The document discusses various novel oral anticoagulants (NOACs) in comparison to traditional warfarin, highlighting their advantages such as fewer side effects, predictable pharmacokinetics, and convenience of administration. It also outlines who is a suitable or unsuitable candidate for NOACs, along with summarizing key studies that demonstrate their effectiveness in preventing strokes and managing conditions like atrial fibrillation. Furthermore, it emphasizes the need for individualized treatment based on patient characteristics and ongoing research for better monitoring and reversal agents for NOACs.

1. D R . S A S I N T H A R R
C A R D I O L O G Y , J I P M E R
Newer oral anticoagulants

2. Problems with warfarin
 Delayed onset & offset
 Narrow therapeutic range
 Unpredictable dose response
 Drug–drug, drug–food interactions
 Problematic monitoring
 Slow reversibility
 Hemorrhage
 Pregnancy
VKORC1 and CYP2C9 polymorphisms
Age
Body weight
4 weekly vs 12 weekly
Variability in INR results

3. IDEAL ANTICOAGULANT
 Effective
 Minimal complications/side effects
 Fixed dosing
 Convenient administration
 Rapid absorption
 Good bioavailability
 Fast on and offset action
 Predictable pharmacokinetics
 No interactions with food or drugs
 No HIT
 No coagulation monitoring
 Reversibility
 Antidote available

4. Betrixaban
YM150
TAK442
V,VII,XI,XIII
NOAC
DOAC
TSOAC
ODI
SODA

5. Who is an appropriate candidate for the Novel
OACs?
 FDA approved indication
 History of good medication compliance
 Frequent medication, diet, or health status changes that
make warfarin management difficult
 Not taking medication s known to interact with NOAC
 Barriers to patient/family education
 Difficulty or hardship with frequent INR monitoring
 Unstable INRs
 CrCl> 30 ml/min
 High risk of IC bleed
 Documented warfarin failure

6. Who is NOT a good candidate for NOACs ?
 Consistent INR
 Renal dysfunction
 Hepatic dysfunction
 Pregnant or breast feeding women
 Medication non-adherence
 Unable to pay
 History of GI bleeding (dabigatran)
 History of coronary artery disease or myocardial
infarction (dabigatran)

7. FDA APPROVED INDICATIONS
1.Approved for VTE prophylaxis following knee or hip surgery only
2.After 5-10 days of parental anticoagulant treatment only

9. Dabigatran etexilate (Pradaxa)

10. The RE-LY (Randomized Evaluation of Long-term anticoagulant
therapY with dabigatran etexilate)

11. 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 .

12. RELY-ABLE
 Assessed the Additional information on the long-term
effects of the two doses of dabigatran in pts 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.

13. VTE TRIALS
 RECOVER and REMEDY –
 RECOVER- Large randomized, double-blind trial
comprised of 2,564 patients with confirmed DVT or
PE
 Non inferior to warfarin in VTE prevention (2.4%
vs 2.1% After 6 months of treatment)
 No differences in major bleeding.
 Discontinuation rate 9% vs 6.8%

14. RIVAROXABAN (Xarelto)

15. 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.

16. VTE TRIALS
EINSTEIN DVT –
 2,900 patients with acute DVT without PE
 15 mg twice-daily dose of rivaroxaban vs 20 mg
oncedaily dose versus enoxaparin followed by a VKA
for 3,6, or 12 months
 Non inferior to warfarin for DVT(2.1% vs 3%) with
similar bleeding risk.
 EINSTEIN PE – non inferior to warfarin for PE with
loer bleeding risk than warfarin.
 EINSTEIN EXTENSION – similar results.

17. Apixaban (Eliquis)

18. 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 f/u 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.

19.  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.

20. 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

21. Edoxaban (Savaysa)
 Recently approved by the FDA but not yet by the
EMA.

22. ENGAGE AF-TIMI
 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 2.8 years f/u, both regimens of edoxaban
were non-inferior to warfarin with respect to the
prevention of stroke or systemic embolism.

23.  Edoxaban was associated with lower, dose-related rates of
bleeding, including major bleeding, intracranial bleeding, and
life-threatening bleeding.
 GI bleeding - occurred more frequently with high-dose edoxaban
but less frequently with low-dose edoxaban compared with
warfarin.
 Finally, the incidence rate of haemorrhagic stroke and the rate of
death from cardiovascular causes were significantly lower with
both edoxaban regimens.
 Patients with severe renal dysfunction (CrCl < 30 mL/min), high
risk of bleeding, use of dual antiplatelet, acute coronary
syndromes or coronary revascularization, and strokes within 30
days were excluded.

24.  HOKUSAI VTE – in DVT it is non inferior to
warfarin and in PE it is superior to warfarin with
similar bleeding risk in both conditions.

25. 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.

