CV - Warfarin

Question 1

Warfarin

Common indications

Answer 1

• To prevent clot extension in DVT and PE (VTE)
• To prevent embolic complictions (stroke) in AF
• To prevent embolic complications after heart valve replacement. Treatment is short term after tissue valve replacement and lifelong after mechanical replacement.

Not used to prevent arterial thrombosis, as this is driven by platelet aggregation, normally prevented by anti-platelet agents (aspirin/clopidogrel)

Question 2

Warfarin

Mechanism of Action

Answer 2

• Inhibits production of Vitamin K-dependant coagulation factors and cofactors
• Vitamin K must be in its reduced form for synthesis of coagulation factors
• Then oxidised during the synthetic process
• An enzyme vitamin K epoxide reductase reactivates oxidised vit K
• Warfarin inhibits vit K epoxide reductase, preventing reactivation of vit K and coagulation factor synthesis

Question 3

Warfarin

Adverse effects?

Answer 3

• The main adverse effect of warfarin is bleeding.
• A slight 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 4

Warfarin

Warnings?

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

Warfarin

Important Interactions?

Answer 5

• Plasma concentration of warfarin required to prevent clotting is very close to the concentration that causes bleeding.
• 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 6

Warfarin

Practical Prescribing?

Answer 6

• Warfarin is taken orally once a day.
• The dose is 5–10 mg on day 1, with the lower dose used for patients who are elderly, lighter or at increased bleeding risk (e.g. due to interacting medicines).
• Subsequent doses are guided by the international normalised ratio (INR).
• After starting warfarin, it takes several days for full anticoagulation to be achieved.
• Patients needing immediate anticoagulation usually start both heparin(fast onset of action) and warfarin.
• Heparin is withdrawn when full anticoagulation with warfarin is achieved.
• A single episode of VTE is treated with warfarin for 3–6 months.
• Lifelong warfarin may be required for recurrent VTE or cardiac disease. However, treatment may be stopped if new bleeding risks exceed potential benefits.

Question 7

Warfarin

Monitoring?

Answer 7

• The INR is the prothrombin time of a person on warfarin divided by that of a non-warfarinised ‘control’.
• INR target values vary by indication for warfarin. For example, in atrial fibrillation and VTE the target range is usually 2.0–3.0.
• INR is measured daily in hospital inpatients and every few days in outpatients commencing warfarin.
• Once a stable dose of warfarin has been established, INR measurement is less frequent.