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130 Anticoagulation Therapy
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*33. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk
pulmonary embolism. N Engl J Med. 2014;370(15):1402-1411.
*34. Sharifi M, Bay C, Skrocki L, et al. Moderate pulmonary embolism treated with
thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111(2):273-277.
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37. Gonzaga T, Jenabzadeh K, Anderson CP, et al. Use of intraarterial thrombolytic therapy
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Stulak, J, Dunlay S, Sharma S, et al. Treatment of device thrombus in the HeartWare
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7
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Chapter
DIRECT ORAL ANTICOAGULANTS
Allison E. Burnett and Candice L. Garwood
INTRODUCTION
Since 2010, four direct oral anticoagulants (DOACs) have become commercially
available in the United States: dabigatran, a direct thrombin inhibitor (DTI); and
rivaroxaban, apixaban, and edoxaban, which are direct factor Xa (FXa) inhibitors
(Table 7-1). The availability of DOACs has significantly changed the therapeutic
TABLE 7-1: Commercially Available Direct Oral Anticoagulants
Dabigatran Rivaroxaban Apixaban Edoxaban
Mechanism of
action
Manufacturer Boehringer-
Brand name(s) Pradaxa Xarelto Eliquis Savaysa (U.S.)
Approved
indications
*Betrixaban, another direct factor Xa inhibitor, was recently FDA-approved for extended prophylaxis
among medical patients. Due to the recency of approval and the limited uptake in clinical practice to
date, this agent will not be discussed in this chapter.
**In the United States, dabigatran is approved only for post-operative VTE prophylaxis in hip arthroplasty.
***European Union only.
****Japan only.
FIIa: thrombin, FXa: Factor Xa, VTE: venous thromboembolism
Direct FIIa
(thrombin) inhibitor
Ingelheim
Post-operative VTE
prevention in knee
or hip arthroplasty**
VTE treatment
and prevention of
recurrence
Stroke and
systemic embolism
prevention in
non-valvular atrial
fibrillation
Direct FXa inhibitor Direct FXa inhibitor Direct FXa inhibitor
Bayer with Ortho
McNeil
Post-operative VTE
prevention in knee
or hip arthroplasty
VTE treatment
and prevention of
recurrence
Stroke and
systemic embolism
prevention in
non-valvular atrial
fibrillation
Acute coronary
syndrome***
Pfizer with Bristol
Myers Squibb
Post-operative VTE
prevention in knee
or hip arthroplasty
VTE treatment
and prevention of
recurrence
Stroke and
systemic embolism
prevention in
non-valvular atrial
fibrillation
Daiichi Sankyo
Lixiana (non-U.S.)
Post-operative
VTE prevention
in knee or hip
arthroplasty****
VTE treatment
and prevention of
recurrence
Stroke and
systemic embolism
prevention in
non-valvular atrial
fibrillation
1-6,*
131
132 Anticoagulation Therapy
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landscape of anticoagulation. Clinician familiarity with these agents, particularly their markedly different pharmacologies compared to conventional
therapies, is needed for optimal patient care (Table 7-2). This chapter will
provide a concise overview of the pharmacology, safety, and efficacy data
as well as some practical management aspects pertaining to DOACs. Refer
to other chapters in this book for additional information regarding optimal
DOAC management.
• Based on safety and efficacy data from large,
randomized controlled trials (Table 7-3) of
over 100,000 patients,
7-17
these agents are
now preferred over conventional therapies
(e.g., vitamin K antagonists, low-molecularweight heparins) for common anticoagulation
indications (e.g., non-valvular atrial
fibrillation, non-cancer-associated venous
thromboembolism).
18-20
PHARMACOLOGY
The DOACs possess intrinsic anticoagulant activity and do not require
binding to cofactors to exert their effect. Thus, they are considered direct
anticoagulants. Because of their small molecular size (~500 daltons) and
lack of binding to bulky cofactors, DOACs are able to penetrate coagulation complexes on phospholipid surfaces and inhibit both clot-bound and
free-floating thrombin. Each DOAC inhibits a single serine protease target
(dabigatran inhibits thrombin [FIIa]; rivaroxaban, apixaban, and edoxaban
inhibit FXa) within the common pathway of the coagulation cascade (Figure
7-1). This specificity provides several practical advantages of DOACs over
conventional anticoagulation therapies.
21
• Compared to conventional anticoagulants (e.g.,
heparins, warfarin) that inhibit multiple serine
proteases within the coagulation cascade, the
DOACs inhibit a single procoagulant target.
