Novel oral anticoagulants recently playing major role in health sector being prescribed more for better efficacy

1. New oral anticoagulants: their advantages and
disadvantages compared with vitamin K
antagonists in the prevention and treatment of
patients with thromboembolic events
POOVARASAN.A
PHARM.D 6th year
KLE College Of Pharmacy, Bengaluru-10
Mail.Id: poovarasan22748@gmail.com

2. INTRODUCTION
• During the last 60 years, vitamin K antagonists (VKAs), which include coumarin
derivatives (eg, warfarin and acenocoumarol), have been the only oral anticoagulants
used;
• However, new substances with anticoagulants effects, referred to as new oral
anticoagulants, have recently been discovered. Compared with VKAs, this new generation
of oral anticoagulants(NOACs) has more predictable anticoagulant responses,
• And NOACs have been shown to be effective in the prevention and treatment of VTE and
in the prevention of stroke and systemic embolism in patients with non-valvular atrial
fibrillation (NVAF)

3. Mechanism of anticoagulants effect of direct anti-IIa and anti-Xa
anticoagulants (NOACs).

4. NOVAL ORALANTICOAGULANTS
• DIRECT FACTOR II-a INHIBITOR
• Dabigatran
• DIRECT FACTOR X-a INHIBITOR
• Rivaroxaban,
• Apixaban and
• Edoxaban

5. DABIGATRAN
Dabigatran was the first approved NOAC in 2008 by the EU and by the Food
and Drug Administration (FDA) in 2010 based on the results of RE-LY trial
(Comparative study between dabigatran and warfarin)
INDICATION : To reduce the risk of stroke and systemic embolism in patients with
non-valvular atrial fibrillation (NVAF)
AVAILABLE DOSES :
Oral capsule :75mg, 110mg, 150mg
Oral pellets : 20mg, 40mg, 30mg, 50mg, 75mg, 110mg, 150 mg ( For paediatric use)

6. MECHANISM OF ACTION
Prodrug lacking anticoagulant activity that is converted in vivo to
the active dabigatran, a specific, reversible, direct thrombin inhibitor
that inhibits both free and fibrin-bound thrombin. Inhibits coagulation
by preventing thrombin-mediated effects, including cleavage of
fibrinogen to fibrin monomers, activation of factors V, VIII, XI, and XIII,
and inhibition of thrombin-induced platelet aggregation

7. PHARMACOKINETICS
ABSORPTION: Rapidly absorbed (with or without food)
• BA : 6-7%
• CMAX : 1.5-2 hrs
• t ½ : 12-14 hrs
• Onset of action : 0.5-2 hrs
EXCRETION : 80% renal
Absorption and bio-conversion occurs in enterocytes, hepatocytes and portal vein
It doesn’t inhibits CYP450 so low potential DDI

8. DOSE AND DOSAGE
Atrial fibrillation/NVAF
• 150 mg BID; 110 mg BID (EU and Canada) in patients with CrCl=30–50
mL/min.
• In case of High risk for bleeding and CrCl=15–30 mL/min is 75 mg BID (US)
VENOUS THROMBOEMBOLISM IN TOTAL HIP REPLACEMENT
• 110 mg given after 1-4 hrs of surgery and 110 mg BD for maximum 10-14
days

9. • VENOUS THROMBOEMBOLISM
• DVT/PE : After at least 5 days with parenteral anticoagulant, transition to dabigatran in
hemodynamically stable patients
ORAL CAPSULE : 150 mg BD
Provoked VTE : 3 months
Unprovoked VTE : > or equal to 3 months depending on risk of VTE, recurrence and
bleeding.
PRE-OP : Discontinue 24-28 hrs prior surgery if CRcl is > or equal to 50ml/min
Discontinue 48-120 hrs prior surgery if CRcl id < 50ml/min
PAEDIATRIC DOSE FOR DABIGATRAN ETEXILATE
C:UserspoovaOneDriveDocumentsPAEDIATRIC DOSE FOR DABIGATRAN ETEXILATE.docx

