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6
CHAPTER
Changing Landscape of Oral Anticoagulants:
The Last Pieces of the Puzzle
Anjan Lal Dutta, Ratnesh N Rokade, Rajarshi Dutta
INTRODUCTION
DABIGATRAN
Vitamin K antagonists (VKAs), like warfarin and related
coumarin derivatives, remained the mainstay of management
of thromboembolic events for more than 5 decades. But
warfarin and allied drugs have its own limitations. Novel oral
anticoagulants (NOACs) have emerged in recent years. They can
be divided broadly into:
•• Direct thrombin inhibitor: Dabigatran
•• Direct factor Xa inhibitors: Rivaroxaban, apixaban, and
edoxaban.
Dabigatran etexilate, a prodrug of dabigatran, is a small molecule
that binds to both free and clot bound thrombin. Dabigatran is
predominantly excreted through kidneys. Creatinine clearance
(CrCl) should be checked in all patients before starting treatment
with dabigatran. Those with CrCl less than 30 mL/min should not
receive this drug. Patients with CrCl between 30 mL/min and 50
mL/min should receive 110 mg twice daily (BID) or 75 mg BID
depending upon other comorbid conditions like concomitant use
of antiplatelet (usually not recommended), strong P-glycoprotein
inhibitors like verapamil, quinidine, dronedarone, etc. When
verapamil taken together, it causes increased area under curve
(AUC) of dabigatran by 12–180%, hence a reduced dose of
dabigatran is suggested when taken with verapamil.1 When used
in low CrCl, regular renal functions should be monitored. The
overdose of dabigatran can be corrected with diuresis.
The drug should be taken with food or water to minimize
dyspepsia. Food does not affect its bioavailability. If a dose is
missed, it should be taken within 6 hours. It can be continued
without interruption, in those undergoing cardioversion.
The NOACs, unlike warfarin and other VKAs, have advantages
as follows:
•• Rapid onset of action: Peak onset 1–4 hours; all of them thus
act more or less immediately over the same time course as the
low-molecular-weight heparin (LMWH).
•• Fixed dose: They can be given in fixed doses. There is no effect
of dietary vitamin K intake on the pharmacological activities
of these drugs.
•• Drug-to-drug interactions are much fewer compared to
warfarin.
•• All NOACs produce a good predictable response and have
an extremely wide therapeutic window for which routine
anticoagulation monitoring is not required.
•• All NOACs have a half-life approximately of 12 hours, therefore
anticoagulant effect mostly last for 24–48 hours, making it
more user-friendly in serious bleeding or urgent surgery.
Clinical indications of these NOACs are however limited
to stroke prevention in nonvalvular atrial fibrillation (AF), the
treatment and prevention of venous thromboembolism (VTE)
and pulmonary embolism (PE). This is unlike warfarin and
its allied drugs which are also used in valvular AF including
prosthetic valves AF in addition to VTE and PE.
RIVAROXABAN
Rivaroxaban is a direct Xa inhibitor, both free and clot associated
and is taken once daily (20 mg/day) with food. It is eliminated
mainly via liver. However, a dose of 15 mg/day is suggested when
CrCl is 15–30 mL/min. Pharmacokinetics of the drug is affected by
P-glycoprotein inhibitors, cytochrome P-450, member CYP3A4,
but not CYP2C9 (like warfarin). Since atorvastatin, simvastatin,
and lovastatin are metabolized through CYP3A4 dose adjustment
of rivaroxaban (reduction of dose) may be required when these
drugs are used concomitantly. Use of potent inhibitors of CYP3A
family like ketoconazole and itraconazole, macrolide antibiotics
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SECTION 1: Clinical and Preventive Cardiology
like erythromycin, clarithromycin (but not azithromycin),
diltiazem, nicardipine, verapamil, and cyclosporine, etc. also
calls for reduction of rivaroxaban dose. Thu, only a minor
interaction between verapamil and rivaroxaban is reported
unlike interaction of verapamil and dabigatran, and verapamil
and edoxaban.1 Fluvastatin and, to a certain extent, rosuvastatin
is metabolized through CYP2C9 and thus its concomitant use
does not call for dose reduction of rivaroxaban. Rivaroxaban can
be continued without switching to warfarin in patient undergoing
cardioversion.