This increased specificity provides a linear dose
response and wide therapeutic index, allows for
fixed dosing, and precludes the need for routine
monitoring of the anticoagulant effect of DOACs
in most patients.
DIRECT ORAL ANTICOAGULANTS 133
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Phase of
coagulaon
Iniaon
Amplificaon
Propagaon
Protein C
TM
Coagulaon
Drug
pathway
TF/VIIa
IX, XI,XII
X
+2
PL, Ca
IXa
VIIIa
Apixaban
Xa
IIa
Va
PLT
II
PLT
Rivaroxaban
PLT
PLT
Edoxaban
PLT
PLT
Dabigatran
FIGURE 7-1. Mechanism of Action of the Direct Oral
Anticoagulants
Ca+2: calcium ions, PL: phospholipid, PLT: platelet, TM: thrombomodulin, TF: tissue
factor, II, IX, X, XI, XII: inactive clotting factors, IIa, Va, VIIa, VIIIa, IXa, Xa: activated
clotting factors
Fibrinogen Fibrin
134 Anticoagulation Therapy
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PHARMACOKINETICS/PHARMACODYNAMICS
OF WARFARIN AND THE DOACS
TABLE 7-2: Comparison of the Pharmacokinetics and
Pharmacodynamics of Oral Anticoagulants
PK/PD
Parameter
Target(s) IIa, VIIa, IXa, XaIIa Xa Xa Xa
Prodrug No Yes No No No
Bioavailability
(%)
Volume of
distribution
(L)
Peak effect 4–5 days 1.5–3 hr 2–4 hr 1–3 hr 1–2 hr
Half-life* 40 hr 12–17 hr 5–9 hr 9–14 hr 10–14 hr
Renal
elimination
Protein
binding
Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban
80–100 6.5 (pH
dependent)
10 50–70 50 23 >107
None 80% 33% 25% 35–50%
>99% 35% 90% 87% 55%
80 50 62
1-4,21
Dialyzable No Ye s No No Possible
Interactions Numerous P-gp 3A4, P-gp 3A4, P-gp P-gp
Coagulation
monitoring
Lab measure INR aPTT
Antidote Vitamin K Idarucizumab No No No
*In patients with normal renal function.
anti-Xa: anti-Factor Xa, aPTT: activated partial thromboplastin time, dTT: dilute thrombin
time, ECT: ecarin clotting time, hr: hour, INR: international normalized ratio, L: liters, P-gp:
p-glycoprotein efflux transporter, PT: prothrombin time, TT: thrombin time, 3A4: cytochrome P450
3A4, IIa: thrombin, Xa: Factor Xa, VIIa: factor VIIa, XIa: factor XIa
COMPLETED AND ONGOING PHASE III
TRIALS OF DOACS
See Table 7-3: Phase III Clinical Trials of DOACs beginning on the next page.
Yes No No No No
Anti-Xa Anti-Xa
TT, dTT, ECTPTAnti-Xa
22
Anticoagulation
Prevention of VTE
STARS-JV
Prevention of VTE
Prevention of VTE in
acute medical illness
Treatment of VTE
Extended treatment
for prevention of
VTE recurrence
Splanchnic vein
Cerebral venous
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DIRECT ORAL ANTICOAGULANTS 135
(continued)
COVET
Dabigatran Rivaroxaban Apixaban Edoxaban
Completed Ongoing Completed Ongoing Completed Ongoing Completed Ongoing
ADVANCE-3 STARS-E3
RECORD-1
RECORD-2
EPCAT II
RE-NOVATE
RE-NOVATE II
ADVANCE-1
ADVANCE-2
RECORD-3
RECORD-4
EPCAT II
RE-MODEL
RE-MOBILIZE
MAGELLAN MARINER ADOPT
AMPLIFY-EXT RENOVE
AMPLIFY HOKUSAI
RENOVE
COVET
EINSTEIN-DVT
EINSTEIN-PE
EINSTEIN-EXT
EINSTEIN-
RE-COVER
RE-COVER II
RE-SONATE
RE-MEDY
NCT02627053
CHOICE
RE-SPECT CVT
Indication
TABLE 7-3: Phase III Clinical Trials of DOACs
in THR
in TKR
thrombosis
thrombosis
136 Anticoagulation Therapy
Anticoagulation
Cancer-associated
APLA-associated
Treatment of VTE in
renally impaired
VTE treatment in
pediatric patients
Stroke prevention in
NVAF cardioversion
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HOUKUSAI
VTE CANCER
CARAVAGGIO
NCT02585713
ENGAGE AF-
TIMI 48
AVERROES
(continued)
PCI
NCT03240120 CASSINI
Dabigatran Rivaroxaban Apixaban Edoxaban
Completed Ongoing Completed Ongoing Completed Ongoing Completed Ongoing
Indication
TABLE 7-3: (Continued)
CALLISTO
MERCURY PE
thrombosis
Outpatient
treatment of
RAPS ASTRO-APS
low-risk PE
thrombosis
VERDICT VERDICT
EINSTEIN Junior NCT02464969 NCT02798471
ROCKET-AF ARISTOTLE
