anticoagulation _NOAC-

1. Oral anticoagulant
by
Mohammed Salah
Ass .lecturer –vas .surgery department

2. content
 Hemostasis
 Role of the platelets
 Coagulation cascade
 Classification of anticoagulant
 History of anticoagulation
 Warfarin
 DTI
 Fxa inhibitor
 Reversal of NOAC

3. Haemostasis
 haemostasis :
is a complex process which causes the
bleeding process to stop. It refers to the
process of keeping blood within a
damaged blood vessel.

4. Hemostasis is maintained in the body
via three mechanisms :
 Vascular spasm - Damaged blood vessels
constrict.
 Platelet plug formation - Platelets adhere to
damaged endothelium to form platelet plug
(primary hemostasis) and then degranulate.
 Blood coagulation - Clots form upon the
conversion of fibrinogen to fibrin, and its
addition to the platelet plug (secondary
hemostasis).

5. Vascular Injury
Second
Stable Fibrin/Platelet Clot
Fibrinolysis [as needed]
Exposure of
Subendothelial Collagen
Vasoconstriction Release of Tissue Factor
First
Platelet Adhesion, Aggregation, and Activation
(Primary Hemostasis)
Coagulation Cascade
(Secondary
Hemostasis) Third

6. Platelets role
Hemostatic system

7. WHAT PLATELETS DO

8. WHAT PLATELETS DO

9. WHAT PLATELETS DO

10. Coagulation Cascade
Hemostatic system

11. Fibrinogen Fibrin
Thrombin
Prothrombin
Xa
Va

12. Fibrinogen Fibrin
Thrombin
Prothrombin
Xa
Va
VIIa
TF
Extrinsic Pathway

13. Fibrinogen Fibrin
Thrombin
Prothrombin
Xa
Va
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway

14. Fibrinogen Fibrin
Thrombin
Prothrombin
Xa
Va
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
XIIIa
Soft clot
Fibrin
Hard clot

15. Fibrinogen Fibrin
Thrombin
Prothrombin
Xa
Va
VIIa
TF
Extrinsic Pathway
IXa
VIIIa
XIa
XIIa
Intrinsic pathway
XIIIa
Soft clot
Fibrin
Hard clot
V
VIII

16. Steps
Coagulation Cascade
Initiation
amplification
propagation

22. Coagulation Cascade
Warfarin typically works on
several calcium-dependent
clotting factors, including
factors II, VII, IX (not shown),
and X.

23. Adapted from Eriksson, Ann Rev Med 62:41, 2011
Rivaroxaban
Apixaban
Dabigatran
Warfarin
Fondaparinux
Heparin LWMH
VII

24. Classification of
anticoagulation

26. History of anticoagulant therapy
1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010
Anticoagulant in
spoiled sweet
clover (K.P. Link)
First clinical use of
4-hydroxycoumarin
(O. Meyer et al)
Warfarin
mechanism
elucidated
(J. Suttie)
Warfarin
dosing/INR
Warfarin
clinical trials
Oral thrombin
and Xa
Heparin
discovered
by medical
student
(McLean)
Clinical use of
heparin
Requirement
for plasma
cofactor
discovered
(K. Brinkhous)
Cont infusion of
heparin; aPTT
monitoring
LMWH
(J. Hirsch)
LMWH trials
Fondaparinux
trials

27. warfarin
Oral anticoagulant

28. 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.

29.  In 1920s cattle affected by an outbreak of an fatal
bleeding, either spontaneously or from minor injuries.
 Mouldy silage made from sweet clover was implicated,
a haemorrhagic factor that reduced the activity of
prothrombin was implicated.
 1940 that Karl Link and his student Harold Campbell in
Wisconsin discovered that the anticoagulant in sweet
clover was (4-hydroxy coumarin).
.
HISTORY

