Guide to oral anticoagulants

ORAL
ANTICOAGULANTS
Satya Mahapatra

COAGULATION PATHWAYS
Harrison's 20th edition

CLASSIFICATION OF ANTICOAGULANTS

CLASSIFICATION OF ORAL
ANTICOAGULANTS
 Coumarin Derivatives:-
Warfarin
Acenocoumarol (Acitrom)
 Indandione Derivatives:-
Phenindione
Anisindione

•NEWER ORAL ANTICOAGULANTS:-
 Direct Thrombin inhibitor –
Dabigatron etexilate
 Direct factor Xa inhibitors:-
Rivaroxaban
Apixaban
Edoxaban
Betrixaban

WARFARIN
 Coumarin derivative, water soluble vit K
antagonist.
 Initially developed as rodenticide.
 Most wildly used anticoagulant in the
world.
 Interfere the synthesis of vit K dependent
clotting factor( factor II,VII,IX,X).
 It also reduces synthesis of vit K
dependent anticoagulant proteins (protein
C and S).

MECHANISM OF ACTION

CONTINUED…..
 Post translation modification add carboxyl
group to the gama-carbon to generate Gama-
carboxyglutamic acid.
 Post translational modification is essential for
expression of activity of clotting factor
because it permits Calcium dependent
binding to negatively charged phospholipid
surface.
 Warfarin inhibit VKOR(vit K epoxide
reductase) therefore blocking the

 So only partially carboxylated clotting factors
was synthesized and these have reduced or
absent clotting activity.
 Anti thrombotic effect of warfarin depends on
reduction in level of factor X and Prothrombin.

Coagulation Factors Plasma half
life(Hours)
II 72-96
VII 4-6
IX 18-24
X 40-60
Protein C 8
Protein S 30
Plasma Half life of vit K dependent proteins

PHARMACOLOGY OF WARFARIN
 Racimic mixture of R and S isomers.
 S isomer is more active.
 Rapidly and completely absorbed from GIT.
 Peak levels in blood after 90 min of
administration.
 Half life is 36-42 hours.
 >97% bound to albumin.

CONTINUED…
 Only unbound form is biologically active.
 Inactive metabolite excreted in urine and stool
 It accumulates in the liver and undergo
CYP2C9 mediated oxidative metabolism.
 Common variant of CYP2C9, CYP2C9*2 and
CYP2C9*3 encodes enzyme with reduced
activity.
 Patient with these variant requires lower
maintenance dose of warfarin.

CYP2C9 GENOTYPE EFFECT ON ANTICOAGULATION
 CYP2C9 SNPs alter warfarin metabolism:-
 CYP2C9*1 (wild type)- normal activity.
 CYP2C9*2 – Low/intermediate activity.
 CYP2C9*3 – low activity.
 Approximately 25% of white have at least
one variant allele of CYP2C9*2 or
CYP2C9*3 and are less common in blacks
and Asians.

 Warfarin dose reduction as follows:-
 Heterozygosity for CYP2C9*2 or CYP2C9*3 allele: 20-
30%
 Homozygosity for CYP2C9*2 or CYP2C9*3 allele: 50-70%

EFFECT OF VKORC1 GENOTYPE ON
ANTICOAGULATION
 Three polymorphic variants of VKORC1
Non-A, Non-A : wild type- Requiring more warfarin dose
Non-A/A: Heterozygous- Requiring 25% dose
reductions
A/A : Homozygous- Requiring 50% dose reduction
 Asians have highest prevalence of VKORC1
variants followed by whites and blacks.
 Polymorphisms in VKORC1 likely explain 30%
of the variability in warfarin dose requirements.
 VKORC1 variants are more prevalent than
CYP2C9 variants.

