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.

UZ "Mogilev City Emergency Hospital"

1. What is Warfarin?

Warfarin belongs to a class of drugs known as anticoagulants. They reduce the blood's ability to form clots in blood vessels. For warfarin to help you, it must be taken correctly, with all the necessary precautions, and strictly following the instructions and advice of your doctor.

It is very important that you understand why you are taking this medicine and follow all your doctor's instructions.

The body functions normally if blood circulates freely through the vessels. Blood clots that interfere with its normal flow are called thrombi. Warfarin slows down the formation of blood clots. Blood clots can form anywhere in the body. During normal operation of the blood coagulation system, only when a blood vessel is damaged, a small clot forms, which stops the bleeding. But if blood clots form spontaneously in the bloodstream, this means that something has gone wrong in the coagulation system. The formation of blood clots is called thrombosis or thromboembolism.

Types of diseases.

This table shows where blood clots form and

2. Rules for taking warfarin.

• Take warfarin in the dose prescribed by your doctor at the same time. Do not double the dose if you miss a dose, as the risk of bleeding may increase.
• Warfarin is taken according to a specific regimen, selected individually for each patient by a doctor (daily, every other day, or according to another regimen).

You cannot change the order of taking Warfarin on your own.

• Follow the frequency of blood tests for INR recommended by your doctor to monitor the state of blood clotting. After each test, visit your doctor or contact him by phone.
• Use a Warfarin diary and write down each dose of the drug. The form for such a diary is located at the end of this brochure. In a notebook or notebook according to the proposed form, draw the corresponding columns. Show your diary at every doctor's visit.
• Store Warfarin in a cool, dark place and keep out of the reach of children.
• Do not store the medicine in the bathroom, near the kitchen sink, or other damp places. Warfarin can be spoiled by heat and moisture.
• Do not keep the medicine if it is expired or if you no longer take it.

3. WARNINGS.

3.1. Signs of a Warfarin overdose.

If you take Warfarin incorrectly or change your lifestyle, diet, or take other medications, signs of side effects or Warfarin overdose may appear.

If you have:

• bleeding gums when brushing teeth
• unexplained nosebleeds or bruising of the skin
• heavy bleeding from cuts, wounds, menstruation
• blood in urine or black (bloody) stool
• hemoptysis
• severe or prolonged pain
• joint pain, swelling or lumps
• bloody or dark-colored vomit

You need to see a doctor immediately.

3.2. Mode

Avoid vigorous sports, heavy lifting, or other activities that could cause falls or injuries.

Visiting the bathhouse (steam room), manual massage, Charcot shower is not recommended.

Eliminate alcohol, snacks and condiments containing vinegar from your diet.

Avoid exposure to the sun. Swimming in the pool, warm pearl baths, and terrincourt are allowed.

3.3 Be sure to tell your dentist, gynecologist and other doctors, especially if you are undergoing surgery, that you are taking Warfarin.

Some medicines can change (strengthen or weaken) the anticoagulant effect of Warfarin: this includes drugs that

that you buy without a prescription, including aspirin or headache medications, including fever reducers.

Do not take any of the following medications without consulting your doctor.

Medicines that enhance the activity of Warfarin:

• preparations containing aspirin (askofen, citramon, askaf, cardiomagnyl, etc.)
• medications used for arthritis, arthrosis: ibuprofen, indomethacin, naproxen, diclofenac, diclobern, voltaren, xefocam, ketorolac, etc.
• In addition, the following can enhance the anicoagulant effect of Warfarin: glibenclamide, thyroxine, ticlopidine.

Medicines that reduce the activity of Warfarin:

Barbiturates, antihistamines, haloperidol, oral contraceptives, antacids.

Therefore, do not take new or stop taking existing medications without talking to your doctor.

3.4 Diet

Always eat a balanced diet. Vitamin K, found in many foods, reduces the effect of Warfarin, and any changes in your daily diet may change the amount of this vitamin. It is best to keep the amount of vitamin K you receive constant. When you are taking Warfarin, it is especially important not to significantly change the amount of these foods in your daily diet.

A sufficient daily dose of vitamin K is 70-140 mg. If the patient eats large amounts of food high in vitamin K, this food will weaken the effect of Warfarin. A diet with a constant allowed amount of foods containing vitamin K is recommended.

Vitamin K content in the product

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.

