This document provides an overview of the hemostatic system and blood coagulation pathways. It discusses warfarin, the most widely used oral anticoagulant, including its mechanism of action, pharmacology, dosing, monitoring, indications, and optimal duration for different clinical settings such as atrial fibrillation, heart valve prostheses, venous thromboembolism, and STEMI. It also covers newer oral anticoagulants that have been developed as alternatives to warfarin.

1. DR SHALINI GARG
SR CARDIOLOGY
LPS, CARDIOLOGY, KANPUR

2. HEMOSTATIC SYSTEM
In Brief…….

3. WHEN DOES BLOOD COAGULATE ?
 Injury to blood vessel. eg: Plaque rupure
 Blood stasis. eg: AF
 Procoagulants > Anticoagulants. eg: Coagulation
disorders

4. OVERVIEW
FROM ENDOTHELIAL DAMAGE TO THROMBOSIS

5. BLOOD COAGULATION PATHWAYS
aPTT
PT/
INR

6. Figure. Classification of established anticoagulants and new anticoagulants that were
recently licensed for use or are in advanced stages of clinical development. fIXa indicates
factor IXa. *Indirectly inhibit coagulation by interacting with antithrombin. †AVE5026 is an
ultralow-molecular-weight heparin that primarily inhibits fXa and has minimal activity against
thrombin.
Eikelboom J W , and Weitz J I Circulation. 2010;121:1523-
1532
Copyright © American Heart Association, Inc. All rights reserved.

7. CLASSIFICATION OF ORAL ANTICOAGULANTS
Coumarin Derivatives e.g. Warfarin, Acenocoumarol (Acitrom)
Indandione Derivatives e.g. Phenindione, Anisindione
Newer anticoagulants
 Direct thrombin inhibitors
Dabigatran etexilate (Pradaxa)
 Direct factor Xa inhibitors
Rivaroxaban (Xarelto)
Apixaban
Edoxaban (DU-176b)
Betrixaban

8. WARFARIN
almost 70 years old and still causing problems…
Still we have to stick with it…

9. HISTORY
 In the 1920s cattle in the Northern USA and Canada were afflicted
by an outbreak of an unusual disease characterized by fatal
bleeding, either spontaneously or from minor injuries. Mouldy
silage made from sweet clover ( Melilotus alba and M. officinalis )
was implicated, and L M Roderick in North Dakota showed that it
contained a haemorrhagic factor that reduced the activity of
prothrombin.
 However, it was not until 1940 that Karl Link and his student
Harold Campbell in Wisconsin discovered that the anticoagulant
in sweet clover was 3,3′methylenebis (4-hydroxy coumarin).
Further work by Link led in 1948 to the synthesis of warfarin,
which was initially approved as a rodenticide in the USA in 1952,
and then for human use in 1954.
 The name warfarin is derived from WARF (Wisconsin Alumni
Research Foundation) and –arin from coumarin.

10. WARFARIN
 Most widely used anticoagulant in the world
 Coumarin derivative, water soluble vit K antagonist
 Low cost and highly effective, if given in right way.

11. Vitamin K-dependent clotting factors
(FII, FVII, FIX, FX, Protein C/S/Z)
Epoxide
Reductase
 -Carboxylase
(GGCX)
MECHANISM OF ACTION: Warfarin inhibits the vitamin K cycle
Warfarin
Inactivation
CYP2C9
Pharmacokinetic
Post translational modification

13. PLASMA HALF-LIVES OF VITAMIN K-DEPENDENT PROTEINS
Factor II 72h
Factor VII 6h
Factor IX 24h
Factor X 36h
Peak anticoagulant effect may be delayed by 72 to 96 hours

14. PHARMACOLOGY
 Recemic micture of R and S isomers (S more active)
 Rapidly and completely absorbed from GI tract
 Blood level peaks about 90 min of administration
 90% of circulating warfarin is bound to albumin
 Plasma t1/2 is 36-42 hrs
 Only small fraction of unbound warfarin is biologically
active
 Warfarin is accumulates in liver, where it undergoes
CYP2C9 mediated oxidative metabolism.
 Inactive metabolites are excreted in urine and stools.

15. • CYP2C9 SNPs alter warfarin metabolism:
 CYP2C9*1 (WT) – normal activity
 CYP2C9*2 (Arg144Cys) - low/intermediate activity
 CYP2C9*3 (Ile359Leu) - low activity
• Two relatively common variants, CYP2C9*2 and CYP2C9*3,
encode an enzyme with reduced activity. requiring lower
maintenance doses of warfarin.
• Approximately 25% of whites have at least one variant allele of
CYP2C9*2 or CYP2C9*3, whereas these variant alleles are less
common in blacks and Asians
• Warfarin dose reduction requires as follow:
• Heterozygosity for CYP2C9*2 or CYP2C9*3 allele : 20%-30%
• Homozygosity for the CYP2C9*2 or CYP2C9*3 allele : 50%-70%
Effect of CYP2C9 Genotype on Anticoagulation

16. Effect of CYP2C9 Genotype on Anticoagulation-Related Outcomes
(Higashi et al., JAMA 2002)
N 127 28 4 18 3 5

17. VKORC1: New Target Protein for Warfarin
Epoxide
Reductase
 -Carboxylase
(GGCX)
Clotting Factors
(FII, FVII, FIX, FX, Protein C/S/Z)
Rost et al. & Li, et al., Nature (2004)
(VKORC1)
5 kb - chr 16

18. Effect of VKORC1 Genotype on Anticoagulation
 Three polymorphic variants of VKORC1
 Non-A,Non-A : wild type – Requiring more warfarin dose
 Non-A/A : Heterozygous – Requiring 25% dose reduction
 A/A : Homozygous - Requiring 50% dose reduction
 Means wild type having more resistance to warfarin while
homozygous is more sensitive.
 Asians have the highest prevalence of VKORC1 variants,
followed by whites and blacks
 Polymorphisms in VKORC1 likely explain 30% of the
variability in warfarin dose requirements.
 VKORC1 variants are more prevalent than variants of CYP2C9
Genotype Freq in Asians (%) Dose reduction
Non-A,Non-A : wild type 7 --
Non-A/A : Heterozygous 30 26
A/A : Homozygous 63 50

19. These findings prompted the U.S. Food and Drug
Administration (FDA) to amend the prescribing
information for warfarin to indicate that lower
initiation doses should be considered for patients with
CYP2C9 and VKORC1 genetic variants.

