NOACS

• PRESENTOR – DR PINKESH PARMAR
• MODERATOR –
DR HASIT JOSHI sir
DR POOJA VYAS mam
DR JIT sir
DR VIKAS sir
DR KEWAL sir
NOACS

TOPICOUTLINE
NEWERORAL ANTICOAGULANTS
• Introduction
• Types of NOAC s and their properties
• Advantages of NOAC s overVKA
• Start-up and follow-up scheme for patients onNOACS
• How to measure the anticoagulant effect ofNOACs
• How to deal with dosing errors and management of
bleeding complications when itoccurs.
• How to switch between various anticoagulant
regimens.
• New guidelines

Introduction
• Vitamin K antagonists (VKAs) are the mainstay of
management of thromboembolic events 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.

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

Dabigatran Etexilate
• Dabigatran etexilate, a prodrug of dabigatran, which
Reversibly inhibits both free and clot bound thrombin,
• It has an oral bioavailability of 6%.
• After oral administration, dabigatran etexilate is rapidly
and completely converted to dabigatran 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 minimisedyspepsia.
• If a dose is missed it should be taken within 6 hours.

DOSE REGIMEN
• for acute VTE: 150mg BD;
• for VTE prevention after knee or hip replacement
surgery (14or 30days, respectively): 110mg (initial
dose) then 220mgdaily.
• For AF – 150mg BD

COMMON SIDE EFFECTS
• Indigestion, upset stomach, or burning ,stomachpain-
35%
• Allergic reaction, including hives, rash, and itching
• Bleeding
• Major bleeding – 2.71% per year
• ICH – 0.12% per year

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
stroke and systemic embolism with similar majorbleeding.
• 110mg BIDdose –non inferior to warfarin for SSEbut 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 by an additional 2.3years.
 RELY-ABLEconfirmed 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 (3.74%) in
comparison with 110 mg (2.99%), and similar rates of stroke
(0.13 and 0.14%) and death (3.02% and 3.10%).

VTE trials
RECOVER and REMEDY–
Non inferior to warfarin in VTE prevention (2.4%vs
2.1%)
No diffrerences in majorbleeding.

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

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 plasma drug levels.
There is only a minor interaction between Rivaroxiban and
verapamil unlike dabigatran and edoxaban.

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

ROCKETAF
The ROCKET AF was a double-blinded study in which 14,264 patients
with non-valvular AF and CHADS2 scores ≥2(mean 3.5) werestudied.
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 betweengroups.

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
patients with a recent acute coronarysyndrome.

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 PEwith 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
1–4h.
It is predominantly metabolized in liver.
It is a mild P- glycoprotein inhibitor.
Compared to other NOACS it has least bleeding
complications and greaterefficacy.

DOSAGE
• AF – 5mg BD
• DVT prophylaxis – 2.5 mg BD 2wks for knee, 5wks for hip
replacement. Start 12-24 hrs after surgery.
• DVT/PE treatment – 10 mg BD for 7days f/b 5mg BD

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
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.

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 ischaemic events

VTE trials
• Treatment – AMPLIFY trial – Apixaban was non inferior to warfarin for
treatment of VTE and significantly less bleeding.
• Prophylaxis – AVERT trial – lower rates of events as compared with
placebo

Edoxaban
Edoxaban is another reversible factor Xa inhibitor, recently
approved by the FDA but not yet by the EMA.
It is rapidly absorbed and reaches peak plasma concentration
within 1–2h.
Up to 50% of edoxaban is eliminated by the kidneys and rest
through multiple pathways.
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%.

ENGAGEAF-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
lower with both edoxabanregimens.
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 30days 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.

Patient need to switch between anticoagulant regimens

TRANSITION OF NOAC TO WARFARIN

OTHERfXainhibitors
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.

Comparisonbetween neworal
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
make complex directcomparisons.

General recommendations

Howto measureeffect

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

Patient hasableeding
Specific antidotes for NOACs are still lacking and the
strategies to reverse anticoagulant effect arelimited.
Time is the best advantage of NOACs, in view of their
relatively short 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 haemodynamic support.

