Dabigatran, rivaroxaban, and apixaban are novel oral anticoagulants (NOACs) that are alternatives to warfarin for preventing strokes in atrial fibrillation and treating deep vein thrombosis. Large clinical trials found these NOACs to be as effective as warfarin with less risk of bleeding. Dabigatran 150mg twice daily was more effective than warfarin at preventing strokes while 110mg twice daily had similar efficacy but lower bleeding. Rivaroxaban and apixaban were noninferior to warfarin with similar or lower risks of bleeding. Edoxaban is another NOAC that was found noninferior to warfarin in

1. DR. NEERAJ VARYANI
ASSISTANT PROFESSOR
CARDIOLOGY DEPARTMENT
SUPER SPECIALITY PAEDIATRIC HOSPITAL &
POST GRADUATE TEACHING INSTITUTE, NOIDA
1
OVERVIEW OF NOVEL ANTICOAGULATION

2. INDICATIONS FOR
ANTICOAGULATION
Atrial Fibrillation (AF)
DVT/PE treatment and prevention (VTE)
Mechanical Valve Replacement
Cardiomyopathy
Thrombophilias
Antiphospholipid Syndrome (APLS)

3. INTRODUCTION
Vitamin K antagonists (VKAs) are the mainstay of
management of thromboembolic events for > 5 decades.
Despite its unquestionable impact to prevent strokes, they
have significant limitations, such as common drug or food
interactions, and the necessity of regular monitoring to
adjust doses, inter personal variation in response.

8. INDICATIONS FOR NOAC’S
Prevention of arterial thromboembolic events in non-
valvular atrial fibrillation and VTE prophylaxis
following hip and knee replacement surgery:
DABIGATRAN, RIVAROXABAN, APIXABAN.
Treatment of deep vein thrombosis :
RIVAROXABAN

10. Coadministration of dabigatran etexilate and amiodarone,
verapamil, quinidine, dronedarone - increases dabigatran
levels.
It should be taken with food or water to minimise dyspepsia.
If a dose is missed it should be taken within 6 hours.

12. DOSE REGIMEN
for acute VTE: 150 mg BID
for VTE prevention after knee or hip replacement surgery (14 or
30 days, respectively): 110 mg (initial dose) then 220 mg daily.
COMMON SIDE EFFECTS:
Indigestion, upset stomach
Allergic reaction, including hives, rash, and itching
Bleeding

13. The RE-LY (Randomized Evaluation of Long-
term anticoagulant therapY with dabigatran
etexilate) phase III trial was a prospective,
randomized, open-label trial comparing two
blinded doses of dabigatran etexilate (110 or
150 mg BID) with warfarin in 18,113 patients
with AF and at least one additional risk factor (a
mean CHADS score of 2.1).

14. RESULTS
150 mg BID dose: superior to warfarin for reduction of
stroke and systemic embolism with similar major
bleeding.
110 mg BID dose: non inferior to warfarin for SSE but
with significant lower bleeding rates.
ICH is significantly low with both doses.

15. RELY-ABLE
Assessed the Additional information on the long-term effects of
the two doses of dabigatran in patients completing RE-LY by
extending the follow-up of patients on dabigatran from a mean
of 2 years at the end of RE-LY by an additional 2.3 years.
RELY-ABLE confirmed the results reported in RE-LY.
Conclusions: During 2.3 years of continued treatment with
dabigatran after RE-LY, there was a higher rate of major
bleeding with dabigatran 150 mg twice daily in comparison with
110 mg, and similar rates of stroke and death.

16. VTE TRIALS
RECOVER and REMEDY:
Non inferior to warfarin in VTE prevention
(2.4% vs 2.1%)
No diffrerences in major bleeding.

17. RIVAROXABAN
Rivaroxaban has a dual mode of elimination;
one third is cleared as unchanged drug via the kidneys,
one third is metabolized by the liver via CYP3A4-dependent
and independent pathways with the metabolites then
excreted in the feces, and
one third is metabolized in the liver with the inactive
metabolites then eliminated via the kidneys.

