Dr. Md. Arifur Rahman SazalMBBS, MD (Cardiology)

Clinical & Interventional Cardiologist National Institute of Cardiovascular Diseases

Dhaka, Bangladesh

WARFARIN

A brief history of warfarin

The discovery of oral anticoagulants is one of the most mysterious story in pharmaceutical

history.

It started with a hemorrhagic disease in cattle in the Midwest US in the 1920s. This was due to

ingestion of spoiled sweet clover. The substance responsible for bleeding was extracted and

identified as a coumarin by Karl Paul Link from University of Wisconsin.

In 1941 it used as a rat and mouse poison, but the survival of a man suffering from

thromboembolic disease after an attempted suicide by the use of a large amount of warfarin-

based rodenticide led to clinical trials of warfarin (Wisconsin Alumni Research

Foundation,WARF), which was approved for medical use in 1954.

Sweet clover sweet smell but bitter

taste

Systematic name

(RS)-4-hydroxy- 3-(3- oxo- 1-phenylbutyl)- 2H- chromen- 2-one

Mechanism of action

Routes Oral

Bioavailability 100%

Protein binding 99.5%

MetabolismHepatic: CYP2C9,

2C19, 2C8, 2C18, 1A2 and 3A4

Half-life 40 hours

Excretion Renal (92%)

Pregnancy cat. D

Pharmacokinetic data

Condition INR range

Preventing DVT (high risk patients, like those

who have had hip replacement) 2.0-3.0

Therapy after DVT or pulmonary embolism 2.0-3.0

Preventing systemic embolism

- Atrial fibrillation

-Valvular heart disease

-Tissue heart valves (first 3 months)

2.0-3.0

2.0-3.0

2.0-3.0

Bileaflet mechanical heart valve (aortic) 2.5-3.5

Mechanical prosthetic heart valve (high risk) 3.0-4.5

Thrombosis in antiphospholipid antibody

syndrome 3.0-4.5

Indication with target INR

Contraindication

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:➞INRAntibiotics - rifampin Antidepressants- trazodone Antiepileptics - carbamazepine , phenobarbitone ,phenytoin.

Drug interaction

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

Vitamin K ,Foods to Avoid while on Warfarin

Complications of Warfarin

Hemorrhage- 2.7% (major- 1.1%-8.1%)

Warfarin Embryopathy -5% -30%

Warfarin necrosis- 0.02%

Osteoporosis- 0.1%

Purple toe syndrome-0.01%

Warfarin Embryopathy (WE) -Di Sala syndrome

A specific pattern of congenital anomalies develop in children born to

mothers exposed to warfarin during the first trimester of pregnancy

(between the 6th and 12th weeks of gestation).

Classical features of WE-

Nasal hypoplasia

Chondrodysplasia punctata

(epiphyseal and vertebral bone

stippling)

Less frequent

malformations-Intraventricular hemorrhage

Hydrocephalus

Cervical spine myelopathy

Finger and toe defects

Calcifications and irregular ossification of lumbar and sacral vertebrae

Chondrodysplasia punctata

21-week stillborn with warfarin embryopathy, extreme nasal hypoplasia.

Nasal hypoplasia

Warfarin necrosis

The onset is usually within the first 2 to 5 days

of warfarin therapy, when the blood tends to

clot more than is normal.

Skin necrosis affects areas of the body with a

high fat content, such as breasts, thighs,

buttocks, hips and abdomen. .

It affects 1 in every 10,000 patients prescribed

warfarin.

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

Mechanism of Warfarin necrosis

Warfarin

Inhibition of protein C

( natural anticoagulant)

Coagulation factor imbalance

Paradoxical activation of coagulation

Thrombosis

Skin necrosis.

Purple toe syndrome

Warfarin cause violaceous painful discoloration of the toes

and the sides of the feet . This typically happens within the

first few weeks of starting warfarin

The problem appears to occur mostly in elderly people

and in people with underlying arteriosclerosis. bleeding

into atheromatous plaques in the blood vessel wall leads to

the release of cholesterol clumps that embolize to the

hands and feet,  leading to obstruction of small arteries.

Purple toe syndrome

Osteoporosis and Warfarin

Warfarin indirectly weaken bones, because vitamin K is involved with the

protein osteocalcin, which is important for bone remineralization .

Warfarin in special situations

Warfarin in pregnancy Warfarin cross the placenta and should be avoided during the first and third

trimesters.