30. HISTORY
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

31. Epoxide'
Reductas
e
MECHANISM OF ACTION: Warfarin inhibits the vitamin
Warfarin
Vitamin K
epoxide
Vitamin KH
y -Carboxylase
(GGCX)
H20
COO coo
Post translational modification
Glutamic acid
CYP2C9
Inactivation
Pharmacokinetic
Y-Carboxyglutamic acid
1
Vitanr in K-dependent clotting factors (Fll,
FVII, FIX, FX, Protein C/S/Z)

33. Descarboxy-
prothrombin (or f.
VII. IX. X)
Prothrombin (or f.
VII. IX. X)
7-glutamyl
carboxylase
Vit K
hydroQuinone
NAD
Vit K
epoxide
NADH
Blocked by oral
anticoagulants
Fig. 44.2: Mechanism of action of oral anticoagulants NAD—
Nicotinamide adenine dinucleotide: NADH—its reduced form

34. Half lifeCoagulation factor
60 hII
4-6 hVII
24hIX
48-72hx
8hProt.c
36Prot .s
PLASMA HALF-LIVES OF VITAMIN K-
DEPENDENT PROTEINS

35. Warfarin: Indications
 Prophylaxis and /or treatment of:
 Venous thrombosis and its extension
 Pulmonary embolism
 Thromboembolic complications associated with AF
and
 Prophylaxis of recurrent thrombosis in APS
 Post MI, to reduce the risk of death,
 recurrent MI,
 stroke
 Systemic embolization
 Prophylaxis of genetic thrombophilia

36. Indications
 Cardiac Valve Replacement
Prophylaxis and treatment of thromboembolic
complications associated with cardiac valve
replacement with prosthetic valve.

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

38. • Most common complication
In form of
• Mild: epistaxis, hematuria
• Severe: Retroperotoneal or gastrointestinal bleeding
• Life-threatening : Intracranial bleed
• Half of the complications occurs because INR exceeds
therapeutic range
•
Can be minimized by keeping INR in therapeutic range
Bleeding

39. • 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
SKIN NECROSIS

40. Warfarin (Coumadin)-induced skin necrosis on the lower abdomen & breast

41. Skin necrosis
 Mechanism :
Not well understood
but a rapid fall in plasma protein C or S levels
(natural anticoagulants) before warfarin exert
anticoagulant effect, results in procoagulant
state triggering thrombosis of adipose tissue
microvasculature.

42. Skin necrosis
Treatment :
Discontinuation of warfarin.
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
Fresh 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

43. • 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 warfrin therapy if such
phenomena are observed.
Consider alternative drugs if continued
anticoagulation therapy is necessary.
Pharmacotherapy. 2003 May;23(5):674-7
Purple toes syndrome

44. • 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,laryngomalacia .trachiomalacia
• Central nervous system abnormalities ventriculomegaly, corpus callosum
agensis
• Coarctation of aorta (Rare malformations described following first
trimester exposure to warfarin)
• Occurs especially if warfarin dose is > 5 mg/day
Teratogenisity

45. Fig. 1 Baby's face, showing nasal abnormality due to mother's
ingestionofwarfarin.
Lateral view X-ray showing calcifications and irregular
ossification of lumbar and sacral vertebrae, consistent with
warfarin embryopathy

46. 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.vit . D ,calcium .
Consider LMWH , Fondaparinux

47. warfarin
Disadvantage

48. Food interaction with warfarin
Caution with VITAMIN K containing food
 daily intake of 90 -120 micrograms of vitamin K.
 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

49. Very High
(>500 pg/l00g serving)
High
(100-500 pg/l00g serving)
Medium
(25-l00iig/l00g serving)
Kale Broccoli (raw) Asparagus (cooked)
Col lards Brussel sprouts (5) Cabbage (cooked)
Parsley Cauliflower (cooked) Celery (3 stalks raw)
Seaweed Chick peas (cooked) Green beans (cooked)
Spinach Chinese cabbage (cooked) Green onions (raw)
Swiss Chard Endive (raw)
Green tomato (raw.
whole)
Turnip Greens Lentils (cooked) Lettuce (1 cup raw)
Green Tea Mung beans (cooked) Okra (cooked)
Soybeans (cooked) Watercress (raw)
Beef liver Green apple (1 small) Bok
choy (cooked) Pistachio
nuts Soybean oil (15ml)
Rolled oats Wheat bran
Wheat flour Wheat germ
Chicken liver Pork liver
Coffee (8 oz/235ml)
Food interaction with warfarin