Warfarin...Death is delayed

The history of the discovery of Warfarin is very interesting and entertaining. In the early 1920s. In the northern territories of the United States and Canada, an outbreak of a very strange and previously unknown disease occurred in cattle. Cows and bulls, after minor injuries such as dehorning or castration, began to die from severe blood loss. Sometimes fatal bleeding occurred spontaneously. The mysterious disease was called “hemorrhagic diathesis” (“hemorrhagic septicemia”). In 1921, Canadian veterinarian Frank Schofield, conducting a postmortem examination of a dead cow, discovered moldy silage from sweet clover (Melilotus alba and M. officinalis) in its intestines. Subsequently, F. Schofield established that only hay from spoiled clover caused fatal hemorrhagic diathesis. To confirm his guess, he conducted an experimental study on rabbits. Those animals that ate moldy clover stems quickly died from multiple bleedings. In 1924, F. Schofield published the results of his research and clearly proved that the cause of hemorrhagic diathesis in cattle is rotten sweet clover, better known in Europe as white clover or sweet clover. Somewhat later, in 1929, a veterinarian from North Dakota (USA) L.M. Roderick (LM Roderick) found that sweet clover sharply reduces prothrombin levels. Also in 1929, the Danish biochemist Henrik Dam (H. Dam) noted the appearance in the skin, muscles and mucous membranes of chickens that were fed completely low-fat food, multiple hemorrhages, similar to the hemorrhagic diathesis of chickens. In 1936, he was able to accurately establish that the cause of increased bleeding was the reduced ability of the blood to clot, resulting from insufficient synthesis of prothrombin in the liver in response to a deficiency of fat-soluble vitamin K. Subsequently, for studying the role and metabolism of vitamin K in 1943, H. Dame and the American biochemist Edward Doisy were awarded the Nobel Prize. Meanwhile, it was not possible to obtain a pure anticoagulant substance from sweet clover until 1940. In 1933, a group of chemists working in the laboratory of the University of Wisconsin (USA) under the leadership of Karl Paul Link (K.R. Link) finally made a decision isolate from spoiled hay and identify the substance causing bleeding. It took another 5 years for K. Link's student Harold Campbell to be able to obtain only 6 mg of crystalline anticoagulant. Next, another student and later business partner of K. Link, Mark Stahmann, began a project to extract 1.8 g of recrystallized anticoagulant, which took him about 4 months. This material turned out to be enough to verify the results of G. Campbell’s work and describe in detail the resulting compound - 3,3′-methylenebis-(4-hydroxycoumarin), later called dicumarol. Then synthetic dicumarol was obtained, which turned out to be completely identical to the agent extracted by K. Link’s group from moldy sweet clover and causing bleeding in animals. This is how the first drug from the class of oral anticoagulants appeared. Already in 1941, the American physician O. Meyer and several other clinicians successfully used dicumarol in several patients who had suffered myocardial infarction. Meanwhile, K. Link and two of his colleagues, Stahmann and Ikawa, continued the scientific search. In 1948, they managed to synthesize and patent an even more powerful anticoagulant substance, called Warfarin - from the abbreviation WARF (Wisconsin Alumni Research Foundation) and the ending -arin, indicating a connection with coumarin. Unfortunately, not being a doctor, K. Link failed to appreciate the relevance of his discovery for clinical medicine and in 1952 he registered Warfarin in the USA as a rodenticide - a poison for rodents. Warfarin was supposed to be extremely toxic to humans, but the failed suicide attempt in 1951 by a US Army recruit who took a very large dose of rat poison and was saved thanks to the timely administration of vitamin K (even then known as a specific antidote), forced clinicians to reconsider their attitude to Warfarin. Renewed clinical trials showed that Warfarin had significantly superior anticoagulant activity to dicoumarol, and in 1954 it was approved for medical use in humans. The first results of the successful clinical use of Warfarin in cardiology were published in 1955. One of the first known patients to receive it was the commander of the Allied army during World War II, general and 34th President of the United States Dwight Eisenhower, who was prescribed Warfarin after suffering a heart attack myocardium in 1955. Since then, Warfarin has become one of the most widely prescribed anticoagulants in the world, and in the United States it is now the 11th most commonly used drug. Interestingly, the exact mechanism of action of Warfarin remained unknown until 1978, when it was proven that the drug inhibits the enzyme epoxide reductase and thereby disrupts the metabolism of vitamin K. Over many years of use, Warfarin has become legendary. Thus, some historians believe that Lavrenty Beria, Nikita Khrushchev and others conspired and poisoned Joseph Stalin with tasteless and colorless Warfarin, which caused a hemorrhagic stroke. Pharmacological action Warfarin interferes with the cyclic transformations of vitamin K - the oxidation of its hydroquinone (active) form into the epoxy (inactive) form, followed by enzymatic reduction back to hydroquinone. The oxidative stage is associated with N-carboxylation of glutamine residues of coagulation factors II (thrombin), VII, IX, X, necessary for the manifestation of their coagulant properties, and carboxylation of regulatory proteins C and S, without which the manifestation of their anticoagulant activity is impossible. Warfarin blocks the recovery stage, which leads to the formation of only partially carboxylated (i.e., functionally inactive) proteins in the liver and into the blood. One of the key enzymes whose activity is inhibited by warfarin is vitamin K epoxide reductase (VKOR, from the English Vitamin K epOxide Reductase), under the influence of which inactive vitamin K epoxide is converted into native vitamin K and the active form - vitamin K hydroquinone. By the way, it is the frequent polymorphism in the gene encoding the synthesis of the most active isomer of vitamin K epoxide reductase, VKORC1, that explains the low sensitivity to Warfarin in a number of patients. Reduced availability of vitamin K and vitamin K hydroquinone inhibits the carboxylation activity of glutamyl carboxylase, which in turn leads to impaired carboxylation of glutamic acid residues in a number of coagulation factor precursors, which lose the ability to bind to the endothelial surface of blood vessels, thereby becoming biologically inactive. Within a few days, the reserves of active hemostasis factors in the body are depleted, and the anticoagulant effect appears. Clotting factors continue to be produced, but their functionality is reduced due to lack of decarboxylation. Such proteins are called PIVKA (proteins induced by vitamin K absence/antagonism). Each such coagulation factor is called PIVKA-x, where x is a number (for example, PIVKA-II). Thus, ultimately, the use of Warfarin reduces the patient's blood clotting. Pharmacokinetics Warfarin is a racemic mixture of 2 active mirror stereoisomers (enantiomers) - R- and S-forms, each of which is excreted from the body in different ways. S-warfarin is 5 times more potent than the R-isomer in antagonizing vitamin K. Warfarin is rapidly and almost completely absorbed from the gastrointestinal tract, reaching peak concentrations after 90 minutes. However, food intake does not affect its bioavailability. The onset of action of Warfarin occurs after 12–62 hours, and the duration of the effect is a maximum of 5 days. (usually 36–72 hours). The plasma half-life for racemic Warfarin ranges from 36 to 42 hours. More than 97% of circulating Warfarin is bound to plasma albumin. The therapeutic concentration of Warfarin in plasma is 1–5 mcg/ml (0.003–0.015 mmol/l). Warfarin is metabolized in the liver (with the participation of the CYP2C9 enzyme system) by hydroxylation to inactive or weakly active metabolites reabsorbed from bile, while the S-isomer is metabolized more quickly. The half-life of racemic Warfarin averages 40–50 hours (1.5–2.5 days). The drug is excreted by the kidneys, dysfunction of which does not affect the rate of drug elimination. If liver function is impaired due to decreased metabolism, the dose of the drug should be reduced. Warfarin crosses the placenta but is not secreted into breast milk. Pharmacogenomics The activity of Warfarin is partly determined by genetic factors, in particular the polymorphism of 2 genes - VKORC1 and CYP2C9. VKORC1 polymorphisms explain the low susceptibility of patients to Warfarin. There are 2 main haplotypes that explain 25% of the variations: the low-dose haplotype of group A and the high-dose haplotype of group B. VKORC1 polymorphisms, in particular, determine the relatively high resistance to Warfarin in African Americans (a high proportion of group B haplotypes) and the higher sensitivity of Asians (a high proportion of haplotypes group A). The presence of the VKORC1 group A haplotype in a patient is accompanied by rapid achievement and exceeding of the target level of the international normalized ratio (INR), as well as the risk of bleeding. Polymorphisms of CYP2C9 explain variations in the dose of Warfarin in patients, do not affect the time to achieve the target INR level, unlike VKORC1, but reduce the time to achieve INR>4. Indications for use Indications for the use of Warfarin include primary and secondary prevention of venous thromboembolic complications (VTEC), prevention of thrombus formation in the cavities of the heart in various types of arrhythmias, atrial fibrillation, the presence of artificial valves, cardiomyopathies, heart failure, condition after prosthetics (including and intravascular) of the aorta and its branches, etc. It should be clearly understood that Warfarin does not serve as an emergency drug and cannot provide a rapid anticoagulation effect, necessary, for example, in pulmonary embolism (PE) or acute myocardial infarction. Warfarin is intended for long-term or lifelong anticoagulant therapy. General principles for monitoring anticoagulant therapy with vitamin K antagonists To monitor the effect of indirect anticoagulants, determination of prothrombin time is usually used. This value increases in response to depression of 3 of the 4 vitamin K-dependent coagulation factors: prothrombin, factors VII and X. The prothrombin time test is performed by adding a mixture of calcium and thromboplastin to citrated plasma. At the beginning of anticoagulant therapy, the prothrombin time indicator primarily reflects depression of factor VII, and during maintenance therapy, factor X deficiency. Standardization of the determination of prothrombin time is carried out according to a calibration model approved by WHO, using INR - International Normalized Ratio (INR). The International Sensitivity Index (ISI) is used to measure the response of thromboplastin, which is used to determine the degree of deficiency of vitamin K-dependent coagulation factors. The lower the ISI, the stronger the reagent reaction and the closer the determined prothrombin time will be to the INR. The INR is the prothrombin time that would be obtained using the WHO reference thromboplastin, which is defined as having an ISI of 1. Two levels of intensity of indirect anticoagulant therapy are recommended: less intense (INR = 2–3) and more intense (INR). =2.5–3.5). Difficulties in using a system to monitor the effectiveness of anticoagulant therapy using the INR indicator arise in cases where the laboratory uses different thromboplastin reagents in the analysis that differ in ISI value; Patients' dietary intake of vitamin K fluctuates; drugs that interact with indirect anticoagulants are used at the same time; with poor patient adherence to prescribed anticoagulant therapy; in the absence of regular monitoring (breaks of more than 4 weeks) or with large fluctuations in the doses of anticoagulant used. Before prescribing Warfarin, in order to avoid possible complications, it is advisable to conduct a clinical and laboratory examination of the patient. Mandatory procedures include a general blood test (signs of anemia), a biochemical blood test (liver enzymes, total protein, bilirubin, creatinine), INR, stool occult blood test, general urinalysis or Nechiporenko urine test, kidney ultrasound, examination by a gynecologist . Additionally, esophagogastroduodenoscopy can be performed (if there is a history of gastric or duodenal ulcer, a positive stool test for occult blood, as well as pain in the abdominal cavity), examination by an ophthalmologist (for patients with high blood pressure and severe diabetes for exclusion of hemorrhages in the fundus), computed tomography or magnetic resonance imaging of the brain (in patients who have had a stroke, to exclude its hemorrhagic nature and assess the consequences). Warfarin dosage regimen Typically, the starting dose of Warfarin is 5–7.5 mg 1 time/day. Use of large, loading doses of 10–30 mg/day. significantly increases the risk of bleeding and other unwanted side effects. In persons with suspected hypersensitivity to Warfarin (elderly age; exhaustion; chronic heart failure; liver disease; recent major surgery; taking drugs that potentiate the effect of Warfarin), it is advisable to reduce the initial dose to 2.5–5 mg/day. In contrast, acute venous thrombosis associated with antiphospholipid syndrome requires high doses of warfarin to achieve target INR values ​​of 2–3. At the same time, monitoring of therapy is complicated by the prolongation of initial INR values ​​under the influence of a lupus anticoagulant. In the future, the dose of the drug is selected individually, focusing on the INR, which should be determined after taking 2 or 3 doses of the drug, i.e. in 2–3 