Vitamin k antagonists

The effect of coumarin derivatives was first discovered in Canada and the northern states of the USA. At that time, animals in this region suffered from an increased tendency to bleed. The cause of the bleeding tendency was found in the spoiled sweet clover that the animals had ingested. These active ingredients contained substances with vitamin K antagonistic properties (Lüllmann 2010).

Vitamin K antagonists have been used in medicine since 1954. There is therefore decades of experience with these drugs (Nüllen 2014).

Vit. K antagonists (VKA) belong to the group of anticoagulants and are used for the prophylaxis and therapy of thromboembolism.

They are orally well absorbable, inexpensive and their effect can be easily compensated for by high doses of vitamin K if necessary (Lüllmann 2010).

One of the vitamin K antagonists is coumarin, the chemical compound phenprocoumon (PPC).

Two coumarin derivatives are available in Germany, which differ only in their half-life (Lüllmann 2010):

• Phenprocoumon with a half-life of 4-6 days (trade name Marcumar®, Falithrom® and others).
• Warfarin with a half-life of 1.5 - 2 days (trade name Coumadin®)

Active ingredients commonly used abroad are (in addition) (Späth 2013):

• Acenocoumarol (Sinthrome® or Sintrom®)
• a. a

Antidote: The antidote is vitamin K1 (trade name Konakion). Caution is advised with regard to Konakion® in the case of a known allergy to peanuts or soy. In this case, Konakion MM 2 mg is available, which should also be given to newborns (Taghizadeh 2017).

Dosage recommendation (Taghizadeh 2017).

• Konakion 5 to 10 mg up to 4 x / d as i. v. administration (slow injection) or oral administration (is preferred).

In addition to the administration of the antidote, immediate heparinization should take place and corticosteroids should also be administered (Herold 2918). More detailed information on dosage is not available. Since the conakion only abolishes the anticoagulant effect after about 24 h, additional PPSB- preparations and blood transfusions can be given in acute severe bleeding (Piper 2012).

Indication: Since the vitamin K antagonists show a delayed effect and regular laboratory checks (checking the INR value) are required during treatment, as well as a dosage adapted to the INR value, the VKAs hardly play a role in the perioperative phase in Europe (Encke 2015).

VKA are used:

• For thromboembolism prophylaxis (the risk of VTE recurrence is reduced to normal levels).

Coumarins are also effective in existing (Lüllmann 2010):

• APC- resistance
• Protein C deficiency
• protein S deficiency
• for thromboembolism prophylaxis in non-valvular atrial fibrillation
• for therapy of thrombosis

Contraindications:

• Diseases with increased risk of bleeding (e.g. renal insufficiency, hemorrhagic diathesis, liver parenchymal disease, severe thrombocytopenia, etc.).
• Diseases with v. a. a lesion of the vascular system (e.g. gastrointestinal ulcers, uncontrolled hypertension, apoplexy, endocarditis lenta, retinopathies with bleeding risk, cerebral artery aneurysms, etc.)
• chronic alcoholism
• seizure disorders
• cavernous pulmonary tuberculosis
• nephrolithiasis
• Gravidity (from the 6th SSW [Encke 2015])
• Lactation
• Lack of compliance of the patient, etc.

Side effects (Encke 2015):

• Bleeding (the risk of intracranial bleeding is about 0.3%/year at an INR of 2.0 to 3.0)
• Hair loss
• hepatitis with or without icterus (rarely occurring)
• gastrointestinal complaints
• coumarin-induced skin necrosis (in the case of existing protein C deficiency, these can occur together with a tendency to thrombosis due to passive hypercoagulability during the period of discontinuation of coumarin treatment)
• allergic skin reactions
• osteopenia
• slowed healing of fractures
• among others.

Interaction:

An increase in the effect of coumarins with an increase in the INR value can lead to:

• NSAIDs (by displacement of coumarins from protein binding)
• Antibiotics (through reduced enteric vitamin K formation or, in the case of erythromycin and clarithromycin, through inhibition of the degradation of phenprocoumon).
• Exchange resins such as cholesterol or lipid-lowering agents in lipid metabolism disorders (due to reduced enteral absorption of vitamin K)
• Platelet aggregation inhibitors (e.g. ASA)
• Heparin
• Fibrinolytics (e.g. streptokinase, urokinase for thrombolysis)
• Numerous other medications (see manufacturer's instructions; if necessary, carry out close INR checks).