20. DOSING
 Usual dose is 5 mg/day (1-20 mg)
 Lower doses require in
 Elderly
 Pt on increased risk of bleeding eg. Pt on aspirin
 Heart failure
 Liver disease
 Renal impairment
 Malnutrition
 Thyrotoxicosis (Opposite in Myxedema)
 Asian patients: Explained by genetic variation in hepatic enzymes
(CYP3C9 & VKORC1 Polymorphism)
 High intake dietary Vit-K (green vegetables e.g. broccoli)
reduces the efficacy of Warfarin.
 Practically best time to give warfarin is ~ 6 PM.

21. Caution with VITAMIN K containing food
Health Canada recommends a daily intake of 90 – 120
micrograms (μg) of vitamin K. The total amount of
vitamin K from day to day may be higher or lower than
the recommended amount. It is okay to eat food with
different levels of vitamin K, but because vitamin K
can interfere with blood-thinning effects of warfarin, it
is important to eat the same amount from day to
day. Do not eat a lot one day and none the next

23. Why to add concomitant parenteral anticoagulation ?
 Because of delayed onset of action, concomitant
parenteral anticoagulant should be given in pts with
established thrombosis or high risk for thrombosis until
INR has been in therapeutic range for at least 2 days.
 Warfarin monotherapy decreases the levels of two
endogenous anticoagulants, proteins C and S, thus
increasing thrombogenic potential. Overlapping
warfarin for at least 5 days with an immediately
effective parenteral anticoagulant counteracts the
procoagulant effect of unopposed warfarin.
 Usually a minimum 5 days of concomitant parenteral
anticoagulation is recommended.

24. Commencement of oral anticoagulant therapy
If the baseline INR≤1.3 the patient will receive 5mg of
warfarin once daily on days 1 and 2. The INR is checked on
day 3 and 4 and the warfarin dose is adjusted according to
the schedule.

25. Monitoring
 B/z of narrow therapeutic window of warfarin
 Standard procedure is to check the PT-INR as follows:
INR daily until it is in therapeutic range
3 times weekly for 2 weeks
Once stable & warfarin dose is known
INR every 3-4 weeks or more frequently if
introduction of any new medications

26. What is PT-INR
 Warfarin therapy is most often monitored using the
prothrombin time, a test sensitive to reductions in the levels of
prothrombin, factor VII, and factor X.
 This test involved addition of thromboplastin (a reagent
containing TF, phospholipid & Ca++) to citrated plasma and
determining the time to clot formation.
 Thromboplastins vary in their sensitivity to reductions in the
levels of the vitamin K–dependent clotting factors
 INR represent the PT according to international reference
thromboplastin, as approved by WHO.

27. INTERNATIONAL NORMALISED RATIO (INR)
INR = [PTpt] ISI
[PTRef]
PTpt – prothrombin time of patient
PTRef – prothrombin time of normal pooled sample
ISI – International Sensitivity Index
 Highly sensitive thromboplastins have an ISI of 1.0
 Most current thromboplastins have ISI values that range from 1.0 to 1.4

29. Indications
 Atrial fibrillation
 Prosthetic heart valve
 Venous thromboembolism
 Primary pulmonary hypertension
 Rarely after Acute MI
(If associated with high risk of thromboembolism e.g. AF, mobile or
pedunculated mural thrombus or prior venous thromboembolism)

30. Warfarin in AF
CLASS I
For patients with nonvalvular AF with prior stroke, transient
ischemic attack (TIA), or a CHA2DS2-VASc score of 2 or greater,
oral anticoagulants are recommended. Options include:
warfarin (INR 2.0 to 3.0) (Level of Evidence: A),
dabigatran (Level of Evidence: B),
rivaroxaban (Level of Evidence: B), or apixaban (Level of Evidence:
B)

31. Heart valve prostheses
The risk of systemic embolism from prosthetic heart valves
depends on the type of valve, its position and other factors that
contribute to the patients’ risk of developing thrombosis, such as
cardiac rhythm and dilatation.

33. Warfarin in Venous thromboembolism
 Warfarin should be initated concurrently with parenteral
heparin.
 For VTE patients, the usual target INR range is between 2.0
and 3.0.
 After 5 days, warfarin alone should be continued for at least 3
months
 Optimal duration of anticoagulation depends on clinical
settings

34. Optimal duration of anticoagulation
CLINICAL SETTING RECOMMENDATION
1st provoked PE/proximal leg DVT 3 to 6 months
1st provoked upper extremity DVT or isolated calf
DVT
3 months
2nd provoked VTE Uncertain
3rd VTE Indefinite duration
Cancer and VTE Consider indefinite duration or until cancer is
resolved
Unprovoked PE/proximal leg DVT Consider indefinite duration
1st unprovoked calf DVT 3 months
2nd unprovoked calf DVT Uncertain

