1. Oral Anti-coagulants
Presenter: Amarendra Chowdary

2. Intrinsic Pathway Extrinsic Pathway
Blood Vessel Injury
XI XIa
IX IXa
X Xa
XII XIIa
Tissue Injury
Tissue Factor
Thromboplastin
VIIa VII
X
Prothrombin(II) Thrombin
Fibrinogen Fribrin monomer
Fibrin polymer
XIII
Factors affected
By Heparin
Vit. K dependent Factors
Affected by Oral Anticoagulants
VIIIa
Va
Va
VIIIa

3. Available Anticoagulants
Parenteral anticoagulants:
– Indirect thrombin inhibitors: Heparin, Low molecular weight heparin, Fondaparinux,
Danaparoid
– Direct thrombin inhibitors: Lepirudin, Bivalirudin
Oral anticoagulants:
– Coumarin Derivative: Bishydroxycoumarin (dicumarol), Warfarin sodium,
Acenocoumarol
– Inandione derivatives: Phenindione

4. New oral anti coagulants
• Direct Thrombin inhibitors:
o Ximelagatron
o Dabigatran
• Factor Xa inhibitors:
o Rivaroxaban
o Apixaban
o Edoxaban
New Parenteral Anticoagulants
o Fondaparinux
o Indraparinux
o Lepirudin
o Argatroban
o Bivaluridin

5. OLD Oral Anti-coagulants

6. MOA (warfarin)
• The oral anticoagulants are
antagonists of vitamin K.
• Coagulation factors II, VII, IX,
and X and the anticoagulant
proteins C and S are
synthesized mainly in the liver
and are biologically inactive
unless 9 to 13 of the amino-terminal
glutamate residues are
carboxylated to form the Ca2+-
binding g-carboxyglutamate
(Gla) residues.

7. Warfarin Mechanism of Action
Warfarin
Synthesis of Non
Functional
Coagulation
Factors
Antagonism
of
Vitamin K
Vitamin K
VII
IX
X
II

8. Contraindication

9. Drug interaction
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.

10. Complications
 Hemorrhage- 2.7% (major- 1.1%-8.1%)
 Warfarin Embryopathy -5% -30%
 Warfarin necrosis- 0.02%
 Osteoporosis- 0.1%
 Purple toe syndrome-0.01%

11. Problems with warfarin
• Genotype testing for CYP2C9 and VKORC1 (FDA suggested)
• Slow onset and offset of action (TTI)
• Narrow therapeutic range
• Regular monitoring (TTR)
• Drug interactions
• Resistance

12. Other Oral Anti-coagulants
Phenprocoumon and Acenocoumarol
• Phenprocoumon (MARCUMAR) has a longer plasma half-life (5 days) than warfarin, as well as
a somewhat slower onset of action and a longer duration of action (7 to 14 days).
• It is administered in daily maintenance doses of 0.75 to 6 mg. By contrast, acenocoumarol
(SINTHROME) has a shorter half-life (10 to 24 hours), a more rapid effect on the PT, and a
shorter duration of action (2 days). The maintenance dose is 1 to 8 mg daily.
Indandione Derivatives
• Anisindione is available for clinical use in some countries. It is similar to warfarin in its kinetics
of action; however, it offers no clear advantages and may have a higher frequency of
untoward effects.
• Phenindione still is available in some countries. Serious hypersensitivity reactions,
occasionally fatal, can occur within a few weeks of starting therapy with this drug, and its use
can no longer be recommended.

13. Newer oral Anti-coagulants

14. Mechanism of Action of new oral anti-coagulants

16. Dabigatran Etexilate
• Onset of action 0.5-2
hours
• Potent and reversible oral
Direct Thrombin Inhibitor
• Inhibiting both clot
bound and free thrombin
• Anticoagulation
monitoring—Not
required
• No food–drug interactions
reported
• Dosing independent of
meals or dietary
restrictions
Rivaroxaban
Onset of action 2-4 hours
• No observed effects on
agonist-induced platelet
aggregation
• No laboratory monitoring
required
• No dosage adjustment for
gender, age, extreme body
weight
• Approved by Europe and
Canadian agencies, and
FDA
Apixaban
• Peak Plasma Levels = 3 hrs
• Eliminated via multiple
pathways
• No laboratory monitoring
required
• Approved for the
treatment of deep venous
thrombosis (DVT) and
pulmonary embolism (PE)
and for the reduction in
the risk of recurrent DVT
and PE
Edoxaban
• Reversible Factor Xa
inhibitor
• Application filed for FDA