Treatment at 6-12 weeks gestation causes Warfarin embryopathy.

Later exposure is associated with central nervous system abnormalities.

Almost 5%- 30% of children (10 of 35) born to mothers with a prosthetic heart

valve were malformed .Heparins do not cross the placenta and do not cause these

problems.

It is safe to breastfeed during warfarin therapy as there is minimal excretion into

breast milk.

Warfarin in Prosthetic heart valves

The ACCP recommends

Bileaflet or tilting disc valves- INR -2.0-3.0 –life long.

Caged ball or disc- 2.5-3.5- life long.

Bioprosthetic (tissue) valve require three months of warfarin -

INR -2.0-3.0.

Combination of aspirin (100 mg/day) with warfarin reduces the

risk of systemic embolism.

Venous Thromboembolism ( DVT and PE )

Target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations.

The duration of treatment is based on the indication as follows: For

patients with a DVT or PE secondary to a transient (reversible) risk

factor, treatment with warfarin for 3 months is recommended.

For patients with two episodes of unprovoked DVT or PE, long-term

treatment with warfarin is recommended

Warfarin in liver disease

Warfarin is associated with a 0.8% to 1.2% risk

of transaminase elevation >3 ULN .

Liver damage in Hepatitis C could be treated with

warfarin.

Warfarin reduces the scarring on the liver

caused by Hepatitis C.

In Hepatitis C, scarring of the liver accelerates in

those patients who are prone to form blood clots..

http://www.news-medical.net/news/2011/07/31/40407.aspx

Warfarin in Renal impairment

There is no evidence that response to Warfarin is altered in renal

impairment , thus dosage adjustments are generally not necessary.

However, patients with renal impairment may cause platelet defects and

may increase risk for bleeding.

Patients with CKD required on average a 25% reduction warfarin

dose.

Journal of the American Society of Nephrology (JASN). April 2009

Antithrombotic Therapy in Cardioversion for Atrial Fibrillation

Timing of cardioversion Anticoagulation

Early cardioversion in patients with AF

for < 48 hrs

Heparin during cardioversion period to achieve

PTT of 1.5 to2.5 times the baseline value

Early cardioversion in patients with AF

for > 48 hrs or an unknown duration, but

without documented atrial thrombi

Heparin during cardioversion period to achieve

PTT of 1.5 to 2.5 times the baseline value.

Warfarin for 4 weeks after cardioversion to

achieve target INR of 2.5 (range: 2.0 to 3.0)

Elective cardioversion in patients with AF

>48 hrs or an unknown duration

Warfarin for 3 weeks before and 4 weeks after

cardioversion to achieve target INR of 2.5 (range:

2.0 to 3.0)

CHADS2 score Condition Points

 C   Congestive heart failure 1

 H  Hypertension: blood pressure consistently above 140/90 mmHg (or treated hypertension on medication)

1

 A  Age ≥75 years 1

 D  Diabetes mellitus 1

 S2  Prior Stroke or TIA 2

Total 6

Guidelines for the management of atrial fibrillation

Estimating the risk of stroke

CHA2DS2 VASc score

European Heart Journal (2010) 31, 2369–2429doi:10.1093/eurheartj/ehq278

Score RiskAnticoagulation

TherapyConsiderations

0 Low

No antithrombotic

therapy (or

Aspirin)

No antithrombotic therapy (or Aspirin 75-325mg

daily)

1 ModerateOral anticoagulant

(or Aspirin)

Oral anticoagulant, either new oral anticoagulant

drug Dabigatran or well controlled warfarin at INR

2.0-3.0 (or Aspirin 75-325mg daily.

2 or greater High Oral anticoagulant

Oral anticoagulant, using either a new oral

anticoagulant drug (Rivaroxaban or Dabigatran) or

well controlled warfarin at INR 2.0-3.0

Anticoagulation (CHA2DS2 VASc score)

European Heart Journal (2010) 31, 2369–2429doi:10.1093/eurheartj/ehq278

Warfarin monitoring- Recommended INR testing guidelines

Managing overdose and bleeding of warfarin therapy

Clinical setting Action

INR >5.0 but < 9.0 (no

bleeding)

Stop warfarin, 1-2.5mg vitamin K1, INR in 6-12 hours,

restart warfarin at reduced dose once INR is < 5.