Genotype Frequency in
Asian
Frequency
in whites
Frequency in
African
Americans
Dose
reduction
compared to
wild type
Non-A/Non-A 7 37 82 --
Non-A/A 30 45 12 26
A/A 63 18 6 50
Frequency of VKORC1 haplotypes in different
population and their effect on warfarin dose
requirements

DOSING
 Starting dose is 5-10 mg/day
 Lower doses require in:
Elderly
Heart failure
Liver disease
Renal impairment
Malnutrition
Thyrotoxicosis
Patient on increased risk of bleeding( eg pt. on Aspirin)
Asian patients
 High dietary intake of vit-K (green leafy vegetables eg.
Broccoli) reduces the efficacy of Warfarin.
Wintrobe’s clinical hematology

CAUTION WITH VIT-K CONTAINING FOOD
 Health Canada recommends daily intake 90-120ug of
vit-k.
 Different food contains different amount of vit k, since
vit-K interfere the effect of warfarin, it is important to
eat the same amount from day to day.
 Eat food with different levels of vitamin k.

Very high
(>500ug/100 gm
serving)
High
(100-500ug/100gm
serving)
Medium
(25-100ug/100gm
serving)
Spinach Broccoli Cabbage.
Seaweed Cauliflower Green beans
Green tea Chick peas Green onions/tomato
Lentils Wheat flour
Soyabeans Coffee
Pork liver
Chicken liver

CONCOMITANT PARENTERAL
ANTICOAGULATION WITH WARFARIN
 Warfarin has delayed onset of action.
 Parenteral anticoagulation should be given
concomitantly in patients with established thrombosis
or high risk for thrombosis until INR has been in
therapeutic range for at least 2 days.
 Warfarin also decrease the anticoagulant proteins C
and S thus increasing thrombogenic potential.
 Overlapping warfarin for at least 5 days with an
immediately effective parenteral anticoagulants
counteracts the procoagulants effects of unopposed
warfarin. Harrison's 20th edition

COMMENCEMENT OF WARFARIN THERAPY AND
MONITORING
 Baseline INR<1.3, the patient will receive 5 mg
of warfarin once daily on day1 and 2. INR is
checked daily from day3 until therapeutic range
of INR achieved and dose adjusted to achieve
INR≥2.
 Then INR monitored 3 times weekly for 2
weeks
 INR monitored every 3-4 weeks when stable
dose of warfarin achieved.
 INR maintained between 2-3 except in
Mechanical heart valve where target INR 2.5-
Harrison 20th edition

J thromb Thrombolysis(2016) 41:187-207
Daneial M. Witt. Nathan P. Clark. Scott

PT-INR
 Warfarin therapy monitored using PT, a test sensitive
to reduction in levels of Prothrombin, factor VII and X.
 This test involve addition of thromboplastin (reagent
containing tissue factor, phospholipid and ca++) to
citrated plasma and determining the time to clot
formation.
 Thromboplastin vary in their sensitivity to reduction in
the levels of the vitamin k dependent clotting factors.

CONTINUED…
 INR represent the PT according to international
reference thromboplastin, as approved by WHO.
 Highly sensitive thromboplastin have an ISI of 1.0
 Most current thromboplastin have ISI values between
1.0-1.4

INDICATIONS
 Atrial fibrillation
 Prosthetic heart valve
 Venous thromboembolism
 Primary pulmonary hypertension.
 Rarely after acute MI.

SIDE EFFECT OF WARFARIN
 Bleeding
 Skin necrosis
 Purple toe syndrome
 Teratogenicity
 Osteoporosis
 Others: Agranulocytosis, leucopenia,
diarrhea, anorexia.

BLEEDING
 Most common complication.
 Mild : epistaxis, hematuria
 Severe: Retroperitoneal or GIT
 Life threatening: intracranial bleed.
 Rate of major bleeding is 1-3%.
 Half of complications occurs when INR exceeds
therapeutic range.