35. WARFARIN IN STEMI
2013 ACCF/AHA Guideline for the Management of ST-Elevation
Myocardial Infarction:
Class I
1. Anticoagulant therapy with a vitamin K antagonist
should be provided to patients with STEMI and AF
with CHADS2 score greater than or equal to 2, mechanical
heart valves, venous thromboembolism, or hypercoagulable
disorder. (Level of Evidence: C)
2. The duration of triple antithrombotic therapy with a
vitamin K antagonist, aspirin, and a P2Y12 receptor
inhibitor should be minimized to the extent possible
to limit the risk of bleeding. (Level of Evidence: C)

36. Class IIa
1. Anticoagulant therapy with a vitamin K antagonist is
reasonable for patients with STEMI and asymptomatic
LV mural thrombi. (Level of Evidence: C)
Duration of treatment is 3 months.
Class IIb
1. Anticoagulant therapy may be considered for patients
with STEMI and anterior apical akinesis or
dyskinesis. (Level of Evidence: C)
2. Targeting vitamin K antagonist therapy to a lower
international normalized ratio (eg, 2.0 to 2.5) might
be considered in patients with STEMI who are receiving
DAPT. (Level of Evidence: C)

37. Side effects of Warfarin
 Bleeding
 Skin necrosis
 Purple toe syndrome
 Teratogenicity
 Osteoporosis
 Others: Agranulocytosis, leukopenia, diarrhoea,
nausea, anorexia.

38. Bleeding
 Most common complication
 In form of
 Mild: epistaxis, hematuria
 Severe: Retroperotoneal or gastrointestinal bleeding
 Life-threatening : Intracranial bleed
 Rate of major bleeding (defined as any visit to hospital for
hemorrhage) is 1- 3% per person-year
 Half of the complications occurs because INR exceeds
therapeutic range
 Can be minimized by keeping INR in therapeutic
range

39. Interventions according to INR/symptoms
Asymptomatic pts with raised INR
INR INTERVENTION
3.5 - 4.5 Withhold warfarin until in therapeutic
range
Decrease the dose of warfarin
> 4.5 Low dose sublingual/oral Vit K (not
routinely)
4.5 – 9.0 Vit k 1 mg
> 9.0 Vit k 2-3 mg
Higher doses of vitamin K (up to 10 mg) can be administered if more rapid reversal of the
INR is required
Although vitamin K administration results in a more rapid reduction in the INR,
there is no evidence that it reduces the risk of hemorrhage

40. Symptomatic pts with raised INR
SYMPTOMS INTERVENTION
Mild bleeding Withhold warfarin
Severe bleeding Vit k 10 mg slow i/v infusion ± FFP (15
ml/kg)
Life threatening bleeding or pt can’t
tolerate volume overload
Prothrombin complex concentrate
(II,IX & X)
Prosthetic valves pts Vit K should be strictly avoided,
unless there is life threatening
intracranial bleed (Valve thrombosis)
Subcutaneous Vit K gives variable results and should be avoided

42. SKIN NECROSIS
 Rare but very serious complication of warfarin
(prevalence of 0.01-0.1 %)
 Occurs 2 to 5 days after initiation of warfarin
 Usually occurs after high dose of warfarin
 Typical presentation is :
Well-demarcated erythematous lesions form on the thighs,
buttocks, breasts, or toes. Typically, the center of the lesion becomes
progressively necrotic. Examination of skin biopsies taken from the
borders of these lesions reveals thrombi in the microvasculature

43. Warfarin (Coumadin)–induced skin necrosis on the lower abdomen & breast

44.  Mechanism : Not well understood but a precipitous fall in plasma protein
C or S levels (natural anticoagulants) before warfarin exert anticoagulant
effect, results in procoagulant state triggering thrombosis of adipose tissue
microvasculatures.
 Treatment :
 Discontinuation of warfarin and reversal with vitamin K, if needed
 An alternative anticoagulant, such as heparin or LMWH, should be given to patients
with thrombosis
 Protein C concentrates or recombinant activated protein C may accelerate healing of
the skin lesions in protein C deficient patients
 Frozen plasma may be useful for those with protein S deficiency
 Occasionally, skin grafting is necessary when there is extensive skin loss.
 Prevention :
 Start with low dose warfarin in pts with known Protein C or S deficiency
 Overlapping with a parenteral anticoagulant when initiating warfarin therapy

45. Purple toes syndrome
 Extremely uncommon cutaneous
complication
 Characterized by the sudden appearance of
bilateral, painful, purple nonhemorrhagic
lesions on the toes and sides of the feet that
blanch with pressure
 Usually develops 3-8 weeks after the start of
warfarin therapy
 Mechanism: release of atheromatous
plaque emboli
 Discontinue COUMADIN therapy if such
phenomena are observed. Consider
alternative drugs if continued
anticoagulation therapy is necessary.
Pharmacotherapy. 2003 May;23(5):674-7

46. Teratogenicity
 Occurs in 3.5 – 6 %
 Depends on time of gestation and dose of warfarin given
 Usually in first trimester of pregnancy
 It causes characteristic embryopathy consist of :
 Nasal hypoplasia and
 Chondrodysplasia punctata (epiphyseal and vertebral bone
 stippling)
 Cleft lip and (or) palate
 Choanal stenosis/atresia
 Central nervous system abnormalities
 Coarctation of aorta (Rare malformations described following first
trimester exposure to warfarin)
 Occurs especially if warfarin dose is > 5 mg/day

47. Lateral view X-ray showing calcifications and irregular
ossification of lumbar and sacral vertebrae, consistent
with warfarin embryopathy

48. OSTEOPOROSIS
 Long- term use of warfarin (> 1 yr)
 More common in males
 60% increased risk of osteoporosis-related fracture in
men
 Mechanism: combination of reduced intake of
vitamin K, which is necessary for bone health, and
inhibition by warfarin of vitamin K-mediated
carboxylation of certain bone proteins, rendering
them nonfunctional
 Beta-adrenergic antagonists may protect against
osteoporotic fractures

51. Warfarin in special conditions…

52. Pregnancy
 It causes…
 Fetal abnormalities (Teratogenic)- in first trimister
 Chances of intracranial bleeding in baby while passage
through birth canal – in third trimister
 Because of this, warfarin is contraindicated in 1st (first
12 weeks) & 3rd trimsters (last 2 weeks)
 Warfarin does not passes in breast milk & is safe for
nursing mothers.

