Current issues of warfarin therapy for practicing physicians

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.

Characteristics of Elekvis

Eliquis is an anticoagulant based on apixaban. It inhibits the release of Hageman factor, which blocks blood clotting. Prothrombinase activity decreases, but there is no direct effect on platelet aggregation. Prothrombin time, APTT, and INR increase. However, these indicators are not required to determine the patient’s well-being.

If taken in tablet form, absorption occurs in the intestines. Bioavailability is average, binding to blood plasma proteins is high. Excretion occurs in the form of metabolites, mainly through the intestines, only partially through the kidneys. Indications for use:

• thromboembolism detected during prosthetics of the musculoskeletal system;
• risk of stroke for patients at risk;
• thrombosis of deep veins or arteries.

The product can be used even for diabetes mellitus and heart failure at the stage of complications. It is these diseases that affect the cardiovascular system, causing increased aggregation. A preliminary examination is carried out.

Side effects and contraindications

The drug affects systemic blood flow and may cause negative consequences. This is especially true for patients who are at risk but use the drug. The following types of adverse reactions are distinguished:

• decrease in red blood cells, platelets;
• atrial fibrillation;
• allergy;
• surges in blood pressure, hematomas, hemoptysis;
• gastrointestinal bleeding, dyspepsia;
• changes in the amount of liver enzymes, jaundice;
• hematuria.

Eliquis has fewer side effects than warfarin or other drugs that do not require INR control. But before prescribing it, a medical history is required. The medicine has the following contraindications:

• increased sensitivity;
• risk of bleeding;
• severe diseases of the liver, kidneys, gastrointestinal tract, the presence of a malignant neoplasm;
• severe damage to the spinal cord and brain, recent surgery, stroke, varicose veins, aneurysm;
• pregnancy, lactation, minor age.

Side effects rarely occur if the drug is used under the supervision of a doctor in a hospital setting. If any of them appears, the remedy is immediately discontinued. After carrying out laboratory and instrumental examination methods, it will be replaced with an analogue without an identical effect.

How to monitor treatment

Carrying out antithrombotic (anticoagulant) therapy can save your life and health, but requires increased attention and mandatory compliance with the doctor’s recommendations. Warfarin is a drug that reduces the ability of blood to clot, so its excess can lead to hemorrhagic complications, i.e. to bleeding. To avoid complications, the required dose of warfarin is monitored using a blood test called INR (International Normalized Ratio). This may sometimes be referred to as INR in laboratory responses. During the entire period of taking warfarin, the INR should be in the range of 2.0 - 3.0. If the INR is less than 2.0, then blood clotting is not reduced and thrombotic complications are possible. If the INR is more than 4.0, hemorrhagic complications are very real. An increase in INR from 2.5 to 4.0 indicates the need to reduce the dose of the drug, but usually does not pose a direct threat. For some diseases, the required upper limit of INR is 4.0 - 4.4.

In the absence of the ability to determine INR, monitoring by prothrombin time (PT) is acceptable, but this method is much less reliable. No other blood tests are needed to calculate your warfarin dose. To identify the side effects of the drug, a general blood test, urine test and some biochemical tests are periodically prescribed.

