Chapter 90
Oral Anticoagulants: Current
Indian Scenario
Gopalakrishnan S, Srinivasan Narayanan
INTRODUCTION
The first coumarin derivative was crystallized in 1940 by Karl Link
and co-workers.1 Fourteen years later Coumadin (warfarin) was
approved for the use as an oral anticoagulant (OAC) medication and
became the most widely prescribed OAC drug. Later, other vitamin
K antagonist (VKA) such as phenprocoumon or acenocoumarol
(Acitrom) that differ mainly in their half-life were developed
and introduced for clinical use. Despite the disadvantages like
narrow therapeutic index, variable pharmacokinetics due to
genetic polymorphisms, variable dose response requiring frequent
monitoring, numerous drug and dietary interactions, the oral VKA
continued to be the most popular OAC as there were no other
options.
The introduction of the newer parenteral anticoagulant like
fondaparinux (selective factor Xa inhibitor approved in 2001) was a
milestone in anticoagulation because it provided proof of the concept
of selective factor Xa inhibition with excellent clinical results.2,3
The direct thrombin inhibitor ximelagatran first approved in 2003
was thought to be a breakthrough in oral anticoagulation, but had
to be withdrawn in 2006 due to a high incidence of hepatotoxicity.4
Since then, several newer OACs inhibiting a single activated clotting
factor either thrombin (factor IIa) (dabigatran etexilate) or factor Xa
(rivaroxaban, apixaban, edoxaban, betrixaban) have been developed.
Three of them have now found place in clinical practice in the West:
the direct factor Xa inhibitors rivaroxaban, apixaban, and the direct
thrombin inhibitor dabigatran etexilate (Table 1). Further factor Xa
inhibitors are in development.5 Of these newer anticoagulants only
dabigatran is currently available in India at present with edoxaban
and rivaroxaban are expected in the near future.
INDICATIONS FOR ORAL ANTICOAGULATION
IN THE PRESENT SCENARIO
The increasing need for OAC therapy for prevention and treatment
of cardioembolism and venous embolism balanced against the risk
of bleeding makes it imperative for the clinicians to optimize their
usage. Table 1 summarizes the indications for OAC therapy in the
present scenario.
ORAL ANTICOAGULANT DRUGS COMMONLY USED IN
INDIA
Warfarin (Coumadin)
The classical vitamin K receptor antagonist warfarin is a difficult drug
to use, with a narrow therapeutic index, with patients on warfarin
TABLE 1 │ Indications for oral anticoagulation
• Prophylaxis of cardiac thromboembolism in atrial fibrillation (AF),
severe left ventricular (LV) dysfunction, mechanical heart valves,
bioprosthetic heart valves (first 3 months), intracardiac thrombi,
heart valve disease with AF, large left atrial (LA) or history of
embolism/clot
• Treatment of deep vein thrombosis (DVT), pulmonary
thromboembolism and prevention of recurrence
• Prophylaxis for prevention of venous thromboembolism (VTE) in
high-risk patients, e.g. postorthopedic surgery
• Stroke prevention in nonvalvular atrial fibrillation (NVAF)
• Embolic peripheral arterial disease
walking a tight rope between bleeding and clotting. Sixty years after it
was introduced warfarin is still the mainstay of OAC treatment in India
and also the Western world. More than 2 million North Americans and
probably many more Indians take it and this number continues to grow
with the aging population. Warfarin comes in many tablet strengths: 1,
2, 2.5, 3, 4, 5, 6, 7.5, and 10 mg. Initiation of warfarin at a dose of 4–5
mg daily is recommended, with smaller doses indicated for the elderly
or debilitated patient. Loading doses are not recommended. Warfarin
may be begun concurrently with low-molecular weight heparin
(LMWH) or unfractionated heparin (UFH) and should be overlapped
for 4–5 days to prevent rebound thrombosis from fall in protein C levels.
Recommended international normal ratio (INR) range is according
to indication. Frequency of INR testing is variable over time, dictated
by dose response and clinical information. Initially check INR at least
four times per week in the first week of therapy followed by every
other day until a therapeutic range is achieved and maintained for two
consecutive tests. International normal ratio can then be checked twice
weekly for next 2–3 weeks as fluctuations are common. When the INR
and warfarin dose remain stable for an additional 2–3 weeks the testing
interval can be made every four weekly. International normal ratio tests
at no greater than 1 month intervals are recommended for patients who
have achieved a stable therapeutic INR.
Acenocoumarol/Nicoumalone (Acitrom)
Acitrom is similar to warfarin but with longer half-life and lesser
interactions. It is available as 1, 2 and 4 mg tablets.
NEWER ORAL ANTICOAGULANTS ON THE
ANVIL (TABLE 2)
Dabigatran is now available in India while edoxaban and rivaroxaban
are expected shortly.
 Section 11 Chapter 90  Oral Anticoagulants: Current Indian Scenario

