Novel anticoagulants

Question 1

Example of novel anticoagulants

Answer 1

Warfarin

Question 2

How do novel anticoagulants work?

Answer 2

Warfarin inhibits hepatic production of vitamin K-dependent coagulation factors and cofactors. Vitamin K must be in its reduced form for synthesis of coagulation factors. It is then oxidised during the synthetic process. An enzyme called vitamin K epoxide reductase reactivates oxidised vitamin K. Warfarin inhibits vitamin K epoxide reductase, preventing reactivation of vitamin K and coagulation factor synthesis.

Question 3

Indications for novel anticoagulants

Answer 3

To prevent clot extension and recurrence in deep vein thrombosis and pulmonary embolism (collectively, venous thromboembolism [VTE]).
To prevent embolic complications (e.g. stroke) in atrial fibrillation.
To prevent embolic complications (e.g. stroke) after heart valve replacement. Treatment is short term after tissue valve replacement and lifelong for mechanical valve replacement.

Warfarin is not used to prevent arterial thrombosis (e.g. myocardial infarction, thrombotic stroke). As this is driven by platelet aggregation, it is prevented by antiplatelet agents, such as aspirin and clopidogrel.

Question 4

Contraindications of novel anticoagulants

Answer 4

Warfarin is contraindicated in patients at immediate risk of haemorrhage, including after trauma and in patients requiring surgery.

Patients with liver disease who are less able to metabolise the drug are at risk of over-anticoagulation/bleeding.

In pregnancy, warfarin should not be used in the first trimester as it causes fetal malformations, including cardiac and cranial abnormalities. It should not be used towards term, when it may cause maternal haemorrhage at delivery.

Question 5

Side effects of novel anticoagulants

Answer 5

Main: bleeding
An excess of warfarin increases the risk of bleeding from existing abnormalities such as peptic ulcers or following minor trauma (e.g. intracerebral haemorrhage after minor head injury). A large excess of warfarin can trigger spontaneous haemorrhage such epistaxis (nose bleed) or retroperitoneal haemorrhage.

Question 6

Interactions of novel anticoagulants

Answer 6

The plasma concentration of warfarin required to prevent clotting is very close to the concentration that causes bleeding (low therapeutic index). Small changes in hepatic warfarin metabolism by cytochrome P450 enzymes can cause clinically significant changes in anticoagulation. Cytochrome P450 inhibitors (e.g. fluconazole, macrolides, protease inhibitors) decrease warfarin metabolism and increase bleeding risk. Cytochrome P450 inducers (e.g. phenytoin, carbamazepine, rifampicin) increase warfarin metabolism and risk of clots. Many antibiotics can increase anticoagulation in patients on warfarin by killing gut flora which synthesise vitamin K.

Question 7

Elimination of novel anticoagulants

Answer 7

Warfarin is almost entirely eliminated by metabolism. Warfarin is metabolized by hepatic cytochrome P-450 (CYP450). Very little Warfarin is excreted unchanged in urine. Urinary excretion is in the form of metabolites.

Question 8

Patient information on novel anticoagulants

Answer 8

Traditionally, warfarin is taken each day at around 18:00 hours for consistent effects on the INR taken the following morning. This may also help patients remember when to take it (around tea time).

It is important for patients to understand how food, alcohol and other drugs can affect warfarin treatment. Patients receive an anticoagulant book (‘Yellow Book’), which acts as an alert to their warfarin therapy and is used to record warfarin doses, blood test results, treatment indication and duration.