50. ‫السبانخ‬
‫البقدونس‬
‫الكرنب‬
‫األخضر‬ ‫الخردل‬
‫البنجر‬
‫األخضر‬ ‫الشاي‬
‫لمش‬ ‫وتؤدي‬ ‫الوافارين‬ ‫تأثير‬ ‫تزود‬ ‫التي‬ ‫المشروبات‬ ‫وهناك‬‫اكل‬
‫بغزارة‬ ‫الدم‬ ‫نزف‬:
‫التوت‬ ‫عصير‬‫البري‬.‫الخباء‬ ‫حاده‬ ‫عنيبه‬cranberry
‫الكحولية‬ ‫المشروبات‬

51. :
A total of 850 drugs are known to interact
with warfarin.
•213 major drug interactions
•432 moderate drug interactions
•205 minor drug interactions
Drug Interactions

52. Drug Interactions with Warfarin:
Potentiation
Level of
Evidence Potentiation
Alcohol (if concomitant liver disease) amiodarone (anabolic steroids,
cimetidine,† clofibrate, cotrimoxazole, erythromycin, fluconazole, isoniazid [600
mg daily] metronidazole), miconazole, omeprazole, phenylbutazone, piroxicam,
propafenone, propranolol,† sulfinpyrazone (biphasic with later inhibition)
Acetaminophen , chloral hydrate , ciprofloxacin, dextropropoxyphene, disulfiram,
itraconazole, quinidine, phenytoin (biphasic with later inhibition), tamoxifen,
tetracycline, flu vaccine
Acetylsalicylic acid, disopyramide, fluorouracil, ifosfamide, ketoprofen,
simvastatin, metozalone, moricizine, nalidixic acid, norfloxacin, ofloxacin,
propoxyphene, sulindac, tolmetin, topical salicylates
Cefamandole, cefazolin, gemfibrozil, heparin, indomethacin, sulfisoxazole
I
II
III
IV
†In a small number of volunteer subjects, an inhibitory drug interaction occurred.

53. Drug Interactions with Warfarin:
Inhibition
Level of
Evidence Inhibition
Barbiturates, carbamazepine, chlordiazepoxide,
cholestyramine, griseofulvin, nafcillin, rifampin, sucralfate
Dicloxacillin
Azathioprine, cyclosporine, etretinate, trazodone
I
II
III

54. Newer Oral Anticoagulants

55. Why we need alternatives to warfarin
???

56. Disadvantages of Warfarin
 Narrow therapeutic index
 Need for frequent monitoring
 Slow onset & offset of action
 Large inter-individual dosing differences
 Drug-Drug and drug-food interactions
 Genetic polymorphisms
 Warfarin skin necrosis
 Warfarin embryopathy

57. The Ideal Oral Anticoagulant
Ideally, an oral anticoagulant would:
 Have high efficacy in reducing thromboembolic events
 Reach therapeutic levels within several hours with
Predictable therapeutic effect with fixed or weight-
based dosing
 Ability to inhibit free and clot bound thrombin
 Require no remote monitoring (but the ability to
monitor if desired
 Have little interaction with food or other drugs

58.  Well defined pharmacokinetics in presence of renal or
hepatic disease
 Cost effective
 Offer a good safety profile with regard to bleeding risk
 Easily reversible with availability of an antidote

59. Classification
• Direct thrombin (Ila) inhibitor
• Dabigatran (Pradaxa)
• Factor Xa inhibitors
• Rivaroxaban (Xarelto)
• Apixaban(eliqus)
• Edoxban(savysa)

61. Direct Thrombin Inhibitor
Dabigatran

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

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

65. Pharmacokinetics
 absorbed as the dabigatran etexilate ester. hydrolyzed, forming
dabigatran, the active moiety. . prodrug
 The t1/2 is 12 to 17 hrs
 80% is excreted unchanged in urine. renal excretion
Absorption
 Oral bioavailability of up to6- 7% .
 Cmax occurs at 1 -2hour post-administration.
 Absorption is delayed by decrease gastric motility or acidity so dec
with fat &PPI .