TABLE 2 │ Profile of newer oral anticoagulants (OACs) in development6-15

Dabigatran Rivaroxaban Apixaban Edoxaban
Brand name Pradaxa®; Xarelto® Eliquis® Lixiana®;
Available in India Available in Japan
Status FDA approved October FDA approved November Under FDA Approved in Japan
2011-stroke prevention 2011-stroke prevention in NVAF, consideration for for VTE prevention
in NVAF primary VTE prevention after hip/ stroke prevention in after orthopedic
Under consideration for knee surgery NVAF surgery. FDA
treatment of DVT and PE Under consideration for treatment approval awaited
of DVT and PE
Target Factor IIa Factor Xa Factor Xa Factor Xa

Time to max plasma 1.25–313 2–414 1–312 1–311

concentration (hours)

T1/2 (hours) 12–1413 7–1114 8–1512 9–1111

Plasma protein binding 35%10 95%6 87%8 40–59%11

Excretion 80% renal13 66% renal15 25% renal12 35% renal

rest hepatic rest hepatic rest hepatic rest hepatic

Food effect Food delays absorption Food delays absorption Not reported Not reported

Drug p-gp inhibitors increases CYP3A4 inhibitors CYP3A4 inhibitors CYP3A4 inhibitors
interactions levels p-gp inhibitors increase levels p-gp inhibitors
increase levels

Dose regimen 110/150 mg/d bid 20 mg/d OD 2 x 2.5–5 mg/d bid 15–30 mg OD

Monitoring No No No No

Specific antidote No No No No
Pregnancy safety No No No No
List of clinical studies RE-NOVATE RECORD I–IV ADVANCE 1–3
RE-MODEL ROCKET-AF ARISTOTLE
RE-LY EINSTEIN-DVT AVERROES
RE-MOBILIZE EINSTEIN-PE
RE-COVER I,II EINSTEIN-EXT
RE-MEDY
Abbreviations: FDA, Food and Drug Administration; NVAF, Nonvalvular atrial fibrillation; DVT, Deep vein thrombosis; PE, Pulmonary embolism; VTE, Venous
thromboembolism; p-gp, P-glycoprotein; RE-LY, Randomized evaluation of long-term anticoagulant therapy; RE-MOBILIZE, RECORD I–IV, Regulation of coagulation
in orthopedic surgery to prevent deep vein thrombosis and pulmonary embolism; ROCKET-AF, Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with
vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation; ARISTOTLE, Apixaban for reduction of stroke and other thromboembolic events
in atrial fibrillation; AVERROES, Apixaban VERsus acetylsalicylic acid to pRevent strOkE in atrial fibrillation patientS who have failed or are unsuitable for vitamin K
antagonist treatment

ISSUES IN ORAL ANTICOAGULANT THERAPY anticoagulation in India. Use of concomitant antituberculous