54. Warfarin modification before surgery
 Pt on long term anticoagulation with warfarin should
stop it 5 days in prior to elective surgery to allow INR
to return to normal level
 Those at high risk of thromboembolism can be
bridged with once or twice daily s/c LMWH once the
INR fall below 2. For pragmatic purposes, to save
monitoring the INR as an out-patient, bridging
therapy can be instituted with therapeutic dose
LMWH 2-3 days after warfarin is stopped i.e. on the
morning after two doses have been omitted.
 The last dose of LMWH should be given 12 or 24 hrs
before depending on bd or od dose respectively

55.  In patients who are receiving bridging anticoagulation with
therapeutic dose UFH, the heparin should be stopped 4 - 6
hours before surgery.
 If possible the INR should be determined the day before
surgery. This allows the administration of oral vitamin K (2 or
2.5 mg) if the INR is ≥ 1.5 so reducing the risk of cancellation.
 The INR should be checked on the day of surgery.
 Heparin should be resumed approximately 24 hours after the
procedure if there is adequate haemostasis but should not be
started until at least 48 hours after surgery in high bleeding
risk surgeries
 Warfarin can be resumed, at the normal maintenance dose,
the evening of surgery or the next morning if there is
adequate haemostasis.

57. Dentistry in anticoagulated patients
The risk of significant bleeding in patients on oral
anticoagulants and with an INR of ≤ 4.0 is small and the risk
of thrombosis may be increased in patients in whom oral
anticoagulants are temporarily discontinued. Oral
anticoagulants should not be discontinued in the majority of
patients requiring out-patient dental surgery including
dental extraction.
The risk of bleeding may be minimised by:
The use of oxidised cellulose (Surgicel) or collagen sponges
and sutures. 5% tranexamic acid mouthwashes can be used
four times a day for 2 days .
For patients stably anticoagulated on warfarin, a check INR
is recommended 72 hours prior to dental surgery.
Patients on warfarin should not be prescribed NSAIDs as
analgesia following dental surgery.

58. Endoscopy in anticoagulated patients
In general, low risk diagnostic procedures including
mucosal biopsy can be performed when the INR is up
to 2.5, without altering anticoagulation. For
therapeutic procedures the risk of post-procedure
bleeding is higher and it is better to adjust
anticoagulation.

60. ACENOCOUMAROL (acitrom)
 Same as warfarin with following differences:
 Shorter half life 10-16 hrs
 More rapid onset of action on PT
 Shorter duration of action (2 days)
 Causes GI disturbances, oral ulcerations and
dermatitis
 4 mg on day one, 4-8 mg on the day 2nd then
maintenance dose 1-8 mg according to response by PT
test

61. THE OVERALL ANTICOAGULATION QUALITY IS SIGNIFICANTLY BETTER
WITH WARFARIN AS COMPARED TO ACENOCOUMAROL
72%
67%
64%
66%
68%
70%
72%
%Responders
Warfarin Acenocoumarol
Thrombosis And Haemostasis 1994; 71(2): 188-191

63. Newer Oral Anticoagulants

64. Why we need alternatives to warfarin
???

65. What’s wrong with warfarin?
1. Narrow therapeutic range
2. Slow onset of action
3. Slow offset of action (long duration of action, long
elimination half life)
4. Multiple drug and dietary interactions
5. Monitoring required to maintain in therapeutic range
6. Difficult to manage for invasive procedures
7. Under-use of therapy due to fear of adverse events and
complexity of management

66. 8. Efficacy is dependent upon infrastructure
Time in therapeutic range (TTR) is associated with
improved safety and efficacy
TTR is greater in countries with more sophisticated
health care infrastructure.

67. What are the attributes of the ideal anticoagulant?
1. Oral administration
2. Rapid onset of action/rapid offset of action
3. Wide therapeutic range
4. Predictable therapeutic effect with fixed or weight-based dosing
5. No food or drug-drug interactions
6. No monitoring required (but the ability to monitor if desired)
7. Well defined pharmacokinetics in presence of renal or hepatic
disease
8. Easily reversible
9. Cost effective

68. Newer oral anticoagulants

69. Classification
 Direct thrombin (IIa) inhibitor
 Dabigatran (Pradaxa)
 Factor Xa inhibitors
 Rivaroxaban (Xarelto)
 Apixaban

70. Dabigatran etexilate (Pradaxa)
 Oral Direct thrombin
(factor IIa) inhibitor
 It is a prodrug & does not
exhibit any
pharmacological activity
 Initially recommended
by FDA on October 19,
2010 for Non-valvular AF

71. Mechanism of Action
Dabigatran and its acyl glucuronides are
competitive, direct thrombin inhibitors. Both free
and clot-bound thrombin, and thrombin-induced
platelet aggregation are inhibited by the active
moieties.