APIXABAN
Apixaban is another direct oral Xa inhibitor, emerging as one with
least bleeding complications and greater efficiency compared to
other NOACs. The drug is predominantly metabolized in liver
and not accumulated in patient with mild-to-moderate renal
impairment. It is metabolized through CYP3A4 and is a mild
P-glycoprotein inhibitor. However clinical studies till date were
found to be safe with concomitant use of drugs metabolized
through these pathways.2 Like rivaroxaban and dabigatran, it can
be continued uninterrupted during cardioversion in AF.
EDOXABAN
Edoxaban is the newest Xa inhibitor approved in Japan for VTE
prevention after elective hip and knee replacement. Although it
has the largest trial for prevention of stroke in 21,105 nonvalvular
AF patients with largest follow-up of 2.8 years across 46 countries
that has been presented in American Heart Association (AHA)
Scientific Session in 2013; till April 2014 it has been not approved
for stroke prevention in AF. The drug is eliminated through
multiple pathways with 49% renal clearance. The usual dose
is 30 mg BID but is reduced to 15 mg/day in the trial protocol
in the following three subpopulation groups: (i) CrCl 30–50
mL/min (CrCl < 30 mL/min were excluded from this study);
(ii) body weight less than 60 kg; (iii) concomitant use of strong
P-glycoprotein inhibitors. Concomitant use of verapamil
increases AUC of edoxaban by 53%, a decrease of edoxaban dose
by 50% is thus recommended when used along with verapamil.1
For stroke prevention in AF, NOACs are found useful and
indicated only in nonvalvular AF. Dabigatran was found to
increase mortality and morbidity compared to warfarin when
used in mechanical heart valve [Randomised phase II to
Evaluate the sAfety and pharmacokinetics of oraL dabIGatran
etexilate in patients after heart valve replacemeNt (RE-ALIGN)
trial].3 Various trials of NOACs in different clinical settings are
enumerated in Table 1.
All these studies suggest that:
•• Novel oral anticoagulants are noninferior to and often
superior to warfarin. This is evident in stroke prevention in AF
in RE-LY (Randomized Evaluation of Long-term anticoagulant
Therapy) study with dabigatran in 150 BID dose and with
apixaban in ARISTOTLE (Apixaban for Reduction in Stroke
and Other Thromboembolic Events in Atrial Fibrillation)
trial.6
•• Bleeding complication, particularly intracranial hemorrhage
(ICH) is significantly lower with dabigatran 110 mg BID dose
and with apixaban compared to warfarin.
•• Gastrointestinal (GI) bleeding was seen more with NOACs.
•• Apixaban has overall lower bleeding events compared to
warfarin.
•• So far as venous thromboembolic (VTE) events are concerned,
NOACs were found to be noninferior to warfarin with similar
to lower bleeding events. In HoKusai VTE trial,15 edoxaban in
a subgroup of patients with severe PE with evidence of right
ventricular dysfunction, reduced number of recurrent VTE
significantly compared to warfarin.
•• Compared to placebo clinical outcomes with NOACs on
VTE were significantly better with more bleeding event than
placebo with rivaroxaban, marginally more bleeding than
placebo with dabigatran and significantly less bleeding events
with apixaban than placebo.
CONCOMITANT USE OF NOAC AND
DIGOXIN
•• Digoxin: It is P-glycoprotein inhibitor and also a commonly
used drug in AF. The question arises how safe it is when used
with NOACs.
•• Dabigatran: Concomitant use of digoxin has been shown
to result in small, clinically nonsignificant, rise of plasma
dabigatran levels. However in practice the concomitant use
appears safe and effective.18
•• Apixaban: Coadministration of digoxin 0.25 mg/day has
neither clinically significant interaction, nor did it cause any
effect on digoxin AUC or maximum plasma concentration
(Cmax) (ARISTOTLE trial).
•• Rivaroxaban: There is no clinically relevant interaction
between digoxin and rivaroxaban.19
•• Edoxaban: No clinically significant difference is noted in
pharmacodynamics or pharmacokinetics of edoxaban and
digoxin when used concomitantly.20
TRANSITION TO ORAL VITAMIN K
ANTAGONISTS FROM NOVEL ORAL
ANTICOAGULANTS
A high incidence of stroke was noted at the end of different trials
(during wash-out period) when patients initially randomized to
NOAC were shifted to warfarin. This was because of short halflife period of NOACs and relatively long starts to action period of
warfarin. It is now recommended that in transition to open label
VKA, an overlap of treatment with NOAC and VKA is to be done
until international normalized ratio (INR) of at least 2 is reached.
BLEEDING IN PATIENTS RECIEVING
NOVEL ORAL ANTICOAGULANTS
By and large, NOACs and warfarin have similar risk of bleeding.