PECULIAR TO INDIA
In India, currently vitamin K antagonist (VKA) drugs like warfarin
remains the number one agent of choice for oral anticoagulation
based on physician comfort due to years of usage and the prohibitive
cost of dabigatran. There are certain issues with warfarin peculiar to
India. Indians with their different dietary habits compared to their
Western brethren are more prone for warfarin-food interactions.
For example, inconsistent consumption of green leafy vegetables
like cabbage, cauliflower, spinach and other foods rich with vitamin
K in the Indian diet would prevent the achievement of target INR on
patients with warfarin/Acitrom and cause lability in INR values. A
lot of Indians are in the habit of taking over the counter medications
[e.g. nonsteroidal anti-inflammatory drugs (NSAIDs)/tramadol] or
alternative herbal products/foods (e.g. garlic, fenugreek) for various
disorders from body aches to fever to jaundice. These medications
again would increase the OAC action of the VKA and may cause
bleeding. Paracetamol is a frequently unrecognized cause of over
drugs like isoniazid (INH) or rifampicin can also alter INR values
and result in under or over anticoagulation. Indians with low body
weight and body mass index (BMI) require lesser doses of VKA to
achieve target INR compared to their Western counterparts and are
more prone to bleeding. Also during concurrent co-morbid illnesses
like fever, diarrhea, etc. lot of Indian patients omit the VKA and end
up in problems of low INR or more commonly take antibiotics like
metronidazole or macrolides and come with high INR/bleeding.
Amoxicillin and clindamycin do not have significant interaction
with warfarin and can be safely prescribed. Rarely the patients on
VKA develop conditions like viral hemorrhagic fevers (dengue)
complicating the overall scenario. Smoking causes enzyme induction
and potentially lowers the INR.
Another issue in India is monitoring of warfarin therapy. Majority
of places including suburbs of large cities lack proper laboratories
with standardized measurement of prothrombin time (PT)/INR.
An Indian study had shown that outpatient anticoagulant control
was generally poor with inadequate pretherapeutic assessment,