26. CONCOMITANT USE OF NOAC and DIGOXIN
 Digoxin is a P-glycoprotein inhibitor and commonly
used drug in AF.
 But there is clinically relavent interaction between
digoxin and NOACS.

27. Comparison between NOACs
 There no direct head-to-head comparisons
between NOACs have been made in RCTs.
 Extrapolation from primary trial data is the best
available strategy for medical prescription.
 However, due to differences in trial design, in the
estimated risk for stroke in the study population,
comparator uniformity, and definitions of efficacy
and safety endpoints make complex direct
comparisons.

28.  Comparative analysis of the four NOACs confirmed
that NOACs significantly reduced the composite of
stroke or systemic embolic events by 19%
compared with warfarin, which very much
depended on large reduction in haemorrhagic
strokes.
 Data for all four NOACS showed that they were
associated with a 14% non-significant reduction in
major bleedings.

29. Which to choose ?

30. How to measure effect ?

32.  Novel reversal agents in clinical development
 There are currently 3 NOAC-specific reversal agents
in clinical development:
(1) Andexanet alfa,
(2) Idarucizumab, and
(3) PER977 (Ciraparantag)

34. Managing NOACs in patients requiring long-
term oral antiplatelets
 Approximately 6 – 8% of patients undergoing PCI have an
indication for long-term OAC with VKA or NOACs due to
various conditions such as AF, mechanical heart valves or
VTE.
 In the absence of safety and efficacy data, the use of prasugrel
or ticagrelor as part of triple therapy should be avoided.
 Gastric protection with a PPI is recommended.
 In patients treated with NOACs, the lowest tested dose for
stroke prevention should be applied (i.e. dabigatran 110 mg
twice a day, rivaroxaban 15 mg once a day, apixaban 2.5 mg
twice a day)

35. Studies evaluating combinations of NOAC or VKA +
antiplatelets post PCI & stenting
 PIONEER AF PCI – Rivaroxaban; ongoing
 RE-DUAL PCI – Dabigatran ; ongoing
 AUGUSTUS - Apixaban ; ongoing
 EVOLVE-AF-PCI – Edoxaban; ongoing
 Unknown whether SAPT/DAPT plus NOAC is safer
than SAPT/DAPT plus VKA or vice versa

36. NOACs vs.vitamin K antagonists in AF pts
with a malignancy
 Active malignancy usually was an exclusion criterion in
NOAC trials.
 When anticoagulant therapy needs to be initiated in a
patient with malignancy, therapy with VKAs or
heparins should be considered over NOACs, because of
the clinical experience with these substances, the
possibility of close monitoring (for VKAs and
unfractionated heparin, UFH), and reversal options
(for VKAs and UFH).

37. NOACs and cardioversion
Electrical cardioversion in patients treated with NOACs has a similar (and
very low) thrombo-embolic risk as under warfarin
Subgroup analyses from:
 RE-LY (dabigatran)
 ROCKET-AF (rivaroxaban),
 ARISTOTLE (apixaban)
The recently published X-VeRT trial confirmed the low pericardioversion
stroke risk in patients treated with rivaroxaban compared with warfarin
Ongoing Clinical Studies:
 ENAMATE – Rivaroxaban
 ENSURE – Adoxaban
 NOACS & Cardioversion
H. Heidbuchel et al. Updated EHRA practical guide for use of the non-VKA oral anticoagulants. Europace 8/2015

39. IDEAL ANTICOAGULANT
 Effective
 Minimal complications/side effects
 Fixed dosing
 Convenient administration
 Rapid absorption
 Good bioavailability
 Fast on and offset action
 Predictable pharmacokinetics
 No interactions with food or drugs
 No coagulation monitoring
 Reversibility
 Antidote available
1.Coadministration of dabigatran and amiodarone,verapamil,
quinidine,dronedarone - strong P-gp inhibitors, increases dabigatran levels
Rivaroxaban is a substrate for P-gp, and concomitant administration of potent inhibitors of both P-gp and
CYP3A4, such as ketoconazole or ritonavir, is contraindicated because they increase plasma drug levels.
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
rivaroxaban.
Edoxaban also is a substrate for P-glycoprotein-concomitant administration
with quinidine, amiodarone, and verapamil will result in a significant increase
of plasma levels of edoxaban

40. CONCLUSION
 NOACs have shown to have a favourable balance between
efficacy and safety compared with VKA s.
 Advantages Of NOACs include fewer interactions with
medications and no interaction with food, rapid onset, fast
clearance, and no need for laboratory monitoring.
 Individualized anticoagulant treatment should be based on
patients’ age, renal function, and concomitant treatments.
 Further research is underway to develop reliable and
accessible measures to monitor the anticoagulant effects of
the new agents, as well as antidotes with the ability to
effectively reverse anticoagulation effect.