INR ≥9.0 (no bleeding) Stop warfarin, 5mg vitamin K1, measure INR in 6-12

hours, restart warfarin at reduced dose once INR is < 5,

clotting factor replacement- if high risk of bleeding

Major bleeding (any

level of INR)

Stop warfarin, give 5mg vitamin K1, clotting factor

replacement, measure INR as required, assess need to

restart warfarin

Future challenges for Warfarin

?

Property Dabigatran Warfarin

Indication for AF Non-valvular atrial fibrillation Valvular or non-valvular atrial

fibrillation

Mechanism of action Direct inhibition of thrombin Reduced synthesis of

prothrombin and other clotting

factors

Administration Oral

Twice daily (for AF)

Oral

Once daily

Dosing Fixed dose, dependent on creatinine

clearance and age

Individualised to each patient

and target INR

Onset of action 0.5–2 hours 36–72 hours

Elimination half-life 12–14 hours 20–60 hours

Duration of action 24 hours 48–96 hours

Comparison of Dabigatran and Warfarin

Property Dabigatran Warfarin

Stable,

predictable

pharmacokinetics

Yes No

Interactions with

diet and alcohol

No Yes

Interactions with

medicines

Interactions largely unknown, clinical

experience over time likely to reveal more.

Known interaction with p-glycoprotein

inhibitors e.g. oral ketoconazole,

verapamil, amiodarone

Multiple

Monitoring No routine monitoring required. INR every one

to eight

weeks

depending on

clinical

situation

Comparison of dabigatran and warfarin

Property Dabigatran Warfarin

Risk of major

haemorrhage

Similar for both medicines

Major GI bleeding rates may be higher than with

warfarin, however, rates of intracranial haemorrhage

and life-threatening bleeding may be lower with

dabigatran.

Similar for both

medicines.

Other adverse

effects

Dyspepsia

Possibly increased risk of MI

Multiple reported,

however, in clinical

practice these are

relatively rare

Antidote None available but can be removed by dialysis Vitamin K

Fresh-frozen plasma

Cost Very expensive- 450 $/ month Very cheap- 30 $/ month

Comparison of dabigatran and warfarin

Trials designed to compare the new oral anticoagulants to prevent thromboembolism with warfarin in AF

Trial Study drug DosingNumber of

patientsDesign

RE-LY Dabigatran110 mg twice daily, 150

mg twice daily18,113

Randomized, open-label, noninferiority

Rocket-AF Rivaroxaban15 mg daily, 20 mg

daily14,000

Randomized, double blind, noninferiority

ARISTOTLE Apixaban 5 mg twice daily 15,000Randomized, double blind,

noninferiority

Engage AF Edoxaban30 mg daily, 60 mg

daily16,500

Randomized, double blind, noninferiority

Altman and Vidal Thrombosis Journal 2011 9:12   doi:10.1186/1477-9560-9-12

The evidence for dabigatran - RE-LY trial The Randomised Evaluation of Long-Term Anticoagulation Therapy Large,

randomised, non-inferiority clinical trial

Event % of incidents per year Significance (P ≥ 0.05)

 Dabigatran 

110 mg

Dabigatran 

150 mgWarfarin  

Stroke or systemic embolism

1.53 1.11 1.69D150 superior to WD110 not inferior to WD150 superior to D110

Myocardial infarction 0.72 0.74 0.53 W superior to D150

Intracranial haemorrhage 0.23 0.30 0.74D110 superior to WD150 superior to W

Life-threatening bleeding 1.22 1.45 1.80D110 superior to WD150 superior to W

Gastrointestinal bleeding 1.12 1.51 1.02W superior to D150D110 superior to D150

Death from vascular causes

2.43 2.28 2.69 D150 superior to W

Death from any causes 3.75 3.64 4.13 No difference

New hope Pharmacogenetics

based warfarin therapy

Pharmacogenetics based warfarin therapy

Pharmacogenetics based warfarin therapy

Mr. Shakil

64 inch

58 kg

03 .08. 69Dr. Tazkera

Mr. Atik

Pharmacogenetics based warfarin therapy

ConclusionWarfarin took more than 20 years to establish its existance as an

effective and adjustable anticoagulant .

Physicians has more than 40 years of experience to use it

It is now in good shape with vast knowledge of handling it

Furthermore Pharmacogenetics based warfarin therapy is getting

popularity.

Newer anticoagulants are in different phases of their trials .

Many more informations and results are still pending -so it will not be

so easy to replace warfarin by newer anticoagulants so early.

Live long Warfarin

Thank you

Dr.Arif