Warfarin, DOACs and Heparins

Question 1

What is the main use of direct oral anticoagulants?

Answer 1

Oral anticoagulation for arterial or venous thromboembolism (prophylaxis and treatment).

Question 2

Name 3 different types of oral anticoagulant that are the P-drugs, and state their class.

Answer 2

1) Warfarin - Vitamin K antagonist.
2) Apixaban/ Rivaroxaban - direct factor Xa inhibitors.
3) Dabigatran - direct thrombin inhibitor.

Question 3

Give the 3 common clinical indications for the use of Warfarin.

Answer 3

1) In VTE to prevent clot extension and recurrence.
2) In AF to prevent embolic complications (stroke).
3) After heart valve replacement to prevent embolic complications.

Question 4

Give the difference between the use of Warfarin for the 2 types of valve replacement.

Answer 4

After a tissue valve replacement = short term use.

After mechanical valve replacement = lifelong use.

Question 5

Why is Warfarin not used to prevent arterial thrombosis (e.g. MI/ thrombotic stroke)?

Answer 5

Because arterial thrombosis is driven by platelet aggregation, and so is prevented by antiplatelet agents (aspirin and clopidogrel), not by anticoagulants.

Question 6

Describe the mechanism of action of Warfarin.

Answer 6

Inhibition of vitamin K epoxied reductase > prevents reactivation of vitamin K to reduced form > reduced synthesis of coagulation factors.

Warfarin inhibits hepatic production of vitamin K dependant coag. factors and cofactors.

Question 7

What is the main adverse effect of Warfarin?

Answer 7

BLEEDING - slight excess increases risk of bleeding from existing abnormalities such as peptic ulcers or from minor trauma.

Large excess - can trigger spontaneous haemorrhage such as epistaxis.

Question 8

1) Give the 2 contraindications to the use of Warfarin.

2) Which types of patients are at risk of over-anticoagulation and bleeding when taking Warfarin and why?

Answer 8

1) Pregnancy and those at immediate risk of haemorrhage (after trauma and patients requiring surgery).
2) Patients with liver disease who are less able to metabolism the drug.

Question 9

What can Warfarin do during the first term and near the end of term during pregnancy?

Answer 9

First term = fetal malformations (cardiac and cranial abnormalities).

Towards term = maternal haemorrhage at delivery.

Question 10

1) What do CYP450 inhibitors do in terms of Warfarin? Name some of these drugs.
2) What do CYP450 inducers do in terms of Warfarin? Name some of these drugs.
3) Why can small changes in hepatic Warfarin metabolism by CYP450 enzymes cause such clinically significant changes?

Answer 10

1) Decrease Warfarin metabolism and increase bleeding risk —> Fluconazole, macrolides, protease inhibitors.
2) Increase Warfarin metabolism and increase risk of clots —> Phenytoin, Carbamazepine, Rifampicin.
3) Because Warfarin has a low therapeutic index.

Question 11

How do antibiotics increase anticoagulation in patients on Warfarin?

Answer 11

They can kill gut flora that can synthesise vitamin K.

Question 12

1) Explain how Warfarin is usually administered, and describe the prescribing schedule followed.
2) Give 3 types of patients that the lower dose of Warfarin would be used for.

Answer 12

1) Warfarin is taken orally OD, with a starting dose of 5-10mg on day 1. Subsequent Warfarin doses are guided by the INR
2) Lower dose used for the elderly, lighter patients, and those at an increased risk of bleeding (E.G. for patients who take other drugs which might interact).

Question 13

Describe how Warfarin and Heparin might be used in conjunction.

Answer 13

Warfarin and Heparin might be used together if a patient needs urgent anticoagulation, as Heparin acts much more quickly. Heparin is then withdrawn when full anticoagulation with Warfarin is achieved.

Question 14

1) How long is a single episode of VTE treated with Warfarin for?
2) When might lifelong Warfarin be required?
3) What is the INR target range for patients on Warfarin for AF/ VTE.

Answer 14

1) 3-6 months.
2) Patients with recurrent VTE or cardiac disease.
3) 2.0-3.0

Question 15

Give the 2 common clinical indications for the use of Heparins and Fondaparinux and state why they are used.