Current issues of warfarin therapy for practicing physicians

Currently, the effectiveness of Warfarin has been proven for the prevention of thromboembolic complications in patients with atrial fibrillation (AF), after heart valve replacement, in the treatment and prevention of venous thrombosis, as well as in the secondary prevention of cardiovascular episodes in patients who have suffered acute coronary syndrome [1,2 ]. Use of Warfarin for atrial fibrillation The main cause of death and disability in patients with AF without damage to the heart valves is considered ischemic stroke (IS), which is cardioembolic in its mechanism [3–6]. The source of thrombotic masses is in most cases thrombosis of the left atrial appendage, less often - the cavity of the left atrium. Cardioembolic strokes in patients with AF are characterized by extensive cerebral infarction, leading to severe neurological deficits, which in most cases entails permanent disability of the patient [7]. According to large studies, the risk of stroke in patients with AF increases 6 times compared to those with sinus rhythm; it is comparable in paroxysmal and permanent forms of AF and does not depend on the success of antiarrhythmic therapy [3–6,8,9]. The reduction in the risk of IS during warfarin therapy in patients with AF without valvular heart disease has been proven by large randomized studies; it is 61% [10–14]. The determining factor in the choice of antithrombotic therapy tactics in each individual patient with AF is the presence of risk factors (RFs) for thromboembolic complications (TEC). The basis for stratifying a patient with AF is the CHADS2 score, first published in 2001 and retained as the initial risk assessment in the updated guidelines in 2011 [1]. Factors such as chronic heart failure (CHF), arterial hypertension (HTN), age ≥ 75 years and diabetes mellitus are scored 1 point, and IS/TIA or a history of systemic embolism – 2 points. The risk is assessed as high if there are 2 or more points. In 2009, a group of researchers from Birmingham led by G. Lip [15] proposed a new system for stratifying patients, which they called CHA2DS2–VASc. The basis was a 1-year follow-up of a cohort of 1577 patients with AF without heart valve disease who did not receive anticoagulant therapy. The CHA2DS2–VASc scale divides factors into “major” and “clinically associated minor.” “Major” includes previous IS/TIA/systemic embolism and age ≥ 75 years (estimated at 2 points), and “clinically associated minor” includes CHF or asymptomatic decrease in left ventricular ejection fraction ≤40%, hypertension, diabetes mellitus, age 65–74 years, female gender and vascular diseases (myocardial infarction, atherosclerosis of peripheral arteries, atherosclerosis of the aorta), scored 1 point. The fundamental changes are the assessment of female gender and vascular diseases as risk factors and the division of age into two gradations (Table 1). The CHADS2 scale is recommended for the initial determination of the risk of VTE in patients with MA. For patients with a CHADS2 score of ≥2, long-term VKA therapy is indicated under the control of an INR of 2.0–3.0, unless there are contraindications. For a more detailed and thorough risk calculation (in patients with a score of 0–1 on the CHADS2 scale), it is recommended to evaluate the presence of “large” and “clinically associated small” risk factors. Patients with 1 “major” or ≥2 “clinically associated small” risk factors are at high risk of TEC and are recommended to receive VKA therapy unless contraindicated. Patients who have 1 “clinically associated minor” risk factor have an average risk of TEC and are recommended to be treated with VKA or acetylsalicylic acid (ASA) at a dose of 75–325 mg per day. Patients who do not have RF or are at low risk may be prescribed ASA 75–325 mg, or they do not need any antithrombotic therapy. In addition to patients with chronic atrial fibrillation, anticoagulants are required for patients who are planning to restore sinus rhythm. The risk of systemic thromboembolism during cardioversion without the use of anticoagulants reaches 5%, and the use of 4-week warfarin therapy before and after cardioversion can reduce this risk to 0.5–0.8% [16–17]. All patients with a paroxysm of AF lasting 48 hours or more, or when the duration of the paroxysm cannot be determined, are indicated for VKA therapy with maintenance of an INR of 2.0–3.0 for three weeks before and four weeks after cardioversion, regardless of the method of restoring sinus rhythm (electrical or pharmacological). The exclusion of thrombosis of the appendage and cavity of the left atrium according to the emergency echocardiography data allows us to approximate the timing of cardioversion and restore sinus rhythm after achieving the target INR range of 2.0–3.0. However, in this case, the patient is advised to take Warfarin therapy for 4 weeks to exclude normalization thromboembolism. after cardioversion. When performing urgent cardioversion, heparin therapy (unfractionated or low molecular weight heparin) is indicated. If the AF paroxysm lasted 48 hours or more or when it is impossible to determine the duration of the