A small note on factor Xa inhibitors

1. FACTOR Xa INHIBITORS
DR. YUGANDHAR

2. COAGULATION CASCADE- INITIATION PHASE

3. COAGULATION CASCADE- AMPLIFICATION PHASE
•

4. COAGULATION CASCADE- PROPAGATION PHASE

5. COAGULATION CASCADE- INTRINSIC PATHWAY

6. OVERALL VIEW

7. FACTOR Xa INHIBITORS
• Rivaroxaban
• Apixaban
• Edoxaban
• OTHERS:-
• Betrixaban
• YM150.
• TAK442.

8. RIVOROXABAN
• Direct factor Xa inhibitor.
• Bioavailability:- 80-100%.
• Administration- Oral.
• Pharmacokinetics:-
• Maximum effect-2hours.
• Half life is 5-9 hours.
• 1/3rd Metabolized in Liver and gets excreted in feces.
• 1/3rd is cleared as unchanged drug in Urine.

9. • Dosage:-
• 20mg daily.
• 15mg Twice Daily for initial 21 days. (Acute venous thrombosis).
• 10mg Daily for post surgical thromboprophylaxis.
• Renal dosage:-
• 30-50ml CCL-15 mg Twice Daily.
• 15-30ml CCL- 10mg Twice Daily.
• <15ml- contraindicated.
• Precautions:-
• Should be taken with food to achieve maximum absorption.
• Avoid in pregnancy and lactating women.
• Avoid in renal and liver failure patients.
• Bleeding manifestations should be monitored frequently in case of patients who are
already in antiplatelets

10. • Indications:-
• Non-Valvular Atrial Fibrillation.
• Deep Vein Thrombosis.
• Pulmonary Embolism.
• Contraindications:-
• Renal & liver failure.
• Already in ketoconazole and ritonavir drugs.
• Rifampicin and Phenytoin can reduce plasma concentrations of drug.
• Antidote- none

11. • ROCKET AF Trial:-
• Double blinded study in 14,264 patients in Non valvular AF and Chads2 score
>2.
• After a median followup of 1.93 years, the rivoroxaban is non-inferior to
warfarin in prevention of Stroke and Embolism.
• No differences in risk of major bleeding.
• The risk of developing intracranial and fatal bleeding is less frequent in
Rivoroxaban group.
• GI bleed and transfusion requirements are more in rivoraxaban group.
• Total mortality was not significantly different between both.

12. • EINSTEIN DVT, EINSTEIN EXT AND EINSTEIN PE TRIALS:-
• Rivoroxaban is non inferior to Enoxaparin/ Warfarin in treatment of DVT without PE
and in PE with or without DVT.
• In EINSTEIN EXT trial, extended rivaroxaban treatment is superior to placebo in
patients who are already treated successfully with Warfarin initially.
• There is no significant difference between major bleeding in all 3 trials.
• In EINSTEIN PE Trial, Rivoroxaban treatment showed significant 51% risk reduction in
major bleeding compared with Warfarin/Enoxaparin treatment.
• ATLAS ACS-2 TIMI 51:-
• Combination of Rivoroxaban with standard antiplatelet therapy.
• Showed reduction in deaths due to CVS complications.
• Showed significant risk of major bleeding not related to CABG.
• 2.5 mg BD showed less frequency of bleeding than 5mg BD.
• US Food and Drug Administration has not approved this.

13. APIXABAN
• Direct factor Xa inhibitor.
• Bioavailability:- 50%.
• Administration- Oral.
• Pharmacokinetics:-
• Maximum effect 3-4hours.
• Half life is 9-14 hours.
• Metabolized in Liver and gets excreted in feces, urine and biliary system.

14. • DOSAGE:-
• 5mg Twice Daily.
• 2.5mg Twice Daily, If:
Age >80 years.
Wieght less than 60 kgs.
Serum Creatinine >1.5mg/dl.
• Precautions:-
• Should be taken with food to achieve maximum absorption.
• Avoid in pregnancy and lactating women.
• No dosage adjustment needed in patients with mild renal and hepatic failure.
• Avoid in moderate to severe liver failure patients.

15. • Indications:-
• Non-Valvular Atrial Fibrillation.
• Deep Vein Thrombosis.
• Pulmonary Embolism.
• Adverse effects:-
• Bleeding manifestations.
• Antidote- none.

16. • ARISTOTLE Trial:-
• Compared Apixaban with dose adjusted warfarin in 18,201 patients with non-
valvular AF.
• After a mean follow-up of 1.8 years, Apixaban was significantly better than warfarin
with fewer complications.
• GI bleed was significantly equal in both groups.
• ICH was significantly less when compared with warfarin.
• Mortality was found to be significantly lower in Apixaban group.
• AVERROES Study:-
• Double-Blinded study done in 5,599 patients who were not suitable candidates for
warfarin treatment.
• After a mean follow-up for 1.1 years, the study was stopped in between due to clear
benefit in favor of Apixaban.

17. EDOXABAN
• Direct factor Xa inhibitor.
• Bioavailability:- 62%.
• Administration- Oral.
• Pharmacokinetics:-
• Maximum effect 1-2hours.
• Half life is 10 hours.
• Metabolized in Liver and gets excreted in feces, urine and biliary system.

18. • DOSAGE:-
• 60mg Once Daily for Non-Valvular AF.
• 30mg Once Daily, If:
Age >80 years.
Wieght less than 60 kgs.
Creatinine Clearance <15ml/min.
• Precautions:-
• Should be taken with food to achieve maximum absorption.
• Avoid in pregnancy and lactating women.
• No dosage adjustment needed in patients with mild renal and hepatic failure.
• Avoid in moderate to severe liver failure patients.

19. • Indications:-
• Non-Valvular Atrial Fibrillation.
• Deep Vein Thrombosis.
• Pulmonary Embolism.
• Adverse effects:-
• Bleeding manifestations.
• Antidote- none.

20. • ENGAGE AF-TIMI:-
• Compared 2 dose regimens of Edoxaban(30mg/24hrs and 60mg/24hrs) with
warfarin in 21,026 patients with non-valvular AF.
• After a follow-up of 2.8 years, both regimens of Edoxaban were non-inferior
to warfarin in prevention of stroke and embolism.
• Edoxaban has lower risk major bleeding.
• GI bleed is more frequent in high dose Edoxaban compared with low dose
Edoxaban.
• HOKUSAI-VTE:-
• Showed in DVT, it is non- inferior to warfarin.

22. TREATMENT OF COMPLICATIONS
• Andexanet alfa:-
• Recombinant modified human factor Xa.
• Developed as a direct factor Xa reversal agent.
• Showed restore of thrombin generation in phase 2 studies.
• Well tolerated.
• Currently in phase 3 clinical trials.(ANNEXA-A and ANNEXA-R).
• PER977(CIREPARANTAG):-
• STILL IN TRIALS.
• Rapidly reversed the effect of multiple anticoagulants.

23. THANK YOU