12. DOSE ADJUSTMENT
• CrCl >50 mL/minute: Initiate warfarin 3 days before discontinuing dabigatran.
• CrCl 30 to 50 mL/minute: Initiate warfarin 2 days before discontinuing
dabigatran.
• CrCl 15 to 30 mL/minute: Initiate warfarin 1 day before discontinuing
dabigatran
• CrCl <15 mL/minute: Dabigatran should not be used.
IN Haemodialysis and paediatrics with <50ml /min CRcl: Use should be avoided

13. ADVERSE DRUG REACTIONS
>10%
• Gastrointestinal: Gastrointestinal signs and symptoms (25% to 40%)
• Hematologic & oncologic: Hemorrhage (10% to 19%; major hemorrhage: ≤6%)
1% to 10%
• Gastrointestinal: Abdominal distress (≤8%), abdominal pain (≤8%), dyspepsia (4% to 8%),
epigastric discomfort (≤8%), esophagitis (≤3%), gastritis (≤3%), gastroesophageal reflux
disease (≤3%), gastrointestinal hemorrhage (≤7%; major: ≤3%), hemorrhagic gastritis
(≤3%), upper abdominal pain (≤8%)

14. <1%
• Cardiovascular: Acute myocardial infarction
• Genitourinary: Genitourinary tract hemorrhage (major)
• Hematologic & oncologic: Retroperitoneal hemorrhage (major)
• Hypersensitivity: Allergic angioedema, anaphylactic shock, anaphylaxis,
hypersensitivity reaction
• Nervous system: Intracranial hemorrhage, subarachnoid hemorrhage, subdural
hematoma
• Neuromuscular & skeletal: Hemarthrosis (major), muscle hemorrhage (major)

15. TRIAL COMPARISONS
TRIAL NUMBER : 1
• In RE-LY trial, dabigatran administered at a dose of 110 mg was associated with low rates
of stroke and systemic embolism that were similar to those associated with warfarin and
also showed lower rates of major hemorrhage.
• Additionally, the same authors found that at a dose of 150 mg, dabigatran was
associated with lower rates of stroke and systemic embolism compared with warfarin,
but with similar rates of major hemorrhage
TRIAL NUMBER : 2
According to RE-COVER trial, the rate of major bleeding episodes in the dabigatran
group was lower (1.6%) compared to the warfarin group (1.9%)

16. TRIAL NUMBER : 3
• Hohnloser et al in the RE-LY trial found that : MI occurred at annual rates of 0.82% with
dabigatran 110 mg twice daily compared with 0.64% with warfarin.
• In the same study, it was found that MI occurred at annual rates of 0.81% with dabigatran 150 mg
twice daily compared with 0.64% with warfarin.
However, according to Artang et al dabigatran is associated with a greater risk of MI than
warfarin. Indeed, a statistically significant difference between dabigatran and warfarin in relation
to risk of MI was reported.
TRIAL NUMBER : 4
• Graham et al showed that dabigatran reduced the risk of ischemic stroke, intracranial
hemorrhage as well as death but increased the risk of major gastrointestinal bleeding compared
with warfarin in elderly patients with NVAF.

17. RIVAROXABAN
• Rivaroxaban is the second NOAC approved in many countries, in 2008 by the
European Medicine Agency and by the FDA based on the results of the
rivaroxaban versus warfarin in non valvular atrial fibrillation (ROCKET AF) trial.
• It is a oxazolidinone derivative which links the intrinsic and extrinsic
coagulation pathways and acts as a rate limiting step in thrombin formation
• AVAILABLE DOSE : 2.5mg,5mg, 10mg, 15mg, 20mg.

18. MECHANISM OF ACTION
Inhibits platelet activation and fibrin clot formation via direct,
selective and reversible inhibition of factor Xa (FXa) in both the intrinsic
and extrinsic coagulation pathways. FXa, as part of the prothrombinase
complex consisting also of factor Va, calcium ions, factor II and
phospholipid, catalyzes the conversion of prothrombin to thrombin.
Thrombin both activates platelets and catalyzes the conversion of
fibrinogen to fibrin.