Answer 15

1) VTE - LMWH first choice agent for pharmacological VTE prophylaxis in hospital inpatients. Also initial treatment for DVT and PE.
2) ACS - LMWH/ Fondaparinux are part of first line therapy to improve revascularisation and prevent intracoronary thrombus progression.

Question 16

1) How do Heparins and Fondaparinux prevent formation and propagation of blood clots?
2) Describe the MoA of Heparins.
3) Name 2 examples of LMWHs.
4) Describe the MoA of Fondaparinux.

Answer 16

1) They inhibit thrombin and FXa which are components of the final coagulation pathway, so prevent formation of a fibrin clot.
2) UFH activates antithrombin that then inactivates FXa and thrombin. LMWHs have a similar MoA but preferentially inhibit FXa.
3) Dalteparin and Enoxaparin.
4) Inhibits FXa only (similar efficacy to LMWH, so has become anticoagulant of choice for ACS treatment in many UK hospitals).

Question 17

1) Give 3 of the important adverse reactions when giving Heparins or Fondaparinux.
2) Give 3 important cautions when prescribing Heparins or Fondaparinux.

Answer 17

1) Bleeding (more common with LMWH/UFH than Fonda), injection site reactions, Heparin induced thrombocytopenia.
2) Caution in patients at risk of bleeding (clotting disorders/severe uncontrolled HTN/ recent surgery or trauma), avoid Heparins around times of invasive procedures, patients with renal impairment (LMWH/Fonda may accumulate so should be used at lower dose or UFH used instead).

Question 18

1) What is the main important interaction for Heparins and Fondaparinux?
2) Give 2 situations when it might be difficult to avoid this combination of drugs.
3) What can be done to reverse anticoagulation, if this is necessary?

Answer 18

1) Combining antithrombotic drugs increases the risk of bleeding.
2) Use of LMWH while initiating Warfarin. Use of antiplatelets with Heparin/Fonda in ACS.
3) Protamine can be given to reverse anticoagulation in bleeding associated with Heparin therapy. Effective for UFH, less effective for LMWH and ineffective for Fondaparinux.

Question 19

1) How are Heparins and Fondaparinux administered?
2) What happens if thrombocytopenia occurs as a result of Heparin/ Fondaparinux use?
3) When might Heparin and Fondaparinux effects need monitoring?

Answer 19

1) LMWH/ Fondaparinux by SC injection into abdominal wall. UFH by IV infusion.
2) Stop the drug and seek specialist advise immediately.
3) Pregnancy.

Question 20

Describe the mechanism of action of DOACs and give 3 examples of these.

Answer 20

Orally active factor Xa inhibitors > bind reversibly to active site of factor Xa > inhibit free FXa and FXa that is bound to prothrombinase complex.

Examples: Apixaban, Rivaroxaban, Edoxaban.

Question 21

1) Give 3 main unwanted effects of DOACs.
2) Name a drug interaction that can occur with DOACs.
3) If substantial bleeding is caused by DOACs, how can this be reversed?

Answer 21

1) Nausea and GI upset, haemorrhage (less risk than with Warfarin overall, but higher risk of GI bleeds),
2) Rivaroxaban excretion can be reduced when combined with Ketaconazole.
3) No direct antidote. Can use IV prothrombin complex concentrates or activates FXa.

Question 22

1) What class of drug is Dabigatran?

2) Describe the MoA of Dabigatran.

Answer 22

1) Direct thrombin inhibitor.
2) Selective direct competitive thrombin inhibitor. Inhibits circulating and thrombus bound thrombin (FIIa). Produces rapid onset of predictable anticoagulation.

Question 23

1) Give 3 unwanted effects of Dabigatran.

2) Name the specific antidote that can be used for Dabigatran.

Answer 23

1) Nausea, Dyspepsia, Diarrhoea, Abdominal pain, Haemorrhage
2) Idracizumab - monoclonal antibody fragment that is a specific antidote for Dabigatran and rapidly reverses anticoagulation.

Question 24

Give the name of 2 substances that can be used for the reversal of anticoagulation with Warfarin and other vitamin K antagonists.

State the classes of these.

Answer 24

Phytomenadione (vitamin K) and Beriplex (prothrombin complex concentrate).