2017 ACC on management of bleeding in patient on
OACs

Drugs and medical condition affecting Warfarin
potency
Potentiator Antagonist
Drugs Medical
condition
Drugs Medical
condition
Acetaminophen Older age Carbamazepine Excess vit-k
Omeprazole liver disease Chlordiazepoxide Hypothyroidism
Propanolol Malabsorption Rifampicin Nephrotic
syndrome
Phenytoin
Hyperthyroidism
Barbiturates
Broad spectrum Fever
Antibiotics Vit-K
deficiency
Adrenal corticosteroid
Fluconazole CHF Sucralfate
Indomethacine Malnutrition
Lovastatin

WARFARIN IN SPECIAL CONDITIONS
 Pregnancy: contraindicated in 1st (teratogenic) and 3rd
trimester(intracranial bleeding chances increases).
Does not passes in milk therefore safe for nursing mother.
 Modification before surgery:-
Pt. on long term anticoagulation with warfarin - stop it 5
days prior to surgery.
Those who are high risk for TE can be bridged with
LMWX.
Last dose of LMWX should be given 12 or 24 hour before
surgery.
Those receiving bridging anticoagulation with therapeutic
dose
UFH, should be stopped 4-6 hour before surgery.

CONTINUED..
 INR checked on day of surgery.
 Heparin resumed about hours after procedures if
there is adequate hemostasis.
 Warfarin can be resumed, at the normal
maintenance dose, at evening of surgery or next
morning if adequate hemostasis.
 OACs should not be stopped in majority of patient
requiring skin biopsy, out patient dental surgery
including dental extraction.
 NSAIDS should not prescribed following dental
surgery in patient of warfarin.

WARFARIN IN VENOUS THROMBOEMBOLISM
 Warfarin should be initiated concurrently with
parenteral heparin.
 For VTE patients target INR range 2-3.
 After 5 days, warfarin should be continued for at least
3 month.
 Optimal duration depends on clinical settings.

Optimal Duration of Anticoagulants
Clinical Course Recommendations
1st provoked PE/Proximal leg DVT 3-6 month
1st provoked upper extremity DVT or
isolated calf DVT
3 month
2nd provoked VTE Uncertain
3rd VTE Indefinite duration
Cancer and VTE Consider indefinite duration or until
cancer is resolved.
Unprovoked PE/Proximal leg DVT Consider indefinite duration
1st unprovoked calf DVT 3 month
2nd unprovoked calf DVT uncertain

ACENOCOUMAROL (ACITROM)
 Short half life of 10-16 hours.
 More rapid onset.
 Shorter duration of action (2 days)
 Dose 4 mg on D1, 4-8 mg on D2 then maintenance
dose of 1-8 mg according to response by PT test.
 Anticoagulant quality is slightly lesser than warfarin.

NEWER ORAL ANTICOAGULANTS
 Why there is need of newer anticoagulants….
 Limitation of Warfarin:-
Narrow therapeutic range.
Slow onset of action.
Slow offset of action.
Multiple drug and dietary interaction.
Monitoring required to maintained in
therapeutic range.
Difficult to manage for invasive procedures.
Adverse events and complexity of management.

ATTRIBUTES OF IDEAL ANTICOAGULANTS
 Oral administration
 Rapid onset of action/rapid offset of action.
 Wide therapeutic range
 Predictable therapeutic effect.
 No food or drug-drug interaction
 No monitoring required.
 Easily reversible.
 Cost effective.
 Well defined pharmacokinetics in presence of renal or
hepatic disease.
European Heart J cardiovascular Pharmacotherapy (2015)1 (2): 134-
145

DABIGATRON ETEXILATE
 Oral direct thrombin(factor IIa) inhibitor.
 Prodrug which is hydrolyzed and form Dabigatron (active
moiety).
 Initially recommended by FDA on Oct, 19 2010 for Non-Valvular
AF.
 Competitive, direct thrombin inhibitors. Both free and clot bound
thrombin, and thrombin induced platelet aggregation are
inhibited by active moieties.
 Oral bioavailability ≈ 6-7%.
 Uptake is reduced by PPI and absorption delayed when taken
with food.

CONTINUED…
 Peak level after 2 hours of oral dose.
 Primarily eliminated by renal clearence.
 Half life 14-17 hours.
 Concurrent administration of p-gp inhibitors
(Ketoconazole, Quinidine) and inducer (Rifampicin)
not advisable.
 Contraindicated with CrCl<15ml/min.
 Monitoring of therapy not required.