days. Subsequently, INR is measured daily or 1 day/2–3 days until stable target values ​​are obtained. Subsequently, INR monitoring is continued 2–3 times/week. for 1–2 weeks. Once the INR has stabilized at the target level, it is monitored every 4 weeks. More frequent assessment is also possible in patients with significant fluctuations in the INR. If it is necessary to reduce or increase the dose of Warfarin, the cycle of more frequent monitoring of the INR is repeated until stable values ​​of the indicator are achieved again. One of the possible schemes for selecting Warfarin is shown in Table 1. Depending on the clinical objectives, the target INR level can vary from 2–3 (prevention and treatment of VTEC) to 2.5–3.5 or even 3.0–4.5 for patients with one or more artificial heart valves. In cardiological practice, Warfarin is often prescribed in combination with antiplatelet drugs (acetylsalicylic acid, clopidogrel, etc.). In this case, to reduce the risk of hemorrhagic complications, it is advisable to maintain the INR at 2–2.5. If long-term or lifelong use is necessary, the dose of Warfarin can be controlled by the patient himself, determining the INR using portable devices - coagulants, the indicators of which should be calibrated using stationary laboratory equipment. If there are significant fluctuations in INR against the background of the selected dose of Warfarin, it is necessary to identify and, if possible, eliminate possible causes, such as inaccuracies in measuring INR (use of different laboratories), intercurrent diseases, alcohol consumption, insufficient adherence to treatment, taking drugs that affect the activity of Warfarin, dietary errors, etc. If, with regular use of Warfarin, the INR does not reach the lower limit of the therapeutic range, then the total weekly dose should be increased by 10–20% and the INR should be monitored more frequently until it stabilizes. In some cases, a deliberately high dose of Warfarin is prescribed once, followed by more frequent determination of the INR and a change in the total weekly dose or without it. Approaches to the management of patients with excessively high INR levels, as well as the development of hemorrhagic complications, are presented in Table 2. Contraindications Absolute contraindications to the use of Warfarin are allergies and individual intolerance, pregnancy, a history of hemorrhagic stroke, hemorrhagic diathesis, platelet count in the blood less than 100x109/ l, active bleeding. Other contraindications: recent or planned operation in the near future, recent trauma, hemorrhagic complications in the history (gastrointestinal bleeding, macrochematuria, metroragia); Aneurysms and malformations of intracranial vessels, relaxing aortic aneurysm, pericarditis or effusion in the pericardium, bacterial endocarditis, malignant arterial hypertension, ulcer of the stomach and DPK in the stage of exacerbation, portal hypertension syndrome with varicose extension of the veins of the esophagus and stomach, severe occasual lack ENTIS , alcoholism, psychoses and severe diseases of the central nervous system (central nervous system), social maladaptation, high risk of injury (parkinsonism, epilepsy, convulsive syndromes, etc.), the lack of the possibility of laboratory control of the MOS. Unwanted side effects and complications using warfarin described a variety of side effects and complications, such as diarrhea, an increase in the activity of liver transaminase, eczema, skin necrosis, vasculitis, hair loss, etc. Bleeding is the most frequent side effect of anticoagulant therapy, especially in those cases when the MU goes beyond the therapeutic framework. The risk of hemorrhagic complications increases significantly with a combination of warfarin with antitromobocytic drugs such as clopidogrel, acetylsalicylic acid, or other non -steroidal anti -inflammatory drugs (NSAIDs), as well as in elderly patients or patients on chronic hemodialysis. Severe, threatening bleeding lives in 0.9–2.7% of patients taking warfarin. The severity of hemorrhagic syndrome can vary widely. Patients note increased bleeding of gums when brushing teeth, periodic epistaxis (nasal bleeding) or hematuria. In severe cases, gastrointestinal bleeding may occur, retroperitoneal or intracranial hematomas may form. To minimize the risk of hemorrhagic complications, it is necessary to adhere to the standard therapeutic boundaries of the INT. In the absence of hemorrhagic complications with an increase in many to 3.5–4.5 warfarin should be canceled to the return of the IN to standard boundaries. If the INC exceeds 4.5, it is advisable to prescribe sublingually small doses of vitamin K. At the values ​​of the TRU 4.9–9, 1 mg of vitamin K is prescribed. The dose of the latter is increased to 2-3 mg with a number of higher 9. In the case of severe bleeding, 10 is administered intravenously. MG Vitamin K, pour freshly frozen plasma, concentrates of the prothrombin complex, as well as the recombinant VIIA factor. Patients receiving warfarin with target indicators and notes hematuria, gastrointestinal or uterine bleeding should be examined to search for the source of the latter (ulcers, tumors, etc.). Varfarin necrosis of warfarin necrosis is a specific, rare, but rather serious complication of warfarin treatment. As a rule, it occurs shortly after the start of taking the drug (for 2–5 days) with patients with a deficiency of proteins C or S, who are natural anticoagulants synthesizing in the liver and overwhelming the activity of warfarin. When prescribing, warfarin reduces the level of proteins C and S faster than other pro -cargulants, which leads to paradoxical hypercoagulation at the beginning of treatment with the possible occurrence of venous and arterial thrombosis, accompanied by skin necrosis and gangrene limbs. Clinically, warfarin necrosis looks like an erythematous spot with clear boundaries on the hips, buttocks, mammary glands or fingers of the limbs. With a typical course in the center of such a spot, necrosis develops rapidly. In biopaths taken from the demarcation zone, thrombped small vessels are found. Treatment of warfarin necrosis consists in canceling warfarin, prescribing specific antidotes, protein C and heparin preparations. To prevent this complication, heparin is prescribed simultaneously with warfarin, which is canceled after reaching the target values ​​of the IS and their preservation over the next 2-3 days. Osteoporosis is a number of reports that warfarin can reduce the mineral density of the bone and initiated randomized clinical tests. In one of them, held in 1999 and included 572 women who took warfarin about deep vein thrombosis, it was revealed that the risk of a fracture of the spine and ribs was increased. The second study completed in 2002 in 1523 patients with an osteoporotic fracture did not find an increased effect of warfarin compared to the effect of its administration in the control group. It was also not possible to connect the risk of fractures with the duration of anticoagulant therapy. At the same time, a retrospective examination of 14,564 patients (2006) who took warfarin for more than 1 year recorded an increase by 60% of the risk associated with osteoporosis, but only in men. The possible decrease in bone density with prolonged intake of warfarin is explained by a decrease in the intake of vitamin K into the body and inhibiting vitamin K vitamin K - indirect carboxylation of some bones of bones with impaired function. Violet finger syndrome syndrome of purple finger is a rare complication that can occur during early treatment with warfarin (usually in the range from 3 to 8 weeks from the beginning). It is believed that this condition occurs as a result of small cholesterol deposits in the blood vessels of the skin of the legs. At the same time, the skin acquires a bluish-violet color, pain may be noted on palpation. The thumb of the legs usually suffers, but other parts of the lower extremities can also be affected, including the plantar surface of the foot. If the violet finger syndrome occurs and progress, warfarin can be canceled. Warfarin antidotes of warfarin can be suppressed by prescribing vitamin K. In the event of severe hemorrhagic complications (bleeding, extensive hematomas, etc.), in addition to the intravenous administration of vitamin K, freshly frozen plasma or a prothrombin complex concentrate containing only factors inhibited by varfarin. Patients with high values ​​of the IN (from 4.5 to 10.0) are enough oral use of small doses of vitamin K or temporary cancellation of warfarin. Warfarin and its interaction with other drugs or food products, warfarin interacts with many widely used drugs, and its metabolism varies significantly in different patients. A number of food products containing a large amount of vitamin K (green tea, spinach, ginger, garlic, liver, coffee, bitter chocolate, etc.) are able to reduce the activity of warfarin. In addition to metabolic antagonism, some drugs (for example, statins) can displace warfarin from serum albumin and cause an increase in many. In such situations, the dose of warfarin is necessary against the background of a more frequent determination of the IN (Table 3). Many widely used antibacterial drugs, such as metronidazole and macrolides, also significantly increase the effect of warfarin by reducing its metabolism. Almost all antibiotics of a wide spectrum of action reduce the amount of normal microflora in the intestines, which produces a large amount of vitamin K, which naturally enhances the effect of warfarin. The thyroid function also affects the activity of warfarin. Thus, hypothyroidism makes patients less sensitive to treatment by warfarin, while hyperthyroidism increases the effect of the anticoagulant. Several mechanisms of this effect are discussed, including Changes in the speed of decay of blood coagulation factors and warfarin metabolism. Patients taking warfarin should avoid excessive use of alcoholic beverages, because Ethanol included in their composition can increase the level of Multi. In addition to food and drugs on the activity of warfarin, various herbal fees, balms, tinctures and biologically active food additives can affect. If necessary, the combined use of warfarin with drugs that increase its activity should be controlled more often. The anticoagulant therapy strategy itself is determined by the possibility of laboratory monitoring. When it is possible, in order to avoid hemorrhagic complications, the dose of warfarin can be reduced by 5-10%. If the laboratory control is difficult, and the prescription of agonist preparations is necessary, then the intake of warfarin should be interrupted. Warfarin and Barfarin's pregnancy are contraindicated during pregnancy, because It passes through a hemato-placental barrier and can cause bleeding in the fetus or mother. Attempts to use warfarin during pregnancy were accompanied by miscarriages, stillbirths, premature births and neonatal mortality. In addition, kumarins (including warfarin) have a teratogenic effect, causing a variety of congenital defects in 5-30% of children, depending on the gestational age at which the drug was prescribed. As a rule, as a result of taking warfarin, 2 different combinations of congenital anomalies occur. When the drug or other derivative of 4-hydroxycumarine is taken during the 1st trimester (especially between 6 and 9 weeks of pregnancy), a group of congenital defects, known as fetal warfarin syndrome (FVS), warfarin embryopathy or cumarin embryopathy, can occur. The FVS is characterized mainly by skeletal defects, which include nasal hypoplasia, prolapse or narrowing of the back of the nose, scoliosis and calcification in the spine, femoral and heel bones. Anomalies of the limbs can also occur, such as brachidactyls (unusually short fingers and legs) or underdeveloped limbs. The use of warfarin in the II and III trimester is accompanied by damage to the central nervous system in the form of seizures, muscle cramps, epileptic seizures; defeat of the organ of vision. In addition, the risk of forming various hematomas increases, including and intracranial, when the child passes through the tribal channel. In this regard, during pregnancy anticoagulant therapy, heparines are used or low molecular weight (NMG), as well as Fontaparinux, which, although they cause a higher risk of bleeding in the mother, do not pass through the placental barrier. And, on the contrary, during breastfeeding, anticoagulant therapy is carried out using warfarin, which is not excreted into milk. Warfarin and the upcoming surgical intervention should be taken by Varfarin 5 days before any invasive procedure (surgical intervention, dental removal, catheterization of large vessels, etc.). In the case of a high risk of relaxed thrombosis, NMG Bridge therapy is carried out after the fall of a lot of 2.0. The last dose of NMG is administered 12–24 hours before the upcoming intervention, depending on whether it was introduced once or twice. After the invasive procedure, the intake of warfarin is resumed in a standard dose under the control of the target values ​​of the IN. The conclusion of the known deficiencies of warfarin, such as the difficulties of selecting and monitoring the dose, the necessary dietary restrictions, the low selectivity of the mechanism of suppression of the coagulation cascade, etc., are the reason for the search for new assemblymen. As a result, over the past few years, direct X-factor inhibitors (Apixban, Rivakoxaban) and thrombin (Dabigatran) have been introduced into clinical practice. Each of these drugs was called the “killer of warfarin” or “the death of warfarin”, but during comparative clinical trials it turned out that with unobvious advantages in the convenience of admission, clinical efficiency and safety, all new anticoagulants lose to warfarin according to the price/quality criterion. So today warfarin still remains a reference drug and an indisputable leader among oral anticoagulants.