The differences between the two are:
•• Intracranial hemorrhage is significantly less with NOACs
as reported in all trials (Table 1). Since major mortality and
morbidity in patients receiving anticoagulation arise from ICH,
this was indeed a major advantage of NOACs over warfarin.
•• There is relatively increased risk of GI bleeding in NOACs
compared to warfarin. Increased GI bleeding in NOACs
has been attributed to decreased absorption of NOAC from
CHAPTER 6: Changing Landscape of Oral Anticoagulants: The Last Pieces of the Puzzle
TABLE 1: Trials with novel oral anticoagulants (NOACs)
Drug
AF
Dabigatran vs warfarin
Study
Outcome
Bleeding risk
RE-LY4 (N = 18,113)
150 mg BID: Superior to warfarin for
reduction of SSE (1.11% vs 1.64%)
110 mg BID: Noninferior to warfarin
Rivaroxaban vs warfarin
ROCKET-AF5 (N = 14,266)
Noninferior to warfarin in preventing
SSE (1.7% vs 2.2%)
Apixaban
ARISTOTLE6 (N = 18,201)
Superior to warfarin in preventing
SSE (1.27% vs 1.6%)
Edoxaban
ENGAGE AF-TIMI 487 (N = 21,105)
60 mg, superior to warfarin
30 mg, noninferior to warfarin
Similar major bleeding with 150 BID
(3.11% vs 3.36%)
Significant lower bleeding rates with
110 mg BID (2.7% vs 3.36%)
Major GI bleeding with 150 mg BID
Significantly lower ICH with both
doses of dabigatran
Similar bleeding events (14.9% vs
14.5%)
Significantly fewer ICH than warfarin
(0.5% vs 0.7%)
Fewer bleeding events (2.13%
vs 3.09%) significantly lower
hemorrhagic stroke
Hemorrhagic strokes reduced by
51% and ischemic stroke by 13%
compared to warfarin
RECOVER8
REMEDY (extended use)9
150 mg BID: Noninferior to warfarin
in VTE prevention (2.4% vs 2.1%)
Noninferior to warfarin, better than
placebo (0.4% vs 5.6%)
Noninferior to warfarin for DVT (2.1%
vs 3.0%)
Noninferior to warfarin for PE (2.1%
vs 1.8%)
Superior to placebo (1.7% vs 7.1%)
Noninferior to placebo (2.3% vs 2.7%)
Superior to placebo (1.7% vs 8.8%)
In DVT, nonsuperior to warfarin
In PE, superior to warfarin
No difference in major bleeding
No significant difference with
warfarin
Reduced mortality from
cardiovascular causes versus placebo
(2.7% vs 4.1%)
No benefit in ischemic events versus
placebo
More major bleeding (2.1% vs 0.6%)
ICH (0.6% vs 0.2%)
VTE
Dabigatran
Rivaroxaban
EINSTEIN DVT10
EINSTEIN PE11
EINSTEIN EXTENSION12
Apixaban
Edoxaban
AMPLIFLY13
AMPLIFLY (EXTENSION)14
HoKusai VTE15
ACS
Rivaroxaban
ATLAS ACS-2 TIMI-5116
Apixaban
APRAISE-217
Similar to warfarin for DVT
Lower than the warfarin for PE
More bleeding events than placebo
(6% vs 1.2%)
Less bleeding than the placebo
Less bleeding than the placebo
Similar (8.5% vs 8.8%)
Early increase in major bleeding
Abbreviations: AF, atrial fibrillation; RE-LY, Randomized Evaluation of Long-term anticoagulant Therapy; BID, twice daily; GI, gastrointestinal; ICH, intracranial hemorrhage; SSE, stroke
and systemic 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 in Stroke and Other Thromboembolic Events in Atrial Fibrillation; ENGAGE AF-TIMI 48, Effective Anticoagulation with Factor Xa
Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48; VTE, venous thromboembolism; RECOVER, Efficacy and Safety of Dabigatran Compared to Warfarin
for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism; EINSTEIN DVT, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep Vein
Thrombosis; DVT, deep vein thrombosis; EINSTEIN-PE, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; PE, pulmonary embolism;
ACS, acute coronary syndrome; ATLAS ACS-2 TIMI-51, Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome Acute
Coronary Syndrome 2-Thrombolysis In Myocardial Infarction 51; APRAISE-2, Apixaban for Prevention of Acute Ischemic Events-2 A Phase 3, Randomized, Double-Blind, Evaluation of the
Safety and Efficacy of Apixaban In Subjects With a Recent Acute Coronary Syndrome
gut. Use of proton-pump inhibitors (PPIs) has not been
adequately studied to ascertain whether it affects absorption
of the drug. Although there is no specific antidote for NOACsinduced bleeding, but its short duration of action (if CrCl is
normal) is an important point of advantage over warfarin.
