Vitamin K Antagonists (VKAs)

1. Mechanism of action of vitamin K antagonists (VKAs): Acenocoumarol and warfarin inhibit the posttranslational modification of coagulation factors II, VII, IX, and X, as well as protein C and protein S, which are necessary for the normal activity of the factors. The anticoagulant effect develops after 3 to 5 days; it depends on the dose as well as on the genetic factors, diet, concomitant drugs (Table 1), and comorbidities (due to the reduction of the endogenous sources of vitamin K, a more potent anticoagulant effect is achieved in the course of long-term antibiotic therapy, in patients with diarrhea, and in patients treated with liquid paraffin).

2. Differences between acenocoumarol and warfarin: The most important difference is half-life, which is shorter for acenocoumarol (8-10 h) than for warfarin (36-42 h). In patients with intolerance of acenocoumarol (eg, due to an allergic reaction) or difficulties in maintaining stable international normalized ratio (INR) values, you may consider replacing it with warfarin (the daily dose of warfarin is usually 1.5-2 times higher than that of acenocoumarol). Warfarin is most widely used in North and South American countries, whereas acenocoumarol is more widely used in European countries.

ContraindicationsTop

Contraindications are the same as in the case of heparins (except for heparin-induced thrombocytopenia) and additionally include pregnancy. Breastfeeding is allowed during treatment with VKAs. Pregnant patients with implanted mechanical heart valves should be referred to a specialist center.

Follow-UpTop

Determine the prothrombin time (PT), which is expressed as the INR.

General Principles of TreatmentTop

Starting Treatment

1. If achieving a rapid anticoagulant effect is necessary (eg, in patients with acute deep vein thrombosis/pulmonary embolism), start with a VKA in combination with heparin or fondaparinux. Otherwise, start treatment with a VKA alone (eg, in patients with atrial fibrillation).

2. Start treatment with the administration of acenocoumarol 6 mg on day 1 and 4 mg on day 2, or warfarin 10 mg on day 1 and 5 mg on day 2 (do not use higher loading doses, ie, >6 mg of acenocoumarol and >10 mg of warfarin). On day 3, determine the INR and adjust the dose. In patients who are elderly (ie, >65 years), malnourished, have severe comorbidities (eg, heart failure), or receive multiple drugs (thus being at risk of drug interaction), start with acenocoumarol 4 mg or warfarin 5 mg. If the VKA was started simultaneously with heparin or fondaparinux, the latter agents may be discontinued once the INR has been maintained in the therapeutic range for 2 consecutive days.

Management: Long-Term VKA Therapy

1. Patient education (Table 2), regular INR determination and follow-up visits, providing the patients with appropriate information on the INR values and the resulting VKA dose adjustments.

2. In adequately educated patients, INR self-determination using a portable coagulometer (eg, CoaguChek, INRatio2) and adjustment of the VKA dose by the patient may be allowed. The use of such devices should be considered particularly in patients at high risk of thromboembolism; patients who probably would discontinue the VKA because of disability, lack of access to a laboratory to perform INR testing, or due to other factors (eg, type of occupation); and patients in whom lifelong anticoagulant treatment is indicated.

3. In patients receiving long-term VKA treatment, the intake of foods rich in vitamin K1 (Table 1) should remain at a relatively constant level.

4. Determine the INR at least once every 4 weeks in patients receiving a constant VKA dose (every 8 weeks is acceptable in selected patients who have shown consistently therapeutic INR values), and more frequently (every 1-2 weeks) if the INR values fluctuate and fall outside the therapeutic range, in patients at increased risk for bleeding, or in patients with comorbidities that may affect INR stability, such as liver disease or heart failure (New York Heart Association class II-III). Determine the INR in the case of concomitant use of drugs that may interact with VKAs (particularly antibiotics and anticonvulsants) for more than 5 to 7 days.

5. If any INR result in a patient with previously stable INR values is ≤0.5 below or above the therapeutic range, continue using the VKA at the current dose and determine the INR within 1 to 2 weeks.

6. Identify potential risk factors for bleeding during VKA therapy and aim to control or eliminate these risk factors. In patients with hypertension ensure good blood pressure control, as this can reduce the risk for intracranial hemorrhage. In patients who are receiving acetylsalicylic acid (ASA), determine whether such treatment is necessary. ASA use for the primary prevention of cardiovascular disease can have very limited clinical benefit but confers an increased risk for major hemorrhage, especially in the elderly (ie, >65 years). Concomitant use of a VKA with ASA or another antiplatelet drug (eg, clopidogrel) should be limited to specific clinical situations (eg, mechanical heart valve, coronary stent). In patients with musculoskeletal problems, avoid the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and consider short courses of other analgesic medications (eg, acetaminophen [INN paracetamol]); if an NSAID is clinically indicated, limit its use to 1 to 2 weeks. In terms of lifestyle factors, encourage patients to not exceed moderate alcohol intake (eg, 1 glass of wine or beer per day with meals) and to avoid extreme dietary changes.