paroxysm, after emergency cardioversion, VKA therapy is indicated for 4 weeks. If the duration of the paroxysm did not exceed 48 hours in a patient who does not have FR TEO, it is possible to perform cardioversion after the administration of heparin without the subsequent administration of Warfarin. In patients with risk factors for stroke or a high probability of recurrent AF, VKA therapy is indicated indefinitely, regardless of maintenance of sinus rhythm immediately after cardioversion. Approaches to anticoagulation therapy for cardioversion performed in connection with atrial flutter are similar to those used for atrial fibrillation [1–2]. Warfarin in patients with artificial heart valves The main danger to the life of patients with artificial heart valves is thromboembolic complications, the source of which are blood clots that form on the surface of the valve prosthesis. The risk of prosthetic valve thrombosis, a life-threatening complication, in the absence of VKA therapy reaches 8–22% per year [2,18]. Prescribing Warfarin reduces the risk of thromboembolism by 75%, therefore, when installing mechanical prosthetic heart valves, VKAs are mandatory and cannot be replaced by ASA. The exception is patients with bioprostheses without FR TEO, the duration of VKA therapy for whom is three months; in all other cases, treatment should be lifelong. Risk factors for patients with artificial heart valves are a history of thromboembolism, AF, circulatory failure, and atriomegaly. The level of anticoagulation in the vast majority of cases should be within the INR range of 2.5–3.5. The exception is patients after implantation of a modern bicuspid aortic valve prosthesis in the absence of other risk factors for thromboembolism, in this case the target INR range is 2.0–3.0 [2.18]. Indications for VKA therapy in patients after heart valve replacement are presented in Table 2. Warfarin in the treatment of venous thrombosis The duration of warfarin therapy in patients after deep vein thrombosis (DVT) or pulmonary embolism (PETA) associated with a reversible factor is 3 months. The duration of warfarin therapy in patients after unprovoked DVT/TEOLA is at least 3 months. In the future, it is necessary to evaluate the risk-benefit ratio of continuing VKA therapy. Long-term (lifelong) use of VKAs is recommended for patients who have experienced a first episode of unprovoked proximal DVT/TEOLA, have adequate INR monitoring, and do not have bleeding risk factors. Long-term VKA therapy is indicated for patients who have experienced a second episode of unprovoked venous thrombosis. The principles of treatment for asymptomatic and symptomatic venous thrombosis are similar. The level of anticoagulation for the prevention of recurrent venous thrombosis corresponds to an INR of 2.0–3.0 [2]. VKA in the secondary prevention of coronary heart disease The effectiveness of Warfarin in the secondary prevention of coronary artery disease was studied in the ASPECT-2, APRICOT-2, WARIS-II, CHAMP studies [19–22]. These studies differed in design, anticoagulation regimens, the presence of concomitant ASA therapy and the dose of the latter. The effectiveness of the combination of Warfarin and ASA was higher than ASA monotherapy, but the risk of hemorrhagic complications was higher in the combination therapy group. In this regard, in routine clinical practice, without special indications, Warfarin is not prescribed to patients with coronary artery disease. Practical aspects of VKA therapy Warfarin therapy should be selected based on a dose titration schedule to achieve target INR values. Before prescribing Warfarin, it is necessary to assess the presence of contraindications, the risk of bleeding in the patient, and also conduct an examination aimed at verifying potential sources of bleeding. Absolute contraindications to the use of Warfarin are an allergy to the drug, a history of hemorrhagic stroke, active bleeding, and significant thrombocytopenia. All other conditions are relative contraindications, and the choice is made based on the individual balance of benefit and risk of bleeding. Before prescribing Warfarin, it is necessary to clarify whether the patient has a history of hemorrhagic complications and to conduct an examination aimed at clarifying the status of potential sources of bleeding. The plan for mandatory and additional examination is presented in Figure 1. It is necessary to assess the risk of bleeding in all patients before prescribing antithrombotic therapy, taking into account the comparable risk of ASA and Warfarin, especially in elderly patients. In 2010, experts from the European Society of Cardiology introduced the HAS-BLED scale, which allows one to calculate the risk of bleeding in a patient. The risk is assessed as high if there are ≥3 points, however, this is not a contraindication for anticoagulant therapy, but regular monitoring is required during VKA or ASA therapy (Table 3). As a starting dose of Warfarin, it is advisable to use 5–7.5 mg during the first two days with further titration of the dose, focusing on the achieved INR level (Fig. 2). Lower starting doses of Warfarin (5 mg or less) are recommended for patients over 70 years of age, with low body weight, CHF or renal failure, as well as for patients with underlying liver dysfunction, concomitant use of amiodarone, and patients who have recently undergone surgery. The American recommendations of 2012 [2] indicate the starting dose of Warfarin (10 mg), however, taking into account the difference between the American population and the Russian population, as well as the increased risk of bleeding during the saturation period, it is advisable not to exceed the initial starting dose 7. 