Heart valve replacement

Question 1

Warfarin

Common indications

Answer 1

1. To prevent clot extension and recurrence in DVT and pulmonary embolism (collectively, venous thromboembolism VTE)
2. To prevent embolic complications (e.g. stroke) in atrial fibrillation
3. 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. MI, thrombotic stroke)
• As this is driven by platelet aggregation, it is prevented by antiplatelet agents such as aspirin and clopidogrel

Question 2

Warfarin

MOA

Answer 2

• Warfarin inhibits hepatic production of Vit-K dependent coagulation factors and co-factors
• Vit-K must be in its reduced form for synthesis of coagulation factors
• It is then oxidised during the synthetic process
• An enzyme called Vit-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

Important 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 of following minor trauma (e.g. intracerebral haemorrhage after a minor head injury)
• A large excess of warfarin can trigger spontaneous haemorrhage such as epistaxis (nose bleed) or retroperitoneal haemorrhage

Question 4

Warfarin

Warnings

Answer 4

• As there is a fine line between thrombosis and haemorrhage in patients taking warfarin, potential risks and benefits must be carefully balanced
• 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 malformation, 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

• 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 P450 enzymes can cause clinically significant changes in anticoagulation
• P450 inhibitors (fluconazole, macrolides, protease inhibitors) decrease warfarin metabolism and increase bleeding risk
• P450 inducers (phenytoin, CBZ, Rifampicin) increase warfarin metabolism and risk of clots
• May antibiotics can increase anticoagulation in patients on warfarin by killing gut flora which synthesise Vit-K

Question 6

Warfarin

Prescription

Answer 6

• Warfarin is taken orally OD. The dose is 5-10mg 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 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

Administration

Answer 7

• 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)

Question 8

Warfarin

Communication

Answer 8

• Advice patients that warfarin treatment is a balance between benefits (preventing clots) and risks (bleeding)
• 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

Question 9

Warfarin

Monitoring

Answer 9

• The INR is the prothrombin time of a person on warfarin divided by that of a non-warfarinsed ‘control’. INR target values vary by indication for warfarin
• For example, in atrial fibrillation and VTE, the target range is usually 2-3 (2.5)
• 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