411
 Therapeutics
an unacceptably high proportion of subtherapeutic PT/INR values
and high complication rates.16 Another Indian study showed that
the knowledge base of clinicians in a large teaching institution was
unsatisfactory as far as OAC targets were concerned.17 There was a
tendency to under coagulate in view of the perceived risk of bleeding.
One Indian study reported that PT monitoring was irregular in 25%
of patients.18 They also found that in patients on mechanical heart
valves on VKAs the morbidity increased over years of follow-up
and inadequate anticoagulation is associated with increased risk
of stroke. In order to achieve better patient compliance and target
INR values as per the recommended guidelines for OAC there is a
pressing need for better patient education and physician/local
practitioner update of the various issues involved.
Recent advancements in pharmacogenetics have estab­ lished
that clinical outcomes in OAC therapy are affected by genetic
factors. There are large inter-individual and ethnic variations in
drug response to warfarin.19 Warfarin is metabolized primarily via
oxidation in the liver by CYP2C9, and exerts its anticoagulant effect
by inhibiting the protein vitamin K epoxide reductase complex,
subunit 1 (VKORC1). Two genetic variants known as CYP2C9`2 AND
CYP2C9`3 can lead to a reduced activity of CYP2C9. Three single
nucleotide polymorphisms (SNPs), two in the CYP2C9 gene and one
in the VKORC1 gene, have been found to play key roles in determining
the effect of warfarin therapy on coagulation.20 These three SNPs
play key roles in determining: (1) the dose of warfarin required to
produce a therapeutic INR (typically 2–3); (2) the risk of bleeding or
of producing supratherapeutic INR (> 4); and (3) the time required
to achieve a stable therapeutic dose. This is especially important
in the initial phases of OAC therapy. Since CYP2C9 AND VKORC1
act independently, the total genomic based warfarin variability
is presently believed to be at least 50%. So the US FDA in January
2010 made specific recommendations for dosage range initiation
in carriers of the CYP2C9 and VKORC1 variants as determined by
genotyping test. As no such testing is available in India we do not
have such recommendations to help us in warfarin dosage.
WHAT ARE THE ISSUES WITH WARFARIN
DOSING IN THE INDIAN POPULATION?
Warfarin is an extremely effective drug for stroke prevention in atrial
fibrillation (AF) patients, reducing stroke by 68% and mortality
by 26%. But about 60% of patients never get warfarin, around half
of patients who do get it stop taking it especially in the developing
world, and of those who still take it only half are in therapeutic range.
So, only a small minority are well treated.
The anticoagulation consensus guidelines that relate specially
to warfarin do not mention the influence of ethnicity on the typical
warfarin maintenance dose. In Asians the starting average dose
requirement was found to be 3.4 mg versus 5 mg in Whites in one
small study.21 The lower dose requirement in Asians was sufficiently
recognized to warrant special notation in the US FDA approved
labeling for warfarin.22 In addition to differences in dose there are
unanswered question about whether the risks of warfarin therapy
also differ by ethnicity. The large trials that established an INR range
of 2–3 to balance the benefits with the risks of warfarin therapy were
conducted exclusively in Whites. Data from Chinese and Japanese
studies suggest that Asians might require lower INR for protection
from thromboembolism and might be at increased risk of bleeding
at lower INR.23,24 Indian studies on warfarin dosing and risk/benefits
are lacking.
WARFARIN IN PREGNANCY: THE INDIAN SCENARIO
Vitamin K antagonists like warfarin should be avoided during
pregnancy unless absolutely indicated like, e.g. women with
mechanical heart valves. Warfarin is associated with up to 5% risk of
412
Section 11
teratogenesis if used between 6 weeks and 12 weeks of gestation. It
also increases the risk of miscarriage, fetal and maternal hemorrhage,
neurological problems in the baby and stillbirth. It is safe after
delivery and during breast-feeding. Warfarin is to be avoided if
pregnant or if contemplating pregnancy. The 2008 American College
of Chest Physicians (ACCP) guidelines25 for antithrombotic therapy
recommended one of three approaches for anti­coagulation during
pregnancy:
1. Aggressive adjusted-dose UFH throughout the pregnancy; heparin
is administered subcutaneously every 12 hours in doses adjusted
to keep the mid-interval activated partial thromboplastin time
(aPTT) at least twice control or to attain an anti-Xa level of 0.35–
