results lies in the different mechanism of action of warfarin and dabigatran ethoxylate: VKA inhibits several blood coagulation factors (II, VII, IX, X), having a blocking effect on both the extrinsic, intrinsic, and general pathways of blood coagulation, while dabigatran ethoxylate inhibits only thrombin, which does not lead to a complex effect on the hemostatic system [26-28].

Thus, at present, patients with ICS and mitral stenosis, both due to AF and sinus rhythm, should use only warfarin for anticoagulant prophylaxis.

Non-valvular AF also quite often requires the prescription of warfarin. If we talk about special categories of patients, in case of severe renal failure (creatinine clearance <15 ml/min), its priority is undeniable.

It cannot be considered advisable to replace warfarin with another antithrombotic drug if its hypocoagulant effect is stable and the dose does not change for many months or even years. This is confirmed by the SPORTIF study, which included 3566 patients, which showed that patients whose INR was within the therapeutic range had not only a significantly lower risk of developing thrombosis and hemorrhage, but also a reduced incidence of deaths [29]. In another study by DM Witt et al. [30] assessed the safety of long-term warfarin use in 2504 patients. The patients were divided into 2 groups. The INR in representatives of group 1 corresponded to the target values ​​for at least 6 months, while the dose of the drug did not change; patients in group 2 required changing the warfarin dose one or more times to maintain the INR. The authors found that in the stable group the incidence of hemorrhagic complications was 3 times less.

Thus, despite the development and introduction of innovative anticoagulant drugs into clinical practice, in certain situations the use of warfarin is more preferable. Moreover, in the current economic situation, anticoagulant therapy with warfarin is the most accessible strategy for the treatment and prevention of TEC.

Information about authors

Tatyana Valentinovna Pavlova

— Doctor of Medical Sciences, Professor of the Department of Cardiology and Cardiac Surgery

Place of work: Samara State Medical University, Ministry of Health of Russia, Samara Regional Clinical Cardiology Dispensary

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Dmitry Viktorovich Duplyakov

— Doctor of Medical Sciences, Deputy Chief Physician

Place of work: State Budgetary Educational Institution of Higher Professional Education "Samara State Medical University of the Ministry of Health and Social Development of Russia" State Budgetary Healthcare Institution "Samara Regional Clinical Cardiological Dispensary"

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