17. Black Box Warning
Dabigatran
Premature discontinuation
• Premature discontinuation of any oral
anticoagulant, including dabigatran,
increases the risk of thrombotic events
Spinal/epidural hematoma
• Epidural or spinal hematomas may
occur in patients who are receiving
neuraxial anesthesia or undergoing
spinal puncture
• These hematomas may result in long-term
or permanent paralysis
Rivaroxaban
Epidural or spinal hematomas
Discontinuing use for atrial fibrillation
o Premature discontinuation of
anticoagulants, including rivaroxaban,
places patients at increased risk for
thrombotic events
Apixaban
Discontinuing in patients with nonvalvular atrial
fibrillation
(risk of stroke)
Spinal/epidural hematoma

18. Dabigatran Etexilate
Dosing and Indications
Stroke Prophylaxis With Atrial Fibrillation
• CrCl >30 mL/min: 150 mg PO BID
• CrCl 15-30 mL/min: 75 mg PO BID
Dosing modifications (atrial fibrillation)
• CrCl >30 mL/min if patient not being treated with a P-glycoprotein (P-gp) inhibitor (eg,
dronedarone, ketoconazole): No dosage adjustment required
• CrCl 30-50 mL/min plus P-gp inhibitor (eg, dronedarone, ketoconazole): Decrease dose to
75 mg PO BID
• CrCl 15-30 mL/min if patient not being treated with a Pgp inhibitor: Decrease dose to 75
mg PO BID
• CrCl 15-30 mL/min plus a Pgp inhibitor: Avoid concurrent use
oCrCl <15 mL/min or dialysis: No data available; not recommended

19. DVT or PE Treatment
• Indicated for treatment of deep vein thrombosis (DVT) and pulmonary embolus (PE)
in patients who have been treated with a parenteral anticoagulant for 5-10 days
• Also indicated to reduce the risk of recurrence of DVT and PE in patients who have
been previously treated
• CrCl >30 mL/min: 150 mg PO BID
• CrCl <30 mL/min or on dialysis: Dosage recommendations cannot be provided
• CrCl <50 mL/min with concomitant use of P-gp inhibitors: Avoid coadministration

20. CLINICAL TRIALS WITH DABIGATRAN
AFIB –FDA approval of 150 mg bid dose, n = 18,111 :
• Re-LY: 150mg or 110mg bid vs warfarin. Event prevention - 150 mg superior p< 0.001;
bleeding non-inferior to warfarin (3.1 vs 3.3%)
Acute DVT/PE Treatment – NOT FDA approved – n = 2564
• RE-COVER: 150 mg bid vs warfarin. VTE - warfarin 2.1 vs dabigatran 2.4%, p< 0.001 for
non-inferiority; bleeding- warfarin 1.9 vs 1.6% dabigatran, non-inferior
Postop THA – NOT FDA approved
• RE-NOVATE I & II – 150 or 220 mg daily vs Enoxaparin 40 mg daily. Events – 150 mg
8.6%, 220mg 6%, enox 6.7% - non-inferior; bleeding, non- inferior
Postop TKA – NOT FDA approved :
RE-MODEL (non-inferior p<.003) & RE-MOBILIZE ( inferior p=.02; bleeding non- inferior

21. Rivaroxaban
Dosing and Indications
DVT Prophylaxis (Orthopedic Surgery)
Knee replacement: 10 mg PO qDay for 12 days; may take with or without food
Hip replacement: 10 mg PO qDay for 35 days; may take with or without food
Nonvalvular Atrial Fibrillation
20 mg/day PO with the evening meal
DVT or PE Treatment
15 mg PO q12hr for 21 days with food, THEN 20 mg PO qDay for 6
months
Reduce risk for recurrent DVT or PE
20 mg PO qDay following initial 6 months of treatment for DVT and/or PE
Renal dosage Adjustment Required incase of renal failure

22. RIVAROXABAN CLINICAL TRIALS
A-fib – ROCKET AF, FDA approved
• 20 mg daily (15 mg CrCl < 30-49) vs warfarin
• Events: warfarin 2.4% vs rivaroxaban 2.1%, p< 0.001
• Bleeding: warfarin 14.5%/y vs rivaroxaban 14.9%, p=.44
THA/TKA – RECORD 1 & 2 & 3 & 4, FDA approved
• 1-3 10 mg daily vs enoxaparin 40 mg qd; 4 enox 30 mg bid
• Events: P< 0.001 for superiority of rivaroxaban in all
• Bleeding: < 1% in all, p<.18, not significant, p< .77
Medical prophylaxis – NOT FDA approved
• 10 mg vs 40 mg enox; event p=.0025 non-inf; bleeding MORE bleeding with rivaroxaban p
< .001