66.  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.

67. Pharmacodynamics
Dabigatran prolongs aptt which targets intrinsic pathway of
coagulation; (curvilinear flattens after certain conc.)
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.(linear rleationship)
has little effect on the prothrombin time and INR, which targets the
extrinsic pathway.

68. ■ Reduction of Risk of Stroke and Systemic
Embolism in Non-valvular Atrial Fibrillation
■ Treatment of Deep Venous Thrombosis and
Pulmonary Embolism
parenteral anticoagulan for 5-10 days.
■ Reduction in the Risk of Recurrence of Deep
Venous Thrombosis and Pulmonary Embolism
Indication

69. indication
Dabigtran trials

70. 70

71. 71
RE-LY
• N = 18,113, Follow-up median 2 years, CHADS2 median
2.1, open-label
• Inclusion: Afib on EKG w/in last 6 months, plus at least
one: CVA, TIA, LVEF < 40%, NYHA class II or great HF
symptoms w/in 6 months and age of at least ≥75 or 65-74
plus DM, HTN, or CAD
• Exclusion: severe heart-valve disorder, stroke w/in 14 days
or severe stroke w/in 6 months, increased risk of bleeding,
CrCl < 30, liver dx, prenancy
• Randomized to 110 or 150 mg of dabigitran BID vs
unblinded warfarin (ASA <100 mg or other antiplatelet
agents allowed)
• Primary outcome: stroke or systemic embolization
• Safety outcome: major hemorrhage (reduction of Hgb by 2
g/dL, 2 units of PRBCs, or symptomatic bleeding in critical
area)

72. Event D %/yr W %/yr
D vs W
RR
P value NNT
Stroke/Embolism 1.11 1.69 0.66 (0.53-0.82) <0.001 172
Stroke 1.01 1.57 0.64 (0.51-0.81) <0.001 178
Stroke-
Hemorrhagic
0.10 0.38 0.26 (0.14-0.49) <0.001 357
MI 0.74 0.53 1.38 (1.00–1.91) 0.048 476 NNH
Death from
vascular causes
2.28 2.69 0.85 (0.72–0.99) 0.04 243
Death any cause 3.64 4.13 0.88 (0.77–1.00) 0.051 204
Non-inferiority margin 1.46

73. Event D %/yr W %/yr
D vs W
RR
P value NNT
Stroke/Embolism 1.11 1.69 0.66 (0.53-0.82) <0.001 172
Stroke 1.01 1.57 0.64 (0.51-0.81) <0.001 178
Stroke-
Hemorrhagic
0.10 0.38 0.26 (0.14-0.49) <0.001 357
MI 0.74 0.53 1.38 (1.00–1.91) 0.048 476 NNH
Death from
vascular causes
2.28 2.69 0.85 (0.72–0.99) 0.04 243
Death any cause 3.64 4.13 0.88 (0.77–1.00) 0.051 204
Non-inferiority margin 1.46
War.
1.69
Dab.
1.11

74. 74

75. 75
War
3.36
Dab.
3.11

76. 76
Dabigatran
and DVT/PE

77. 77
December 6, 2009

78. 78
RE-COVER
• N = 2564, Follow-up 6 months, double-blind
• Inclusion: DVT or PE with planned tx for 6 months
• Exclusion: Symptoms longer than 6 months, PE
with HD instability or use of TPA, indication for
warfarin, unstable heart disease, high risk of
bleeding, transaminases, life expectancy < 6
months, CrCl < 30, pregnancy
• Randomized to 150 mg dabigatran BID vs warfarin
• Primary outcome: symptomatic VTE or death 2/2
VTE