Literature 1. Metelitsa V.I. Handbook of clinical pharmacology of cardiovascular drugs. 2nd ed. M.: Binom - St. Petersburg: Nevsky Dialect, 2002. 926 p. 2. Kirienko A.I., Panchenko E.P., Andriyashkin V.V. Venous thrombosis in the practice of physicians and surgeons. M.: Planida, 2012. 336 p. 3. Russian clinical recommendations for the diagnosis, treatment and prevention of venous thromboembolic complications // Phlebology. 2010. No. 1. Issue. 2. 4. Yavelov I.S. Anticoagulant therapy in the prevention and treatment of venous thromboembolic complications // Phlebology. 2010. No. 4 (4). pp. 4–14. 5. Handbook of Venous Disorders. Guidelines of the American Venous Forum. 3-d edition. Edited by P. Gloviczki. Hodder Arnold. 2009. 744 p. 6. Venous and Lymphatic Diseases. Edited by N. Labropoulos, G. Stansby, Taylor & Francis. 2006. 559 p. 7. Cronenwett JL, Johnston KW Rutherford's vascular surgery (7th edition) // Saunders Elsevier. 2010.

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.

Reminder for patients taking warfarin.

- The drug is taken daily once a day at the same time in the evening - it is not recommended to take the drug with food, it is better after a meal - it can be taken on an empty stomach - the drug can be prescribed for an unlimited period (the course of treatment is prescribed by your attending physician). Patients taking warfarin should be under strict medical supervision. You will need to regularly and quite often donate blood for INR (especially at the beginning of the prescribed treatment, weekly). The dose of WARFARIN is selected individually, taking into account INR values. WARFARIN is a drug that prevents the formation of blood clots and helps improve blood circulation in organs and tissues; it is directed against blood clotting. The risk of myocardial infarction, stroke, thrombosis of arteries and veins increases if you do not take WARFARIN. WARFARIN can be taken at the same time as other medicines. NEVER CHANGE THE DOSE BY YOURSELF! If you forget to take the drug, take it as soon as you remember, if you do not remember whether you took it today, skip the dose and start taking the drug the next day as prescribed. To be sure that you have taken WARFARIN, we recommend keeping a diary, especially in the initial stages of treatment. HOW TO TAKE CARE OF YOUR SAFETY! When taking warfarin, bruises, bleeding gums, and nosebleeds may occur; with paresis, the blood does not stop for a long time. When signs of increased bleeding appear. Tell your doctor. Your doctor will determine your further actions based on your medical history and concomitant therapy. If there are signs of serious bleeding or loss of consciousness, call an ambulance immediately! Be sure to inform the arriving team, dentist or other doctor that you are taking WARFARIN. Call an ambulance if you experience: -Black (tarry) stools -Pink or red urine -Excessive bleeding from the nose or gums -Unusually heavy or prolonged bleeding during menstruation -Large bruises or swelling on the body for no apparent reason -Prolonged bleeding from small wounds, more than 10 minutes - Appearance of shortness of breath, palpitations, chest pain - Dizziness, difficulty speaking - Visual impairment. Warfarin acts on blood clotting through vitamin K, which is found in varying amounts in food. The maximum amount of vitamin K is found in green leafy vegetables and herbs. There is no need to avoid foods. Nutrition should be complete. Care should be taken to ensure that there are no significant changes in 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 can greatly weaken its effect and lead to blood clots! The maximum amount of vitamin K is found in dark green leafy vegetables and herbs (spinach, parsley, cabbage in any form), green tea. Mayonnaise, legumes, olive and rapeseed oils contain vitamin K from 300-1000 mcg/kg. Regular consumption of berries and cranberry juice may increase the effect of warfarin. Vitamin K content in products: beef liver………………… ..93 Cheese……………………………………………………….35 Butter………………….30 Egg…… ………………………………..11 Soybean oil……………………….193 Broccoli………………………………175 Cabbage………………… ………………125 Salad…………………………………….129 Tomatoes…………………………….…80 Beans……………………… ………….45 Cucumbers………………30 Green tea…………………………712 Alcohol is not allowed during treatment with Warfarin. What to avoid: - traumatic sports where blows, bruises, and falls are possible. -intramuscular injections -repeated medication intake during the day. Care should be taken to ensure that there are no significant changes in 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 can greatly weaken its effect and lead to blood thickening and blood clots (with an INR of less than 2.0)! The maximum amount of vitamin K is found in dark green leafy vegetables and herbs (spinach, parsley, cabbage in any form), green tea. Mayonnaise, legumes, olive and rapeseed oils contain vitamin K from 300-1000 mcg/kg. Regular consumption of berries and cranberry juice can enhance the effect of warfarin (that is, thin the blood - increase the risk of bleeding) and the INR will be more than 3.0. Vitamin K content in products: Beef liver………………… ..93 Cheese……………………………………………………….35 Butter………………….30 Egg…… ………………………………..11 Soybean oil……………………….193 Broccoli………………………………175 Cabbage………………… ………………125 Salad…………………………………….129 Tomatoes…………………………….…80 Beans……………………… ………….45 Cucumbers………………30 Green tea…………………………712 Alcohol is not allowed during treatment with Warfarin.

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.

Frequently asked questions about warfarin treatment

1. Why is warfarin prescribed?

Warfarin is an anticoagulant - a drug that reduces blood clotting (the ability to form blood clots). Warfarin is prescribed in cases where the risk of unwanted blood clots is particularly high. The most common indications for prescribing warfarin: artificial heart valve, atrial fibrillation (the so-called “atrial fibrillation”), deep vein thrombosis, pulmonary embolism, sometimes after a heart attack, stroke, with thrombophilia (a disease in which blood clotting is increased and constantly appears). blood clots).

2. How does warfarin work?

Warfarin blocks part of vitamin K, from which prothrombin is synthesized in the liver, a substance necessary for the formation of blood clots. Vitamin K enters the body with food from green vegetables, and is also produced by bacteria living in the human intestines. Warfarin “neutralizes” part of vitamin K and the liver does not receive enough “building material” to create prothrombin. Warfarin does not dissolve existing blood clots.

3. How quickly does warfarin start and stop working after taking it?

Since warfarin interferes with the creation of new prothrombin without neutralizing the one already formed, its effect does not appear immediately. The effect of warfarin can be seen only in 3-5 days (when the previously created prothrombin is destroyed). It also takes 3-5-7 days for the liver to produce a sufficient amount of prothrombin after stopping warfarin, and blood clotting returns to normal.

4. Is warfarin dangerous? Will I have any side effects?

Warfarin is a serious drug. Failure to follow the rules for taking it can lead to serious complications. At the same time, when prescribing it, the doctor weighed the possible risks of warfarin and the risks without it, and came to the conclusion that there would be more benefit from warfarin than danger. In general, following the rules for taking warfarin and regularly monitoring blood clotting, in most cases, allows you to avoid serious complications.

5. When should you take warfarin?

The main condition is that warfarin must be taken every day, without skipping. Therefore, determine the time for taking warfarin for yourself when you will not forget to take it! In addition, you should always take warfarin at the same time and on an empty stomach. Food affects the absorption of warfarin, so it is better not to combine them. It is best to take warfarin once a day in the evening.

6. How long will I have to take warfarin?

This depends on the reason you were prescribed warfarin. For example, after installation of an artificial mechanical heart valve or with thrombophilia, warfarin will have to be taken for life. After some other heart surgeries or deep vein thrombosis, warfarin is usually prescribed for six months to a year.

7. What should I do if I forget to take warfarin?

Don't forget to take your next dose :). Under no circumstances take a double dose at your next dose! Just wait until your next dose and take your regular dose for that day.

8. I don't remember if I took warfarin. What should I do?

Nothing. If you skip one dose, there will be less harm than if you take a double dose. And in order to prevent this situation from happening again, use a pill bottle or put warfarin and other medications aside for the day in a separate box/jar. This way you will always know what you have already drunk and what you haven’t yet.

9. Should I somehow monitor the progress of warfarin treatment?

Yes, monitoring the progress of treatment is the basis of all basics. If you are not going to control your blood clotting, it is best not to start warfarin therapy at all. Treatment with warfarin is a constant balancing act between the risk of thrombosis and the risk of bleeding. And without regular tests it is impossible to maintain this balance.

About INR

10. What is INR?

INR (international normalized ratio) is one of the indicators of the blood coagulation system. It is sometimes referred to as “INR” in analyses. It is by this indicator that the effectiveness of warfarin treatment is determined.

11. What is the “target INR range”?

The normal INR for humans is about 1 (0.8 – 1.3). The purpose of prescribing warfarin is to reduce blood clotting to a level where the risk of thrombosis is significantly reduced, but the risk of bleeding is not yet too high. For different conditions, this balance point is between certain INR numbers. For example, with a mechanical heart valve, it is recommended to keep the INR between 2.5 and 3.5. These numbers are called the “target INR range”. This range may be different for different conditions.

12. How often should I check my INR?

At the stage of selecting the dose of warfarin, INR should be monitored every 3-5 days, after reaching the target range - once every 5-7 days, after receiving 3 consecutive tests in the target range, you can switch to measuring once every two weeks. In general, it is necessary to measure INR at least once a month, and preferably once a week or two. It is also necessary to check the INR if you change the dose of warfarin, change your diet, add new medications and other situations that could affect blood clotting. Remember that changes in INR levels will only be noticeable after 3-5-7 days.

13. What does it mean if my INR is BELOW the target range? What to do about it?

This means that the dose of warfarin is insufficient and there is a risk of thrombosis. In order to return to the range, you need to either reduce the amount of vitamin K in food or increase the dose of warfarin. It's better to start with the first one. If the INR has dropped below 1.6 (for a target range of 2.0-3.0) or 2.0 (for a target range of 2.5-3.5), you may need to temporarily add heparin or Clexane (ask your doctor!) .

