US Pharm. 2014;39(4):69-74.
ABSTRACT: Although for decades warfarin has been the gold standard
for prevention of thromboembolic events, management is complicated by
the drug’s relatively narrow therapeutic window and the high incidence
of interactions. Target-specific oral anticoagulants (TSOAs) are an
attractive alternative to warfarin because they do not require routine
monitoring and are associated with a low number of clinically relevant
drug interactions. TSOAs include dabigatran, apixaban, and rivaroxaban.
Pharmacology, dosing, clinical efficacy, and special considerations for
these TSOAs are reviewed.
For decades, warfarin (Coumadin) has been the gold standard for
long-term anticoagulation in patients at high risk for thromboembolic
events (TEEs). The two most common indications for warfarin are
prevention of embolic or ischemic stroke in patients with atrial
fibrillation (AF) and primary treatment and secondary prevention of
TEEs, including deep venous thrombosis (DVT) and pulmonary embolism
(PE). Without proper anticoagulation, the risk of TEEs in these patients
is high: Those with AF and a CHADS2 (Congestive heart failure; Hypertension; Age ≥75 years; Diabetes; prior Stroke,
transient ischemic attack, or thromboembolism) score ≥2 have an
estimated risk of 4.5% to 9.6% per year, and those with a history of
unprovoked DVT have a 10% risk of recurrence at 1 year and a 30% risk of
recurrence at 5 years.1,2 These risks are significant, since
a TEE can result in death or permanent disability. Multiple trials have
demonstrated that, compared with placebo, warfarin can reduce the risk
of death by 25% and that of nonfatal stroke by up to 67% in AF patients.1
In addition, extended therapy (>3 months) has been shown to reduce
the risk of recurrent TEEs by 82% in patients with a history of
unprovoked DVT or PE.2
Despite overwhelming evidence demonstrating the benefits of warfarin
therapy, management is complicated by drug-drug, drug-food, and
drug-disease interactions, all of which necessitate frequent
international normalized ratio (INR) monitoring, dosage adjustments, and
patient education. Even when therapy is managed by a specialized
anticoagulation clinic with a high level of provider and patient
vigilance, time in therapeutic range (TTR) averages only 63%.
Furthermore, TTR is reduced by 11% to 12% when therapy is monitored by
the community practitioner,3 and at least one study examining
patients with AF found that the risk of bleeding and stroke increases
significantly when TTR drops below 54%.4 The challenges
associated with maintaining warfarin within its relatively narrow
therapeutic range render target-specific oral anticoagulants (TSOAs) an
attractive option because these agents do not require routine monitoring
and are associated with a low number of clinically relevant drug
This article will review the pharmacology, dosing, and precautions
for the factor Xa (FXa) inhibitors apixaban and rivaroxaban and the
direct thrombin (factor IIa, FIIa) inhibitor dabigatran. Additionally,
the clinical efficacy and safety of these agents used in nonvalvular AF
or for the treatment of DVT or PE will be summarized.
Pharmacology, Dosing, and Interactions
Apixaban: Apixaban (Eliquis) binds selectively and reversibly to FXa.5
This agent currently is FDA-approved only for TEE prophylaxis in
patients with nonvalvular AF (NVAF), but there is mounting evidence of
the drug’s efficacy and safety for the treatment and prophylaxis of
recurrent DVT or PE. The most severe adverse effects (AEs) associated
with apixaban use involve bleeding; accordingly, patients should be
counseled regarding signs and symptoms of severe bleeding and about
medications with antiplatelet activity (e.g., nonsteroidal
anti-inflammatory drugs [NSAIDs]). In rare cases, hypersensitivity and
anaphylactic-type reactions have occurred (<1%). Apixaban may be
taken with or without food, and the recommended dosage for most patients
is 5 mg orally twice daily (see TABLE 1 for dosage adjustments).
Apixaban has a prolonged absorption period and, as a result, has a
half-life of approximately 12 hours with repeat dosing despite the
shorter elimination half-life. This allows for twice-daily dosing, but
also means that the anticoagulant effect lasts for approximately 24
hours when the agent is stopped.
Apixaban is partially metabolized by the liver and then undergoes renal and biliary elimination.5
Major inhibitors of CYP3A4 and the efflux transporter P-glycoprotein
(Pgp) (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir) can
reduce apixaban elimination, thereby increasing the risk of bleeding.
Dosage adjustments for apixaban in combination with one of these agents
have been recommended (TABLE 1). Conversely, major inducers of
these enzymes (e.g., rifampin, carbamazepine, phenytoin, St. John’s
wort) can reduce exposure to apixaban and increase the risk of TEEs;
therefore, concomitant use should be avoided. Owing to its inhibition of
FXa, apixaban interferes with laboratory tests such as prothrombin time
(PT), INR, and activated partial thromboplastin time (aPTT); the
magnitude of this effect is highly variable between patients, so these
tests cannot be used to monitor apixaban’s efficacy.