CONTINUED…..
 Side effects : Bleeding, Dyspepsia, higher GI bleeding and
myocardial ischemia as compared to warfarin.
 In case of overdose, rapid administration of charcoal may
decrease absorption and hemodialysis can remove 60 % of
plasma drug level.
 Approved in India since Dec 2011 for stoke/systemic embolism
prophylaxis in non-valvular AF patient
 For prevention of venous thromboembolic events in patient
undergoing orthopedic surgery from feb 2013 by CDSCO.

ALGORITHM FOR STARTING DABIGATRON
European Heart J cardiovascular Pharmacotherapy (2015)1 (2): 134-145

RIVAROXABAN
 First oral direct factor Xa inhibitor.
 Reversible direct factor Xa inhibitor that bind and to
inactivate both plasma factor Xa and clot bound factor
Xa.
 Bioavailability : 60-80 %
 Peak action 2-3 hours.
 Half life: 7-11 hours.
 Metabolized by CYP3A4 dependent and independent
pathways.
 Potent combined P-gp and CYP3A4 inhibitors
(ketoconazole,PI) and inducer (Carbamazepine,
Phenytoin, Rifampicin) should be avoided.

Algorithm for Indication, dosing and interactions of
Rivaroxaban.

CONTINUED..
 Approved for VTE(CDSCO) prophylaxis in post op
cases of THA/TKA since Jan 2010.
 Approved for prevention of atheroembolic events in
adult patients after an ACS with elevated cardiac
marker from july 2015.
 Pregnancy category C.
 Available as Xarleto (Bayer pharma).

APIXABAN
 Reversible direct factor Xa inhibitor that bind and to inactivate
both plasma factor Xa and clot bound factor Xa.
 Oral bioavailability >45%.
 Peak level after 3 hour of oral intake.
 Half life 8-14 hours.
 Eliminated via multiple mechanism(predominantly via liver)
 Potent combined P-gp and CYP3A4 inhibitors (Ketoconazole,
PI) and inducer (Carbamazepine, Phenytoin, Rifampicin) should
be avoided.
 Pregnancy category B
 Approved for prevention of stroke in non-valvular AF patients by
FDA in Dec 2012.

CONTINUED…
 Approved for prevention of VTE for hip and
knee replacement surgery (CDSCO).
 Approved for treatment of DVT and PE in adult
patient in may(CDSCO).

Indications, dosing and Interaction of Apixaban

EDOXABAN
 Another reversible direct factor Xa inhibitor.
 Reaches peak plasma level within 1– 2 hr.
 50% excreted through kidney and rest through
multiple mechanism.
 Associated with lower rate of bleeding, including major
bleeding, intracranial bleeding.
 GI bleeding more frequently than warfarin when used
with high dose but less frequently with low dose.
 Patient with CrCl<30 ml/min, high risk of bleeding, use
of dual antiplatelet, ACS, and stroke with 30 days were
excluded.

CONTINUED..
 Pregnancy Cat C.
 No antidote
 FDA approved in Jan to prevent embolic
events in non-valvular AF.
 Available doses:15,30,60 mg

Algorithm for Indicatons, dosing and interactions of
Edoxaban

OTHER FACTOR XA INHIBITORS
 Betrixaban:-
Approved by FDA on Oct 2015 for VTE prophylaxis in
hospitalized medically ill patients at risk of thromboembolism.
Excreted through bile, can be given to ESRD.
Minimal drug interactions.
Doses 160 mg on D1 f/b 80mg/day for 35-42 days.
 Darexaban (YM-150):-
Discontinue in sep 2011.
 TAK 442:
In trial phase.