23. RIVAROXABAN VTE TREATMENT TRIALS
Treatment of acute DVT (EINSTEIN DVT study)
• 15mg bid X 3wk, 20 mg daily vs enox-warfarin INR 2-3
• Events: p<.001 for non inferiority of rivaroxaban
• Bleeding: 8.1% for both, p=.77
Treatment of acute PE (EINSTEIN PE Study)
• 15mg bid X 3wk, 20 mg daily vs enox-warfarin INR 2-3
• Events: p<.003 for non inferiority of rivaroxaban
• Bleeding: 11.4% warfarin vs 10.3% warfarin p=.23
Continued treatment DVT / PE (EINSTEIN-EXT)
• 20 mg daily for additional 6-12 months AFTER initial treat
• Events: 7.1% placebo vs 1.3% riva; Bleeding 0.7% p=.11

24. Apixaban
Dosing and Indications
Stroke Prophylaxis with Atrial Fibrillation
5 mg PO BID
Postoperative Prophylaxis of DVT/PE
Initial: Give 2.5 mg PO 12-24 hr after surgery
Duration of therapy (hip replacement): 2.5 mg PO BID for 35 days
Duration of therapy (knee replacement): 2.5 mg PO BID for 12 days
DVT or PE Treatment
10 mg PO BID x 7 days, then 5 mg BID
Reduce risk for recurrent DVT or PE
2.5 mg PO BID
No Renal and Hepatic Dosage Adjustments Required

25. APIXABAN CLINICAL TRIALS
A-fib – AVERROES and ARISTOTLE, FDA approved
• ROSES - 5 mg bid vs aspirin – terminated apixaban better
ARISTOTLE – 5 mg bid vs warfarin.
• EVENT: apixaban non- inferiority p < 0.001, superiority p = 0.01
• Bleeding: apixaban 2.1% vs warfarin 3. 1%, p< 0.001
THA/TKA – ADVANCE 1 & 2 & 3 , not FDA approved
• A1- 2.5 mg bid vs enox 30 mg bid; A2&3 - enox 40 mg daily
• Events: A1 P< 0.06 non-inferior, A2 p < 0.001 superior, A3 p< 0.001 for superior. for
A-1 for superiority of rivaroxaban in all
• Bleeding: A1 apixaban 2.9%, enox 4.3% p=0.03; A2 apixaban 3.5% , enox 4.8%
p=.09; A3 apixaban 4.8%, enox 5% p=.72

26. Ximelagatran
• Ximelagatran is a novel drug that is readily absorbed after oral administration and is
rapidly metabolized to melagatran, a direct thrombin inhibitor. Therefore, its onset of
action is much faster than that of warfarin.
• Ximelagatran has been used successfully in clinical trials for prevention of venous
thromboembolism (Francis et al., 2003; Schulman et al., 2003).
• Ximelagatran causes elevation of hepatic transaminases in about 6% of patients, but
this side effect usually is asymptomatic and often is transient. The drug has not yet
been approved for use in the United States

27. A Meta-analysis Of Randomized Trial
• Comparison of the efficacy and safety of new oral anticoagulants with
warfarin in patients with atrial fibrillation

28. Aim
• To assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on
important secondary outcomes
Methods:
• Articles of Medline from Jan 1, 2009, to Nov 19, 2013,
• The main outcomes were stroke and systemic embolic events, ischaemic
stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major
bleeding, intracranial haemorrhage, and gastrointestinal bleeding.
• Relative risks (RRs) and 95% CIs for each outcome was calculated. Subgroup
analyses was done to assess whether differences in patient and trial
characteristics affected outcomes.
• A random-effects model was employed to compare pooled outcomes and
tested for heterogeneity.

29. Findings
• New oral anticoagulants significantly reduced stroke or systemic embolic events by 19%
compared with warfarin
• New oral anticoagulants also significantly reduced all-cause mortality and intracranial
hemorrhage but increased gastrointestinal bleeding.
• Noted that no heterogeneity for stroke or systemic embolic events in important subgroups,
but there was a greater relative reduction in major bleeding with new oral anticoagulants
when the center-based time in therapeutic range was less than 66% than when it was 66%
or more.
• Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or
systemic embolic events to warfarin and a more favorable bleeding profile but
significantly more ischemic strokes.

30. Interpretation
• New oral anticoagulants had a favorable risk–benefit profile, with significant reductions
in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for
warfarin, but increased gastrointestinal bleeding.
• The relative efficacy and safety of new oral anticoagulants was consistent across a wide
range of patients.

31. Interesting Discussion points

33. References
1. Christian T Ruff: Comparison of the efficacy and safety of new oral
anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis
of randomized trials: Published Online December 4, 2013
http://dx.doi.org/10.1016/S0140-6736(13)62343-0 Lancet Article
2. GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS -
11th Ed.
3. Medscape.com
4. Uptodate 20.2 version