Story of Warfarin

TAHER SAIDAss, Lecturer of Cardiology

Islamic Cardiac CentreAl Azhar University

Outlines

• Warfarin from Rodenticidal to life Saver.• Mechanism of action.• Pharmacokinetics.• Indications.• Adverse effect.• Advantage and disadvantage in comparison to

NOACs.• Future.

Warfarin from Rodenticidal to life Saver.

Warfarin from Rodenticidal to life Saver

• The story started in 1920s in the Midwest US with hemorrhargic disease in cattels, this was due to ingestion of spoilet sweet clover.

• The substance responsible for bleeding was extracted and identified as Coumarine by KARL PAUL from university of wisconsin.

• 1941 it was used as a rat poison but the survival of a man suffering from thrombo-embolic disease after an attempted suicidal by the use of a large amount of warfarin based Rodenticide led to clinical trials of warfarin.

• 1954 used as a human oral anticoagulant.

Mechanism of action

• Block the Vitamin K-dependent glutamate carboxylation of precursor clotting

factors II, VII, IX and X• Also inhibits Proteins C & S• Recovery needs synthesis of new clotting

factors• Action is reversed with vitamin K

Pharmacokinetics

• Highly plasma protein bound

• Metabolised by liver

• Substrate of CYP450 enzymes

CYP1A2 (minor), 2C8/9 (major), 2C19 (minor), 3A4

(minor); Inhibits CYP2C8/9 (moderate), 2C19 (weak)

• Excreted in urine and stool.

Indications

• Prophylaxis and treatment of:-

1. Venous thrombosis

2. Pulmonary embolism

3. Thromboembolic disorders

4. Atrial fibrillation with risk of embolism

5. Prophylaxis of systemic embolism post MI (LV thrombus)

Adverse Effects

• Bleeding (2.7%), (major 1.1- 8.1%) (risk depends on both the INR and patient factors)

• Contraindicated in pregnancy - teratogenic effects (warfarin Embryopathy 5%- 30%)

• Warfarin induced skin necrosis (0.02%) - paradoxical local thrombosis - increased in patients with protein C or S deficiency

• "Purple toes syndrome," cholesterol microembolization

• Osteoporosis (0.1%):- - As vit K is involved with the protein osteocalcin which is impaortant in bone

remineralization.

Warfarin Embryopathy(Di Sala Syndrome)

• Specific pattern of congenital anomalies occurs in children born to mothers exposed to warfarin during the 1st Trimester (5% to 30%)

• Classic features of Warfarin Embryopathy: - Nasal hypoplasia. - Chondrodysplasia Punctata (Epiphyseal and

vertebral bone stippling).

Calcifications and irregular ossification of lumbar and sacral vertebrae

Chondrodysplasia punctata

Warfarin necrosis (0.02%)

• Onset usually within the 1st 2-5 days of warfarin (specially with large doses) therapy when blood tend to clot more than normal.

• Affects area with high fat content such as breasts, thighs, buttocks, hips and abdomen.

D/D of Warfarin necrosis: Pyoderma gangrenosum ,,Necrotizing fasciitis.

InteractionsWith foods

Vegetables that include cauliflower, kale, Brussels

sprouts, asparagus, spinach, alfalfa, turnip greens,

mustard greens and collard greens

Beverages such as herbal teas (green tea) and coffee.

Vegetable oils that include soybean, olive.

Peas and green onions

Dairy products such as yogurt

Increased bleeding risk due to increased effect of warfarin: ➞ INR

Antiarrhythmics - amiodarone , propafenone

Antibiotics - amoxicillin , cephalosporins , fluoroquinolones,

macrolides.

Anticonvulsants - phenytoin ,sodium valproate

Antidepressants -duloxetine ,venlafaxine, SSRI.

Antifungals- fluconazole , itraconazole , ketoconazole.

Antihyperlipidemics - Ezetimibe , fenofibrate ,Atorvastatin,

fluvastatin ,rosuvastatin Decreased effect warfarin:➞INR

Antibiotics - rifampin Antidepressants- trazodone Antiepileptics - carbamazepine , phenobarbitone ,phenytoin.

Drugs interactions

Interactions

• Alcohol and Warfarin

• Acute ethanol ingestion decreases the

metabolism of warfarin and increases PT/INR

• Chronic daily ethanol use increases the

metabolism of warfarin and decreases PT/INR

Advantage and disadvantage in comparison to NOACs

As regard PharmacokineticsRivaroxaban Apixaban Dabigatran Warfarin

Characteristics

79 66 6-7 98 Bioavailability (%)

7-13 8-15 7-17 20-60 t1/2 (h)

95 87 35 99 Protein binding(%)