79. 79
NIM 2.75

80. 80
NIM 2.75
War.
2.1
Dab.
2.4

81. 81

82. 82
Dab.
1.6
War.
1.9

83. 83
Summary
• Non-inferior for prevention of stroke/embolism in Afib
• Non-inferior for treatment of DVT/PE
• Probable reduced hemorrhagic stroke rate
• Reduced rate of fatal bleeding events
• Increased incidence of GI bleeds
• Perhaps increased incidence of MIs with dabigatran
• Cost of drug/year $3000

84. Dosage
Paradxa

85. Dose in stroke prevention
Stroke prevention in A fib: 110-150 mg
bid
110 mg dose not available in US
For patients with CrCl 15-30: 75 mg
bid
Not recommended for CrCl < 15 or
dialysis dependent

86.  for acute VTE: 150 mgBID;5-10 days
LMWH overlap.
 for VTE prevention after knee or hip
replacement surgery (14 or 30 days,
respectively): 110 mg (initial dose) 1-4hour
after surgery then 220 mg daily after first
day.
VTE TTT&VTE Prophylaxis

87. SOME SPECIAL POINTS TO
MENTION....

88.  Missed dose , 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.

89. 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

90. 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> 50 ml/min)
• 24 hrs (CrCl< 50 ml/min) after last dose of dabigatran before starting
parenteral anticoagulant
Converting pts from or to parenteral
anticoagulants

91. 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

93. Dabigatran in pts planned for emergency surgery
• Because specific antidote is not widly 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

94. • It depends almost exclusively on the postoperative risk
of bleeding
• Procedures 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
Postoperative management

95. • 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
(~o.2% increased risk for a AMI re-ly trial)
Adverse effects

96. • No Need 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
Monitoring of dabigatran

97. "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.
Contraindication

98. • 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.
Drug interaction

100. Factor Xa inhibitors
• Rivaroxaban
• Apixaban
• Edoxban

101. Rivaroxaban (Xarelto)

102. •
Pharmacokienitcks
 • 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.
 •66% renal excretion &33% biliary .
Rivaroxaban (Xarelto)

104. 104

105. 105
ROCKET-AF
• N = 14,264, Follow-up median 1.6 yrs, CHADS2
median 3, double-blind
• Inclusion: Non-valvular Afib by EKG w/ hx of
stroke, TIA, or embolism or with at least a
CHADS2 ≥ 2
• Randomized to rivaroxaban 20 mg daily or 15
mg daily depending on CrCl vs warfarin
• Primary outcome: stroke and embolism
• Safety end point: major and non-major clinically
relevant bleeding

106. 106
Non-inferiority margin
1.46

107. 107
Non-inferiority margin
1.46
Riva.
1.7
War.
2.2

108. 108

109. 109
Riva.
3.6 War.
3.4

110. 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.”

111. 111
December 2010

112. 112
EINSTEIN-DVT
• N = 3449, most tx for 6 months, open-label
• Inclusion: DVT w/o PE
• Exclusion: CrCl <30, liver disease, active
bleeding or high risk for bleeding, HTN,
contraindication to anticoagulation, or received
UFH/LMWH for > 48 hrs
• Randomized to rivaroxaban at 15 mg BID for 3
weeks then 20 mg daily for 3, 6, or 12 months vs
warfarin
• Primary outcome: symptomatic recurrent VTE

113. 113

114. 114
NIM 2.0

115. 115
NIM 2.0
Riva.
2.1
War.
3

116. 116

117. 117
War.
8.1
Riva
8.1

118. 118

119. Rivaroxaban: FDA Approval
(First approved in July 1st, 2011)
• To reduce the risk of DVTs and PEs in patients
undergoing knee or hip replacement surgery (jui 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)
indication

120. 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

122. 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

124. Apixaban (Eliquis)

125. 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

126. • 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

127. AVERROES
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
(p < 0.001)
Stroke or system ic embolism
Apixaban Aspirin
www.cardiosource.org
Results
• 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 .
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

128. FDA recommendation
(FDA first approved on Dec. 28, 2012)
 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)
 TTT and prvention of DVT & PE.
 VTE prophylaxis .