NCT02197416
NCT01895777
RE-LY
RELY-ABLE
NVAF
NVAF ablation RE-CIRCUIT VENTURE-AF
CAPITAL PCI AF AUGUSTUS ENTRUST-AF-
X-VERT AFTER-CV ENSURE-AF
PCI
NVAF and PCI REDUAL-PCI PIONEER AF
Anticoagulation
Secondary stroke
AREST
Cryptogenic stroke
Mechanical heart
defibrillator surgery
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ATTICUS
DIRECT ORAL ANTICOAGULANTS 137
BRUISE-
CONTROL-2
APPRAISE
(continued)
X-TRA
Dabigatran Rivaroxaban Apixaban Edoxaban
Completed Ongoing Completed Ongoing Completed Ongoing Completed Ongoing
Indication
TABLE 7-3: (Continued)
NVAF with LA
thrombus
prevention
NAVIGATE
ESUS
RE-SPECT
ESUS
ACS RE-DEEM ATLAS I
ATLAS 2
RE-ALIGN
Elective PCI X-PLORER
valves
BRUISE-
BRUISE-
TAVR GALILEO ATLANTIS
Pacemaker or
CONTROL-2
CONTROL-2
HF and CAD COMMANDER HF
CAD or PAD COMPASS
138 Anticoagulation Therapy
Anticoagulation
revascularization
NVAF left atrial
appendage closure
NVAF with ESRD
ACS: acute coronary syndromes, APLA: antiphospholipid antibody syndrome, CAD: coronary artery disease, DOAC: direct oral anticoagulant, ESRD: end-stage renal
disease, HD: hemodialysis, HF: heart failure, LA: left atrium, NVAF: non-valvular atrial fibrillation, PAD: peripheral artery disease, PCI: percutaneous coronary intervention, PE:
pulmonary embolism, TAVR: transcatheter aortic valve replacement, THR: total hip replacement, TKR: total knee replacement, VTE: venous thromboembolism
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AXADIA
RENAL-AF
VOYAGER PAD
Dabigatran Rivaroxaban Apixaban Edoxaban
Completed Ongoing Completed Ongoing Completed Ongoing Completed Ongoing
Indication
TABLE 7-3: (Continued)
PAD with
ADRIFT
on HD
DIRECT ORAL ANTICOAGULANTS 139
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• Compared to warfarin, DOACs have a much
shorter half-life and thus a more rapid onset
and offset of action. Their short time to onset
produces a rapid therapeutic effect in treatment
of acute thrombosis and precludes the need for
bridging therapy around invasive procedures
(see Chapter 10). Their rapid offset requires a
high degree of adherence with therapy to avoid
subtherapeutic levels of anticoagulation.
• All of the DOACs are renally eliminated to some
degree. None of the major randomized controlled
trials of DOACs included patients with severe
renal impairment (CrCl <25–30 mL/min via
the Cockcroft-Gault equation using actual body
weight). Therefore, routine use in this population
is not recommended. When considering a patient
for DOAC therapy, careful evaluation of their
renal function at baseline and periodically during
therapy is imperative (see Chapter 11 for further
details).
• Idarucizumab is the specific antidote for
dabigatran. Andexanet alfa is approved for
reversing the oral anti-Xa anticoagulants
apixaban and rivaroxaban (see Chapters 8
and 9).
DRUG INTERACTIONS
All of the DOACs are substrates of the P-glycoprotein (P-gp) efflux transporter system. Apixaban and rivaroxaban are also substrates of the hepatic
isoenzyme cytochrome P450 3A4 (CYP 3A4). Inhibition of these pathways
may lead to accumulation of DOACs, whereas induction speeds elimination
of substrates and may lead to lower DOAC plasma concentrations. Available
data on DOAC drug interactions are limited and based solely on pharmacokinetic data. Recommendations for management of studied drug interactions
are provided in DOAC labeling. However, DOAC drug interactions are far
more numerous, and clinicians must routinely use available drug interaction
databases and clinical judgment to assess for interactions significant enough
to warrant a dose adjustment or avoidance of DOAC therapy. Tables 7-4
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