19. PHARMACOKINETICS
ABSORPTION : Rapidly absorbed
• BA : 60-80%
• CMAX : 2.5-4 hrs
• Onset of action : 2-4 hrs
• t ½ : 7-13 hrs
METABOLISM : CYP3A4/5 and CYP2J2
EXCRETION : 70% - Renal ; 30% - feces

20. DOSE AND DOSAGE
NON-VALVULAR ATRIAL FIBRILLATION (NVAF)
• 20mg once daily ( mostly preferred in night)
In case of stent placement
• 15mg once daily
CORONARY ARTERY DISEASE
2.5mg BD with low dose aspirin + clopidogrel and continue rivaroxaban for
approximately 1 year
HEPARIN INDUCED THROMBOCYTOPENIA
15mg BD for approx. 21 days or till platelet recovery followed by 20mg BD
If any other anticoagulant is going <21 days recommended

21. LEFT VENTRICULAR THROMBUS (PROPHYLAXIS/TREATMENT)
• 20mg OD for approx. 3 months in MI (or)
• > or equal to 3-6 months in distant MI
PERIPHERAL ARTERY DISEASE : 2.5mg BD
SUPERFICIAL VEIN THROMBUS : 10mg OD for 45 days
VENOUS THROMBOEMBOLISM
15mg BD for 21 days followed by 20mg OD
DOSE ADJUSTMENT
CRcl 15-50ml/min and patient who is undergoing hemodialysis use should be avoided.

23. ADVERSE DRUG REACTIONS
>10%
• Endocrine & metabolic: Heavy menstrual bleeding (adolescents: 27%)
• Gastrointestinal: Gastroenteritis (paediatric patients: 13%), vomiting (paediatric patients: 11% to
14%)
• Hematologic & oncologic: Haemorrhage (paediatric patients and adults: 5% to 36%; major
haemorrhage: ≤4%)
• Respiratory: Cough (paediatric patients: 16%)
1% to 10%
• Cardiovascular: Syncope (1%)

24. • Dermatologic: Pruritus (2%), skin blister (1%), skin rash (paediatric patients: 9%), wound secretion
(3%)
• Gastrointestinal: Abdominal pain (3%), gastrointestinal haemorrhage (2%)
• Hepatic: Increased serum transaminases (Watkins 2011)
• Nervous system: Anxiety (1%), depression (1%), dizziness (2%), fatigue (paediatric patients: 7%;
adults: 1%), insomnia (2%)
• Neuromuscular & skeletal: Back pain (3%), limb pain (paediatric patients and adults: 2% to 7%),
muscle spasm (1%)
<1%
• Hematologic & oncologic: Haemophthalmos, surgical bleeding Nervous system: Haemorrhagic
stroke, intracranial haemorrhage

25. TRIAL COMPARISON:
TRIAL NUMBER : 1
• According to Mega et al a twice daily 2.5-mg dose of rivaroxaban reduced the rates of
death from cardiovascular causes
• However, these authors did not find a survival benefit from twice daily 5-mg dose of
rivaroxaban.
TRIAL NUMBER : 2
• According to a EINSTEIN-DVT trial included 3449 patients has concluded that recurrence
of VTE low in patient taking rivaroxaban that is 2.1% compared to enoxaparin which is
3.0%

26. APIXABAN
• Apixaban is another NOAC that is a reversible direct Xa antagonist. It exerts
a similar anticoagulant activity as rivaroxaban, by the direct inhibition of
factor Xa, which is formed by both intrinsic and extrinsic coagulation
pathways.
• Apixaban is the third NOAC that was approved by the FDA and by the
European Medicine Agency, in 2011 based on the results of ARISTOTLE
(Apixaban for Reduction in Stroke and Other Thromboembolic Events in
Atrial Fibrillation)
AVAILABLE DOSES : 2.5mg and 5mg

27. MECHANISM OF ACTION
Inhibits platelet activation and fibrin clot formation via direct,
selective and reversible inhibition of free and clot-bound factor Xa (FXa). FXa,
as part of the prothrombinase complex consisting also of factor Va, calcium
ions, and phospholipid, catalyzes the conversion of prothrombin to
thrombin. Thrombin both activates platelets and catalyzes the conversion of
fibrinogen to fibrin.