129.  Reduction of Risk of Stroke and Systemic Embolism in Patients with
Nonvalvular Atrial Fibrillation 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
Recommended dose

130. 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.

131. 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.

132. Anticoagulation shifting
CONVERSION RECOMMENDATION
warfarin to apixaban
stop warfarin and start apixaban when
INR < 2
apixaban to warfarin
(NOTE: apixaban is not intended to
be used as a short term "bridge" to
warfarin. These recommendations
refer to transitioning patients who
are taking apixaban on a long term
basis and are switching to warfarin
instead)
start warfarin and stop apixaban 3
days later
OR IF continuous, uninterrupted
anticoagulation is necessary:
a) Stop apixaban
b) Begin both a parenteral
anticoagulant (LMWH/fondaparinux or
UFH) and warfarin at the same time
that the next dose of apixaban would
have been given
c) Stop the parenteral anticoagulant
when INR is > 2.

133. Anticoagulation shifting
LMWH/fondaparinux to apixaban
stop LMWH/fondaparinux and start
apixaban at the same time that the next
dose of LMWH/fondaparinux would
have been given
IV heparin to apixaban
Stop IV heparin and start apixaban
simultaneously
apixaban to parenteral anticoagulant
stop apixaban and administer first dose
of parenteral anticoagulant at the time
that the next dose of apixaban would
have been given
apixaban to oral anticoagulant other
than warfarin
stop apixaban and begin the other
anticoagulant at the time that the next
scheduled dose of apixaban would
have been given

134. edoxaban
 New Xa inhibitor approved in 2015
 First used in japan &Canada
 Recently Approved in us.
 Trade name lixiana , SAVAYSA (edoxaban)
tablets for oral use Initial U.S. Approval: 2015

135.  15mg 30mg 60mg
 Stroke Prophylaxis with Atrial Fibrillation
Indicated to reduce risk of stroke and systemic
embolism associated with nonvalvular atrial fibrillation
(NVAF) 60 mg PO qDay
 DVT or PE Treatment
Indicated for treatment of deep vein thrombosis (DVT)
and pulmonary embolus (PE) in patients who have been
initially treated with a parenteral anticoagulant for 5-
10 days
>60 kg: 60 mg PO qDay
≤60 kg: 30 mg PO qDay

136. Transition from edoxaban
 To non-vitamin-K-dependent oral anticoagulants:
Discontinue edoxaban and start the other oral
anticoagulant at the time of the next dose of edoxaban.
 To parenteral anticoagulants: Discontinue edoxaban
and start the parenteral anticoagulant at the time of the
next dose of edoxaban.

137. Drug shifting
 To warfarin (oral option)
 If taking edoxaban 60 mg/day, reduce dose to 30
mg/day and begin warfarin concomitantly
 If taking edoxaban 30 mg/day, reduce dose to 15
mg/day and begin warfarin concomitantly
 Once a stable INR ≥2.0 is achieved, discontinue
edoxaban and continue warfarin

138. Drug shifting
 To warfarin (parenteral option)
Discontinue edoxaban and administer a
parenteral anticoagulant and warfarin at the time
of the next scheduled edoxaban dose Once a
stable INR ≥2.0 is achieved, discontinue the
parenteral anticoagulant and continue warfarin

139. Comparative Features of Warfarin and New Oral Anticoagulants

141. NOAC & APS
 Not approved for thomboprophylaxsis in APS.
 largest studyNOACs in patients with APS was a trial of 35
patients with previous VTE who had poor anticoagulation
control with vitamin K antagonists.
 Patients in that study were treated with rivaroxaban, and the
data appeared to support the use of a NOAC for secondary
thromboprophylaxis for patients with antiphospholipid
syndrome with previous VTE who require a target INR of 2 to
3.
 But use in patients with previous arterial thrombosis or in those
who require a target INR above 3 "is still a matter of discussion

142. Rivaroxaban use in patients with
antiphospholipid syndrome and
previous venousthromboembolism.
Sciascia S, Breen K, Hunt BJ.

