Vitamin K Antagonists

Chapter: Vitamin K Antagonists
McMaster Section Editor(s): James Douketis
Section Editor(s) in Interna Szczeklika: Krystyna Zawilska†, Anetta Undas, Wiktoria Leśniak
McMaster Author(s): James Douketis
Author(s) in Interna Szczeklika: Anetta Undas, Krystyna Zawilska†
† Deceased.
Additional Information

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 3.1-2), 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 differences include the time necessary to achieve maximum blood levels (2-3 hours and 1.5 hours, respectively) and half-life (8-10 hours and 36-42 hours). 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).

Contraindications Top

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-Up Top

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

General Principles of Treatment Top

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 uncomplicated 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 “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, 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/fondaparinux, the latter agents may be discontinued once the INR has been maintained in the therapeutic range for 2 consecutive days.

Management of Patients Receiving Long-Term VKA

1. Patient education (Table 3.1-3), 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 the devices should be considered particularly in patients at high risk of thromboembolism, patients who probably would discontinue the VKA because of disability, living far from the clinic, or due to other factors (eg, type of occupation), as well as in 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 3.1-2) should remain at a relatively constant level.

4. Determine the INR at least once every 4 weeks in patients receiving a constant VKA dose (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, or in patients concomitantly treated with antiplatelet drugs and patients with 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.

Management of Patients With INR Below Therapeutic Range

1. You can increase the dose by 5% to 20%, using the total weekly dose as the basis.

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 of Patients With INR Above Therapeutic Range

Table 3.1-4.

Patients Treated with VKAs 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, acetylsalicylic acid [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. PubMed 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. PubMed 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.

Discontinuation of VKAs 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 a bridging heparin treatment depends on the risk of thromboembolic complications associated with the discontinuation of VKA (Table 3.1-5).

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

b) Moderate risk: Bridging anticoagulation is usually not required; alternatively consider prophylactic doses of subcutaneous UFH or 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 risk: Major vascular surgery, major orthopedic surgery, abdominal or thoracic surgery (including cardiac surgery), neurosurgery, prostatectomy, bladder surgery, polypectomy, implantation of a cardiac pacemaker or implantable cardioverter-defibrillator, biopsy of an organ/tissue than cannot be compressed (eg, liver, prostate, bronchus, bone marrow), and puncture of an artery that cannot be effectively compressed. In these cases it is usually necessary to discontinue the anticoagulant treatment.

b) Low 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.

2. Temporary discontinuation of VKA:

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 discontinuation of VKA:

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 therapeutic 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 in Women Receiving Long-Term Anticoagulants

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. However, according to the European Society of Cardiology guidelines, it is preferable to continue the use of VKAs throughout the pregnancy due to their superior efficacy compared with LMWHs in the prevention of prosthetic valve thrombosis.

Complications Top

1. Bleeding: Management: Table 3.1-4.

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

Table 3.1-2. Clinically significant interactions with VKAs (acenocoumarol, warfarin)

Drug/substance class

Effects on VKA anticoagulant activity

Potentiation

Inhibition

Antimicrobials

A: Ciprofloxacin, erythromycin, fluconazole, isoniazid (600 mg/d), sulfamethoxazole/trimethoprim, metronidazole, miconazole,a voriconazole

B: Amoxicillin + clavulanic acid, azithromycin, itraconazole, ketoconazole, clarithromycin, levofloxacin, ritonavir, tetracycline

A: Griseofulvin, nafcillin, ribavirin, rifampicin

B: Dicloxacillin, ritonavir

Cardiovascular drugs

A: Amiodarone, diltiazem, fenofibrate, clofibrate, propafenone, propranolol, sulfinpyrazoneb

B: Quinidine, fluvastatin, acetylsalicylic acid, ropinirole, simvastatin

A: Cholestyramine

B: Bosentan, spironolactone

Analgesics, anti-inflammatory and immunomodulatory drugs

A: Phenylbutazone

B: Interferon, acetylsalicylic acid, acetaminophen (INN paracetamol), tramadol

A: Mesalamine

B: Azathioprine

Central nervous system drugs

A: Alcohol (in patients with coexisting liver disease), citalopram, entacapone, sertraline

B: Disulfiram, chloral hydrate, fluvoxamine, phenytoin,c tricyclic antidepressants (amitriptyline, clomipramine), benzodiazepines

A: Barbiturates, carbamazepine

B: Chlordiazepoxide

Gastrointestinal drugs and foods

A: Cimetidine,c mango, fish oil, omeprazole

B: Grapefruit juice, prokinetic agents (particularly cisapride)

A: Avocado (in large quantities), foods rich in vitamin K1,d enteral nutrition

B: Soy milk, sucralfate

Other drugs

A: Anabolic steroids, zileuton, zafirlukast

B: Fluorouracil, gemcitabine, levamisole with fluorouracil, paclitaxel, tamoxifen, tolterodine, thiamazole, L-thyroxine

A: Mercaptopurine

B: Raloxifene, multivitamin supplements, influenza vaccines, chelating agents

A, causation is highly probable. B, causation is probable.

a Oral topical gel and vaginal suppositories.

b Initial potentiation followed by inhibition.

c Applies to warfarin.

d For instance, kale, spinach, different varieties of cabbage (Chinese, mustard greens, sauerkraut), beet leaves, Brussels sprouts, broccoli, dandelion (leaves), various types of lettuce, green parsley, asparagus, onions (spring onions and shallots), chicory. Frozen foods are usually richer in vitamin K than fresh foods. One cup (~250 mL) of the foods listed in the table contains ≥80 microg of vitamin K1 (daily requirement, 80-120 microg).