Management: INR Below Therapeutic Range

1. You can increase the dose by 5% to 20%, using an individual patient’s total weekly dose as the baseline dose.

2. Alternatively, you can determine the INR more frequently and wait for the values to return to the therapeutic range without adjusting the dose of the drug.

3. Make sure that the patient is compliant with the dietary recommendations. A reduction in the intake of green vegetables with a high vitamin K content is usually associated with an increase in the INR by an average of 0.5. In practice, a significant reduction in the INR may be caused by carbamazepine; other drugs rarely cause a significant reduction in the anticoagulant effect.

4. Do not use routine add-on heparin treatment in patients with previously stable INR values in whom this parameter was found to be below the therapeutic range on one occasion; in such cases, repeat INR determination after 7 days.

Management: INR Above Therapeutic Range

See Table 3.

1. After implementing the corrective measures for an INR above the therapeutic range, attempt to identify the cause of the elevated INR.

2. If the elevated INR is attributable to a transient factor, such as antibiotic use (eg, trimethoprim) or excessive alcohol consumption, the frequency of INR testing can remain as before after a 2- to 4-week period of more frequent monitoring.

3. If the elevated INR is attributable to a longer-lasting factor, such as prolonged medical illness (eg, chronic diarrhea, liver decompensation, heart failure), a reduction in the VKA dose combined with more frequent INR testing is warranted.

4. In patients with a diarrheal illness or those who have received an extended course of antibiotics, both of which can reduce endogenous vitamin K synthesis, encourage a diet rich in vitamin K to restore vitamin K levels while monitoring the INR more frequently.

5. In all patients who are receiving a VKA, but especially those who are prone to elevated INR levels, determine if patients are receiving an antiplatelet drug (eg, ASA, clopidogrel) or NSAID and reassess the need for such drugs that will further increase bleeding risk.

Patients Treated With VKA and Antiplatelet Agents

1. Duration of antiplatelet therapy after stenting in patients with atrial fibrillation treated with VKAs: Treatment should be tailored to perceived risk of thrombotic versus bleeding events. Recent data indicate that it is safe to use a combination of a VKA and clopidogrel instead of triple antithrombotic therapy (VKA, ASA, and clopidogrel). An increasingly used option is the combination of a direct oral anticoagulant (DOAC) with antiplatelet therapy, usually up to 1 year. Possibilities include low-dose rivaroxaban, 10 to 15 mg daily, combined with clopidogrel; or apixaban, 5 mg bid, combined with clopidogrel.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Gibson CM, Mehran R, Bode C, et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med. 2016 Dec 22;375(25):2423-2434. doi: 10.1056/NEJMoa1611594. Epub 2016 Nov 14. PMID: 27959713. Lopes RD, Heizer G, Aronson R, et al; AUGUSTUS Investigators. Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. N Engl J Med. 2019 Apr 18;380(16):1509-1524. doi: 10.1056/NEJMoa1817083. Epub 2019 Mar 17. PMID: 30883055.

2. Factors that increase the risk of bleeding in patients treated with VKAs in combination with antiplatelet agents:

1) Age >75 years.

2) Female sex.

3) Chronic kidney disease (creatinine clearance <30 mL/min).

4) History of severe bleeding.

5) INR above the therapeutic range.

3. Radial artery access is recommended during coronary angiography, particularly in patients at high risk of bleeding (eg, with a history of severe bleeding).

Switching to Another Oral Anticoagulant

1. Patients treated with VKAs may be switched to an oral factor Xa inhibitor if the INR value is ≤2.0. This may be attained by stopping the VKA and waiting 2 to 3 days to start the oral factor Xa inhibitor.

2. Switching from an oral factor Xa inhibitor or thrombin inhibitor to a VKA requires the initial concomitant administration of the VKA and the new anticoagulant until an INR value of ≥2.0 is reached.

VKA Discontinuation Before Invasive Procedures

Also see Perioperative DOAC Management.

1. The decision to discontinue a VKA before the procedure is made jointly by physicians (usually a surgeon and an anesthesiologist) and the patient after having considered the following:

1) The decision to use bridging heparin therapy depends on the risk of thromboembolic complications associated with the discontinuation of VKA (Table 4).

a) Low risk: Bridging anticoagulation is usually not required.

b) Moderate risk: Bridging anticoagulation is usually not required; alternatively consider prophylactic doses of subcutaneous LMWH.

c) High risk: Consider a therapeutic dose of subcutaneous LMWH (the preferred option); alternatively IV UFH may be used.

2) Risk of bleeding associated with the procedure:

a) High bleeding risk: Major vascular surgery; major orthopedic surgery; major abdominal or cardiothoracic surgery lasting >1 hour; any intracranial, spine, bladder, or kidney surgery; polypectomy; biopsy of a highly vascular organ or tissue (eg, liver, kidney, prostate). In these cases it is necessary to discontinue the anticoagulant treatment.

b) Low to moderate bleeding risk: All other types of surgeries that typically are <1 hour in duration. In these cases it is necessary to discontinue the anticoagulant treatment.

c) Minimal bleeding risk: Dental procedures (eg, extraction of 1-2 teeth), arthrocentesis, minor skin surgery (eg, excision of a mole), coronary angiography, selected diagnostic endoscopy (eg, without multiple biopsies, polypectomy), and cataract surgery. In these situations it is usually not necessary to discontinue the anticoagulant treatment. After tooth extraction you may recommend rinsing the mouth with tranexamic acid and applying an ice pack to the cheek for 30 minutes after the surgery. Stitching after tooth extraction does not reduce the risk of bleeding. Implantation of a cardiac pacemaker or implantable cardioverter-defibrillator can also be done without VKA interruption.

