This document summarizes several studies on newer oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation. It finds that dabigatran 150mg twice daily, apixaban 5mg twice daily, and edoxaban 60mg once daily were superior or non-inferior to warfarin in reducing strokes and systemic embolisms while reducing major bleeding events. Rivaroxaban was found to be non-inferior to warfarin with similar rates of ischemic strokes, mortality, and major bleeding, but increased gastrointestinal bleeding. Idarucizumab and andexanet alfa show promise as reversal agents for dabigatran and factor Xa inhibitors respectively.

1. SOUMYA KANTI DUTTA
IPGMER SSKM

2.  Dabigatran 150 mg twice daily reduced stroke and
systemic embolism by 35% compared with
warfarin without a significant difference in major
bleeding events.
 Dabigatran 110 mg twice daily was non-inferior to
warfarin for prevention of stroke and systemic
embolism, with 20% fewer major bleeding events.
 Both dabigatran doses significantly reduced
haemorrhagic stroke and intracranial
haemorrhage.

3.  Dabigatran 150 mg twice daily significantly
reduced ischaemic stroke by 24% and vascular
mortality by 12%, while gastrointestinal
bleeding was significantly increased by 50%.
 There was a non-significant numerical increase
in the rate of myocardial infarction with both
dabigatran doses, which has not been
replicated in large post-authorization analyses.

4.  Apixaban 5 mg twice daily(2.5 mg with 2 of the
follwing high risk features: age>80 yrs,wt <60
kg, Sr creat>1.5mg/dl) reduced stroke or
systemic embolism by 21% compared with
warfarin, combined with a 31% reduction in
major bleeding and an 11% reduction in all-
cause mortality (all statistically significant).
 Rates of haemorrhagic stroke and intracranial
haemorrhage, were lower on apixaban.
 Rates of gastrointestinal bleeding were similar
between the two treatment arms.

5.  Apixaban is the only NOAC that has been
compared with aspirin (AVERROES) in AF
patients; apixaban significantly reduced stroke
or systemic embolism by 55% compared with
aspirin, with no or only a small difference in
rates of major bleeding or intracranial
haemorrhage.Howerver,the incidence of minor
bleeding was higher (6.3% vs 5% per
year:p=0.05) with apixaban.

6.  Edoxaban 60 mg once daily and edoxaban 30 mg
once daily were compared with adjusted-dose
warfarin.
 Edoxaban 60 mg once daily was non-inferior to
warfarin . In an on-treatment analysis, edoxaban 60
mg once daily significantly reduced stroke or
systemic embolism by 21% and significantly
reduced major bleeding events by 20% compared
with warfarin.
 while edoxaban 30 mg once daily was non-inferior
to warfarin for prevention of stroke and systemic
embolism but significantly reduced major bleeding
events by 53%.

7.  patients were randomized to rivaroxaban 20 mg once daily or
VKA, with a dose adjustment to 15 mg daily for those with
estimated CrCl 30–49 mL/min by the Cockroft–Gault formula .
 Rivaroxaban was non-inferior to warfarin for the prevention of
stroke and systemic embolism in the intent-to-treat analysis, while
the per-protocol on-treatment analysis achieved statistical
superiority with a 21% reduction in stroke or systemic embolism
compared with warfarin.
 Rivaroxaban did not reduce the rates of mortality, ischaemic
stroke, or major bleeding events compared to VKA.
 There was an increase in gastrointestinal bleeding events, but a
significant reduction in haemorrhagic stroke and intracranial
haemorrhage with rivaroxaban compared with warfarin.
 The incidence of death and MI are similar.