143. Contraindications
Known hypersensitivity to ingredients of NOAC
Clinically significant active bleeding
Renal impairment <30ml/min
Hepatic disease (child pugh – C)
Recent high risk bleeding lesion (eg. ICH < 6 months)
Pregnancy or breast feeding
Recent stroke, surgery, GI bleed or ulcer
Concomitant warfarin therapy

144. Clinical Challenges With New Anticoagulants
 No validated tests to measure
anticoagulation effect
 No established therapeutic range
 No antidote for most agents
 Assessment of compliance more difficult
than with vitamin K antagonists
 Potential for unknown long-term adverse
events
 Balancing cost against efficacy
 Lack of head-to-head studies comparing
new agents
Phillips & Ansell J. Thromb Haemost 2010;103:34-39.

145. How to treat with anticoagulants ?

146. 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

147. 1. Good level of control with warfarin
Why?
ACC/AHA guideline noted that " because of the twice
daily dosing and greater risk of non hemorrhagic side
effects, patients already taking warfarin with excellent INR
control may have little to gain by switching to dabigatran.”
This recommendation suggests that patient values and
preferences should influence the decision to initiate
dabigatran.

148. 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.

149. 2. Renal failure pts
Why ?
 • severe renal failure (CrCl < 30 mL/min) were excluded from the RE-LY
(dabigatran) and ROCKETAF trial.
 Dabigatran is (80%) renal excretion , while Rivaroxaban is less 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

150. 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]

151. 4. Gastrointestinal disease pts & elderly pts
Why ?
• Lower GI bleeding is significantly increased with dabigatran
(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

152. 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 NOAC coupled with its short half-life
so missing a dose will quickly experience a complete loss of
antithrombotic efficacy. ====== high risk of stroke
So first marker of noncompliance is probably stroke or other
thrombotic complications.

153. • 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.

154. 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

155. 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

156. i. Unexplained poor warfarin control
Why ?
• Warfarin-experienced patients who continue to have
variable INR results, have lower rates of stroke and
other complications when treated with NOAC
• However, it is crucial to determine the reasons for
instability because if instability is the result of
noncompliance, warfarin remains the anticoagulant of
choice

157. 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.

158. 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.

159. Reversal of NOAC

160. MANAGEMENT OF BLEEDING
 Discontinue anticoagulant short half-lives (range from
5 to 17 hours), reversal drugs in emergency situations
such as life-threatening major bleeding or non-elective
major surgery anticoagulation
 Control active bleeding.
 Maintain adequate fluid, oxygen and hemodynamic
support.
 Transfuse packed red blood or initiate massive
transfusion protocols, if necessary.
 Consider platelets in thrombocytopenia or on anti-
platelet therapy .
 Order routine lab tests: CBC , LFT , screen for DIC .

161. COAGULATION ASSAYS
 (aPTT),intrinsic pathway,curvilinear fashion in
patients taking both IIa and Xa inhibitors;
dependent upon the reagent used.
 At therapeutic levels of dabigatran aPTT
prolonged, still be clinical anticoagulation effects
of dabigatran with a normal aPTT; however, the
patient’s serum levels would fall below the
therapeutic range (<80μg/L).
 At therapeutic levels “Xabans,” a PTT will not
reliably be prolonged. only useful in patients at
supra-therapeutic levels.

162. International Normalized Ratio
(INR)
 (PT) / (INR) At therapeutic levels of dabigatran,
normal PT/INR is expected. an elevated INR is an
indication of serum levels three to four times the upper
limit of normal therapeutic concentrations.
 Of the Xa inhibitors, rivaroxaban has the strongest
effect on the PT/INR. At therapeutic level both
rivaroxaban and edoxaban to cause elevation of the
PT/INR.
 Apixaban weakly affects the PT/INR levels.
 normal PT/INR does not exclude some degree of
anticoagulant effect, only level below that expected at
therapeutic dosing.