5 mg. In addition, immediately prescribing high starting doses of Warfarin (10 mg or more) is not recommended, as this leads to a decrease in the level of the natural anticoagulant protein C, which can lead to the development of venous thrombosis. During dose selection, INR monitoring is carried out once every 2–3 days. After receiving the INR results within the target range, the dose of Warfarin twice is considered selected, and in the future, INR monitoring is carried out once a month. The target INR range for patients with AF without heart valve damage and after venous thrombosis when using Warfarin without antiplatelet agents is 2.0–3.0, when combined with antiplatelet agents – 2.0–2.5. In patients after implantation of artificial heart valves, in most cases the target INR is 2.5–3.5. Currently, polymorphisms have been identified in the main biotransformation gene of Warfarin - CYP2C9 and the target molecule of its action - VKORC1. Carriers of mutant alleles require a lower maintenance dose of Warfarin, while the frequency of bleeding and episodes of excessive hypocoagulation is higher. Currently, there are algorithms for calculating the dose of Warfarin based on genotyping [23–28], the implementation of which is quite possible both from the point of view of routine practice and from an economic point of view. However, the recommendations [1–2] state that in the current absence of data from specific randomized trials, the use of a pharmacogenetic approach to VKA prescription for all patients is not recommended. Warfarin is a drug that is characterized by interindividual differences in drug response due to a number of factors, both external (diet, drug interactions) and internal (the patient's physical condition, age), as well as genetically determined. To exclude unwanted drug interactions when prescribing concomitant therapy, preference should be given to drugs whose effect on the anticoagulant effect of Warfarin is insignificant (Fig. 3). The use of drugs that affect the metabolism of VKA requires monitoring the INR after 3–5 days and, if necessary, adjusting the dose of Warfarin. Patients taking anticoagulants require a patronage system, which is due to the need for regular monitoring of INR, drug dose adjustment and assessment of other factors affecting INR values. It is advisable to give the patient a reminder. Fluctuations in INR values ​​can be caused by several factors: 1. Laboratory error. 2. Significant changes in dietary vitamin K intake. 3. The influence of changes in somatic status, taking medications, alcohol and substances of plant origin on the metabolism of Warfarin. 4. Lack of adherence to treatment with Warfarin. To exclude food interactions, patients taking Warfarin should be advised to adhere to the same diet, limit alcohol consumption, and not take medications and herbal substances on their own without consulting a doctor, taking into account the possibility of their influence on the metabolism of Warfarin. INR values ​​from measurement to measurement in the same patient may vary within the therapeutic range. Fluctuations in INR that are slightly outside the therapeutic range (1.9–3.2) are not grounds for changing the dose of the drug. It is necessary to monitor the INR value after 1 week, after which, if necessary, adjust the dose of Warfarin. To avoid significant fluctuations in the level of anticoagulation, it is advisable to reduce the dosage of Warfarin at INR values ​​of more than 3.0 but less than 4.0, without skipping the next dose of the drug. There is no average daily dose of Warfarin. The dose should be adjusted based on the target range. The question of what is considered true resistance to Warfarin remains open to this day. It may be worth talking about true resistance if the prescription of a dose of Warfarin exceeding 20 mg per day did not lead to the achievement of a therapeutic level of anticoagulation. This is the so-called “pharmacodynamic (or true) resistance”, which can be confirmed by identifying a high concentration of Warfarin in the blood plasma in the absence of an increase in INR values. The number of such cases among patients, according to specialized studies, does not exceed 1% [27,28]. Risk of bleeding during VKA therapy The development of hemorrhagic complications is the most dangerous side effect of VKA therapy and the main reason for non-prescription of drugs in this group. The incidence of major bleeding during warfarin therapy is about 2%, and fatal bleeding is about 0.1% per year [3–7,29–32]. Non-hemorrhagic side effects of Warfarin are very rare - allergic reactions (itching, rash), gastrointestinal disorders (nausea, vomiting, abdominal pain), transient baldness. The main risk factors for hemorrhagic complications are the degree of hypocoagulation, advanced age, interactions with other drugs and invasive interventions, and initiation of therapy [29–32]. To improve the safety of therapy, it is necessary to identify contraindications and potential sources of bleeding, take into account concomitant pathology (CHF, chronic renal failure, liver failure, postoperative period) and therapy. The occurrence of major bleeding (i.e., leading to death, cardiac/respiratory problems, other irreversible consequences, requiring surgical treatment or blood transfusion) always requires urgent hospitalization of the patient to find its cause and quickly stop it. Resumption of warfarin therapy after major bleeding is possible only if the cause of the bleeding is found and eliminated. The target INR range should be reduced to 2.0–2.5. The occurrence of minor hemorrhagic complications (any internal or external bleeding that does not require hospitalization, additional examination and treatment) requires temporary discontinuation of Warfarin until the bleeding stops, a search for its possible cause and dose adjustment of Warfarin. In the event that small bleeding occurs against the background of the values ​​of the TC> 4.0, it is necessary to find out the possible causes of the development of excessive hypocoagulation (primarily the intake of drugs affecting AV metabolism). It is possible to resume therapy with warfarin after stopping small bleeding with many <3.0. In the case of recurrence of small hemorrhages, the target level of the INC must be reduced to 2.0–2.5. Excessive anticoagulation is the predictor of the development of bleeding, so the doctor’s attention requires any, even asymptomatic increase in the level of many higher therapeutic range. It is necessary to clarify in the patient the possible causes of increasing many (primarily drug interactions, as well as such reasons for the development of excessive hypocoagulation as COL, liver failure, hyperthyroidism, alcohol consumption). Identification in the patient of asymptomatic increase in the Multi in the absence of the need for invasive intervention requires a temporary cancellation of warfarin with the subsequent adjustment of its dose, but there is no need to introduce freshly frozen plasma or a prothrombin complex concentrate. Vitamin K contributes to the synthesis of vitamin -depending factors of Curtains De Novo due to the effect of carboxylation processes, so the effect after taking it occurs slowly and it is useless to quickly restore vitamin -dependent coagulation factors. The domestic drug phytomenadion in capsules at 0.1 g, which contains a 10% solution in vitamin K1 oil, cannot be used to reduce the dose of vitamin K equal to 10 mg, causes resistance to the action of AVK during the disposal 7-10 days. The risk of bleeding increases during invasive interventions and surgical operations. The basis of the correctly selected periodic tactics in a patient taking warfarin is an assessment of the risk of bleeding and thromboembolic complications (Fig. 4). In 2010, the ESC [1] recommendations prescribe the early resumption of anticoagulant therapy in patients with high risk of thromboembolic complications, subject to adequate hemostasis. ESC experts also published an addition to existing recommendations [33] about the absence of the need to cancel warfarin in patients with a high risk of stroke during dental extraction, removal of cataracts and endoscopic removal of polyps from the gastrointestinal tract, provided that modern technology is used and adequate hemostasis. In this case, in the author’s own opinion, it is advisable to skip the intake of warfarin on the eve of the intervention, provided that adequate hemostasis is observed. Currently, there are portable devices for measuring the level. The meta -analysis conducted by S. Heneghan in 2006 [34] showed that the self -control of the IMB improves the outcome of patients receiving warfarin. However, a necessary condition for adequate self -control using a portable device is medical observation for the correct interpretation of the results of the resulting analysis and correction of factors that affect anticoagulant therapy. The conclusion is currently warfarin is the main drug for the prevention of thromboembolic complications in patients with MA, after prosthetics of heart valves, transferred venous thrombosis. The vitamin K antagonists determining the effectiveness of therapy with the antagonists is the target range of the IN, which every patient needs to be achieved. The frequency of hemorrhagic complications, as well as the need for constant laboratory control, are the main causes of the unnowanment or cancellation of warfarin in real clinical practice. The emergence of new antitrombotic drugs that do not require regular laboratory control also requires the acquisition by doctors of practical clinical experience. Existing selection algorithms for an individual supporting dose of warfarin, the patronage system and regular laboratory control of the INC can increase the safety of anticoagulant therapy.