72. Pharmacokinetics
Dabigatran etexilate mesylate is absorbed as the dabigatran
etexilate ester. The ester is then hydrolyzed, forming dabigatran,
the active moiety. The t1/2 is 15 to 17 hrs.
90% is excreted unchanged in urine.
Absorption
The absolute bioavailability of dabigatran following oral
administration of dabigatran etexilate is approximately 3 to 7% .
Cmax occurs at 1 hour post-administration in the fasted state.
Coadministration of PRADAXA with a high-fat meal delays the
time to Cmax by approximately 2 hours but has no effect on the
bioavailability of dabigatran; PRADAXA may be administered with
or without food.

73.  Minimal metabolism of dabigatran by CYP3A4
enzymes is clinically insignificant
 No dose modification required in hepatic impairment
 Dabigatran is also a substrate for P- glycoprotein ( a
trans-membrane pump expelling drugs out of cell). So
P- glycoprotein inhibitors (e.g. amiodarone, verapamil
& clarithromycin) can increase whereas inducers (e.g.
rifampicin, st. john’s wart) may reduce dabigatran level
in plasma.

74. Pharmacodynamics
Dabigatran prolongs aptt which targets intrinsic pathway of
coagulation; thrombin clotting time (TT), which directly assesses
the activity of thrombin in a plasma sample; and the ecarin
clotting time, which is a specific assay for thrombin generation.
However, at clinically relevant plasma concentrations, dabigatran
has relatively little effect on the prothrombin time and INR, which
targets the extrinsic coagulation pathway. The TT assay is the
most sensitive to prolongation by dabigatran, followed by the
ecarin clotting time and aPTT.

75.  The relationship between plasma concentrations of
dabigatran and the TT, and ecarin clotting time is linear
(ie, dabigatran prolongs the TT, and ecarin clotting time
in a concentration dependent fashion over therapeutic
concentrations), whereas the aPTT concentration-response
curve is curvilinear and flattens at higher concentrations
(200 ng/mL).

77. A dilute thrombin time assay (Hemoclot test,
Hyphen Biomed, France) has been certified in
Europe since late 2010 for the quantitative
determination of dabigatran plasma levels. It can be
calibrated with dabigatran standards.

78. INDICATIONS AND USAGE
 Reduction of Risk of Stroke and Systemic
Embolism in Non-valvular Atrial Fibrillation
 Treatment of Deep Venous Thrombosis and
Pulmonary Embolism
Pradaxa is indicated for the treatment of deep venous
thrombosis and pulmonary embolism in patients who
have been treated with a parenteral anticoagulant for
5-10 days.
 Reduction in the Risk of Recurrence of Deep
Venous Thrombosis and Pulmonary Embolism

79. Recommended dose

80. SOME SPECIAL POINTS TO
MENTION….

81. If a dose of PRADAXA is not taken at the scheduled
time, the dose should be taken as soon as possible on
the same day; the missed dose should be skipped if it
cannot be taken at least 6 hours before the next
scheduled dose. The dose of PRADAXA should not be
doubled to make up for a missed dose.

82. Dabigatran hydrolyze over time when exposed to humidity, causing a
breakdown of active ingredient, and rendering the medication less effective

83. Converting pts from or to Warfarin
 From warfarin to dabigatran
 Stop warfarin & start dabigatran once INR fall below 2
 From dabigatran to warfarin
 Adjust the starting time of warfarin based on creatinine clearance
CrCL (ml/min) Days before stopping
dabigatran
> 50 3 days
50 - 30 2 days
30 - 15 1 day
< 15 or dialysis not recommended

84. Converting pts from or to parenteral anticoagulants
From parenteral anticoagulants to dabigatran
 Intermittent parenteral anticoagulant
 Start dabigatran 0-2 hrs before next dose
 Continuous parenteral anticoagulant (e.g. UFH)
 Start dabigatran at the time of stopping parenteral
anticoagulant
 From dabigatran to parenteral anticoagulants
 Wait for 12 hrs (CrCl> 30 ml/min) or 24 hrs (CrCl< 30 ml/min)
after last dose of dabigatran before starting parenteral
anticoagulant

85. Dabigatran in pts planned for elective surgery
 If possible, stop dabigatran 1-2 days before (CrCl> 50
ml/min) or 3-5 days before (CrCl< 50 ml/min)
invasive or surgical procedures.
 Longer periods may be considered if pt undergoing
1. Major surgery
2. Spinal puncture
3. Placement of spinal or epidural catheter or port

86. Dabigatran in pts planned for emergency surgery
 Because specific antidote is not available, options are
 Either have to wait until the anticoagulant effect has
spontaneously diminished
Or
 Undergo their procedure with the knowledge that they
have a increased risk of bleeding

87. Postoperative management
 It depends almost exclusively on the postoperative risk
of bleeding
 Procedures with with good hemostasis shortly after the
end of the procedure, resumption on same evening can
be done (i.e. minimum of 4 to 6 hours after surgery)
starting with a half dose (75 mg) for the first dose, and
thereafter the usual maintenance dose.
 For major abdominal surgery or urologic surgery with
incomplete hemostasis, resumption should be delayed
until there is no drainage or other evidence of active
bleeding

89. BLEEDING ON DABIGATRAN TREATMENT

90. Monitoring anticoagulant effect of dabigatran
 Need not to assess regularly (ex. In the setting of
emergency surgery)
 In emergency most accessible tests are
1. TCT
2. aPTT
 If the TCT is normal, it is safe to assume that the level
of dabigatran is very low and that the patient’s risk of
bleeding development is similar to that of other
patients undergoing the procedure

91. Antidote
 Specific agent not available
 Though limited data, following agents may be used
 Activated prothrombin complex concentrate
 Recombinant factor VIIa
 Concentrate of coagulant factors II, IX and X
 Hemodialysis (because only 35% of dabigatran is bound to
plasma proteins)
Protamine sulfate and Vit-K are not helpful