14. What does it mean if my INR is ABOVE the target range? What to do about it?

This means that the dose of warfarin is excessive and the risk of bleeding is increased. It is necessary to either increase the intake of vitamin K from food or reduce the dose of warfarin. If the INR is no more than 4.0-4.5, then it is better to start with the first option. And only if the INR does not decline within a week, then reduce the dose of warfarin.

15. I can't seem to stay within my target range. Is it even possible?!

Maybe! It just takes time to learn how to regulate blood clotting. For this:

A. Monitor your INR regularly

b. Stick to a diet (see below)

V. To more accurately select the dose of warfarin, use combinations of tablets with different warfarin contents (2.5, 3 and 5 mg are available in Ukraine) and their parts.

d. Use an alternating regimen for taking warfarin: one dose one day, another - another, the third - the same as the first, etc. In this way, you can select the average daily dose more accurately.

d. Don't forget about the interactions of warfarin with medications, herbs, vitamins and foods!

e. Change the dose of warfarin very carefully, by 10-20% at a time and allow time for changes to appear (5-7 days).

16. For several tests in a row, my INR has been in the target range. Does this mean that the warfarin dose has been adjusted and I can stop checking my INR?

No, it doesn't mean that. INR monitoring is necessary while you are taking warfarin because clotting can vary significantly depending on external factors (food, medications, stress, etc.). Even if the indicator is stable, it is necessary to monitor the INR once a week or two and in no case less than once a month!

17. In what situations do I need an unscheduled INR check?

If there is reason to suspect or predict an exit from the target range. For example, if unmotivated large bruises appeared on the body, nosebleeds or other bleeding appeared. An unscheduled INR measurement is also necessary if your diet has changed radically or you have added/removed some medication that can affect the INR.

About lifestyle

18. Can I combine warfarin with other medications?

You can, but your warfarin dose may need to be adjusted. There is a whole list of drugs that enhance the effect of warfarin and no less those that weaken its effect. Always pay attention to the “drug interactions” section in the medication annotations and if warfarin is indicated there, be sure to check the INR 5 days after starting the drug and possibly change the warfarin dose. Don't forget to check your INR and return to your original warfarin dose after you finish taking the new drug.

19. I periodically take herbs/vitamins/dietary supplements. Could this have any effect on warfarin?

Maybe! Many vitamins (eg vitamin C, vitamin E) affect the action of warfarin. Many multivitamins contain small amounts of vitamin K, which means they significantly reduce the effect of warfarin. When choosing multivitamins, pay attention to this; take those that do not contain vitamin K. The same applies to many herbs and dietary supplements. Before taking them, think carefully about whether the expected benefit from taking them is so great as to risk “shaking” the INR. And if you still decide to take herbs/vitamins/dietary supplements, be sure to check your INR 5-7 days after they start and after they end.

20. Do I have to follow any special diet while taking warfarin?

Yes, there are certain dietary rules for people taking warfarin. They consist in the fact that there should be a stable content of vitamin K in food every day. It can be high or low, it doesn’t matter, the main thing is that it is approximately the same every day! Green vegetables and green tea contain the most vitamin K.

21. Should I change my lifestyle if I take warfarin?

Sometimes yes. To avoid dangerous bleeding, you should avoid activities and entertainment that involve an increased risk of injury (contact sports, working with cutting objects, or with a high risk of falling, even from your own height).

22. I want to go on a trip/hiking. Will warfarin therapy interfere with this?

Basically no. Just remember to take an adequate supply of warfarin with you and check your INR before leaving. Don't forget about your diet - when traveling, food often differs significantly from usual, and this can affect the INR. It is better to avoid long (more than 2 weeks) trips unless there is an opportunity to check the INR (with a portable device or at the nearest hospital). Also, always have a card/piece of paper with you indicating that you are taking warfarin and for what indications.

23. I want to get pregnant and have a baby. Would warfarin interfere with this?

Unfortunately it will interfere. Warfarin is extremely harmful to the baby, so if you are planning a pregnancy, discuss with your doctor the possibility of replacing warfarin with heparin during pregnancy.

24. Should I tell doctors that I am taking warfarin?

Yes, it is necessary, since many manipulations cannot be carried out with warfarin or require special training or support. Be prepared for the fact that doctors in some specialties may not know what warfarin is and what risks it carries, so it is better to have the instructions for the drug with you.

25. I am about to have an operation or other medical procedure. What to do with warfarin?

It all depends on how traumatic the manipulation is. For any operation, warfarin will have to be temporarily removed, perhaps replaced with heparin for a while. The same applies to such manipulations as gastroscopy, bronchoscopy, etc. Tooth extraction may require a dose reduction or discontinuation of warfarin. Other dental manipulations can be carried out without changing the dose of warfarin, but you should be prepared for prolonged bleeding from the gums, etc.

26. In what situations should I consult a doctor immediately?

a. If you have had an injury to the abdomen, chest, or head. Even if you feel well, but the blow can be described as severe, it is better to go to the hospital and make sure that there is no internal bleeding.

b. If you notice blood in your sputum, stool, urine, or if you are vomiting blood. You should also consult a doctor if you have nosebleeds that do not stop within 10-15 minutes.

c. If you have numerous large bruises on your body.

d. If you suddenly have headaches, weakness in one half of the body, blurred vision, speech impairment, abdominal pain, etc.

In each of these cases, be sure to tell your doctor that you are taking warfarin and your latest INR value.

27. Can I combine warfarin with alcohol?

You can, but it is not advisable to do so. Alcohol, by affecting the liver, enhances the effect of warfarin. In addition, even small doses of alcohol impair coordination and increase the risk of accidental injury, which can be life-threatening in a person taking warfarin.

TO MAKE AN APPOINTMENT WITH A SPECIALIST AT OUR MEDICAL CENTER, PLEASE CLICK HERE

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.

Indirect anticoagulants: warfarin

20s of the XX century. North America. An epidemic of an unknown disease among... cattle. Death of bulls from bleeding during castration and after removal of horns. Spontaneous bleeding during milking in cows. It's all due to moldy clover.

In 1921, local veterinarian Frank Scholfield noticed that all these animals were feeding on sweet clover (Melilotus) silage, which had become moldy in the damp conditions. Scholfield conducted a series of experiments on rabbits and confirmed his hypothesis: the rabbits actually died from bleeding after feeding with moldy sweet clover.

A group of rabbits that ate uninfected hay were alive, active and healthy. Farmers' financial situation did not allow them to replace feed, and the situation remained deplorable and bleeding. American veterinarian L. M. Roderick in 1929 established exactly how blood stops clotting: this is due to dysfunction of coagulation factor II - prothrombin. What kind of substance affects clotting was discovered only 11 years later, and this merit rightfully belongs to a research group at the University of Wisconsin led by Professor Karl Link. One of the researchers, Harold Campell, isolated dicumarol.

Dicumarol is a derivative of plant coumarin, the smell of which we smell next to freshly cut grass. However, coumarin itself does not affect coagulation, but acquires anticoagulant properties only after fermentation (metabolism by fungi of the genera Fusarium, Stachybotrys, Aspergillus, Monopodium and bacteria Clostridium Perfrigens, Escherichia Coli), which is what happened with moldy clover. The result is a full-fledged mycotoxin - dicoumarin.

People first started talking about it as a medicine in 1941. Karl Link, the same professor from Wisconsin, decided to profit financially from his work and register a new rat poison, which was in great demand on farms at that time. Especially for this purpose, in 1948, a new anticoagulant was synthesized and called it warfarin, not forgetting to reflect the group of discoverers (Wisconsin Alumni Research Foundation) in the name. The ending “-arin” hints at coumarin, of course, of which it is a derivative (4-hydroxycoumarin). And only 6 years later it began to be used for medical purposes. The mechanism of action was unknown for a long time, but today we can fully describe it.

Warfarin is called a vitamin K antagonist because it disrupts the synthesis of vitamin K-dependent blood coagulation factors, which are II (prothrombin), IX (Christmas factor), VII (proconvertin), X (Stuart-Prower factor), as well as proteins C (vitamin K-dependent proteolytic enzyme) and S (plasma glycoprotein). The listed coagulation factors depend on vitamin K functionally: the epoxy (oxidized) form of vitamin K is reduced to its hydroquinone form (reduced vitamin K) under the action of the enzyme vitamin K epoxide reductase. Oxidation to the epoxide form (reverse) occurs with the help of gamma-glutamyl carboxylase. It is this enzyme that converts inactive forms of coagulation factors into biologically active ones by carboxylation of their glutamate residues. After carboxylation, coagulation factors can interact with phospholipids of the vascular endothelium and participate in the hemostatic cascade (Fig. 1).

Figure 1 | The mechanism of action of warfarin
But then warfarin bursts in and irreversibly blocks the enzyme vitamin K epoxide reductase, therefore, vitamin K is not restored, and the entire cycle of transformations stops. Gamma-glutamyl carboxylase does not activate clotting factors. The latter circulate in the blood in a functionally inactive form; they are even given the special name PIVKA (proteins induced by vitamin K absence).

For example, the second factor blocked by warfarin, contained in the blood in an inactive form, is called PIVKA-II. Other indirect anticoagulants (phenindione, acenocoumarol, neodicoumarin) also work by this mechanism, but only warfarin has firmly entered into cardiological practice as the drug of choice for the prevention of thrombosis.

Since all these processes occur in the liver, at a systemic level, it is not possible to recreate the effect of the drug in vitro, as is the case with heparin. For the same reason, the effect of hypocoagulation does not occur immediately (after 5–6 days for warfarin, 4–5 days for acenocoumarol), but when the reserves of active coagulation factors in the blood are depleted.

