noacs-160604175152.pptx

Dr. k. nagendra prasad
NEWER ORAL ANTICOAGULANTS

TOPIC OUTLINE
⚫Introduction
⚫Types of NOAC s and theirproperties
⚫Advantagesof NOAC soverVKA
⚫Start-upand follow-upscheme forpatientson NOACS
⚫How to measure theanticoagulanteffect of NOACs
⚫How to deal with dosing errors and management of
bleeding complicationswhen itoccurs.
⚫How to switch between various anticoagulant
regimens.

SPECIAL SITUATIONS
⚫patients undergoing a planned surgical intervention or
ablation.
⚫patients undergoing an urgentsurgical intervention.
⚫patientswith AF and coronary arterydisease.
⚫NOACsvs. VKAs in AF patientswith a malignancy.

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

Indications for NOAC s
⚫Prevention of arterial thromboembolic events in non-
valvular atrial fibrillation and VTE prophylaxis
following hipand knee-replacementsurgery –
DABIGATRAN ,RIVAROXABAN, APIXABAN.
⚫Treatmentof deepvein thrombosis - RIVAROXABAN

Dabigatran Etexilate
⚫Dabigatran etexilate, a prodrug of dabigatran, which
reversibly inhibits both freeand clot bound thrombin,
⚫It has an oral bioavailabilityof 6%.
⚫After oral administration, dabigatran etexilate is rapidly and
completelyconverted todabigatran byesterases.
⚫Plasma levels of dabigatran peak 2 hours after drug
administration.
⚫Dabigatran has a half-life of 14 to 17 hours, which permits
once- or twice-daily administration, and 80% of the drug is
excreted unchanged by the kidneys.

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

DOSE REGIMEN
⚫foracuteVTE: 150 mgBID;
⚫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, upsetstomach, or burning ,stomach pain
⚫Allergic reaction, including hives, rash, and itching
⚫Bleeding

⚫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).

RESULTS
⚫150 mg BID dose – superior to warfarin for reduction of
strokeand systemicembolism 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 .

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
byan 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.

VTE trials
⚫RECOVER and REMEDY–
Non inferior towarfarin in VTE prevention (2.4% vs
2.1%)
 Nodiffrerences in major bleeding.

RIVAROXABAN
⚫It has an oral bioavailabilityof 80%.
⚫Rivaroxaban has a rapid onset of action and a half-life of 7
to 11 hours.
⚫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.

⚫Rivaroxaban
is a substrate for P-gp, and concomitant
administration of potent inhibitors
CYP3A4, such as ketoconazole
of both P-gp and
or ritonavir, is
contraindicated because they increase plasmadrug levels.
⚫There is only a minor interaction between Rivaroxiban and
verapamil unlikedabigatran and edoxaban.
⚫Co adminstration of FLUVASTATIN or ROSUVASTATIN
with thisdrug does not need dose reduction of rivaroxiban.

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

ROCKET AF
⚫ The ROCKET AF was a double-blinded study in which 14,264 patients
with non-valvularAF and CHADS2 scores ≥2 (mean 3.5) werestudied.
⚫ After a median follow-up of 1.93 years, rivaroxaban was noninferior to
warfarin forthepreventionof stroke orsystemicembolism.
⚫ 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 mortalitywas notsignificantlydifferent between groups.

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

⚫ 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 signifi cantly lower with rivaroxaban 2.5 mg
compared with placebo but notwith rivaroxaban 5 mg (4.0%).

⚫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.
⚫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 ischaemicand low bleeding risks

CONCLUSION -
⚫In patients with a recent acute coronary syndrome,
rivaroxaban reduced the risk of the composite end point of
death from cardiovascular causes, myocardial infarction, or
stroke.
⚫Rivaroxaban increased the risk of major bleeding and
intracranial hemorrhage but not the risk of fatal bleeding.

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 loer
bleeding risk than warfarin.
⚫EINSTEIN EXTENSION – similarresults.

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

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 amean followup 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
ischaemicstrokes.
⚫ Patients treated with apixaban had significantly fewer intracranial
bleeds, but GI bleedingsweresimilar between bothgroups.
⚫ All-cause mortality was found to be significantly lower in the apixaban
group.

⚫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.

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 ischaemicevents

Edoxaban
⚫Edoxaban is another reversible factorXainhibitor, recently
approved by theFDA but not yet by the EMA.
⚫It is rapidly absorbed and reaches peak plasma
concentration within 1–2 h.
⚫Up to 50% of edoxaban is eliminated by the kidneys and
rest through multiplepathways.
⚫It is also 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 , body weight < 60 kg, or moderate–
severe renal impairment (CrCl < 50 mL/min), edoxaban
dose should be reduced by 50%.

ENGAGE AF-TIMI
Generation in Atrial Fibrillation–Thrombolysis
⚫The Effective Anticoagulation with Factor Xa Next
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.

⚫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
lowerwith 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 wereexcluded.

⚫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.

OTHER fXa inhibitors
⚫Theseare 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.

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

Comparison between new oral
anticoagulants
⚫There no direct head-to-head comparisons between these
drugs.
⚫NOACs have been made in randomized, controlled trials,
and 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
makecomplex direct comparisons.

⚫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
haemorrhagicstrokes.
⚫Data for all four NOACS showed that they were associated
with a 14% non-significant reduction in major bleedings.

General recommendations

How to measure effect

⚫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 presenceof factorXa inhibitors.
⚫Quantitative tests for DTI and FXa inhibitors - diluted
thrombin-timeand 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.