28. PHARMACOKINETICS
ABSORPTION : Rapidly absorbed
• BA : 66% Onset of action : 1-3hrs
• Tmax : 1-2 hrs Cmax : 3 hrs
• t1/2: 8-15 hrs
DISTRIBUTION :
• Protein bound : 87%
• Vdss : 21L

29. METABOLISM :
• Metabolized mainly by CYP3A4
• Metabolized with minor contributions from CYP1A2, 2C8, 2C9, 2C19 and
2J2
• Major sites of biotransformation: O-demethylation and hydroxylation at
the 3-oxopirperidinyl moiety
• Metabolites: No active circulating metabolites Substrate of P-gp and BCRP
EXCRETION: 25% in urine and feces as metabolites

30. DOSE AND DOSAGE
NON VALVULAR ATRIAL FIBRILLATION
• P/O : 5mg BD
• If the patient is > or equal to 80 years and weight less than 60 kg : 2.5 mg BD
HEPARIN INDUCED THROMBOCYTOPENIA AND VTE
• P/O : 10mg BD for 7 days followed by 5mg BD
LEFT VENTRICULAR THROMBUS
P/O : 5mg BD for approx. 3 months with acute MI
> or equal to 3-6 months in patients with distant MI
If LVEF < 40 % : 5mg BD for 1-3 months

32. DOSE ADJUSTMENT
• If creatinine clearance is 15-29ml/min advised dose is 2.5 mg BD
• Use is avoided in child Turcotte pugh class C

33. ADVERSE DRUG REACTION
• >10%
• Hematologic & oncologic: Hemorrhage (≤15%; major hemorrhage: ≤2%; clinically relevant nonmajor hemorrhage: 4%)
• 1% to 10%
• Endocrine & metabolic: Heavy menstrual bleeding (1%)
• Gastrointestinal: Gingival hemorrhage (≤1%), nausea (3%)
• Genitourinary: Hematuria (≤2%)Hematologic & oncologic: Anemia (3%), bruise (1% to 2%), hematoma (1% to 2%),
rectal hemorrhage (≤1%)
• Respiratory: Epistaxis (≤4%), hemoptysis (≤1%)
• <1%
• Dermatologic: Dermal hemorrhage, skin rash, wound secretionEndocrine & metabolic: Increased gamma-glutamyl
transferase

34. • Cardiovascular: Perioperative blood loss, syncope
• Gastrointestinal: Gastrointestinal hemorrhage, hematemesis, hematochezia, hemorrhoidal bleeding, melena
• Genitourinary: Abnormal uterine bleeding, genital bleeding
• Hematologic & oncologic: Hemophthalmos, periorbital hematoma, petechia, postoperative hematoma (incision site),
postprocedural hemorrhage, puncture site bleeding, thrombocytopenia, wound hemorrhage
• Hepatic: Increased serum alkaline phosphatase, increased serum bilirubin, increased serum transaminases
• Hypersensitivity: Allergic angioedema, anaphylaxis
• Local: Hematoma at injection site, incision site hemorrhage
• Nervous system: Intracranial hemorrhage
• Neuromuscular & skeletal: Muscle hemorrhage
• Ophthalmic: Conjunctival hemorrhage, retinal hemorrhage

35. TRIAL COMPARISON
In ARISTOTLE trial it’s been concluded that Apixaban is non-
inferior to warfarin in preventing stroke and systemic embolism in
patients with atrial fibrillation
Low mortality rate was observed in the apixaban group compared
with warfarin group