Pharmacokinetics

The drug is used primarily for oral administration, as it is well absorbed from the gastrointestinal tract (80–90%) - therefore, it is convenient for long-term self-administration, but is also used in the form of intravenous injections.

Bioavailability when taken orally reaches 100%. The maximum concentration in the blood is after 4 hours. Capable of accumulation, both material (in the liver, especially with its pathology), and functional, reducing the rate of synthesis of coagulation factors. An important aspect is that warfarin binds to plasma albumin by 97–99%, and the drug has its effect only in free form.

Thus, it is necessary to be careful when combining warfarin with other drugs that also actively bind to blood proteins, since they can displace warfarin from binding to the protein, which increases the level of free (active) warfarin in plasma, and therefore increases the risk of bleeding.

Other drugs that increase the risk of bleeding when used together with warfarin:

• Antidepressants (serotonin reuptake inhibitors). They block platelet aggregation, and their administration together with warfarin increases the risk of bleeding.
• Antibiotics that inhibit the intestinal microflora that synthesizes vitamin K,
• Acetaminophen. Its active metabolite (N-acetylbenzoquinoneline) blocks vitamin K carboxylase even at a therapeutic dose, which is reflected when measuring INR.

99% of the drug undergoes biotransformation in the liver, and this is another pressing issue regarding the combination of drugs. Warfarin, in particular its active S-form, is metabolized in the liver with the participation of cytochrome P450.

Some drugs (for example, cotrimoxazole, metronidazole, ciprofloxacin, norfloxacin, pefloxacin, amiodarone, etc.) block cytochrome P450 and interfere with the biotransformation of warfarin in the liver, resulting in an increase in its concentration in the blood and an increased risk of bleeding.

But there are also drugs that increase the activity of cytochrome, for example, rifampicin, when taken the opposite occurs: warfarin is actively metabolized and excreted from the body, as a result of which the risk of thrombosis increases. Metabolites do not have anticoagulant activity and are excreted by the kidneys (90%) and bile (10%). The drug penetrates the placenta and, as you understand, we will return to this point in the “contraindications” section.

A minute of personalized medicine

The CYP2C9 gene encodes an enzyme involved in the metabolism of warfarin - cytochrome P450. Some alleles of this gene (CYP2C9*2 and CYP2C9*3) determine low enzyme activity, which means slow metabolism of warfarin, high concentration of the drug in the blood and its long-term presence there, hence a strong anticoagulant effect. Such patients require lower doses of the drug to achieve a therapeutic effect.

The VKORC1 gene is also known, encoding the enzyme vitamin K epoxide reductase, the “target” of warfarin. Patients with a G to A substitution at position 1639 of the polynucleotide express less enzyme and are more sensitive to warfarin, and therefore lower doses of the drug are indicated for them.

It seems that this does not find clinical use in modern realities, but the figures vary strikingly: 95% of the population of Asian countries have the A allele and are sensitive to low doses, while among Africans only 14% have it. Mutations in this gene can lead to complete resistance to warfarin.

Indications

The drug is used to prevent thrombosis and thromboembolism. Four pathologies are absolute indications for the use of warfarin for the prevention of thromboembolic complications:

1. Atrial fibrillation;
2. Venous thrombosis;
3. TELA;
4. Prosthetic heart valves.

It is also possible to use it in combination with antiplatelet agents to prevent thromboembolic complications in patients with myocardial infarction. It is also used in patients with AF after stenting in the form of triple antiplatelet therapy in combination with acetylsalicylic acid and a P2Y12 inhibitor (clopidogrel/ticagrelor).

However, recent studies show that replacing warfarin with dabigatran in TAT in the combination of aspirin + clopidogrel/ticagrelor has undeniable advantages due to a reduced risk of major or clinically significant minor bleeding.

Dosage regimen

To select the dose and monitor efficacy and safety, the international normalized ratio (INR) is used. This is an assessment method based on comparing the patient’s prothrombin time with the norm, which is expressed by the ratio (note - ISI - international sensitivity index, factory indicator of thromboplastin activity, written on the reagent label):

Prothrombin time, as we know from the course of normal physiology, is the time during which a fibrin clot forms in the blood when calcium chloride and thromboplastin are added to it, thanks to which it is possible to evaluate the external path of hemostasis and the activity of factors I, II, V, VII and X, three of which are blocked by warfarin.

The INR norm for a healthy person not taking warfarin is: 0,8–1,2.

The target INR values ​​when taking warfarin are different for each pathology: for atrial fibrillation, the target INR range is 2–3 , for patients with a prosthetic valve, the INR is 2.5–3.5 .

It is worth remembering that when the INR increases above the recommended figures, there is a high probability of bleeding; when the INR decreases below 2, there is a risk of thrombosis, therefore, when treating with indirect anticoagulants, its strict control is necessary.

Since indirect anticoagulants reveal their therapeutic potential approximately on the 4th day of administration, to prevent thrombosis after cardiovascular accidents, its combination with LMWH (enoxaparin) is recommended according to the following scheme:

In case of asymptomatic risk of bleeding, proceed according to the following scheme:

• INR = 3.5–4.0 : reduce the single dose of the drug by a quarter of a tablet, check the INR after 1 day;
• INR = 4.0–5.0 : reduce the dose by half a tablet, control the INR every other day;
• INR more than 5 : discontinue the drug for a day, control after one day, start therapy with INR less than 3.5; subsequently the dose is reduced by 1 tablet.

If it is necessary to switch to NOAC therapy, it is necessary to bring the INR to <2 (drug discontinuation and daily monitoring of the INR). For your convenience, dear subscribers, we invite you to familiarize yourself with two algorithms for prescribing warfarin: British and American.

Side effects of warfarin

1. Bleeding (mainly from the gastrointestinal tract, genitourinary system and even into the ventricles of the brain)
2. Liver dysfunction;
3. Allergic reactions;
4. Necrosis of the skin of the extremities due to thrombosis in the first days of taking the drug (anticoagulant activity appears on the 4th day of use, therefore a combination of low molecular weight heparins and indirect anticoagulants according to the above scheme is necessary);
5. Purple toe syndrome (big toe) - it is believed that indirect anticoagulants contribute to the deposition of cholesterol in the veins of the extremities, resulting in impaired blood flow, blood stagnation and soft tissue swelling;
6. Teratogenic effect (warfarin penetrates the placenta and can affect the fetus, as it blocks osteocalcin, which leads to hypoplasia of the skull bones, in particular the nose);
7. Miscarriages, uterine bleeding, fetal bleeding: all these are terrible consequences of taking warfarin during pregnancy.

Contraindications to taking warfarin

1. Pregnancy;
2. Erosive diseases of the gastrointestinal tract (erosive gastritis, peptic ulcer and duodenum, ulcerative colitis), the combined use of warfarin with NSAIDs for the listed pathologies increases the likelihood of bleeding from the gastrointestinal tract;
3. Urolithiasis, hematuria;
4. With caution - in case of liver pathology;
5. Age over 80 years;
6. Hemorrhagic stroke.

However, it is possible to use warfarin for chronic kidney disease of any stage, unlike NOACs. In case of massive bleeding (often gastrointestinal bleeding), a transfusion of fresh frozen plasma is necessary.

Also, in case of an overdose of warfarin, vitamin K preparations are used. A careful study of the mechanism of action of warfarin begs the question: it is not the vitamin that is blocked, but the enzyme that restores it - how can taking vitamin K change the situation?

The fact is that in addition to vitamin K-epoxide reductase, epoxide can also be reduced by DT-diaphorase, the action of which requires a significantly larger amount of vitamin K, which we will provide by introducing a vitamin K preparation, for example, Vicasol (menadione) or phytomenadione.

Vikasol is administered intramuscularly at a dose of 10–15 mg 2–3 times a day; oral administration of 15–30 mg three times a day is possible. It is also used three days before surgery to prevent massive bleeding. Phytomenadione is taken orally at 0.01–0.02 mg 3–4 times a day. Strict INR control is necessary to prevent thrombosis.

In conclusion, I would like to note that despite the fact that warfarin is the drug of choice for the prevention of thromboembolic complications of cardiovascular accidents, it is imperfect in many aspects: narrow therapeutic window, frequent laboratory monitoring, the influence of food and other drugs on the anticoagulant effect, slow onset and the end of the action.

They were replaced by NOACs, but were never forced out of use: warfarin is cost-effective, it can be used for CKD of any stage, and it is possible to assess the level of coagulation and select the dose, despite the obligation to frequently monitor them.

Sources:

1. Wardrop D., Keeling D. The story of the discovery of heparin and warfarin //British journal of haematology. – 2008. – T. 141. – No. 6. – pp. 757-763.
2. Kester M., Karpa KD, Vrana KE Elsevier's Integrated Review Pharmacology E-Book: with Student consult Online Access. – Elsevier Health Sciences, 2011.
3. Kukes V. G., Mosolov S. N. Clinical pharmacology. – 2004.
4. Richard D.H. et al. Lippincott's illustrated reviews: Pharmacology //Philadelphia. – 2006. – T. 3. – P. 413-415.
5. Kharkevich D. A. Pharmacology. – GEOTAR-MED, 2003.
6. Dean L. Warfarin therapy and the genotypes CYP2C9 and VKORC1. – 2016.
7. Juurlink DN Drug interactions with warfarin: what clinicians need to know //Canadian Medical Association Journal. – 2007. – T. 177. – No. 4. – pp. 369-371.
8. Martsevich S. Yu., Lukina Yu. V. Warfarin and its significance in the era of new oral anticoagulants. Issues of monitoring the effectiveness and safety of treatment // Rational pharmacotherapy in cardiology. – 2017. – T. 13. – No. 5.

