CVS: warfarin, heparin, DOAC

Question 1

Indications of warfarin?

Answer 1

VTE (DVT & PE)
- Initial concomitant therapy with heparin is required as it takes several days for anticoagulation with warfarin to be fully established.
- DOACs are alternatives for this indication.

PREVENTION OF ARTERIAL EMBOLSIM IN PTS WITH AF or PROSTHETIC HEART VALVES

Question 2

MOA of warfarin?

Answer 2

Warfarin inhibits hepatic production of vitamin K-dependent coagulation factors (factors II, VII, IX, and X, and proteins C and S).

It does this by inhibiting vitamin K epoxide reductase.

VitK epoxide is responsible for restoring vitamin K to its reduced form, necessary as a co-factor in the synthesis of these clotting factors.

Question 3

Adverse effects of warfarin? How is warfarin effect reversed?

Answer 3

Minor over-warfarinisation:
Increase risk of bleeding due to:
- Minor injury + warfarin = intracerebral haemorrhage
- Peptic ulcers

Severe over-warfarinisation:
Spontaneous bleeding -epistaxis or retroperitoneal haemorrhage.

Warfarin can be reversed with phytomenadione (vitamin K1) or dried prothrombin complex.

Question 4

Warnings of warfarin?

Answer 4

Avoid in pts with:
- immediate risk of haemorrhage (trauma, pre-surgery)
- liver disease (can’t metabolise drug so increase SEs of warfarin)
- first trimester pregnancy (teratogenicity -cardiac and cranial abnormalities)
- later in pregnancy (risk of peripartum haemorrhage)

Question 5

Interactions of warfarin?

Answer 5

Narrow therapeutic index.

Small changes in hepatic warfarin metabolism by CYP450 enzymes can cause clinically significant changes in anticoagulation.

CYP inducers = increase warfarin metabolism

CYP inhibitors = decrease warfarin metabolism

Other abx can increase the effect of warfarin by killing gut flora that synthesis vitamin K.

Question 6

Monitoring of warfarin?

Answer 6

INR is monitored:
- daily in hospital inpatients
- every few days in outpatients

Once a stable dose of warfarin has been established, INR is less frequently measured.

INR = 2-3 in AF and VTE.
Higher INR = metallic prosthetic cardiac valves

Question 7

Pt education of warfarin?

Answer 7

Warfarin aims to prevent clots.

Food, alcohol and other tx can affect warfarin.

Pts receive an anticoagulant yellow book:
- records warfarin dose, blood test results, tx indication and duration.
- pts with AF -they can decide warfarin or DOAC.

Warfarin
- well-established
- requires regular blood test
- may interact with alcohol, food, drugs.

DOACs:
- newer drugs
- don’t require frequent blood test
- may interact with other drugs but not food.

Question 8

Indications of heparin?

Answer 8

VTE (DVT & PE)
- initial tx of VTE until oral anticoagulation (warfarin, DOAC) is established

ACS
- heparin used alongside antiplatelet agent

Question 9

MOA of heparin?

Answer 9

Heparins and fondapariunx act by enhancing the anticoagulant effect of antithrombin (AT).

The size of heparin molecules determine their molecular specificity:
- unfractionated heparin (large and small molecules -promotes inactivation of both factors IIa and Xa (2a and 10a)
- low molecular weight heparin (small molecules) -is more specific for inactivating factor Xa.

Fondaparinux is a synthetic pentasaccharide that mimics the sequences of the binding site of heparin to antithrombin and is very specific for factor Xa.

Question 10

Adverse effects of heparin?

Answer 10

• Haemorrhage (lower risk with fondaparinux than LMWH or UFH)
• Bruising or other reactions at the injection site
• Hyperkalaemia (occurs due to an effect on adrenal aldosterone secretion)
• Heparin-induced thrombocytopenia (low platelet count and thrombosis -less likely in LMWH than UFH, does not occur with fondaparinux)

Question 11

Warnings of heparin?