0.70 U/mL. After a stable dose is achieved, the aPTT should be
measured at least weekly.
2. Adjusted-dose subcutaneous LMWH therapy throughout the
pregnancy in doses adjusted according to weight to achieve
the manufacturer’s recommended anti-Xa level 4 hours after
subcutaneous injection.
3. Unfractionated heparin or LMWH therapy (as above) until the
13th week, a change to warfarin until the middle of the third
trimester, and then restarting UFH or LMWH until delivery.
Long-term anticoagulation should be resumed postpartum
regardless of which regimen is used. Heparin can be restarted 12
hours post-cesarean delivery and 6 hours post-vaginal birth, if no
significant bleeding has occurred. Heparin is either continued
or replaced with warfarin (stopping the heparin when the INR is
therapeutic). All this needs close monitoring, frequent visits to an
anticoagulant clinic and is difficult to practice in the rural Indian
context where these facilities are lacking. The introduction of newer
anticoagulants like dabigatran is unlikely to change this scenario as
these newer agents are contraindicated in pregnancy as well.
This textbook recommendation for OAC in pregnancy is difficult
to practice in India as it is common for pregnancy to be diagnosed late
in the first trimester and for patients to continue warfarin26 in view of
them not being properly briefed earlier about the teratogenic effects.
Women of childbearing age receiving warfarin should be warned
about the teratogenic and harmful effects of warfarin especially in
early pregnancy. They should be advised to use secure methods of
contraception while on warfarin. If pregnancy is suspected, early
pregnancy test 5 weeks from last menstrual period must be offered.
Conversion to therapeutic once daily LMWH prior to conception is
difficult to practice in India.
WHAT IS THE ROLE OF NEWER ANTICOAGULANTS IN
THE INDIAN SCENARIO?
Current Indications for Newer Anticoagulants27
• Postoperative thrombotic prophylaxis after major ortho-pedic
surgery
• Stroke prophylaxis in nonvalvular atrial fibrillation (NVAF)
• Treatment of DVT and prevention of recurrent thrombo-
embolism and treatment of pulmonary embolism (PE) are
evolving indications.
Advantages and Disadvantages of Newer
Anticoagulants28
Advantages
• Rapid onset of action, so no need for bridging therapy
• Short half-life, so easy control of anticoagulant effect
• Little or no food interaction, so no dietary restrictions like
warfarin
• Limited drug interactions unlike warfarin
• Predictability of anticoagulation effect without a need for routine
coagulation monitoring.
 Section 11 Chapter 90  Oral Anticoagulants: Current Indian Scenario
Disadvantages
• Prohibitively high cost resulting in poor compliance
• No monitoring is possible if needed
• No specific antidote
• Serious bleeding in renal impaired patients and elderly more
than 80 years. If glomerular filtration rate (GFR) is 15–30 mL/min,
warfarin should be preferred.
WILL THE NEWER AGENTS COMPLETELY
REPLACE WARFARIN?
The obvious first groups of patients who should be candidates for the
new drugs are:
• Patients with unexplained poor control due to unavoidable drug
interaction (unless contraindicated)
• New patients naive to oral anticoagulation after briefing them on
the various issues involved
• Those with unstable INRs on warfarin.
Should we decide to extend the use of these agents to other patient
subsets like valvular AF, mechanical valves and hypercoagulable
states?29 The answer seems to be no especially in cases with renal
failure or gastrointestinal disease (ulcerations, polyps, tumors)
who are prone to bleed. Also patients with mechanical heart valve
prosthesis should remain on VKA because the newer anticoagulants
have not been tested for this indication. All newer anticoagulants are
contraindicated in pregnancy and lactation. It shall be a while before
warfarin is replaced in clinical practice!
CONCLUSION
Cost factors, compliance and dietary patterns need to be kept in mind
while prescribing OACs in India. It remains to be seen how the new
agents will perform in the long run in real-life situations in the Indian
population compared to the good old warfarin with which we all are
familiar with for over 50 years. Future research should attempted to
find out the best pharmacodynamics monitoring tools for factors Xa
and IIa inhibitors, the best therapeutic targets and dosing strategies
so that we can use OACs in a safe and efficacious manner for various
extended indications.
REFERENCES
1. Campbell HA, Roberts WL, Smith WK, et al. Studies on the hemorrhagic
sweet clover disease. I. The preparation of hemorrhagic concentrates. J
Biol Chem. 1940;136:47-55.
2. Bauer KA, Eriksson BI, Lassen MR, et al. Fondaparinux compared