92. Adverse effects
 Bleeding – increases with age
 GI events
 Dyspepsia (12%)
 Abdominal pain
 Gastritis including GERD, esophagitis, erosive gastritis,
gastric hemorrhage and GI ulcers
 Hypersensitivity reaction (<0.1%)
 An unexplained increase in acute myocardial
infarction in the dabigatran group versus warfarin
(~0.2% increased risk for a AMI re-ly trial)

94. Contraindication
“Recently the FDA added a contraindication to the dabigatran
label against using the drug in patients with mechanical heart
valves” [12/19/2012 - Drug Safety Communication - FDA]
Based on
A clinical trial in Europe (the RE-ALIGN trial) was recently
stopped because dabigatran (Pradaxa) users were more likely to
experience strokes, heart attacks, and blood clots forming on the
mechanical heart valves than those were on warfarin. There was
also more bleeding after valve surgery in the Pradaxa users than
in the warfarin users.

95. Drug interaction
 Concomitant use with P-glycoprotein inducers e.g.
rifampin, st. john’s wart reduces its anticoagulant
effect while inhibitors (e.g. amiodarone, verapamil &
clarithromycin) can increase its plasma level
 No other drug interactions are noted.

99. 1
RE-COVER
 Primary outcome (recurrent VTE or death
due to VTE): 2.4% vs. 2.1%
 Mortality: 1.6% vs. 1.7% (p > 0.05)
 Major bleeding: 1.6% vs. 1.9%; Major +
clinically relevant bleeding: 5.6% vs. 8.8.%
(p = 0.002)
Trial design: Evaluated the safety and efficacy of dabigatran 150 mg twice daily (n 1274)
vs. warfarin (n 1265) for the treatment of acute VTE. Patients were followed for 6 months.
Results
Dabigatran
(n = 1,274)
• Dabigatran 150 mg twice daily is noninferior to
warfarin for the treatment of acute VTE, with a
slightly better bleeding profile
• Complements other studies showing safety
and efficacy of dabigatran, as compared with
warfarin in other settings, such as AF
2.4
2.1
%
0
4
(p < 0.001*)
Conclusions
Warfarin
(n = 1,265)
1
2
3
Primary endpoint Major bleeding
%
(p = 0.38)
1.6
1.9
Schulman S, et al. N Engl J Med 2009;361:2342-52
5
* For noninferiority
0
4
1
2
3
5

100. Factor Xa inhibitors
Rivaroxaban
Apixaban

101. Rivaroxaban (Xarelto)

102. Rivaroxaban (Xarelto)
 Direct factor Xa inhibitor
 Half life: 7 - 9 hours
 Peak plasma concentration 0.5 – 3 hours after
administration
 Have excellent bio-availability of 80-100%
 2/3rd of rivaroxaban is metabolized by CYP3A4 system
in liver
 1/3rd of rivaroxaban excreted unchanged in urine while
½ of the metabolized excreted renally while other half
via fecal route.

104. In contrast, bleeding from gastrointestinal sites, including upper,
lower, and rectal sites, occurred more frequently in the rivaroxaban
group, as did bleeding that led to a drop in the hemoglobin level or
bleeding that required transfusion

105. Conclusion of ROCKET-AF trial
“In patients with atrial fibrillation, rivaroxaban was
noninferior to warfarin for the prevention of stroke or
systemic embolism with no significant difference in the
risk of major bleeding, although intracranial and fatal
bleeding occurred less frequently in the rivaroxaban
group.”

106. Trial design: Patients with recent ACS(<7 days) were randomized in a 1:1:1 fashion to
rivaroxaban 2.5 mg twice daily, 5 mg twice daily, or placebo, in addition to dual antiplatelet
therapy (DAPT) with aspirin and a thienopyridine in 93%. Patients were followed for 2
years.
Results
Conclusions
(p = 0.008)
Rivaroxaban
2.5 mg
(n = 5,174)
Primary efficacy endpoint
0
10
20
9.1 8.8
%
Rivaroxaban
5 mg
(n = 5,176)
10.7
Placebo
(n = 5,176)
ATLAS ACS 2−TIMI 51
• Primary endpoint: CV death/MI/stroke for
rivaroxaban vs. placebo: 8.9% vs.10.7%, p = 0.008.
True for 2.5 mg (9.1%) and 5 mg (8.8%) doses
individually. Greatest efficacy for ischemic endpoints
with the 2.5 mg daily dose, including mortality (2.9%
vs. 4.5%, p = 0.002)
• Non-CABG TIMI major bleeding: 2.1% vs. 0.6%, p <
0.001. Similar for 2.5 mg (1.8%) and 5 mg (2.4%)
Mega JL, et al. N Engl J Med 2012;366:9-19
• Addition of very low dose rivaroxaban (2.5 mg twice
daily) in patients with a recent ACS (most of whom
were on DAPT) ↓ mortality, and ischemic events as
compared with placebo. However, bleeding was
simultaneously ↑
• First successful large trial with an oral anti-Xa agent
in patients with ACS taking antiplatelet agents; use
will require assessment of ischemia/bleeding risks

108.  To reduce the risk of DVTs and PEs in patients
undergoing knee or hip replacement surgery (Jul 1, 2011)
 For prevention of thromboembolism and stroke in
patients with nonvalvular atrial fibrillation (Nov 4, 2011 )
 Treatment of deep vein thrombosis (DVT) and
pulmonary embolism (PE), as well as to reduce the risk
of recurrent DVT and PE (Nov 2, 2012)
Rivaroxaban: FDA Approval
(First approved in July 1st, 2011)

109. Doses of rivaroxaban
 Therapeutic dose : 20 mg once daily
 Prophylactic dose : 10 mg once daily
 No specific dose adjustment advised in moderate renal
function impairment but it should be used with
caution
 Contraindicated in severe renal impairment
 No dose adjustment required for body weight