10. RISK FACTOR SCORE BLEEDING RISK
HYPERTENSION
ABNORMAL LIVER RENAL
STROKE
BLEEDING HISTORY
LABILE INR
ELDERLY>65 YRS
DRUGS ALCOHOL
0
1
2
3
4
5
6-7
0.9
3.4
4.1
5.8
8.9
9.1
HIGH
≥ 3 HIGH RISK

11.  Ziad Hijazi and colleagues (June 4, 2016 lancet)
provides a comprehensive validation of the age,
biomarkers, and clinical history (ABC)-bleeding
score, using age, three biomarkers (haemoglobin,
cardiac troponin T, and GDF-15), and clinical
history of bleeding to predict major bleeding
events in anticoagulated patients with atrial
fibrillation.
 META-MICROBLEEDS: cerebral microbleeds
detected by MRI—reflecting small extravasated
blood deposits from nearby small vessels prone to
haemorrhage—hold great promise as a candidate
biomarker of future stroke risk.

12.  Predicts bleeding among patients with OAC.
 O:older >75 yrs—1 point.
 R:reduced Hb(<13 in male<12 in
female,haematocrit(<40 in male <36 in
female orr history of anaemia –2 points
 B:bleeding history 2 points.
 I:insufficient renal function(eGFR<60)-1
point
 T:treatment with antiplatelet-1 point
 LOW:0-2,MEDIUM-3,HIGH≥4

14.  Lower rates of bleeding and ischaemic events
for patients receiving dual antithrombotic
therapy (warf and clopidogrel)compared with
tripple antithrombotictherapy.
(warf,clopidogrel and aspirin)
 One year follow up data :bleeding episodes
were observed in 19.4% with dual
antithrombotic therapy vs 44.4 % receiving
tripple anti thrombotic therapy.(p<0.0001).

15.  15,526 patients with recent ACS
 Twice daily 2.5 BD or 5 BD rivaroxaban
 Primary efficacy end point composite of death
from cardiovascular causes,MI and stroke.
 2.5 mg rivaroxaban reduced the rates of death.
 But 5 mg did not fulfil the criteria.
 Rivaroxaban increased the risk of mojor
bleeding and ICH but not fatal bleeding.

16.  NOACS in association with DAPT
(aspirin+clopidogrel) ?
 Approximately 5-8% of PCI having AF.
 In all NOACS trials( RELY, ROCKET-AF,
ARISTOTLE, ENGAGE-AF) patients were
excluded from enrollment if receiving new
P2Y12.
 And conversely, AF patients requiring OAC
were systematically excluded from recent ACS
trials.

19.  2124 Patients.
 Group I: low dose rivaroxaban(15 mg OD) plus
P2Y12 inhibitor 12 months.
 Group II:very low dose rivaroxaban (2.5 mg BD)
plus DAPT for 1,6,or 12 months.
 Group III:standard therapy with dose adjustd vit k
antagonist OD plus DAPT for 1,6 or 12 months
 Primary safety outcome:clinically significant
bleeding (a composite of major bleeding or minor
bleeding according to TIMI criteria or bleeding
requiring medical attention.

20.  Inclusion criteria:documented AF that occurred
within 1 year before screening.
 Patients more than one year before screening who
are receiving OAC for atleast for AF for atleast 3
months preceding the index PCI.
 Exclusion criteria:history of stroke or TIA,clinically
significant GI bleed within 12 months.calculated
creatinine clearance <30 ml/min.,anaemia with
unknown origin with Hb<10 gm/dl or any other
condition known to increase the risk of bleeding.
 Randomisation occurred within 72 hrs of sheath
removal, once INR was 2.5 or lower.

21.  The rates of clinically significant bleeding were
lower in two groups receiving standard
therapy.(16.8 % in group 1, 18 % in group 2,
26.7% in group 3.
 The rates of death from cardiovascular
causes,myocardial infarction or stoke were
similar in three groups.

22.  Secondary end points: incidence of each
component of primary safety end point as well as
composite of death from cardiovascular causes
,MI,stroke.each component of major adverese
cardiovascular event and stent thrombosis.
 TTR in group 3(INR 2-3) was 65%.
 MACE occurred in 6.5% in group 1,5.6% in group
2,6.0% in group 3.
 The rates of stent thrombosis were low and similar
in all 3 groups.
 Hazard ratio bleeding ISTH and GUSTO criteria.
 group 1 vs group 3 was 0.61(<0.001)
group 2 vs group 3 was 0.67(p=0.002)

23.  In patients with AF undergoing PCI with
placement of stents,the administration of either
low dose rivaroxaban plus P2Y12 inhibitor for
12 months or very low dose rivaroxaban plus
DAPT for 1,6 or 12 months associated with a
lower rate of clinically significant bleeding than
that of standard therapy with vitK antagonist
plus DAPT for 1,6 or 12 months.
 The three groups had similar efficacy rates.