Haemodialysis can
accelerate drug removal patientsin those
in life-threateningreceiving dabigatran; however, its benefit
bleeding has not been established.
In contrast, dialysis is not effective for factor Xa inhibitors due
to their high plasma binding and lower renalclearance.
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)andexanet alfa,
(2) idarucizumab, and
(3) PER977

“Andexanet alfa” is a recombinant, modified human factor Xa that is
being developed as a direct factor Xa reversalagent.
It has been shown to rapidly attenuate the anti-FXa activity of apixaban,
rivaroxaban, edoxaban, and enoxaparin and to restore thrombin
generation in phase 2studies in healthy human volunteers.
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 high affinity andspecificity.
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 3trials.
Idarucizumab has been generally well tolerated in healthy human
volunteers and is studies in the RE- VERSEAD trial.
The recommended dose of idarucizumab is 5 g, provided as two
separate vials each containing 2.5 g/50 mL idarucizumab.

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 multiple anticoagulants,
purportedly via hydrogenbonding.
Itis currently in phase 1to 2clinical testing in healthy humanvolunteers.

Patient undergoesintervention
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 their renal 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 commonly possible.
Intervention should not be performed at peak concentrations
but 12 or 24 h after the last intake, depending on their specific
regimen dosing.

Managingoral antiplatelet agentsinpatients
requiring long-term oAC
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 heart valves or venousthromboembolism.
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 proton pump inhibitoris 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 twice aday)

Studies evaluating combinations of NOAC or VKA +
antiplatelets post PCI & stenting
PIONEER AF PCI – Rivaroxaban;
RE-DUAL PCI – Dabigatran ;
AUGUSTUS - Apixaban ; ongoing
ENTRUST-AF-PCI – Edoxaban; ongoing

RE-DUAL PCI
• RE-DUAL PCI was an international, multicenter, randomized open-
label trial of 2,725 patients with nonvalvular AF who had undergone
PCI with stenting.
• Patients were randomized to receive 1 of 3 treatments:
• double therapy with dabigatran (110 mg twice daily) plus either clopidogrel
or ticagrelor (110-mg dual-therapy group),
• double therapy with dabigatran (150 mg twice daily) plus either clopidogrel
or ticagrelor (150-mg dualtherapy group), or
• triple therapy with warfarin plus aspirin (100 mg daily) and either clopidogrel
or ticagrelor (tripletherapy group).

RE-DUAL PCI
• The incidence of major or clinically relevant nonmajor bleeding was
higher in the tripletherapy group than in the 110-mg dual-therapy
group and the 150-mg dual-therapy group.
• In addition, the 2 dual-therapy groups combined were noninferior to
the triple-therapy group with regard to the composite efficacy
endpoint of thromboembolic events (MI, stroke, or systemic
embolism), death, or unplanned revascularization.
• Clopidogrel was the most common P2Y12 inhibitor used (88%).
• Notably, the study was not powered to evaluate risk of stent
thrombosis or systemic thromboembolism

PIONEER AF-PCI
• PIONEER AF-PCI was an international, multicenter, randomized,
open-label trial of 2,124 patients with AF (without moderate to
severe mitral stenosis or a mechanical heart valve) who had
undergone PCI with stenting.
• Patients were randomized in a 1:1:1 ratio to
• low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months
(Group 1);
• very-low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12
months (Group 2);
• or standard therapy with a dose-adjusted vitamin K antagonist (once daily)
plus DAPT for 1, 6, or 12 months (Group 3).