When interpreting these results, consider
⚫when the lastdoseof NOACwasadministered
⚫patientcharacteristics, and renal function –
determinantsof elimination half-life

⚫DABIGATRAN –
 aPTT level (i.e. 12–24 h after ingestion) of ≥2 the upper
limit of normal or
 ECT ≥3 times and a dTT(Hemoclot) - .200 ng/mL after 12 h
of the last dose
is associated with a higherrisk of bleeding.

Patient has a bleeding complication
⚫Specific antidotes for NOACs are still lacking and the
strategies to reverseanticoagulanteffectare limited.
⚫Time is the best advantage of NOACs, in view of their
relativelyshort elimination half-lives.
⚫If a major bleeding complication occurs, standard
supportive measurements must be started. These include
mechanical compression, surgical haemostasis, fluid
replacement, and additional haemodynamicsupport.

⚫ Haemodialysis can
accelerate drug removal patients
in those
in life-threatening
receiving dabigatran; however, its benefit
bleeding has not beenestablished.
⚫ In contrast, dialysis is not effective for factor Xa inhibitors due to
their high plasma binding and lowerrenal clearance.
⚫ The administration of prothrombin complex concentrate (PCC) or
activated prothrombin complex (aPCC) concentrates can be
considered in life-threatening bleeding, despite the scarce evidence.
⚫ Administration of PCC could start at a dose of 25 U/kg and can be
repeated if clinically indicated.

⚫Novel reversal agents in clinical development
⚫There are currently 3 NOAC-specific reversal agents in
clinical development:
(1) andexanetalfa,
(2) idarucizumab, and
(3) PER977

⚫“Andexanet alfa” is a recombinant, modified human factor Xa
that is being developed as adirect factorXa reversal agent.
⚫It has been shown to rapidly attenuate the anti-FXa activity of
apixaban, rivaroxaban, edoxaban, and enoxaparin and to
restore thrombin generation in phase 2 studies in healthy
humanvolunteers.
⚫Andexanet alfa has been generally well tolerated and is
currently in phase 3 clinical trials (ANNEXA-A [apixaban] and
ANNEXA-R [rivaroxaban]).

⚫Idarucizumab” is a fully humanized antibody fragment (Fab)
that binds dabigatran with highaffinityand specificity.
⚫Idarucizumab rapidly reverses the anticoagulant effect of a
220 mg twice daily dose of dabigatran in healthy human
volunteers and is currently being evaluated in phase 3 trials.
⚫Idarucizumab has been generally well tolerated in healthy
human volunteers and is currently in clinical trials in the RE-
VERSE AD study.

⚫PER977 (ciraparantag)” is a water-soluble small-molecule
nonspecific reversal agent.
⚫In preclinical testing and during testing with edoxaban in
healthy male volunteers, it rapidly reversed the effect of
multipleanticoagulants, purportedlyvia hydrogen bonding.
⚫It is currently in phase 1 to 2 clinical testing in healthy human
volunteers.

Patient undergoes intervention
⚫ The most appropriate management should be individualized
depending on the NOAC used, the type of surgery, the required
anaesthetic regimen, and the patients’ characteristics,
particularly, on theirrenal function.
⚫ For patients undergoing minor interventions,NOACs can be
continued around the time of the procedure, similar to VKA-
treated patients.
⚫ Some examples include skin cancer removal, joint injection,
cataract removal, or tooth extraction in which an adequate local
haemostasis is commonlypossible.
⚫ Intervention should not be performed at peak concentrations
but 12 or 24 h after the last intake, depending on their specific
regimen dosing.

Managing oral antiplatelet agents in patients
requiring long-term oral anticoagulants
⚫ Approximately 6 – 8% of patients undergoing PCI have an indication for
long-term OAC with VKA or NOACs due to various conditions such as
atrial fibrillation, mechanical heartvalvesorvenous thromboembolism.
⚫ In the absence of safety and efficacy data, the use of prasugrel or ticagrelor
as partof triple therapy should beavoided.
⚫ Gastric protectionwith a proton pump inhibitor is recommended.
⚫ The dose intensity of OAC should be carefully monitored with a target INR
of 2.0 – 2.5 in patients treated with VKA & 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 twicea day)

⚫new-generation DESs are recommended over BMSs in
patients requiring OACat low bleeding risk (HAS-BLED ≤2).
⚫For patients at high bleeding risk (HAS-BLED ≥3)
undergoing PCI who require OAC, the choice between a BMS
and a new-generation DES needs to be individualised.
⚫it is not known whether there are differences according to
the typeof OAC (NOACsversus VKA) orstent platform.

Evaluation of Dual Therapy With Dabigatran vs. Triple
Therapy With Warfarin in Patients With AF That Undergo
a PCI With Stenting (REDUAL-PCI)
⚫ The main objective of this study is to compare a Dual
Antithrombotic Therapy (DAT) regimen of 110mg dabigatran
etexilate b.i.d. plus clopidogrel or ticagrelor (110mg DE DAT) and
150mg dabigatran etexilate b.i.d. plus clopidogrel or ticagrelor
(150mg DE-DAT) with a Triple Antithrombotic Therapy (TAT)
combination of warfarin plus clopidogrel or ticagrelor plus ASA
<= 100mg once daily (warfarin-TAT) in patients with Atrial
Fibrillation that undergo a PCI with stenting (elective or due to
an Acute Coronary Syndrome).
⚫ The study aims to show non-inferiority of each dose of DE-DAT
when compared to Warfarin-TAT in termsof safety.
⚫ Safety will be determined by comparing the rates of bleeding
events and Clinically Relevant Non MajorBleeding Events.

New oral anticoagulants vs.vitamin K antagonists in
atrial fibrillation patients 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 (forVKAs and UFH).

Patient need to switch between anticoagulant regimens

Conclusion
⚫New oral anticoagulants have shown to have a favourable
balance between efficacy and safetycompared 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.

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