24.  PIONEER–AF-PCI is not powered to detect
differences in stroke rates…
 it will still remain uncertain if rivaroxaban 2.5
mg b.i.d. would adequately reduce strokes in
AF, even when combined with antiplatelet
agents…

26.  Nonvalvular AF either treatment naïve or
receiving on OAC or stable CAD ,successfully
treated with BMS or DES.
 Dabigatran 110 /150 with P2Y12
inhibitor(clopidogrel or ticagrelor),prasugrel is
not used because of 4 fold increased chance of
bleeding.
 Warf arm tripple therapy:aspirin to be
discontinued after 1 month of BMS and 3
months after DES.

27.  1 Noninferiority of 110 mg DE-DAT to warfarin–triple
antithrombotic therapy in major bleeding events/clinically
relevant nonmajor bleeding events
 2 Noninferiority of 150 mg DE-DAT to warfarin–triple
antithrombotic therapy in major bleeding events/clinically
relevant nonmajor bleeding events
 3 Noninferiority of 150 mg DE-DAT and 110 mg DE-DAT
combined to warfarin–triple antithrombotic therapy in death or
thrombotic event and unplanned revascularization by
PCI/CABG
 4 Superiority of 110 mg DE-DAT to warfarin–triple
antithrombotic therapy in major bleeding events/clinically
relevant nonmajor bleeding events
 5 Noninferiority of 150 mg DE-DAT and 110 mg DE-DAT
combined to warfarin–triple antithrombotic therapy in death or
thrombotic event
 6 Superiority of 150 mg DE-DAT to warfarin–triple
antithrombotic therapy in major bleeding events/clinically
relevant nonmajor bleeding events.
 If any of the above steps fails to meet statistical significance, the
testing procedure will stop and subsequent tests will not be
performed

31.  idarucizumab, a humanized monoclonal
antibody fragment with >350 times the affinity
for dabigatran compared to thrombin, as a
specific antidote for dabigatran-associated
coagulopathy.

32.  Safety of 5 g of intravenous idarucizumab and its
capacity to reverse the anticoagulant effects of
dabigatran
 In patients who had serious bleeding (group A) or
required an urgent procedure (group B).
 The primary end point was the maximum
percentage reversal of the anticoagulant effect of
dabigatran within 4 hours after the administration
of idarucizumab, on the basis of the determination
at a central laboratory of the dilute thrombin time
or ecarin clotting time.
 A key secondary end point was the restoration of
hemostasis.

33.  90 patients who received idarucizumab (51
patients in group A and 39 in group B).
 The median maximum percentage reversal was
100% (95% confidence interval).
 Idarucizumab normalized the test results in 88
to 98% of the patients, an effect that was
evident within minutes.
 One thrombotic event occurred within 72 hours
after idarucizumab administration in a patient
in whom anticoagulants had not been
reinitiated

35.  Andexanet alfa is a biologic agent, a
modified recombinant derivative of factor Xa (fXa).
 It acts as a decoy receptor — it has a
higher affinity to the fXa inhibitor than natural fXa,
and consequently the inhibitor binds to the drug
rather than to fXa itself.
 The drug does not seem to be effective against
the factor IIa inhibitor dabigatran.
 Andexanet alfa corrected increases in blood loss
resulting from anticoagulation
by enoxaparin and fondaparinux.

36.  A drug under investigation as an antidote for a
number of anticoagulant (anti-blood clotting)
drugs, including factor Xa inhibitors
(rivaroxaban, apixaban and edoxaban),
dabigatran, low molecular weight
heparins and unfractionated heparin.
 The substance binds directly to anticoagulants
via hydrogen bonds from or to various parts of
the molecule.

37. NEWER ORAL ANTICOAGULANTS