111. Antidote
 Like dabigatran, no specific antidote is available
 Unlike dabigatran, rivaroxaban is not dialyzable
because of a high degree of albumin binding in plasma
(92%-95%)
 Some effects are reversed by a 4-factor PCC (dose of 50
IU/kg) in case of acute major hospital or clinic
bleeding, clinical data are still lacking

112. Rivaroxaban: drug interactions
 CYP3A4 system realated
 Inhibitors : Ketoconazole, ritonavir, clarithromycin, erythromycin
(increase rivaroxaban levels 30-100%)
 Inducers : Rifampicin (decrease rivaroxaban levels 50%)
 P glycoprotein mediated
 Inhibitors : amiodarone, verapamil & clarithromycin (increases
rivaroxaban level)
 Inducer : rifampin, st. john’s wart (decreases rivaroxaban level)
So caution is advised but no dose adjustment are advised

113. Apixaban (Eliquis)

114. Apixaban (Eliquis)
 Direct factor Xa inhibitor
 Half life – 8 to 11 hours
 Peak plasma concentration 1 – 3 hours after
administration
 Have excellent bio-availability of 66%
 Metabolized in liver
 25 % of apixaban is renally excreted, so no dose
adjustment are required in renal failure pts
 75% excreted by fecal route

115.  Apixaban only partially metabolized by CYP3A4
system, so strong CYP3A4 inhibitor/ inducer may
affect its plasma level but this appears to be minimal
as per its anticoagulants effect are concerned
 Apixaban is minimally interact with P glycoprotein
hence its effects are not affected significantly.
Hence no clinically significant drug interactions

116. ARISTOTLE
 Primary efficacy outcome (stroke/systemic
embolism) for apixaban vs. warfarin: 1.27%/year vs.
1.6%/year; pnoninferiority < 0.001, psuperiority = 0.01
 All strokes:1.19%/year vs. 1.51%/year, p = 0.01; all-
cause mortality: 3.52%/year vs. 3.94%/year, p = 0.047
 Primary safety outcome (ISTH major bleeding):
2.13%/year vs. 3.09%/year, p < 0.001
Trial design: Patients with atrial fibrillation (AF) and at least one additional risk factor for
stroke were randomized to either apixaban 5 mg twice daily or dose-adjusted warfarin
(titrated to a target INR of 2.0-3.0). Patients were followed for a median of 1.8 years.
Results
Conclusions
Granger CB, et al. N Engl J Med 2011;365:981-92
(p < 0.001)*
Apixaban
(n = 9,120)
Primary efficacy
outcome
• Landmark trial, demonstrates superiority of
apixaban over warfarin in patients with AF for
efficacy, with a significant reduction in bleeding
0
5
10
1.27 1.6
(p < 0.001)
2.13
3.09
5
Primary safety
outcome
Warfarin
(n = 9,081)
0
10
%%
* For noninferiority

117. 0
2
4
stroke
AVERROES
 Stroke or systemic embolism: 1.6%/year with
apixaban vs. 3.7%/year with aspirin (p < 0.001)
 Stroke: 1.6%/year vs. 3.4%/year (p < 0.001)
 Clinically relevant nonmajor bleeding:
3.1%/year vs. 2.7%/year (p = 0.35)
 Fatal bleeding: 0.1%/year vs. 0.2%/year (p =
0.53)
Trial design: Patients with atrial fibrillation and elevated risk for stroke who were not
suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n = 2,808) vs.
aspirin 81-324 mg daily (n = 2,791).Median follow up was 1 yr
Results
Conclusions
• Among patients with atrial fibrillation and
elevated risk for stroke who were not suitable for
warfarin therapy, apixaban was beneficial
• Apixaban reduced the risk for the primary
outcome of stroke or systemic embolism
compared with aspirin, without increasing the
risk for major bleeding
Connolly SJ, et al. N Engl J Med 2011;364:806-17
(p < 0.001)
Apixaban Aspirin
%peryear
Stroke or systemic embolism
1.6
3.7

118.  To reduce the risk of stroke and dangerous blood clots
(systemic embolism) in patients with atrial fibrillation
that is not caused by a heart valve problem (Dec 28, 2012 )
FDA recommendation
(FDA first approved on Dec. 28, 2012)

119. Recommended Dose
Reduction of Risk of Stroke and Systemic Embolism in Patients
with Nonvalvular Atrial Fibrillation
The recommended dose of ELIQUIS for most patients is 5 mg
taken orally twice daily.
The recommended dose is 2.5 mg twice daily in patients with any 2 of
the following characteristics:
• age ≥80 years
• body weight ≤60 kg
• serum creatinine ≥1.5 mg/dL

120. Prophylaxis of Deep Vein Thrombosis Following
Hip or Knee Replacement Surgery
The recommended dose is 2.5 mg taken orally twice
daily. The initial dose should be taken 12 to 24
hours after surgery.
• In patients undergoing hip replacement surgery,
the recommended duration of treatment is 35
days.
• In patients undergoing knee replacement surgery,
the recommended duration of treatment is 12 days.

121. Treatment of DVT and PE
The recommended dose of ELIQUIS is 10 mg taken orally
twice daily for 7 days, followed by 5 mg taken orally twice
daily.
Reduction in the Risk of Recurrence of DVT and PE
The recommended dose of ELIQUIS is 2.5 mg taken orally
twice daily after at least 6 months of treatment for DVT or
PE.