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How to take the drug

Warfarin is available in 2.5 milligram tablets. Most often, the “starting” and “maintenance” doses of the drug are 5 milligrams (2 tablets) per day. In many cases, for more “fine” adjustments, you will change the dose of the medicine that you take not per day, but per week. This may require either dividing the tablet in half or taking different numbers of tablets on different days. To make it easier to monitor your treatment, you may be given a special account book, or you can keep a notebook with a treatment diary, where it is useful to note the doses of warfarin, INR level, and other laboratory data.

Warfarin is taken in the entire daily dose at one time, preferably at 17:00 - 19:00. Take the tablets with water. It is not recommended to take it with food, but can be taken on an empty stomach. Phenyline is usually taken in 2 doses.

Warfarin analogues - review of new generation drugs with prices

The drug is an anticoagulant, prevents blood clotting, and can be used for a long time. Warfarin is available in the form of tablets with the same active ingredient. If it is not suitable for the patient due to allergies or lack of effect, it is replaced with analogues. Your doctor will help you choose a drug.

General information about the drug Warfarin

The medicine has an indirect anticoagulant effect, inhibits the synthesis of substances in the liver that ensure blood clotting. It prevents the formation of new blood clots and prevents the expansion of existing ones. Compound:

The drug is used for the prevention and treatment of diseases. Indications for use:

• deep vein thrombosis;
• atrial fibrillation;
• pulmonary embolism;
• myocardial infarction;
• prosthetic heart valves.

The tablets are taken orally once a day at the same time. The dose depends on the severity of the disease and the result of blood clotting control (laboratory indicator - INR). Do not change the dosage or stop treatment on your own. In the first 2 days, take 2.5–5 mg of Warfarin, then the dose is adjusted depending on the INR.

If the indicator is 2–4.5 units, a maintenance dosage is prescribed

Elderly, debilitated patients who are at risk are initially prescribed lower doses.

Contraindications and side effects

The product should not be taken if you are hypersensitive to the components of the composition. Other contraindications:

• internal bleeding;
• bacterial endocarditis;
• liver, kidney failure;
• obstructive jaundice;
• acute DIC syndrome;
• protein deficiency;
• thrombocytopenia;
• hemorrhagic diathesis;
• exacerbation of stomach ulcers;
• alcoholism;
• cerebral hemorrhage;
• childhood;
• intolerance to the components of the composition;
• severe hypertension;
• recent or future complex operations, diagnostic procedures;
• there is no possibility of assessing the blood coagulation system in the laboratory.

When treated with Warfarin, side effects occur infrequently. Possible:

• increased bleeding;
• anemia;
• vomiting, nausea, diarrhea, abdominal pain;
• eosinophilia;
• rash, urticaria, skin itching, eczema, necrosis;
• vasculitis;
• jaundice;
• hair loss;
• nephritis, urolithiasis;
• tubular necrosis;
• hand-foot syndrome.