The following can lead to a reduction in the coumarin effect with a lowering of the INR value:

1) by enzyme induction in the liver:

• Barbiturates
• Antiepileptic drugs
• Rifampicin
• and others

2) by:

• Digitalis
• Diuretics
• Corticosteroids
• Vitamin K-rich food (such as cabbage, spinach, etc.)
• a. o.

Dosage: Before a planned anticoagulation, the Quick- value or INR- value must first be determined. During initiation of treatment with coumarins, overlapping therapy with heparin should be given initially, otherwise there is no initial protection against thrombosis. Heparin therapy can be discontinued when the INR reaches the therapeutic range.

Therapy is monitored by determining the thromboplastin time. This can be done by determining the Quick- value or the INR- value (International Normalized Ratio). The INR value was developed to ensure an internationally comparable standard of therapy with anticoagulants. The INR value is opposite to the Quick value. For standard anticoagulation, the therapeutic INR value is between 2.0 and 3.0. For stronger anticoagulation with INR values above 3.0, increased bleeding complications must be expected.

In the case of Quick or INR values that are initially in the normal range, the following dosage can be started in adults:

• Marcumar® 3 mg 2 x 1 tbl./taf in the first 3 days, then dose adjustment according to the result of the INR value.
• Alternatively, the preparation Falithrom® 3 mg can be given in the same dosage.

Note: Foods rich in vitamin K (e.g. broccoli, cabbage, spinach, etc.) do not have to be avoided during therapy, but they should not be consumed in excess and spread over the week. All drugs with an increased risk of bleeding (e.g., NSAIDs, antiplatelet agents, etc.) should be avoided during treatment with coumarins. If short-term therapy with NSAIDs proves unavoidable, it should be given only with additional administration of a proton pump inhibitor (e.g., omeprazole 20 mg/d). Patients who require long-term anticoagulation should be introduced to coagulation self-management (e.g., with CoaguCheck) if they are suitable. Studies have shown that this improves the quality of the setting:

• the risk of bleeding can be reduced
• the number of thromboembolic complications decreases
• the survival rate increases

The INR value should optimally be more than 70 % in the target range. After discontinuation of coumarin therapy, the prolonged bleeding time normalizes after 7 - 14 days. In studies, tapering of coumarins has not been shown to be more beneficial than abrupt discontinuation.

If surgery becomes necessary in a patient who is already receiving drug-based thromboembolic prophylaxis, it is recommended that the risk of bleeding due to anticoagulation be weighed against the risk of thromboembolism after discontinuation of anticoagulation in each individual case (Herold 2018).

If therapy with vitamin K antagonists:

• the risk of bleeding is low, a temporary reduction of the dose with the target value of an INR of 1.5 should be applied.
• If there is a medium risk of bleeding and a high risk of thromboembolism, the vitamin K antagonist should be discontinued until the 1st day after surgery. Studies have shown that bridging the risk of thromboembolism with heparin is not successful. However, the risk of bleeding increased under heparin.
• If there is a high risk of bleeding and/or low risk of thromboembolism, it is recommended to discontinue the vitamin K antagonist preoperatively and to perform the operation at a time when the INR value has returned to normal.

(Herald 2918)

If acute bleeding occurs as a complication of anticoagulation with vitamin K antagonists, or if emergency surgery is necessary, the following procedure is recommended:

• Immediate discontinuation of medication and administration of PPSB infusions (human prothrombin concentrate) until coagulation normalizes. The target value is an INR of < 1.5 or a Quick of > 50%.

(Herold 2918)

1. Encke A et al. (2015) S3- Guideline: Prophylaxis of venous thromboembolism (VTE) AWMF Guidelines- Register No. 003/001
2. Herold G et al (2018) Internal Medicine. Herold Publisher S 836
3. Lüllmann H et al (2010) Pharmacology and Toxicology: Understanding drug effects - targeted use of drugs. Thieme Publishing House SS 200- 202
4. Nüllen H et al (2014) VTE- Venous thromboembolism 143: 218, 251 - 252, 261 - 262
5. Piper W (2012) Internal Medicine. Springer Publishing House S 716
6. Späth G (2013) Poisoning and acute drug overdoses: Mechanism of action, immediate measures and intensive therapy. Walter de Gruyter Publisher SS 439 - 440
7. Taghizadeh H (2017) Pocket Guide Anaesthesia Springer Verlag SS 21 - 22