124. How to treat with anticoagulants ?

125. Pts best treated with warfarin are…
1. Good level of control with warfarin
2. Renal failure pts
3. Mechanical heart valve replacement pts
4. Gastrointestinal disease pts & elderly pts
5. Poor compliance pts
6. Drug cost

126. 1. Good level of control with warfarin
Why?
ACC/AHA guideline noted that “Because of the twice
daily dosing and greater risk of nonhemorrhagic side
effects, patients already taking warfarin with excellent
INR control (TTR≥65.5) may have little to gain by
switching to dabigatran.” This recommendation
suggests that patient values and preferences should
influence the decision to initiate dabigatran.

127. A recent trial, in which patients with a stable warfarin
dose were randomized to 4-weekly or 12-weekly INR
testing demonstrated that the longer interval was
noninferior for the primary outcome of TTR, This
reduced INR monitoring frequency for selected
patients further reduces the perceived inconvenience
of warfarin treatment
Blood. 2009;114(5):952-956.

128. 2. Renal failure pts
Why ?
 Patients with severe renal failure (CrCl ≤ 30 mL/min) were excluded
from the RE-LY (dabigatran) and ROCKET AF trial. Dabigatran is
mainly (80%) eliminated via the kidneys, while Rivaroxaban is less
dependent on renal elimination. In the ROCKET AF trial, patients with a
CrCl of 30 to 49 mL/min received a reduced dose of 15 mg daily. These
observations suggest that warfarin remains the treatment of choice
for patients with a calculated creatinine clearance close to or less than
30 mL/min

129. 3. Mechanical heart valve replacement pts
Why ?
 These new drugs have not been evaluated in patients
with mechanical heart valve prosthesis
 And also
“ Recently the FDA added a contraindication to the
dabigatran label against using the drug in patients with
mechanical heart valves”
[12/19/2012 - Drug Safety Communication - FDA]

130. 4. Gastrointestinal disease pts & elderly pts
Why ?
 Lower GI bleeding is significantly increased with dabigatran
compared with warfarin (probably because of low bioavailability,
which results in high concentrations of active drug in the feces)
 Treatment with rivaroxaban was also associated with a
significant increase of the risk for gastrointestinal bleeding
 Hence, patients with intestinal angiodysplasia, inflammatory
bowel disease, or diverticulosis, or those with a history of other
forms of GI bleeding may experience a deterioration on
treatment with dabigatran or rivaroxaban

131.  In the RE-LY trial, discontinuation of dabigatran was
more frequent as a result of gastrointestinal distress,
and 11.3% to 11.8% of patients on this drug complained
of dyspepsia. This has been attributed to both tartaric
acid contained in the capsule (required for absorption) and
to a high concentration of active drug in the colon. This
again suggests that dabigatran may not be an ideal
agent for patients with a history of GI diseases.

132. 5. Poor compliance pts
Why ?
 Patients with documented poor adherence to the
treatment with warfarin (OD dose) can not be seen as a
candidate for dabigatran (BD dose)
 Inability to monitor dabigatran (t1/2 14-17 hrs) or
rivaroxaban (t1/2 11-13 hrs) coupled with its short half-life
would imply that patients who are poorly compliant are
at high risk of stroke because missing a dose will quickly
experience a complete loss of antithrombotic efficacy. So
first marker of noncompliance is probably stroke or other
thrombotic complications.

133.  While
For patients treated with warfarin and who undergo INR
monitoring, the clinician is at least aware of inadequate
levels, suggesting that aggressive measures to increase
compliance can be put in place.

134. 6. Drug cost
Why ?
 Most common cause for non-compliance
 Acquisition costs of novel agents will be higher than for
warfarin
 The estimated cost of one of the new agents already on
the market is $3000 per year versus $50 per year for
warfarin
Circulation. 2011;123:2519–2521

135. Pts best treated with newer anticoagulants are…
1. Unexplained poor warfarin control
2. Poor level of control because of unavoidable drug-
drug interaction
3. New patients on anticoagulation therapy for AF

136. 1. Unexplained poor warfarin control
Why ?
 Warfarin-experienced patients who continue to have
variable INR results, corresponding to a TTR of less
than 65%, have lower rates of stroke and other
complications when treated with dabigatran 150 mg
twice daily.
 However, it is crucial to determine the reasons for
instability because if instability is the result of
noncompliance, warfarin remains the anticoagulant
of choice

137. 2. Poor level of control because of unavoidable drug-
drug interaction
Why ?
 Patients with frequent need for antibiotic treatment,
chemotherapy, amiodarone, frequent use of
acetaminophen, azathioprine, or a large number of
concomitant medications, particularly if the exposure
to these medications varies, will probably do better with
the new anticoagulants.

138. 3. New patients on anticoagulation therapy for AF
Why ?
 For warfarin-naive patients who can afford newer
agents, it is very tempting to go straight for the new
anticoagulants to avoid the initial several weeks of
frequent dose adjustments of warfarin
But
 Patients should be informed of the advantages and
disadvantages of the alternatives & allowing them to
make an informed decision on their preferred therapy.

139. Take Home Massage
"Warfarin is not going to go away”
 Patients with stable INRs in the therapeutic range may best be left on warfarin.
 Others who better treated with warfarin are
1. Renal failure pts
2. Mechanical heart valve replacement pts
3. Gastrointestinal disease pts & elderly pts
4. Poor compliance pts
5. Drug cost
 Groups of patients who should be candidates for the new drugs as:
1. Poor level of control because of unavoidable drug-drug interaction
2. New patients on anticoagulation therapy for AF
3. Unexplained poor warfarin control
(it is important to establish that the unstable INR is not due poor compliance)
 Dabigatran should be avoided in severe renal failure. Renal function is not so much of a
problem with rivaroxaban .
 For ACS patients, there are better data for rivaroxaban (in low dose) from the ATLAS
trial.