Reception features

The International Normalized Ratio (INR) is a standard for determining the coagulation activity of blood elements. When taking Warfarin, you need to monitor the indicator. Its normalization is inversely proportional to coagulability. At high INR values ​​it slows down and hypocoagulation increases.

Under different conditions of the body, the norm of the indicator changes:

• healthy body – 0.85–1.25;
• chronic atrial fibrillation – 2–3;
• mechanical valve prosthesis – 2–3;
• pulmonary embolism, heart defects – 2–3;
• prevention of thrombosis in deep veins after operations, treatment of venous thrombosis – 2–3.

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• When the INR is less than 2, the blood is considered thick, the drug is ineffective, so its dosage is increased.
• If the value is greater than 3, the blood is thin and bleeding may develop; the dosage is reduced.
• Many factors influence the value of the indicator. This:

• violation of the diet - an increase in canned food rich in acetylsalicylic acid increases the INR value, vitamin K decreases it;
• alcohol, smoking;
• improper collection of venous blood - the indicator can be affected by temperature, time the blood is in the test tube, and accidental ingestion of drugs;
• age – in children and the elderly the indicator is often underestimated;
• diseases of the kidneys, thyroid gland, infectious complications.

New generation warfarin analogues

Taking the pill comes with many complications, including constantly measuring the International Normalized Ratio value. New blood thinners have been developed. It is not always possible to take a Warfarin analogue without INR control. The drugs have fewer side effects and are used for treatment and prevention.

Disadvantages: high cost, they are rarely on sale.

Pradaxa

A new generation antithrombotic substitute for Warfarin is used for the prevention of venous thromboembolism, stroke, systemic thromboembolism, and atrial fibrillation. Pradaxa capsules are taken 1 pc. 1-2 times a day, regardless of meals. Description:

1. Active ingredient: dabigatran etexilate.
2. Mechanism of action: anticoagulant effect, inhibits thrombin activity.
3. Side effects in comparison with the analogue: thrombocytopenia, urticaria, bronchospasm, intracranial bleeding, hematomas, hemoptysis, dyspepsia, dysphagia, gastroesophagitis, hyperbilirubinemia, hemarthrosis, hematuria, arrhythmia, hypertension.
4. Contraindications: renal failure, active bleeding, hemorrhagic diathesis, liver and kidney dysfunction, age under 18 years.
5. Price, rubles: 3175 for 60 capsules.

Xarelto

A direct-acting anticoagulant is indicated for the prevention of venous thromboembolism after major surgery. Xarelto is taken orally, regardless of food intake, 10 mg once a day for a course of 2-5 weeks. Description:

1. Active ingredient: rivaroxaban.
2. Mechanism of operation: prolongs the time of thrombus formation, protects against internal coronary bleeding.
3. Side effects compared to the analogue: anemia, hemorrhagic complications, weakness, dizziness, shortness of breath, angina, hematomas, dyspepsia, headache, allergic dermatitis, fever, jaundice.
4. Contraindications: internal bleeding, pregnancy, lactation, age under 18 years, atherosclerosis, cardiovascular failure.
5. Price, rubles: 9475 for 100 tablets.

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.

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.

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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.

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.

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:

• 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.

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.

Warfarin

• When used simultaneously with anticoagulants and drugs with antiplatelet activity, the risk of bleeding increases.
• When used simultaneously with anticholinergic drugs, memory and attention problems may occur in elderly patients.
• When used simultaneously with inhibitors of microsomal liver enzymes, the anticoagulant effect of warfarin is enhanced and the risk of bleeding increases.
• When used simultaneously with hypoglycemic agents, sulfonylurea derivatives may enhance their hypoglycemic effect.

With simultaneous use, the anticoagulant effect of warfarin is reduced by: inducers of microsomal liver enzymes (incl.

barbiturates, phenytoin, carbamazepine), glutethimide, griseofulvin, dicloxacillin, coenzyme Q10, mianserin, paracetamol, retinoids, rifampicin, sucralfate, phenazone, cholestyramine, glutethimide, vitamin K, acitretin, diuretics (spironolactone and chlorthalidone), aminoglutethimide, mercaptopurine, mitotane, cisapride, ginseng preparations, glucagon.