PIONEER AF-PCI
• Clopidogrel was the most common P2Y12 inhibitor used (.90%). The
rates of clinically significant bleeding were lower in Groups 1 and 2
than in Group 3. The rates of death from cardiovascular causes, MI,
or stroke were similar in the 3 groups.
• It is important to note that the dose of rivaroxaban used in that study
was lower than the dose recommended for stroke prophylaxis in AF.
The study was not powered to evaluate risk of stent thrombosis or
systemic thromboembolism

Recommendations for AF Complicating ACS
• For patients with ACS and AF at increased risk of systemic
thromboembolism (based on CHA2DS2-VASc risk score of 2
or greater), anticoagulation is recommended unless the
bleeding risk exceeds the expected benefit
• If triple therapy (oral anticoagulant, aspirin, and P2Y12
inhibitor) is prescribed for patients with AF at increased risk
of stroke (based on CHA2DS2-VASc risk score of 2 or greater)
who have undergone PCI with stenting for ACS, it is
reasonable to choose clopidogrel in preference to prasugrel

Recommendations for AF Complicating ACS
• In patients with AF at increased risk of stroke (based on CHA2DS2-
VASc risk score of 2 or greater) who have undergone PCI with
stenting for ACS, double therapy with P2Y12 inhibitors
(clopidogrel) and lowdose rivaroxaban 15mg daily OR dabigatran
150 mg twice daily is reasonable to reduce the risk of bleeding as
compared with triple therapy
• If triple therapy (oral anticoagulant, aspirin, and P2Y12 inhibitor)
is prescribed for patients with AF who are at increased risk of
stroke (based on CHA2DS2-VASc risk score of 2 or greater) and
who have undergone PCI with stenting (drug eluting or bare
metal) for ACS, a transition to double therapy (oral anticoagulant
and P2Y12 inhibitor) at 4 to 6 weeks may be considered

NOACS AND VALVULARHEART DISEASE
RE-ALIGN STUDY
• DABIGATRAN VERSUS WARFARIN IN PATIENTS WITH AORTIC OR MITRAL
VALVE REPLACEMENTS
• 12 WEEK PHASE 2 DOSE FINDING STUDY
• STUDY TERMINATED EARLY DUE TO EXCESS STROKE ANDBLEEDING WITH
DABIGATRAN
• ENROLLED 252 RATHER THAN INITIAL TARGET OF 405
• STROKE (9 VS 0 PATIENTS)
• PERICARDIAL BLEEDING (4 VS 2)
• 32% OF ALL DABIGATRAN PATIENTS REQUIRED DOSE ADJUSTMENT OR
DISCONTINUATION

New oral anticoagulants vs.vitamin Kantagonists 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 (for VKAs and UFH).

2019 AHA/ACC/HRS focused update of the 2014
AHA/ACC/HRS guideline for the management of
patients with aF
• For patients with AF and an elevated CHA2DS2-VASc score of 2 or
greater in men or 3 or greater in women, oral anticoagulants are
recommended.
• NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) are
recommended over warfarin in NOAC-eligible patients with AF
(except with moderate-to-severe mitral stenosis or a mechanical
heart valve)
• For patients with AF who have mechanical heart valves, warfarin is
recommended
• Selection of anticoagulant therapy should be based on the risk of
thromboembolism, irrespective of whether the AF pattern is
paroxysmal, persistent, or permanent

patients with aF
• Renal function and hepatic function should be evaluated before
initiation of a NOAC and should be reevaluated at least annually
• For patients with AF (except with moderate-to-severe mitral stenosis
or a mechanical heart valve) who are unable to maintain a
therapeutic INR level with warfarin, use of a NOAC is recommended.
• For patients with AF who have a CHA2DS2-VASc score of 2 or greater
in men or 3 or greater in women and who have end-stage chronic
kidney disease (CKD; creatinine clearance [CrCl] ,15 mL/min) or are
on dialysis, it might be reasonable to prescribe warfarin (INR 2.0 to
3.0) or apixaban for oral anticoagulation

patients with aF
• In patients with AF and end-stage CKD or on dialysis, the direct
thrombin inhibitor dabigatran or the factor Xa inhibitors rivaroxaban
or edoxaban are not recommended because of the lack of evidence
from clinical trials that benefit exceeds risk

Conclusion
New oral anticoagulants have shown to have a favourable
balance between efficacy and safety compared with VKAs.
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.

NOACS

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