with enoxaparin for the prevention of venous thromboembolism after
elective major knee surgery. N Engl J Med. 2001;345:1305-10.
3. Eriksson BI, Bauer KA, Lassen MR, et al. Fondaparinux compared with
enoxaparin for the prevention of venous thromboembolism after hip-
fracture surgery. N Engl J Med. 2001;345:1298-304.
4. Testa L, Bhindi R, Agostoni P, et al. The direct thrombin inhibitor
ximelagatran/melagatran: a systematic review on clinical applications
and an evidence based assessment of risk benefit profile. Expert Opin
Drug Saf. 2007;6:397-406.
5. Weitz JI. Factor Xa and thrombin as targets for new oral anticoagulants.
Thromb Res. 2011;127:S5-12.
6. Xarelto: Summary of Product Characteristics. [online] Available from
www.xarelto.com/en/information-on-xarelto/summary-of-product-
characteristics. [Accessed December, 2012].
7. Tzeis S, Andrikopoulos G. Novel anticoagulants for atrial fibrillation: a
critical appraisal. Angiology. 2012;63:164-70.
8. Eliquis. Summary of Product Characteristics. [online] Available from
www.eliquis.eu/eliquis_smpc.aspx. [Accessed December, 2012].
9. Cabral KP, Ansell J, Hylek EM. Future directions of stroke prevention
in atrial fibrillation: the potential impact of novel anticoagulants and
stroke risk stratification. J Thromb Haemost. 2011;9:441-9.
10. Pradaxa. Summary of Product Characteristics. [online] Available from
www.pradaxa.com. [Accessed December, 2012].
11. Ogata K, Mendell-Harary J, Tachibana M, et al. Clinical safety,
tolerability, pharmacokinetics, and pharmacodynamics of the novel
factor Xa inhibitor edoxabanin healthy volunteers. J Clin Pharmacol.
2010;50:743-53.
12. Raghavan N, Frost CE, Yu Z, et al. Apixaban metabolism and
pharmacokinetics after oral administration to humans. Drug Metab
Dispos. 2009;37:74-81.
13. Stangier J, Rathgen K, Stahle H, et al. The pharmacokinetics,
pharmacodynamics and tolerability of dabigatran etexilate, a new oral
direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol.
2007;64:292-303.
14. Kubitza D, Becka M, Wensing G, et al. Safety, pharmacodynamics, and
pharmacokinetics of BAY 59-7939—an oral direct Factor Xa inhibitor—
after multiple dosing in healthy male subjects. Eur J Clin Pharmacol.
2005;61:873-80.
15. Weinz C, Schwarz T, Kubitza D, et al. Metabolism and excretion of
rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and
humans. Drug Metab Dispos. 2009;37:1056-64.
16. Kakkar N, Kaur R, John M. Outpatient oral anticoagulant management:
an audit of 82 patients. JAPI. 2005;53:847-52.
17. Kakkar N, Kaur R. Knowledge base of clinicians regarding oral
anticoagulant therapy in a teaching institution: a questionnaire based
survey. JAPI. 2004;52:868-72.
18. Praveen SV, Sankar V, Fassaludeen M, et al. Predictors of morbidity in
mechanical prosthetic heart valves. Indian Heart J. 2005;57:464.
19. Rathore SS, Agarwal SK, Pande S, et al. Pharmacogenetic aspects
of coumarinic oral anticoagulant therapies. Indian J Clin Biochem.
2011;26:222-9.
20. Shah SH. (2011) Warfarin Dosing and VKORC1/CYP2C9. [online]
Available from emedicine.medscape.com/article/ 1733331-overview.
[Accessed December, 2012].
21. Dang MT, Hambleton J, Kayser SR. The influence of ethnicity on
warfarin dosage requirement. Ann Pharmacother. 2005; 39:1008-12.
22. Huang SM, Temple R. Is This the Drug or Dose for You?: ­Impact and
Consideration of Ethnic Factors in Global Drug Develop­ment, Regulatory
Review, and Clinical Practice. [online] ­ Available from www.fda.gov/
downloads/Drugs/Science­Research/Research Areas/Pharmacogenetics/
UCM085483.pdf. [Access date 7th December, 2012].
23. You JH, Chan FW, Wong RS, et al. Is INR between 2.0 and 3.0 the optimal
level for Chinese patients on warfarin therapy for moderate-intensity
anticoagulation? Br J Clin Pharmacol. 2005;59:582-7.
24. Suzuki S, Yamashita T, Kato T, et al. Incidence of major bleeding
complication of warfarin therapy in Japanese patients with atrial
fibrillation. Circ J. 2007;71:761-5.
25. Bates SM, Greer IA, Pabinger I, et al. Venous thromboembolism,
thrombophilia, antithrombotic therapy, and pregnancy: American
College of Chest Physicians Evidence-Base Clinical Practice Guidelines
(8th edn). Chest. 2008;133:844S.
26. Bharat V, Sinha R, Das NK, et al. Pregnancy in women with mechanical
heart valves. The anticoagulation dilemma. Indian Heart J. 2005;57:462.
27. Graf L, Tsakiris DA. Anticoagulant treatment: The end of the old agents?
Swiss Med Wkl. 2012;142:w13684.
28. Moser M, Bode C. Anticoagulation in atrial fibrillation – a new era has
begun. Hamostaseologie. 2012;32:37-9.
29. Kaluski E, Maher J, Gerula CM. New oral anticoagulants: good but not
good enough. JACC. 2012;60:1434.
413