2. Temporary discontinuation of VKAs:

1) Discontinue acenocoumarol for 2 to 3 days and warfarin for 5 days before the procedure to allow for the normalization of INR values.

2) If despite the discontinuation of the VKA the INR is ≥1.5, you may administer 1 to 2 mg of oral vitamin K1 1 to 2 days before the procedure.

3) When a rapid neutralization of the anticoagulant effect of the VKA becomes necessary before an emergency invasive procedure, use 2.5 to 5 mg of vitamin K1 orally or IV. If the anticoagulant effect must be neutralized immediately, you may additionally administer fresh-frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa concentrate.

3. The use of bridging heparin therapy during the period of VKA discontinuation:

1) In patients receiving subcutaneous LMWHs at therapeutic doses, administer the last LMWH injection 24 hours before the invasive procedure at a dose amounting to approximately half the daily dose of LMWH.

2) In patients receiving IV UFH, stop the infusion ~4 hours before the procedure.

4. Resuming the anticoagulant treatment after the procedure:

1) In patients undergoing minor invasive procedures who have been receiving subcutaneous LMWHs at therapeutic doses during the period of discontinuation of the VKA, you may resume the administration of the LMWH ~24 hours after the surgery as long as adequate hemostasis is ensured.

2) In patients undergoing major invasive procedures or procedures associated with a high risk of postsurgical bleeding who have been receiving subcutaneous LMWHs or IV UFH at thferapeutic doses during the period of discontinuation of the VKA, administer subcutaneous LMWH or IV UFH at therapeutic doses 48 to 72 hours after the surgery as long as adequate hemostasis is ensured. Alternatively, you may use subcutaneous LMWH or UFH at prophylactic doses. It is acceptable not to use heparin immediately after the procedure.

3) VKA treatment may be resumed 12 to 24 hours after the surgery (eg, on the evening of the same day or the next morning) as long as adequate hemostasis is ensured. However, it may be resumed later if necessary because of the patient’s clinical condition.

Pregnancy and Long-Term Anticoagulant Therapy

1. In women receiving long-term VKA treatment who plan to become pregnant, a recommended safe and convenient management regime is frequent pregnancy testing based on the assumption that VKAs can safely be used during the first 4 to 6 weeks of pregnancy. Once the patient becomes pregnant, she should be switched from VKA to LMWH or UFH.

2. An alternative approach is to switch from VKA to LMWH before attempting to become pregnant.

3. According to the American College of Chest Physicians guidelines, in women receiving long-term VKA treatment because of an implanted mechanical heart valve it is recommended either to switch from VKA to LMWH (while monitoring anti-Xa activity) or to UFH at therapeutic doses for the entire pregnancy, or to use LMWH or UFH for the first 13 weeks of pregnancy and then switch to VKA, which should be used until approximately week 36 of an uncomplicated pregnancy. We follow the approach of limiting the use of VKAs throughout pregnancy to highly selected, rare, circumstances (eg, prior valve thrombosis or stroke, old valve type).

ComplicationsTop

1. Bleeding: Management: Table 3.

2. Teratogenic effects: Acenocoumarol and warfarin cross the placenta and impair gamma-carboxylation of proteins in the bones, thus posing a risk of chondrodysplasia punctata and nasal hypoplasia in children whose mothers have received VKAs between weeks 6 and 12 of pregnancy. Nervous system defects have also been reported in children whose mothers used VKAs in the first (after 6 weeks) and second trimesters of pregnancy.

3. Skin necrosis: Rare (more common in individuals with protein C or protein S deficiency), usually develops on the trunk in female patients between days 3 and 8 of VKA treatment. Skin necrosis is caused by thrombosis in the capillaries and small veins of the subcutaneous adipose tissue. If it develops, replace VKA with heparin for a few days or weeks (depending on the severity of the necrosis). If the patient requires long-term anticoagulant treatment, resume VKA starting with a low dose and gradually titrating it up. In severe cases of patients with protein C deficiency, administer protein C concentrate. Reports have been published on the safe use of dabigatran in the case of skin necrosis in patients with protein C deficiency.

4. Allergic reactions: Most often urticaria.

5. Liver damage: This occurs in ~1% of cases, mostly in patients with latent liver disease, such as chronic viral hepatitis. An increase in plasma aminotransferase levels is transient and normalizes within 2 weeks of the discontinuation of VKAs.

6. Warfarin nephropathy (see Acute Kidney Injury).

7. Alopecia.

TablesTop