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.

Instructions for use WARFARIN

It is not recommended to start or stop taking other medications, or change the dosage of medications taken, without consulting your doctor. When prescribing simultaneously, it is also necessary to take into account the effects of stopping the induction and/or inhibition of the action of Warfarin by other drugs.

The risk of severe bleeding increases when taking Warfarin simultaneously with drugs that affect platelet levels and primary hemostasis:

• acetylsalicylic acid, clopidogrel, ticlopidine, dipyridamole, most NSAIDs (except COX-2 inhibitors), penicillin antibiotics in high doses.

You should also avoid the combined use of Warfarin with drugs that have a pronounced inhibitory effect on the cytochrome P450 system, for example, cimetidine and chloramphenicol, when taken for several days the risk of bleeding increases. In such cases, cimetidine can be replaced, for example, with ranitidine or famotidine.

The effect of Warfarin may be enhanced when taken simultaneously with the following medications; Acetylsalicylic acid, allopurinol, amiodarone, azapropason, azithromycin, alpha and beta-interferon, amitriptyin, bezafibibrat, vitamin A, vitamin E, glibenclamide, glucagon, hemfibrosil, heparin, Grepafsacin, Danazole, derthoproopen, diazopoxin, digoxyide, digoxid , dizopiramid, disulfits, zafirlukast, indomethacin, ifosfamide, itraconazole, ketoconazole, clarithromycin, clofibrate, codeine, levamisole, lovastatin, methovasone, methotrexate, metronidazole, miconazole (including in the form of oral gel), nalidixic acid, norfloxacin, ofloxacin, omeprazole, oxyphenbutazone, paracetamol (especially after 1-2 weeks of continuous use), paroxetine, piroxicam, proguanil, propafenone, propranolol, influenza vaccine, roxithromycin, sertraline, simvastatin, sulfafurazole, sulfamethizole, sulfamethoxazole-trimethoprim, sulfafenazole, sulfinpyrazone, sulindac, steroid hormones ( anabolic and/or androgenic), tamoxifen, tegafur, testosterone, tetracyclines, thienylic acid, tolmetin, trastuzumab, troglitazone, phenytoin, phenylbutazone, fenofibrate, feprazone, fluconazole, fluoxetine, fluorouracil, fluvastatin, fluvoxamine, flutamide, quinine, quinidine, chloral hydrate , chloramphenicol, celecoxib, cefamandole, cephalexin, cefmenoxime, cefmetazole, cefoperazone, cefuroxime, cimetidine, ciprofloxacin, cyclophosphamide, erythromycin, etoposide, ethanol.

Preparations of some medicinal plants (official or unofficial) can also enhance the effect of Warfarin:

• for example, ginkgo (Ginkgo biloba), garlic (Allium sativum), angelica sinensis (Angelica sinensis), papaya (Carica papaya), sage (Salvia miltiorrhiza);
• and reduce: for example, ginseng (Panax ginseng), St. John's wort (Hypericum perforatum).

Warfarin and any St. John's wort preparations should not be taken at the same time, but it should be taken into account that the inducing effect of Warfarin may persist for another 2 weeks after stopping the use of St. John's wort preparations. If the patient is taking St. John's wort preparations, MHO should be measured and discontinuation. MHO monitoring must be careful because... its level may increase when St. John's wort is discontinued. After this, Warfarin can be prescribed.

Quinine contained in tonic drinks can also enhance the effect of Warfarin.

Warfarin may enhance the effect of oral sulfonylurea hypoglycemic agents.

The effect of Warfarin may be weakened when taken simultaneously with the following drugs:

• azathioprine, aminoglutethimide, barbiturates, valproic acid, vitamin C, vitamin K, glutethimide, griseofulvin, dicloxacillin, disopyramide, carbamazepine, cholestyramine, coenzyme Q10, mercaptopurine, mesalazine, mianserin, mitotane, nafcillin, primidone, retinoid, ritonavir, rifampicin, rofecoxib, spironolactone, sucralfate, trazodone, phenazone, chlordiazepoxide, chlorthalidone, cyclosporine. Taking diuretics in the case of a pronounced hypovolemic effect can lead to an increase in the concentration of clotting factors, which reduces the effect of anticoagulants. In the case of combined use of Warfarin with other drugs indicated in the list below, it is necessary to monitor MHO at the beginning and end of treatment, and, if possible, after 2-3 weeks from the start of therapy.

Foods rich in vitamin K weaken the effect of Warfarin; Decreased absorption of vitamin K caused by diarrhea or laxatives potentiates the effect of warfarin. Most vitamin K is found in green vegetables, so when treating with Warfarin, you should eat the following foods with caution:

• amaranth greens, avocado, broccoli, Brussels sprouts, cabbage, canola oil, chayo leaf, onion, coriander (cilantro), cucumber peel, chicory, kiwi fruit, lettuce, mint, mustard greens, olive oil, parsley, peas, pistachios, red seaweed, spinach greens, spring onions, soybeans, tea leaves (but not tea drink), turnip greens, watercress.

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.

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. If minor bleeding occurs against the background of an INR value > 4.0, it is necessary to find out the possible reasons for the development of excessive hypocoagulation (primarily taking medications that affect the metabolism of VKA). Warfarin therapy can be resumed after stopping minor bleeding if the INR is <3.0. In case of recurrence of small hemorrhages, the target INR level should be reduced to 2.0–2.5. Excessive anticoagulation is a predictor of bleeding, so any, even asymptomatic, increase in INR levels above the therapeutic range requires the attention of a doctor. It is necessary to clarify with the patient the possible reasons for the increase in INR (primarily drug interactions, as well as such reasons for the development of excessive hypocoagulation as CHF, liver failure, hyperthyroidism, alcohol consumption). Detection of an asymptomatic increase in INR in a patient in the absence of any immediate need for invasive intervention requires temporary withdrawal of Warfarin with subsequent adjustment of its dose, but there is no need to administer fresh frozen plasma or prothrombin complex concentrate. Vitamin K promotes de novo synthesis of vitamin K-dependent coagulation factors due to its influence on carboxylation processes, so the effect after its intake occurs slowly and it is useless for the rapid restoration of vitamin K-dependent coagulation factors. The domestic drug phytomenadione available to doctors in capsules of 0.1 g, containing a 10% solution of vitamin K1 in oil, cannot be used to reduce the level of INR, since a dose of vitamin K equal to 10 mg causes resistance to the action of VKA for 7–10 days. The risk of bleeding increases during invasive interventions and surgical operations. The basis for correctly selected perioperative tactics in a patient taking Warfarin is an assessment of the risk of bleeding and thromboembolic complications (Fig. 4). In 2010, ESC guidelines [1] recommend early resumption of anticoagulant therapy in patients at high risk of thromboembolic complications, provided there is adequate hemostasis. ESC experts also published an addition to the existing recommendations [33] that there is no need to discontinue warfarin in patients at high risk of stroke during dental extraction, cataract removal and endoscopic removal of polyps from the gastrointestinal tract, provided that modern technology is used and adequate hemostasis is ensured. In this case, in the author’s own opinion, it is advisable to skip taking Warfarin on the eve of the intervention, provided that adequate hemostasis is maintained. Currently, there are portable devices for measuring INR levels. A meta-analysis conducted by S. Heneghan in 2006 [34] showed that self-monitoring of INR improves the outcomes of patients receiving warfarin. However, a necessary condition for adequate self-monitoring using a portable device is medical supervision for the correct interpretation of the results of the analysis and correction of factors that influence anticoagulant therapy. Conclusion Currently, Warfarin is the main drug for the prevention of thromboembolic complications in patients with myocardial infarction after heart valve replacement and venous thrombosis. The determining factor in the effectiveness of therapy with vitamin K antagonists is the target INR range, which should be attempted in every patient. The frequency of hemorrhagic complications, as well as the need for constant laboratory monitoring, are the main reasons for non-prescription or discontinuation of Warfarin in real clinical practice. The emergence of new antithrombotic drugs that do not require regular laboratory monitoring also requires doctors to acquire practical clinical experience. Existing algorithms for selecting an individual maintenance dose of Warfarin, a system of patronage and regular laboratory monitoring of INR can improve the safety of anticoagulant therapy.