Answer 11

Caution in:
- clotting disorders
- severe uncontrolled HTN
- recent surgery or trauma

Withheld in:
- before and after invasive procedures (e.g. lumbar puncture, spinal anaesthesia)

RENAL IMPAIRMENT:
Use lower dose of LMWH or fondaparinux (as drug can accumulate) OR use UFH.

Question 12

Interactions of heparin? How is heparin effect reversed?

Answer 12

Additive effect if combing with other antithrombotic drugs (warfarin, antiplatelets).

In major bleeding, PROTAMINE can reverse heparin anticoagulation -works for UFH.

Andexanet alpha is in development and appears to be an effective reversal agent.

Question 13

Monitoring of heparin?

Answer 13

Monitor antifactor Xa activity in cases like renal impairment and pregnancy.

Before treatment, check:​
- FBC​
- Baseline clotting ​
- Renal profile​

In prolonged therapy (>4 days), monitor:​
- Platelet count​ (risk of thrombocytopneia)
- Serum K conc (risk of hyperkalaemia)

Seek specialist advice if platelet count drops significantly -may indicate HIT -requires urgent management.

Question 14

Pt education of heparin?

Answer 14

Offering a daily injecting to reduce risk of blood clots.

Discuss the risks and benefits of anticoagulation.

Avoid activities that may increase risk of bleeding.

Advise to inform healthcare professionals they encounter that they take anticoagulants.

Pt and their carer will need to be trained in SC injection technique. Otherwise a district nurse may need to be arranged.

Question 15

Indications of DOAC?

Answer 15

VTE (DVT & PE)

AF
- DOAC used alongside anticoagulation -prevent stroke and embolism, HF, HTN, DM.

Question 16

MOA of DOAC?

Answer 16

DOACs act on the final common pathway of the coagulation cascade, compromising factor X, thrombin, and fibrin.

Factor X (Xa) is directly inhibited by apixaban, edoxaban, and rivaroxaban. - - This prevents conversion of prothrombin to thrombin.

Dabigatran directly inhibits thrombin, preventing the conversion of fibrinogen to fibrin.

Therefore, all DOACs inhibit fibrin formation, preventing clot formation or extension in the veins and heart.

Question 17

Adverse effects of DOAC?

Answer 17

Bleeding
- epistaxis
- GI and GU haemorrhage

Intracranial haemorrhage and major bleeding is LESS with DOACs than warfarin.

• GI upset
• Anaemia
• Dizziness
• Elevated liver enzymes

Question 18

Warnings of DOAC?

Answer 18

Avoid in:
- significant active bleeding
- risk factors for major bleeding (peptic ulceration, cancer, recent surgery or trauma)
- pregnant women
- breastfeeding women

Reduce dose or use an alternative agent in:
- hepatic or renal disease.

Question 19

Interaction of DOAC?

Answer 19

Increase risk of bleeding if combined with other antithrombotic agents.

CYP inducers/inhibitors affect metabolism of DOACs.
Other drugs can affect DOAC excretion.

Anticoagulant effect increased by:
- macrolides
- protease inhibitors
- fluconazole

Anticoagulant effect decreased by:
- rifampicin
- phenytoin

Question 20

Monitoring of DOAC?

Answer 20

Does not require routine monitoring.

Reversal agents for DOACs can be used if major bleeding occurs.

Andexanet alpha is a potential reversal agent for factor Xa inhibitors.

Question 21

Pt education of DOAC?

Answer 21

DOAC aims to reduce the ability of the blood to clot, hence the main side effect is increased risk of bleeding.

Pts receive an alert card and should show it to all healthcare contacts, particularly if starting on new meds, surgery, or accident.

Must seek medical advice if they develop prolonged or serious bleeding, weakness, tiredness, or breathlessness that could be signs of anaemia.

Take DOAC at same time each day until told to stop.