Rivaroxaban: Rivaroxaban (Xarelto) is approved not only
for NVAF and for treatment and long-term prevention of recurrent DVT or
PE, but also for prophylaxis of TEEs associated with hip- or
knee-replacement surgery.6 Like apixaban, rivaroxaban
selectively inhibits the active site on FXa. The most severe AEs, as
expected, are related to bleeding. Other AEs reported in clinical trials
include abdominal discomfort, musculoskeletal pain, and pruritus. Food
enhances the absorption of rivaroxaban 15 mg or 20 mg, and patients
should be counseled to take each dose consistently at the same time
every day with a meal; the tablet may be crushed and taken with
applesauce or via a feeding tube. Because the oral bioavailability of
the 10-mg dose is nearly 100%, food does not affect absorption. Dosing
depends upon the indication (TABLE 2), and there are several recommended adjustments.
Approximately 50% of the rivaroxaban dose is metabolized by the liver, with metabolites eliminated via urine and feces.6
Nearly one-third of the dose is removed unchanged in the urine via Pgp.
It is not recommended to use rivaroxaban with strong combined
inhibitors of CYP3A4 and Pgp (e.g., ketoconazole, itraconazole,
ritonavir) or strong combined inducers of these enzymes (e.g.,
rifamycin, carbamazepine, phenytoin, St. John’s wort). Coadministration
with short courses of erythromycin or clarithromycin was not found to
increase the risk of bleeding and therefore is not contraindicated.6
Dabigatran: Dabigatran (Pradaxa) is FDA-approved for the prevention of TEE in patients with NVAF.7
Dabigatran and its active metabolites bind directly to thrombin,
thereby preventing conversion of fibrinogen to fibrin during the
coagulation cascade. Like the other TSOAs, dabigatran affects PT, aPTT,
and INR, but the effects are unpredictable and small in magnitude;
therefore, these tests are not reliable for monitoring the drug’s
efficacy. AEs that led to discontinuation of dabigatran in clinical
trials include bleeding, gastrointestinal (GI) hemorrhage,
gastritis-like symptoms, dyspepsia, nausea, and diarrhea. The
recommended dosage in patients with NVAF is 150 mg twice daily, but
adjustments are recommended in patients with renal impairment and in
those taking certain interacting medications (TABLE 3).
Dabigatran is converted to four active glucuronide metabolites, and
the drug and metabolites are nearly 80% renally cleared; significant
renal impairment requires dosage adjustment.7 Strong inducers
of Pgp reduce dabigatran concentrations by up to 70%, so concomitant
use should be avoided. Pgp inhibitors have variable effects on
dabigatran concentration and elimination; ketoconazole and dronedarone
require dosage reductions of dabigatran, but amiodarone, verapamil,
quinidine, and clarithromycin do not alter the pharmacokinetics of
dabigatran in a manner expected to be clinically significant.
Efficacy and Safety
AF: The 2012 guidelines developed by the American
College of Chest Physicians (ACCP) recommend that providers assess the
risk of stroke or TEE in AF patients on an individualized basis to
determine whether antiplatelet therapy or anticoagulant therapy is more
appropriate.1 For patients with a CHADS2 score ≥1,
anticoagulation is recommended over antiplatelet therapy; dabigatran is
recommended over dose-adjusted warfarin for patients without valvular
heart disease (e.g., mitral stenosis, mechanical heart valve) who are
candidates for anticoagulation therapy.1 These guidelines do
not specifically address apixaban or rivaroxaban for TEE prevention in
patients with NVAF because at that time they had been inadequately
studied in this population. All three agents now carry FDA approval for
Each agent has been compared with warfarin in a major double-blind, controlled trial (TABLE 4).
Rivaroxaban was noninferior to warfarin, and apixaban and dabigatran
were superior to warfarin, for prevention of stroke and TEEs in patients
with NVAF.8-10 Compared with warfarin, apixaban
significantly reduces the risk of all-cause mortality. Apixaban has a
lower risk of both major bleeding and intracranial bleeding compared
with warfarin, and it does not increase the risk of GI bleeding. The
risk of major bleeding with dabigatran and rivaroxaban appears to be
similar to that for warfarin, but both agents have a slightly higher
risk of GI bleeding events. Despite this, dabigatran and rivaroxaban
have a lower risk of intracranial bleeding compared with warfarin, and
rivaroxaban has a lower risk of fatal bleeds.
DVT/PE Treatment and Long-Term Prophylaxis for Recurrent DVT/PE: The ACCP recommends ≥3 months of anticoagulation therapy for patients who experience an acute DVT or PE.2
For patients with a coagulopathy (e.g., protein C deficiency) or
recurrent TEEs, or for those with an unprovoked TEE who have a
low-to-moderate risk of bleeding, the guidelines advise indefinite
(lifetime) prophylactic therapy with anticoagulants.