18. Ketoconazole or ritonavir are contraindicated because they
increase plasma drug levels.
There is only a minor interaction between Rivaroxiban and
verapamil unlike dabigatran and edoxaban.
Co adminstration of FLUVASTATIN or ROSUVASTATIN with
this drug does not need dose reduction of rivaroxiban.

21. DOSE REGIMEN
for acute VTE: 20 mg daily (15 mg twice daily for
initial 21 days);
for VTE prevention after knee or hip replacement
surgery (14 or 30 days, respectively): 10 mg daily

22. ROCKET AF
The ROCKET AF was a double-blinded study in which 14,264
patients with non-valvular AF and CHADS2 scores ≥2 (mean 3.5)
were studied.
After a median follow-up of 1.93 years, rivaroxaban was noninferior to
warfarin for the prevention of stroke or systemic embolism.
There were no differences in the risk of major bleeding, although
intracranial and fatal bleeding occurred less frequently in the
rivaroxaban group.
Gastrointestinal bleeding and transfusion requirements were greater
with rivaroxaban.
Total mortality was not significantly different between groups.

23. ATLAS : Background - Acute coronary
syndromes arise from coronary atherosclerosis
with superimposed thrombosis. Since factor Xa
plays a central role in thrombosis, the inhibition
of factor Xa with low-dose rivaroxaban might
improve cardiovascular outcomes in patients
with a recent acute coronary syndrome.

24. ATLAS ACS 2-TIMI 51 trial compared rivaroxaban 2.5 mg or 5 mg
twice daily (unlike the 20 mg once-daily dose for atrial fibrillation) with
placebo in 15 526 patients following ACS.
At a mean follow-up of 13 months, the primary efficacy endpoint of CV
death, MI or stroke was 10.7% with placebo, 9.1% with rivaroxaban
2.5 mg and 8.8% with rivaroxaban 5mg with no interaction by ACS
subtype.
Rates of definite, probable or possible stent thrombosis were 2.2%
and 2.3% with 2.5 and 5 mg rivaroxaban, respectively, vs. 2.9% with
placebo .
Rates of CV death were significantly lower with rivaroxaban 2.5 mg
compared with placebo but not with rivaroxaban 5 mg (4.0%).

25. Non-CABG major bleeds occurred in 1.8% and 2.4% with 2.5 and 5 mg
rivaroxaban, respectively, compared with 0.6% with placebo.
Intracranial haemorrhage rates were 0.4% with 2.5 mg and 0.7% with 5 mg
rivaroxaban vs. 0.2% with placebo but no increase in fatal bleeding in
rivaroxaban groups.
The use of rivaroxaban 2.5 mg twice daily, might be considered in
combination with aspirin and clopidogrel if ticagrelor and prasugrel are not
available for NSTEMI patients who have high ischaemic and low bleeding
risks.

26. VTE TRIALS
EINSTEIN DVT: non inferior to warfarin for DVT (2.1%
vs 3%) with similar bleeding risk.
EINSTEIN PE: non inferior to warfarin for PE with
lower bleeding risk than warfarin.
EINSTEIN EXTENSION: similar results.

27. APIXABAN
Apixaban is a direct, reversible, competitive, and selective inhibitor
of factor Xa and the last NOAC approved by the FDA for the
prevention of stroke and embolism in non-valvular AF.
It is well absorbed achieving peak plasma concentration in 1–4
hours.
It is predominantly metabolized in liver.
It is a mild P- glycoprotein inhibitor.
Compared to other NOACS it has least bleeding complications and
greater efficacy.