Taking dabigatran with food and water may decrease risk of
GI bleeding without interfering bioavailability. Apixaban in
particular is associated with reduced GI bleeding. Overall
incidence of bleeding with NOACs tends to be greater with
greater decrease in renal functions, particularly in case of
dabigatran. Concomitant use of antiplatelet and non-steroidal
anti-inflammatory drugs (NSAIDs) increases the risk of GI
bleed.
ACUTE CORONARY EVENTS AND
NOVEL ORAL ANTICOAGULANTS
The original RE-LY study4 suggested a small increase in
myocardial infarction with dabigatran. A subsequent metaanalysis confirmed this increased risk (1.19% vs 0.79%)21 which
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SECTION 1: Clinical and Preventive Cardiology
was also noted in extended-use study of VTE in which acute
coronary syndrome (ACS) occurred in 13 patients on dabigatran
as against three patients in warfarin group.22 The unusual
difference was thought to be due to better risk reduction with
warfarin rather than increased risk due to dabigatran.2
RENAL IMPAIRMENT AND NOVEL
ORAL ANTICOAGULANTS
Novel oral anticoagulants should not be given to patients with
severe renal impairment (CrCl < 15–30 mL/min) and those on
dialysis. Dabigatran is renally cleared and may not be the choice
in patients with renal impairment patients. However if it is used,
then it should be used in reduced dosage as 110 mg BID in patient
with CrCl 30–49 mL/min, and as 75 mg BID with CrCl 15–30 mL/
min with constant renal function monitoring. No NOACs should
be used when CrCl is less than 15 mL/min.
If CrCl is 15–49 mL/min rivaroxaban should be given 15 mg
once daily instead of 20 mg once daily.
Although bleeding rates are surprisingly low with apixaban
in renal impairment, because of its reduced dependency on renal
clearance, yet in CrCl 15–29 mL/min, apixaban is recommended
to be given at dose of 2.5 mg BID instead of usual dose of 5 mg BID.
There is no data available about edoxaban use in renal
impairment in HoKusai VTE trial.15
WARFARIN VERSUS NOVEL ORAL
ANTICOAGULANTS: A REVISIT
Managing AF with warfarin with good INR is equally effective as
NOACs. In the treatment with warfarin, average individual time
in therapeutic range (TTR) and the risks of stroke and major
bleed are inversely correlated. If TTR is less than 50%, it means
INR remains abnormal in half of the time. So the chance of
cardioembolic stroke is high if abnormality of INR is in the form
of lower than optimal range and hemorrhagic stroke is high if
INR is more than optimal range. Patient on warfarin having TTR
more than 70% will have a low risk of stroke and hemorrhage. In
patients who cannot achieve high TTR, NOACs may be a good
choice. However it is unclear whether high TTR translates to
equally good outcomes only in patients with AF or also in VTE.2
One of the inconvenience of warfarin is its monitoring. However
Schulman et al23 have shown that INR monitoring at every 4
week is as safe as every 12 weeks and that TTR does not differ
much (74.1% with 4-weekly monitoring vs 71.6% with 12-weekly
monitoring). NOACs remain a better option when adjusting
warfarin dose is not feasible, in different situations as follows:
•• Logistics and lifestyle issues for which INR monitoring is not
properly done.
•• Patients with side effects of warfarin like hair loss, skin rashes.
•• Patients with wide fluctuations if INR is probably due to
genetic polymorphisms.
•• Patients taking other drugs that interfere with metabolism of
warfarin.
•• Patients taking frequent short courses of antibiotics because
of recurrent infections.
CONCLUSION
Arrival of NOACs in the treatment of AF and VTE has equipped us
to deal with disadvantages of warfarin and allied drugs. However,
beyond trial reports, lessons should be learnt from real world
cases. Use of NOACs should be encouraged, but then all NOACs
are not the same; which one to use and when should depend to
a large extent on patient’s characteristics and physician’s choice.
Junior doctors and nursing staff should be familiar with these
agents as they are with warfarin. However the last piece of puzzle
remains the cost of these newer medicines in India. Hopefully
this stumbling stone will, in near future, with greater use and
lower price, turn into stepping stone that will help us manage
anticoagulation with great ease.
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