lecture about non-Vitamin K Oral Anti-coagulants Novel Oral Anti-Coagulants Direct Oral Anti-Coagulants

1. NOACs
Non-Vitamin K Oral Anti-Coagulants
Presented by :
Clin. Ph. : Ayat Yaseen Al-Ani

2. NOACs
Dabigatran
03
Apixaban
01
Rivaroxaban 02
Edoxaban 04

3. INTRODUCTION
Two classes of NOACs are currently
available, the oral direct thrombin inhibitors
(DTIs; e.g. dabigatran) and oral direct factor
Xa inhibitors (e.g. rivaroxaban, apixaban,
and edoxaban). Unlike VKAs, which block
the formation of multiple active vitamin K-
dependent coagulation factors (factors II,
VII, IX, and X), these drugs block the activity
of one single step in coagulation.

4. Action of the anti-coagulants in the coagulation cascade

5. Indications

6. Dabigatran (Pradaxa®)
Dabigatran etexilate was the first NOACs studied and FDA approved. Dabigatran is a highly
specific and competitive direct thrombin inhibitor, which is orally administered as an inactive
drug and after complete esterase-mediated conversion it is metabolised to its active form.
In contrast to VKAs, dabigatran has no major drug–food interactions and few drug–drug
interactions.

8. Rivaroxaban (Xarelto®)
Rivaroxaban is a competitive and dose-dependent direct inhibitor of factor Xa and the
second NOAC approved by the FDA and EMA based on the ROCKET AF (Rivaroxaban Once
Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of
Stroke and Embolism Trial in Atrial Fibrillation).
It is administered 20 mg once daily with a large meal to increase bioavailability.
A 15 mg dose is recommended for patients with mild renal impairment, high
risk of bleeding, and/or potential drug– drug interactions .

10. Apixaban (Eliquis®)
Apixaban is a direct, reversible, competitive, and selective inhibitor of factor Xa and approved by
the FDA and EMA for the prevention of stroke and embolism in non-valvular AF.
Current recommended dosing is 5 mg BID daily for patients with normal renal function and 2.5
mg BID for patients with two of the following characteristics : age 80 years, body weight ,60
kg, and serum creatinine .1.5 mg/dL. It is predominantly metabolized by the liver and similar
to rivaroxaban, apixaban is contraindicated in concomitant use with drugs capable of
inducing or inhibiting CYP3A4.

12. Edoxaban ( Lixiana® )
Edoxaban is another reversible factor Xa inhibitor, approved by the FDA and recently by the
EMA
Since it is a substrate for P-glycoprotein, concomitant administration with quinidine,
amiodarone, and verapamil will result in a significant increase of plasma levels of
edoxaban. Therefore, in patients under concomitant use of potent glycoprotein inhibitors
(verapamil or quinidine), body weight ,60 kg, or moderate–severe renal impairment (CrCl
50 mL/min), Edoxaban dose should be reduced by 50%.

14. edverse effects
Rivaroxaban edoxaban apixaban
Dabigatran
•bruising
• minor bleeding
•nausea,
•abdominal pain,
•stomach upset,
•indigestion,
•heartburn,
•diarrhea,
•skin rash,
•itching.
•bleeding
•fainting,
•itching,
•pain in arms or legs,
•muscle pain,
•muscle spasms.
•Abnormal liver function tests
•Rash
•Anaemia
•Interstitial lung disease
•Major bleeding
•Bleeding
•skin rash,
•allergic reactions,
•fainting, nausea, and
•anaemia.

15. Comparison between NOACs
DABIGATRAN RIVAROXABAN APIXABAN EDOXABAN
Time to peak ( h ) 1.5 - 3 2-3 3-4 1-2
Oral bioavailability 3-7 % 68 % without food
>80% with food
50 % 60 %
Absorption with food No effect 40% more No effect 6-22% minimal
effect
Half- life ( h ) 14 - 17 5-9 8 - 15 10 - 14
Renal excretion ( % ) >80 66 25 50
Antidote Idarucizumab Andexxa Andexxa -
Dose 150 mg BID
110 mg BID
(75 mg BID)
20 mg OD
15 mg OD
10 mg OD
5 mg BID
2.5 mg BID
60 mg OD
30 mg OD
Approved for CrCl ≥30 ml/min ≥15 ml/min ≥15 ml/min ≥15 ml/min

16. NOAC drug–drug interactions
 Contraindicated drugs(increased NOAC activity):
 Azole antifungals
 Dronedarone
 HIV protease inhibitors
 Immunosuppressants: Calcineurin inhibitors
 Verapamil
 Contraindicateddrugs (antithrombotic interactions)
 Anticoagulants
 Antiplatelets: Dual-antiplatelets, ticagrelor
 Cautioneddrugs(increasedNOAC activity)
 Amiodarone
 Macrolides
 Selective serotonin re-uptake inhibitors/serotonin noradrenaline re-uptake inhibitors

17. NOAC drug–drug interactions ( cont… )
 Cautioned drugs (antithrombotic interactions)
 Antiplatelets
 Non-steroidal anti-inflammatory drugs
 Cautioned drugs (reduced NOAC activity)
 Anticonvulsants: Phenytoin, carbamazepine, phenobarbital.
 Rifampicin
 St John’s wort

18. How to deal with dosing errors
Missed dose
Twice daily: take missed dose up to 6 h after scheduled intake. If not
possible skip dose and take next scheduled dose.
Once daily: take missed dose up to 12 h after scheduled intake. If not
possible skip dose and take next scheduled dose.
Double dose
Twice daily: skip next planned dose and restart twice daily after 24 h.
Once daily: continue normal regimen.
Uncertainty about
intake
Twice daily: continue normal regimen.
Once daily: take another dose then continue normal regimen.
overdose ( Hospitalisation advised. )
activated charcoal to reduce absorption (standard dosing scheme of 30 to
50 g for adults).
Consider coagulation tests to assess possible bleeding risk.
In absence of bleeding, wait-and-see approach.

19. When to stop NOACs before a planned surgical intervention
 For procedures with immediate and complete haemostasis, the NOAC can be resumed 6–8
hours after the intervention.

20. Considerations prior to commencing NOACs
 C/I :
 CrCl <15 mL/min ( <30 in Dabigatran )
 Child-Pugh B-C ( Dabigatran in C )
 Crush & Mix : Xa inhibitors tablets can be crushed and mixed with water while
Dabigatran capsule shouldn’t be crushed or even removed from packaging until the
time of administration.

22. Thank you for your
listening