30. ARISTOTLE
The Apixaban for Reduction In STroke and Other ThromboemboLic Events in AF
(ARISTOTLE) compared apixaban (5 mg BID) with dose-adjusted warfarin in 18,201 patients
with non-valvular AF (a mean CHADS2 scoreof2.1).
After a mean follow up of 1.8 years, apixaban was significantly better than warfarin, with
fewer primary outcomes (overall strokes and systemic emboli), but with no significant
differences in rates of ischaemic strokes.
Patients treated with apixaban had significantly fewer intracranial bleeds, but GI bleedings
were similar between both groups.
All-cause mortality was found to be significantly lower in the apixaban group.

31. Apixaban was also compared with aspirin alone in the AVERROES study,
a double-blinded study of 5599 patients who were not suitable candidates
for VKA treatment (mean CHADS2 score of 2).
After a mean follow-up of 1.1 years, the study was prematurely stopped
due to a clear benefit in favour of apixaban.
Patients with severe renal impairment (serum creatinine 2.5 mg/dL or
CrCl 25 mL/min) were excluded from the ARISTOTLE and AVERROES
trials.

32. APPRAISE
The Apixaban for Prevention of Acute Ischaemic Events
(APPRAISE) 2 study assessed the effects of the oral factor Xa
inhibitor apixaban 5 mg twice daily compared with placebo, in
addition to standard-of-care antiplatelet therapy following ACS;
It was terminated early (median 8 months) due to a markedly
increased risk of severe bleeds, including intracranial
haemorrhage, without any apparent benefit in terms of ischaemic
events

33. ENGAGE AF-TIMI
The Effective Anticoagulation with Factor Xa Next Generation
in Atrial Fibrillation Thrombolysis in Myocardial Infarction
(ENGAGE AF-TIMI 48) compared the two dose regimens of
edoxaban (30 and 60 mg once daily) with warfarin in a total of
21,026 patients with non-valvular AF.
After a follow-up of 2.8 years, both regimens of edoxaban
were non-inferior to warfarin with respect to the prevention of
stroke or systemic embolism.

34. FEW MORE STUDIES

35. Objective: To study the effectiveness and safety of the nonvitamin
K antagonist oral anticoagulants (novel oral
anticoagulants, NOACs) dabigatran, rivaroxaban, and
apixaban compared with warfarin in anticoagulant
naïve patients with atrial fibrillation.
Design: Observational nationwide cohort study.
Setting: Three Danish nationwide databases, August 2011 to
October 2015.

36. Participants: 61 678 patients with non-valvular atrial
fibrillation who were naïve to oral anticoagulants and
had no previous indication for valvular atrial fibrillation
or venous thromboembolism. The study population
was distributed according to treatment type: warfarin
(n=35 436, 57%), dabigatran 150 mg (n=12 701,
21%), rivaroxaban 20 mg (n=7192, 12%), and
apixaban 5 mg (n=6349, 10%).

37. Conclusion: All NOACs seem to be safe and
effective alternatives to warfarin in a routine
care setting. No significant difference was found
between NOACs and warfarin for ischaemic
stroke. The risks of death, any bleeding, or
major bleeding were significantly lower for
apixaban and dabigatran compared with
warfarin.

38. OTHER fXa inhibitors
These are betrixaban, YM150, and TAK442.
Betrixaban has the unique features of a 15-hour half-life
and extrarenal clearance.
Betrixaban and YM150 are undergoing phase II evaluation
for stroke prevention in AF, whereas TAK442 is
undergoing phase II evaluation for prevention of recurrent
ischemia in ACS patients.

39. HOW TO MEASURE EFFECT

40. The activated partial thromboplastin time (aPTT) may provide a qualitative
assessment of the presence of dabigatran.
The prothrombin time (PT) may provide a qualitative assessment of the
presence of factor Xa inhibitors.
Quantitative tests for DTI and FXa inhibitors: diluted thrombin-time and
chromogenic assays, respectively,
But they may not (yet) be routinely available in most hospitals.
Moreover, there are no data on a cut-off of these specific tests below
which elective or urgent surgery is ‘safe’, and therefore their use in this
respect cannot be recommended at this time.

41. Patient need to switch between
anticoagulant regimens

42. GENERAL RECOMMENDATIONS

43. Thank you