It is possible to enhance the anticoagulant effect of warfarin and increase the risk of bleeding when used simultaneously with heparin, NSAIDs (including acetylsalicylic acid), pyrazolone derivatives (including

with phenylbutazone, sulfinpyrazone), tramadol, dextropropoxyphene, a combination of paracetamol and codeine, antiarrhythmic drugs (including amiodarone, quinidine, propafenone, moracizine), antimicrobial and antifungal agents (including

with chloramphenicol, metronidazole, cefamandole, cefmetazole, cefoperazone, cefazolin, erythromycin, azithromycin, roxithromycin, clarithromycin, co-trimoxazole, miconazole, ketoconazole, itraconazole, fluconazole, nalidixic acid, ciprofloxacin, norf loxacin, ofloxacin, aminosalicylic acid, benzylpenicillin, doxycycline, isoniazid , neomycin, tetracyclines, aztreonam), glibenclamide, valproic acid, quinine, proguanil, cyclophosphamide, methotrexate, fluorouracil, with combinations of etoposide and vindesine or carboplatin, ifosfamide with mesna, tamoxifen, flutamide, interferon alpha (for chronic hepatitis C), interferon beta , saquinavir, clofibrate, ciprofibrate, fenofibrate, gemfibrozil, cimetidine, lovastatin, fluvastatin, simvastatin, piracetam, danazol, tramadol.

1. When used simultaneously with tricyclic antidepressants, disopyramide, felbamate, terbinafine, allopurinol, dipyridamole, chloral hydrate, ranitidine, ascorbic acid, and tocopherol, data on drug interactions are ambiguous.
2. In patients with chronic alcoholism taking disulfiram, an increase in the effects of warfarin was observed.
3. When used simultaneously with cholestyramine, the absorption and bioavailability of warfarin is reduced.

Cases of liver damage have been reported when used concomitantly with ticlopidine. The anticoagulant effect of warfarin does not change.

• When used simultaneously with phenazone, the concentration of warfarin in the blood plasma decreases.
• When used concomitantly with phenytoin, an initial increase in anticoagulant activity followed by a decrease has been reported.
• When used simultaneously with fluoxetine, trazodone, and vitamin E, there are reports of increased effects of warfarin.
• When used simultaneously with cyclosporine, a mutual decrease in effects is observed.
• When used simultaneously with enoxacin, the clearance of the R-isomer, but not the S-isomer, decreases, while the prothrombin time does not increase.

When used simultaneously with ethacrynic acid, the diuretic effect and hypokalemia may be enhanced, because as a result of competition for binding to plasma proteins, the concentration of free (active) ethacrynic acid increases.

Regular alcohol consumption may reduce the effects of warfarin, apparently due to the induction of liver enzymes. However, if the liver is damaged, the effects of warfarin may be enhanced.

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 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.

How effective is it to use analogues?

If a man or woman is at risk of thrombosis, it is dangerous to his health and life. Necrosis of part of the tissue or the entire organ may occur. For example, with stroke and ischemic heart attack. Therefore, people at risk require anticoagulant therapy. Warfarin is most often used. However, in the process of its use, it is necessary to constantly analyze the quality of the coagulation system, APTT, and INR. This is inconvenient for patients undergoing outpatient treatment.

Therefore, it is recommended to use Pradaxa, Eleuvis, Xarleto; only 3 of these drugs are considered the most effective and do not require INR control.

Other anticoagulants can be dangerous to health. This is due to the fact that there is no direct effect on the coagulation system.

There is only suppression of the formation of the Hageman factor, due to which the entire effect is formed.

Despite the improved performance during therapy with these drugs, they have side effects and contraindications. Therefore, they are not sold without a doctor’s prescription. It is necessary to conduct laboratory and instrumental examination methods to make a diagnosis, identifying the need to use anticoagulants.