163. Known as Thrombin Clotting
Time
 Thrombin time (TT) directly assesses the
activity of thrombin. This test is useful in
patients receiving dabigatran (Pradaxa).
 A normal TT excludes dabigatran activity; the
degree of elevation of the TT is not a direct
correlate of serum levels

164. Chromogenic Anti-Factor Xa
 Chromogenic anti-factor Xa testing measures
the concentration of anticoagulants that inhibit
factor Xa.
 This test is useful in patients receiving
LMWHs, fondaparinux (Arixtra) and direct oral
factor “Xabans.

165. Dabigatran reversal algorithm

166. Rivaroxban reversal algorithm

167. Apixaban reversal algorithm

168. SPECIFIC REVERSAL AGENTS
Idarucizumab (Praxbind)
 Idarucizumab (Praxbind)
 idarucizumab is the only FDA-approved agent
for reversal agent of the direct oral
anticoagulants, and it only works on
dabigatran.
 It is a monoclonal antibody fragment that binds
with high affinity dabigatran .reverse the
coagulation effects of dabigatran.
 idarucizumab is recommended for reversal of
anticoagulant effects for patients taking
dabigatran.

173. Group A
98%
Group B
93%

174. Andexanet Alfa
 Andexanet alfa Recombinant and inactivated
form of factor Xa with high specificity both oral
and injectable factor Xa inhibitors .
 It has been developed as an antidote to
reverse the anticoagulant activity of oral direct
(apixaban, edoxaban, and rivaroxaban) and
injectable indirect (enoxaparin and
fondaparinux) factor “Xabans.”
 Not FDA approval and it. This drug is not
currently available.

176. Prothrombin Complex Concentrates
(PCCs)
 Prothrombin complex concentrates contain
highly concentrated coagulation factors .
 Depending on the agent used, they may
contain three factors (II, IX, X) or four factors
(II, VII, IX, X)
either activated (FEIBA),or inactive (octaplex)
 Clotting factors are 25 times more
concentrated than fresh frozen plasma (FFP)
and INR reverses within minutes (15–20
minutes), while it may take FFP 6 to 24 hours.

177.  Disadvantages of PCCs vs FFP include
 a small but real pro-thrombotic risk,
 availability at some institutions
 and cost

178. Recombinant Human Factor VIIa (rFVIIa,
NovoSeven)
 Recombinant human Factor VIIa (rFVIIa)
activates the coagulation cascade via the
extrinsic pathway and has been used off label
in the reversal of VKAs
 Because of the high doses required and the
concern for the possibility of thrombotic
sequelae, rFVIIa is not recommended for the
treatment of bleeding in patients on NOAC
therapy.

179. Fresh frozen plasma (FFP)
 Fresh frozen plasma (FFP) is derived from
whole blood and thus, contains all inactive
components of the coagulation cascade in
physiologic concentrations

180. Tranexamic Acid (TXA)
 Tranexamic acid inhibits fibrinolysis by
inhibiting the binding of plasma to fibrin.
 While no studies have looked at the efficacy of
TXA, the cost and overall risk of administering
therapy (adverse reaction, thrombotic
sequelae) is low.
 Therefore, the recommendation is that TXA
should be considered for reversal of bleeding
in patients taking DOAC

181. Desmopressin (DDAVP)
 Desmopressin is a synthetic analogue of
vasopressin.
 It affects thrombosis by stimulating the release
of von Willebrand factor (vWF) and increasing
production of factor VIII.
 Similar to TXA, the overall cost and risk of
administration of desmopressin is low.
Therefore, it should be considered for use in
the treatment of significant bleeding in patients
on DOACs.

182. Hemodialysis
 Dabigatran excretion is 80–85% renal which
makes hemodialysis an option.
 Direct factor Xa oral inhibitors are mainly
protein bound with only 25 to 35% renal
excretion, therefore hemodialysis is not an
option for the direct factor “Xabans

183. Oral Activated Charcoal
 Oral activated charcoal, 100gm PO/NG ×1, is
an option to reduce absorption for all DOACs
in the appropriate patient.
 Charcoal can be considered if the dose was
taken within eight hours for rivaroxaban, six
hours apixaban and within two hours of
ingestion for edoxaban and dabigatran.