36. EDOXABAN
• Edoxaban (DU-176b) is an oral direct, specific inhibitor of FXa with an
approximate 10,000-fold selectivity for FXa over thrombin.
• The compound was developed by Daiichi Sankyo (Tokyo, Japan) and approved in
July 2011 in Japan for the prevention of VTE following lower-limb orthopedic
surgery.
NOTE : Like other NOAC’s edoxaban is also a substrate for the efflux transporter of
P-gp
• AVAILABLE DOSES : 15mg, 30mg, 60mg

37. MECHANISM OF ACTION
Edoxaban, a selective factor Xa inhibitor, inhibits free factor Xa
and prothrombinase activity and inhibits thrombin-induced platelet
aggregation. Inhibition of factor Xa in the coagulation cascade reduces
thrombin generation and thrombus formation.

38. PHARMACOKINETICS
• ABSORPTION : Rapidly absorbed
• BA : 58.3% Cmax : 1-2 hrs
• DISTRIBUTION
• Disposition is biphasic
• Steady-state reached: 3 days
• Vd (steady-state): 107 L
• Protein bound: 55%

39. • METABOLISM : Unchanged edoxaban is the predominant form in plasma
• Minimal metabolism via hydrolysis (mediated by carboxylesterase 1), conjugation,
and oxidation by CYP3A4
• <10% is hydrolyzed to the predominant metabolite M-4Exposure to other
metabolites is <5%
• Half life elimination : 9-11 hrs
• EXCRETION : 1/3rd of drug is eliminated via kidney and reminder via feces

40. DOSE AND DOSAGE
• STROKE PROPHYLAXIS WITH ATRIAL FIBRILLATION
• 60 mg PO q1Day
• REDUCED EFFICACY IN NVAF and CRcl >95ml/ min
A) NVAF
Weight >60kg ; P/O : 60mg OD
weight < 60kg ; P/O : 30mg OD

41. B) VTE
Weight >60kg ; P/O : 60mg OD
weight < 60kg ; P/O : 30mg OD
Provoked VTE : Approx 3 months
Unprovoked VTE : > or equal to 3 months
DOSE ADJUSTMENT
• CRcl : 15-50ml/min : 30mg OD
• If CRcl is < 15ml/miN, HD and PD : Use should be avoided.

42. ADVERSE DRUG REACTION
>10%
• Hematologic & oncologic: Hemorrhage (7% to 26%), major hemorrhage (1% to 13%)
1% to 10%
• Dermatologic: Dermal hemorrhage (6%), skin rash (4%)
• Gastrointestinal: Gastrointestinal hemorrhage (≤4%), oral hemorrhage (≤3%)
• Genitourinary: Gross hematuria (≤2%), urethral bleeding (≤2%), vaginal hemorrhage (9%)
• Hematologic & oncologic: Anemia (2%)Hepatic: Abnormal hepatic function tests (5% to 8%)Local: Puncture site
bleeding (1%)
• Respiratory: Epistaxis (5%), pharyngeal bleeding (≤3%), Interstitial lung disease
• Nervous system: Intracranial hemorrhage

43. TRIAL COMPARISON
TRIAL NUMBER : 1
• In ENGAGE AF-TIMI 48 trial, administration of DU-176b resulted in with a dose-dependent decrease in VTE, without
increases in blending events
• In another reported Phase II trial in which DU-176b was investigated at 30 mg and 60 mg either once a day or twice daily
compared to dose-adjusted warfarin in patients with AF, doses of 60 mg twice daily was accompanied by increased
bleeding events
TRIAL NUMBER : 2
• In the HOKUSAI trial, Enoxaparin with dose of 20mg BD is compared with Edoxaban 20 mg BD results showed that
Edoxaban is superior to enoxaparin in efficacy
TRIAL NUMBER : 3
• According to Rognoni et al edoxaban is not inferior to warfarin for preventing stroke and systemic embolisms in patients
with NVAF, with a lower rate of intracranial bleeding.

44. THANK YOU…!!!