Delayed absorption No

Delayed absorption Yes Food effect

Once Twice Twice Once Dosing regimen

30% Renal70% Liver

75% Liver25% Renal

80% Renal20% Liver

100% Liver Metabolism/elimination

As regard PharmacokineticsRivaroxaban Apixaban Dabigatran Warfarin

Characteristics

3A4, 2J2 3A4 No 2C9, 3A4 Substrate CYP

Yes Yes Yes No Substrate P-gp

No No No Yes Food interaction

No No No INR Monitoring required

Xa Xa II II, VII, IX, X, P-S, P-C

Target

??Andexanet ??Andexanet ?Idarucizumab YES Antidote

As regard PharmacokineticsRivaroxaban Apixaban Dabigatran Warfarin

Characteristics

**10 mg once daily (VTE prophylaxis)

**15 mg twice daily (1–21) followed by 20 mg once daily (DVTtreatment/prevention of recurrent VTE)

**20 mg once daily (AF)

**2.5 bid (VTE prophylaxis)

**150 mg or 220 mg once daily (VTE prophylaxis)

**75 mg or 150 mg twice daily (AF)

** INR Guided Typical effective

dose

As regard PharmacokineticsRivaroxaban Apixaban Dabigatran Warfarin

Characteristics

**As Dabigatran and Apixaban Plus**treatment of acute DVT and prevention of VTE recurrence

**Approved for VTE prevention after elective hip or knee replacement in adults.

** Stroke prevention and systemic emolization in nonvalvular AF

**Approved for VTE prevention after elective hip or knee replacement in adults

** prevention of stroke and systemic embolism in patients with nonvalvular AF

**Approved for VTE prevention and treatment of thromboembolic complications associated with AF

**cardiac valve replacement,

** Secondary prevention after MI

Approved indications

As Regard Renal impairment

– Warfarin is not contra-indicated in renal impairment.

– Dabigatran: avoid if creatinine clearance <30ml/min; caution advised if eGFR 40-50.

– Rivaroxaban: avoid if creatinine clearance <15ml/min; caution if creatinine clearance 15-29ml/min; caution advised if eGFR 40-50.

– Apixaban: avoid if creatinine clearance <15ml/min; caution if creatinine clearance 15-29ml/min; caution advised if eGFR 40-50.

Risk of bleeding

• Dabigatran: less major bleeding on lower dose compared to warfarin

• Rivaroxaban: more nose bleeds and haematuria, less intracranial haemorrhage, less fatal bleeding compared to warfarin

GI Bleeding

Dabigatran standard dose (150mg twice daily) causes a higher risk of GI bleeding, and at both doses is associated with increased GI side effects, compared to warfarin

Rivaroxaban causes a higher risk of GI bleeding, and is associated with increased major GI bleeding and increased GI side effects, compared to warfarin

Emergent Reversal of Warfarin and NOACs

• Urgent reversal of the old as well as new oral anticoagulants is of paramount importance and is often required in emergency surgery, or bleeding associated with intracranial hemorrhage.

In case of warfarin

In case of NOACs

In life threatening BleedingTherapeutic options Drug

Vitamin K (10mg slow iv infusion may be repeated if needed)Fresh Frozen PlasmaProthrombin complex concentrate

Warfarin

- Stop treatment with OACs - Haemodialysis - PCC (25 U/kg, repeat if needed) - rFVIIa (90 μg/kg)

Dabigatran

Stop treatment with OACs -PCC (25 U/kg, repeat if needed) FEIBA (50 IE/kg, max 200 IE/day) - rFVIIa (90 μg/kg) Rivaroxaban

Stop treatment with OACs -PCC (25 U/kg, repeat if needed) FEIBA (50 IE/kg, max 200 IE/day) - rFVIIa (90 μg/kg) Apixaban

Periprocedural Management of Patients on Warfarin and Chronic NOACsTherapy

Warfarin

When to stop NOACs

Postoperative resumption of new oral anticoagulants:

High bleeding risk surgery Low bleeding risk surgery Drug

Resume 2–3 days after surgery (48–72 h postoperative), 150 mg twice daily

Resume on day after surgery (24 h postoperative), 150 mg twice daily

Dabigatran

Resume 2–3 days after surgery (48–72 h postoperative), 20 mg once daily

Resume on day after surgery (24 h postoperative), 20 mg once daily

Rivaroxaban

Resume 2–3 days after surgery (48–72 h postoperative), 5 mg twice daily

Resume on day after surgery (24 h postoperative), 5 mg twice daily

Apixaban

Finally: Money talks

Cost Number of tablets Dosage Form Drug

10 ,14 EP 100 tablets 3 mg, 5 mg Warfarin

UP To 550EP 60 capsules 75mg, 110mg, 150mg Dabigatran (Paradaxa)

645EP 28 tablets 15mg, 20mg Rivaroxaban (Xarelto)

Future :(pharmacogenetic based warfarin therapy)

• Warfarin level depend on two enzymes (CYP2C9& VKORC1).

• CYP2C9: Sets the rate (accumulation and elimination).

• VKORC1: Sets the amount (effective concentration).

• Will help for more rapid determination of stable therapeutic dose than clinical method alone.

Take home message• Although, Warfarin has no typical effective dose, need regular

monitoring and Interact with many drugs and foods, warfarin still the only one has approved and available antidote and the only one approved for VTE prophylaxis in valvular AF plus the cheapest and widely available (in our country).

• Also Warfarin took more than 20years to establish its existence as an effective and adjustable anticoagulant.

• Also Physicians has more than 60years of experience to use it• Pharmacogenetics based warfarin therapy is getting popularity.• Newer anticoagulant are in different phases of their trials.

Thank you