Warfarin. Most used oral anticoagulant in the world. In some cases it has no alternative. Has many side effects. Careful monitoring and judicious titration of dose can make it best. Live long Warfarin.

1. Dr. Md. Arifur Rahman Sazal
MBBS, MD (Cardiology)
Clinical & Interventional Cardiologist
National Institute of Cardiovascular Diseases
Dhaka, Bangladesh

2. WARFARI
N

3. 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.

4. Sweet clover
sweet smell but bitter
Systematic name
(RS)-4-hydroxy- 3-(3- oxo- 1-phenylbutyl)- 2H- chromen- 2-one

5. Mechanism of action

6. Routes Oral
Bioavailability 100%
Protein binding 99.5%
Metabolism
Hepatic: CYP2C9, 2C19,
2C8, 2C18, 1A2 and 3A4
Half-life 40 hours
Excretion Renal (92%)
Pregnancy cat. D
Pharmacokinetic data

7. 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
Indication with target INR

8. Contraindication

9. 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.
Drug interaction

10.  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

11. 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%

12. 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

13. Calcifications and irregular ossification of lumbar and sacral vertebrae
Chondrodysplasia punctata

14. 21-week stillborn with warfarin embryopathy, extreme nasal hypoplasia.

15. Nasal hypoplasia

16. 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.

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

18. Mechanism of Warfarin necrosis
Warfarin
Inhibition of protein C
( natural anticoagulant)
Coagulation factor imbalance
Paradoxical activation of
coagulation
Thrombosis
Skin necrosis.

19. 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.

20. Purple toe syndrome

21. Osteoporosis and Warfarin
 Warfarin indirectly weaken bones, because vitamin K is involved with the
protein osteocalcin, which is important for bone remineralization .

22. Warfarin in special
situations

23. 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.

24. 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.

25. 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

26. 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

27. 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

28. 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)

29. 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

30. CHA2DS2 VASc score
European Heart Journal (2010) 31, 2369–2429doi:10.1093/eurheartj/ehq278

31. Score Risk
Anticoagulation
Therapy
Considerations
0 Low
No antithrombotic
therapy (or
Aspirin)
No antithrombotic therapy (or Aspirin 75-325mg
daily)
1 Moderate
Oral 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

32. Warfarin monitoring-
Recommended INR testing guidelines

33. 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

34. Future challenges for
Warfarin
?

35. 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

36. 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

37. 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

38. Trials designed to compare the new oral anticoagulants to prevent
thromboembolism with warfarin in AF
Trial Study drug Dosing
Number of
patients
Design
RE-LY Dabigatran
110 mg twice daily, 150
mg twice daily
18,113
Randomized, open-label,
noninferiority
Rocket-AF Rivaroxaban
15 mg daily, 20 mg
daily
14,000
Randomized, double blind,
noninferiority
ARISTOTLE Apixaban 5 mg twice daily 15,000
Randomized, double blind,
noninferiority
Engage AF Edoxaban
30 mg daily, 60 mg
daily
16,500
Randomized, double blind,
noninferiority
Altman and Vidal Thrombosis Journal 2011 9:12 doi:10.1186/1477-9560-9-12

39. 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 mg
Warfarin
Stroke or systemic
embolism
1.53 1.11 1.69
D150 superior to W
D110 not inferior to W
D150 superior to D110
Myocardial infarction 0.72 0.74 0.53 W superior to D150
Intracranial haemorrhage 0.23 0.30 0.74
D110 superior to W
D150 superior to W
Life-threatening bleeding 1.22 1.45 1.80
D110 superior to W
D150 superior to W
Gastrointestinal bleeding 1.12 1.51 1.02
W superior to D150
D110 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

40. New hope
Pharmacogenetics
based warfarin therapy

41. Pharmacogenetics
based warfarin therapy

42. Pharmacogenetics based warfarin therapy

43. Mr. Shakil
64 inch
58 kg
03 .08. 69
Dr. Tazkera
Mr. Atik

44. Pharmacogenetics based warfarin therapy

45. Conclusion
Warfarin 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.

46. Live long Warfarin
Thank you
Dr.Arif