Adapted from Arch Intern Med. 2005;165(10):1095-106.

INN, international nonproprietary name; VKA, vitamin K antagonist.

Table 3.1-3. Education of patients treated with VKAs (or their caregivers)

– Explain reasons for using the anticoagulant treatment

– List all generic and trade names of the used anticoagulant(s) and discuss how they reduce the risk of thrombosis and its complications

– Explain the expected duration of treatment

– Explain why it is necessary to determine the INR

– Explain the target INR values recommended for the patient and the narrow therapeutic range

– Emphasize the need for frequent and regular INR determinations in order to reduce the risk of bleeding or thrombosis. Inform the patient about the possibility of self-monitoring of the INR in capillary blood using a portable coagulometer (eg, CoaguCheck)

– Describe the most common symptoms of bleeding and the appropriate management

– Describe how to avoid injuries and bleeding

– Describe the most common symptoms and management in case of deep vein thrombosis or pulmonary embolism

– Discuss the effect of foods containing vitamin K1 on the anticoagulant effect of VKAs (see Table 3.1-2)

– Discuss the effects of taking certain drugs (both prescription and over-the-counter) on the anticoagulant effect of VKAs (see Table 3.1-2) and the management when switching drugs

– Discuss the increased risk of bleeding associated with concomitant treatment with antiplatelet drugs

– Discuss the need for limiting or refraining from alcohol consumption

– In female patients likely to become pregnant, discuss the risks associated with using VKAs

– Explain the reason and emphasize the need to inform doctors, dentists, and other medical professionals about the use of VKAs

– Explain at what time of day a VKA should be taken and discuss what to do in case of missing a dose

– Suggest that the patient carries relevant information concerning the use of VKAs (eg, medical information cards together with an ID, a bracelet)

– Document discussing these topics with the patient and/or his/her caregiver in the medical records

Adapted from Ann Pharmacother. 2008;42(7):979-88.

INR, international normalized ratio; VKA, vitamin K antagonist.

Table 3.1-4. Management of patients with INR values above the therapeutic range

Clinical situation

Management

4.5 <INR <6.0 without bleeding

1) Discontinue VKA until the INR is 2.0-3.0a

2) Do not administer vitamin K1 routinely

INR 6.0-10.0 without bleeding

1) Discontinue VKA until the INR is 2.0-3.0

2) You may administer 2.5-5 mg of POb vitamin K1c

INR >10.0 without bleeding

1) Discontinue VKA

2) Administer 2.5-5 mg of POb vitamin K1

Severe bleeding associated with VKA

1) Discontinue VKA

2) Immediately neutralize the anticoagulant effect by administering a 4-factor prothrombin complex concentrated rather than fresh-frozen plasmae

3) In the case of refractory life-threatening bleeding, consider a recombinant factor VIIa concentrate

4) Additionally administer 2.5-5 mg of vitamin K1 in a slow IV infusion

a Discontinuation of the treatment for 1-2 days is usually sufficient.

b Use of high doses of vitamin K1 may cause resistance to VKAs lasting ~7 days.

c Some experts (including the American College of Chest Physicians) do not recommend the routine administration of vitamin K1.

d In patients with an INR >6.0, administration of a prothrombin complex concentrate in a dose 50 U/kg usually results in INR normalization within 10-15 minutes; such treatment is necessary particularly in patients with intracranial or other life-threatening bleeding.

e The optimum dose of fresh frozen plasma has not been established; the usual dose is 10-15 mL/kg (1 U corresponds to ~200 mL). Time to INR normalization is much longer than in the case of a prothrombin complex concentrate.

Based on Chest. 2012; 141 (2 Suppl): e1S–e801S.

INR, international normalized ratio; VKA, vitamin K antagonist (acenocoumarol, warfarin); PO, oral.

Table 3.1-5. Risk stratification of venous or arterial thromboembolism in patients receiving long-term VKA treatment

Indications for VKA treatment

Estimated risk of thromboembolism

Low

Moderate

High

Mechanical heart valve

Mechanical bileaflet aortic valve with no additional stroke risk factors

Mechanical bileaflet aortic valve and one of the following risk factors: atrial fibrillation, history of stroke/TIA, hypertension, diabetes mellitus, congestive heart failure, age >75 years

– Mechanical mitral valve; old-type mechanical aortic valve (caged-ball, tilting-disc)

– History of stroke or TIA in prior 6 months

Atrial fibrillation

CHADS2 score 0-2 and no history of stroke or TIA

CHADS2 score 3-4

– CHADS2 score 5-6

– History of stroke or TIA in prior 3 months

– Rheumatic heart disease

VTE

History of one VTE event >12 months ago, currently no other risk factors for VTE

– History of VTE in the prior 3-12 months or recurrent VTE

– Milder forms of thrombophilia (eg, heterozygotes for prothrombin G20210A gene or factor V Leiden)

– Cancer (treatment in prior 6 months or palliative therapy)

– History of VTE in prior 3 months

– Severe thrombophilia (eg, antithrombin, protein C or protein S deficiency, APS, several coexisting conditions)

CHADS2 score: see Table 3.4-3.

APS, antiphospholipid syndrome; TIA, transient ischemic attack; VKA, vitamin K antagonist; VTE, venous thromboembolism.

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