Literature 1. Guidelines for the management of patients with atrial fibrillation 2011. The task force for the management of patients with atrial fibrillation of European Society of Cardiology. 2. ACCP American college of Chest Physicians Evidence–Based Clinical Practice Guidelines (9th Edition) // Chest. – 2012. in press. 3. Wolf PA, Dawber TR, Thomas E. Jr et al. Epidimiologic assessment of chronic atrial fibrillation and risk of stroke: The Framingham Study // Neurol. – 1978. – Vol. 28. – P. 973–977. 4. Onundarson PT, Thorgeirsson G., Jonmundsson E. et al. Chronic atrial fibrillation – Epidimiologic features and 14 year follow-up: A case control study // Eur. Heart. J. – 1987.– Vol. 3. – P.521–27. 5. Flegel KM, Shipley MJ, Rose G. Risk of stroke in non-rheumatic atrial fibrillation // Lancet. – 1987.– Vol. 1.– P.526–529. 6. Tanaka H., Hayashi M., Date C. et al. Epidemiologic studies of stroke in Shibata, a Japanese provincial city: Preliminary report on risk factors for cerebral infarction // Stroke. – 1985. – Vol. 16.– P. 773–780. 7. Hylek MPH, Alan S. Go, Yuchiao Chang et al. Effect of Intensity of Oral Anticoagulation on Stroke Severity and Mortality in Atrial Fibrillation // NEJM. – 2003. –Vol. 349. – P.1019–1026. 8. Wyse DG, Waldo AL, DiMarco JP et al. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation // NEJM. – 2002. – Vol. 347. – P.1825–1833. 9. Stefan H. Hohnloser, Karl–Heinz Kuck, Jurgen Lilienthal. For the PIAF Investigators Rhythm or rate control in atrial fibrillation—Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomized trial // Lancet. – 2000. – Vol. 356. –P. 1789 – 1794. 10. Petersen P., Boysen G., Godtfredsen J. et al. Placebo–controlled, randomized trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study // Lancet. – 1989. – Vol. 28;1(8631). – P.175–179. 11. Secondary prevention in nonrheumatic atrial fibrillation and transient ischemic attack or minor stroke. EAFT (European Atrial Fibrillation Trial) Study Group // Lancet. – 1993. – Vol. 342. – P. 1255–1262. 12. Hart RG, Pearce LA, McBride R. et al. Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I–III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators // Stroke. – 1999. –Vol. 30(6). – P.1223–1229. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. 13. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators // NEJM. – 1990. – Vol. 323. – P.1505–1511. 14. Ezekowitz MD, Bridgers SL, Javes KE et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation // NEJM. – 1992. – Vol. 327, No. 20. – P. 1406–1413. 15. Lip GYH, Nieuwlaat R., Pisters R. et al. Refining Clinical Risk Stratification for Predicting Stroke and Thromboembolism in Atrial Fibrillation Using a Novel Risk Factor–Based Approach The Euro Heart Survey on Atrial Fibrillation // Chest. – 2010.– Vol. 137. – P. 263–272. 16. Arnold AZ, Mick MJ, Mazurek RP Role of prophylactic anti-coagulation for direct cardioversion in patients with atrial fibrillation or atrial flutter // J. Am. Coll. Cardiol.– 1992.– Vol. 19.– P. 851–855. 17. Manning WJ, Silverman DI, Keighley CS et al. Transesophageal echocardiographically facilitated early cardioversion from atrial fibrillation using short term anticoagulation: final results of a prospective 4.5–year study // J. Am. Coll. Cardiol. – 1995. – Vol. 25(6). – P.1354–1361. 18. Dzemeshkevich S.L, Panchenko E.P. Anticoagulant therapy in patients with valvular heart disease // RMZh. – 2001. – T. 9, No. 10. – P. 427–430. 19. Anticoagulants in the Secondary Prevention of Events in Coronary Thrombosis (ASPECT) Research Group. Effect of long-term oral anticoagulant treatment on mortality cardiovascular morbidity after myocardial infarction // Lancet. – 1994.– Vol. 343. – P. 499–503. 20. Brouwer MA, van den Bergh PJ, Aengevaeren WR et al. Aspirin plus coumarin vs aspirin alone in the prevention of reocclusion after fibrinolysis for acute myocardial infarction: results of the Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis (APRICOT)–2 Trial // Circulation. – 2002. – Vol.106. – P.659–665. 21. Hurlen M., Smith P., Arnesen H. et al. Warfarin–Aspirin Reinfarction Study II WARIS –II // NEJM. – 2002. – Vol. 347. – P.969–974. 22. Fiore LD, Ezekowitz MD, Brophy MT et al. For the Combination Hemotherapy and Mortality Prevention (CHAMP) Study Group Warfarin combined with low dose aspirin in myocardial infarction did not provide clinical benefit beyond that of aspirin alone // Circulation. – 2002. – Vol.105. – P. 557–563. 23. Holbrook AM, Jennifer A. Pereira, Renee Labiris et al. Systematic Overview of Warfarin and Its Drugand Food Interactions // Arch. Intern. Med. – 2005. – Vol. 165. – P. 1095–1106. 24. Rieder MJ, Reiner AP, Gage BF et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose // NEJM. – 2005. –Vol. 352(22). – P.2285–2293. 25. Higashi MK, Veenstra DL, Kondo LM et al. Association between CYP2C9 genetic variants and anticoagulation–related outcomes during warfarin therapy // JAMA. – 2002. –Vol. 287. – P.1690–1698. 26. Tabrizi AR, Zehnbauer BA, Borecki IB et al. The frequency and effects of cytochrome P450 (CYP) 2C9 polymorphisms in patients receiving warfarin // J. Am. Coll. Surg. – 2002. – Vol. 194. – P.267–273. 27. Harrington DJ, Underwood S, Morse C et al. Pharmacodynamic resistance to warfarin associated with a Val66Met substitution in vitamin K epoxide reductase complex subunit 1 // Thromb. Haemost. – 2005. – Vol. 93. – P. 23–26. 28. Bodin L., Horellou MH, Flaujac C. et al. A vitamin K epoxide reductase complex subunit–1 (VKORC1) mutation in a patient with vitamin K antagonist resistance // J. Thromb. Haemost. –2005. – Vol. 3. – P.1533–1535. 29. Fihn SD, McDommel M, Matin D et al. Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study Group // Ann. Intern. Med. – 1993. – Vol. 118(7). – P. 511–520. 30. Mhairi Copland, Walker ID, Campbell R. et al. Oral Anticoagulation and Hemorrhagic Complications in an Elderly Population With Atrial Fibrillation // Arch. Intern. Med. – 2001. – Vol. 161, No. 17. – P. 24. 31. Levine MN, Raskob G., Landefeld S., Kearon C. Hemorrhagic complication of anticoagulant treatment // Chest. – 2001. – Vol. 19(1 Suppl). – P.108S–121S. 32. Palareti G., Leali N., Cocceri S., Poggi M. et al. Hemorrhagic complications of oral anticoagulant therapy: results of a prospective multicenter study ISCOAT (Italian Study on Complications of Oral Anticoagulant Therapy) // G. Ital. Cardiol. – 1997. – Vol. 27(3).– P.231–243. 33. Skolarus LE, Morgenstern LB, Froehlich JB et al. Guidline–Discordant Perioprocedural Interruption in warfarin therapy // Circ. Cardiovasc. Qual. Outcomes. – 2011. –Vol. 4. 34. Heneghan C., Alonso–Coello P., Garcia–Alamino JM et al. Self-monitoring of oral anticoagulation: a systematic review and meta-analysis // Lancet. – 2006. – Vol. 367. – P. 404–411.

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 NYCOMED

Side effects

Adverse reactions to the drug are ordered by system-organ class and are consistent with the terms of preferred use (in accordance with the Medical Dictionary for Regulatory Activities - MedDRA). Within the system-organ class category, reactions are distributed according to the frequency of occurrence according to the following scheme: very often (≥1/10), often (≥1/100 to <1/10), infrequently (≥1/1000 to <1/100), rare (≥10,000 to <1/1000), very rare (<1/10,000).

Bleeding.
Over the course of a year, bleeding occurs in approximately 8% of patients. receiving warfarin. Of these, 1.0% are classified as severe (intracranial, retroperitoneal), resulting in hospitalization or blood transfusion, and 0.25% as fatal. The most common risk factor for intracranial hemorrhage is untreated or uncontrolled hypertension. The likelihood of bleeding increases if MHO is significantly higher than the target level. If bleeding begins with MHO within the target level, there are other underlying conditions that should be investigated.

Examples of such complications are nosebleeds, hemoptysis, hematuria, bleeding from the gums, bruising on the skin, vaginal bleeding, subconjunctival bleeding, bleeding from the rectum and other parts of the gastrointestinal tract, intracerebral bleeding, prolonged or heavy bleeding after injury or surgery.
Bleeding, including severe bleeding, can be expected in any organ. Bleeding leading to death, hospitalization, or the need for blood transfusion has been reported in patients receiving long-term anticoagulant treatment. Independent risk factors for significant bleeding during warfarin use include older age, high levels of anticoagulation, history of stroke, history of gastrointestinal bleeding, comorbidities, and atrial fibrillation. Patients with CYP2C9 polymorphisms (see Pharmacokinetics section) may be at increased risk of excessive anticoagulant effects and bleeding episodes. In such patients, hemoglobin and MHO levels should be carefully monitored. From the digestive system:
vomiting, nausea, diarrhea.
Necrosis .
Coumarin necrosis is a rare complication of warfarin treatment. Necrosis usually begins with swelling and darkening of the skin of the lower extremities and buttocks, or (less commonly) elsewhere. Later the lesions become necrotic. In 90% of cases, necrosis develops in women. Lesions are observed from the 3rd to the 10th day of taking the drug and the etiology involves a deficiency of the antithrombotic protein C or S. Congenital deficiency of these proteins can cause complications, so taking warfarin should begin simultaneously with the introduction of heparin and small initial doses of the drug . If a complication occurs, warfarin is discontinued and heparin is continued until the lesions heal or scar.

Hand-foot syndrome.

A very rare complication during warfarin therapy, its development is typical among men with atherosclerotic diseases. Warfarin is suspected to cause hemorrhages of atheromatous plaques, leading to microembolisms. There are symmetrical purple lesions on the skin of the fingers and soles of the feet, accompanied by burning pain.

After stopping warfarin, these symptoms gradually disappear.

Other.

Hypersensitivity reactions, manifested in the form of skin rash, and characterized by a reversible increase in the concentration of liver enzymes; cholestatic hepatitis, vasculitis, priapism, reversible alopecia and tracheal calcification. Independent risk factors for the development of serious bleeding during treatment with warfarin are: older age, high intensity of concomitant anticoagulant and antiplatelet therapy, a history of strokes and gastrointestinal bleeding.

The risk of bleeding is increased in patients with polymorphism of the CYP2C9 gene.