REVERSAL AGENTS
 IDARUCIZUMAB:
Fully humanized antibody fragments that binds dabigatron with high affinity
and specificity.
FDA approved its use in Oct 2015.
REVERSE-AD Trial shows its beneficial effect in reversing effect of
Dabigatron in patient with severe bleeding or who require urgent procedure
with in 4 hours.
Available as Praxbind.
 ANDEXANET ALFA:
Recombinant modified human factor Xa reversal agent.
It rapidly attenuate the anti factor-Xa activity of Apixaban, Rivaroxaban,
Edoxaban, Enoxaparin.
well tolerated and currently in phase 3 trial.

CONTINUED..
 CIRAPARANTAG(PER977):
Water soluble non-specific reverse agent.
In preclinical testing and during testing with Edoxaban in
healthy male volunteers.

USE OF ANTICOAGULANTS ACCORDING TO
PATIENT CHARACTERISTIC
Patient charactertics NOAC Dose regimen
High risk of Stroke (High
CHADS-VASC score)
Dabigatron 150 mg BD
Previous stroke Rivaroxaban 20 mg OD
High risk of bleeding or previous
life-threatening bleeding
Dabigatron
Apixaban
110 mg BD
5 mg BD
Dyspepsia Rivaroxaban
Apixaban
20 mg OD
5 mg BD
GI Bleeding Apixaban 5 mg BD
Medication compliance problem Rivaroxaban 20 mg OD
Elderly (>80 year) and impaired
renal function
Apixaban 2.5 mg BD
European Heart J cardiovascular Pharmacotherapy (2015)1 (2): 134-
145

PRE AND POSTOPERATIVE MANAGEMENT OF
PATIENTS TAKING NOACS

RECOMMENDATION ON HOW TO SWITCH BETWEEN
DIFFERENT ANTICOAGULANT REGIMENS
Switching How?
VKA to NOACs Once the INR lower than 2
Intravenous UFH to NOAC After 2 hr of stopping UFH(longer in case of
renal impairment)
LMWH to NOAC When the next dose of LMWH was advised
NOAC to VKA Concomitant treatment until INR 2-3
NOAC to Parenteral
anticoagulant
(UFH, LMWH)
When next dose of NOAC was planned
One NOAC to another When the next dose of NOAC was planned(
longer in case of renal impairment)

ORAL ANTICOAGULANTS IN AF
 AF and an CHA2DS2-VASc score of >2 in men or >3 women, OAC
recommended.(COR I, LOE A).
 NOACs (Dabigatron, Rivaroxaban, Apixaban, and Edoxaban) are
recommended over warfarin in NOAC-eligible patients with AF(I A)
 Warfarin preferred - moderate-to-severe mitral stenosis or a
mechanical heart valve(I B).
 With warfarin measure INR -at least weekly during initiation of anticoagulant
therapy and at least monthly when anticoagulation (INR in range) is stable(I
A).
 Renal and hepatic function- Evaluate before initiation of a NOAC and re-
evaluate at least annually(I B).
 AF ( CHA2DS2-VASc Score > 2 in men or >3 in women) with CKD
(ESRD;CrCl <15 mL/min) Warfarin (INR 2.0 to 3.0) or Apixaban (IIb-B).
ACC/AHA 2019 guideline

THROMBOEMBOLISM PREVENTION IN AF
 AF or Atrial flutter ≥ 48 hrs or of unknown duration:
 Warfarin (INR 2.0 to 3.0),factor Xa inhibitor, direct thrombin
inhibitor is recommended for at least 3 weeks before and at least 4
weeks after cardioversion,(regardless of the CHA2DS2-VASc score
or the method used to restore sinus rhythm)[I B-R]
 Who have not been anticoagulated for the preceding 3 weeks, do
TEE before cardioversion and proceed with cardioversion if no left
atrial thrombus is identified, including in the LAA(IIa B)
 AF or Atrial flutter <48 hrs and CHA2DS2-VASc Score >2(men) and < 3
(women):
 warfarin (INR 2.0 to 3.0), factor Xa inhibitor, direct thrombin inhibitor
is recommended as soon as possible before cardioversion ,followed
by long-term anticoagulation therapy(IIa B)
ACC/AHA 2019 guideline

Guide to oral anticoagulants

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