Low-molecular-weight heparin (LMWH) and warfarin are weakly favored over
agents such as apixaban, rivaroxaban, and dabigatran owing to the lack
of postmarketing safety data available at that time. TABLE 5 summarizes the clinical trials of TSOAs for treatment of acute venous thromboembolism (VTE) or prophylaxis for recurrent VTE.
Rivaroxaban is the only TSOA FDA-approved for treatment of acute DVT
or PE and prophylaxis for recurrent TEE. In clinical trials, rivaroxaban
15 mg twice daily was administered for the first 3 weeks, followed by
20 mg daily for the remainder of the treatment period.11,12 Compared with standard anticoagulation with LMWH and warfarin, rivaroxaban was noninferior for treating acute DVT or PE.11,12
In both trials, the bleeding risk was similar between the two
comparator groups; however, there was a significantly lower risk of
major bleeding in rivaroxaban patients versus warfarin patients in the
treatment of acute PE. In an extension of the original acute DVT and PE
trials, patients who had completed 6 to 12 months of anticoagulant
therapy and for whom there was clinical equipoise about whether to
continue anticoagulation were randomized to rivaroxaban 20 mg daily or
placebo. Rivaroxaban significantly reduced the risk of recurrent VTE
without increasing the risk of bleeding.11
When used for the acute treatment of DVT or PE, apixaban 10 mg twice
daily for 7 days followed by 5 mg twice daily was noninferior to
standard anticoagulation with LMWH and warfarin, but it had a
significantly lower risk of major and clinically relevant bleeding.13
When apixaban was continued for an additional 12 months after initial
treatment, both 5 mg twice daily and 2.5 mg twice daily were superior to
placebo for preventing recurrent TEEs.14 Although neither
regimen increased the risk of major bleeding compared with placebo, the 5
mg twice daily regimen increased the risk of clinically relevant
Dabigatran 150 mg twice daily was noninferior to warfarin for both
acute treatment of VTE and extended prophylaxis of recurrent VTE, and it
carried a lower risk of major and clinically relevant bleeding.15,16 Dabigatran was associated with a higher rate of acute coronary syndrome (ACS) versus warfarin when therapy was extended.16
In addition, unlike patients in the trials investigating the other
TSOAs, dabigatran patients in this trial received at least 5 days of
parenteral anticoagulation (e.g., LMWH) upon initiation of therapy for
Special Populations and Considerations
Older patients are more likely than younger patients to require oral
anticoagulation; however, elderly patients are more likely to experience
AEs as a result. Although warfarin has been used successfully for
years, it remains one of the primary reasons for AEs in elderly patients
in the emergency department.17 Most data supporting the use
of TSOAs in AF are based on patients younger than 80 years. Only 17% of
patients in the RE-LY trial and 13% of those in ARISTOTLE were 80 years
or older.9,10 The ROCKET-AF trial included no patients 80 years and older.8
The 2012 Beers criteria warn against the use of dabigatran in patients
aged 75 years and older, since dabigatran confers a higher extracranial
bleeding risk compared with warfarin.18,19 The increase in major GI bleeds associated with rivaroxaban causes some concern with the use of this agent in older patients.8 Apixaban may be a safer alternative, as it has been associated with a lower rate of major and GI bleeding versus warfarin.9
Renal dysfunction requires a careful analysis of the anticoagulant
options. With all three TSOAs, reduced dosing is recommended for
patients with renal dysfunction; however, not all adjustments have been
evaluated for safety and efficacy. The lower dosage of apixaban—2.5 mg
twice daily—has been assessed in clinical trials; however, patients with
a creatinine clearance (CrCl) <25 mL/min were excluded. The
dabigatran dosage in AF patients with a CrCl <30 mL/min is a 50%
reduction from the original dosage and was determined by pharmacokinetic
modeling, not clinical trials.20 In trials evaluating the
efficacy and safety of dabigatran in patients with AF or VTE, patients
with a CrCl <30 mL/min were excluded.10,15,16 The reduced dosage of rivaroxaban—15 mg daily—has been evaluated in patients with a CrCl of 15 to 49 mL/min and NVAF8; however, for TEE treatment or prevention, rivaroxaban is not recommended in patients with a CrCl <30 mL/min.6
In pregnancy, oral anticoagulants are not favored, as data supporting
their safety and efficacy are not available. LMWH remains the standard
in pregnant patients requiring anticoagulant therapy.21
As noted in the RE-MEDY trial, compared with warfarin, dabigatran may
increase the risk of ACS. A meta-analysis of seven noninferiority
trials comparing dabigatran with warfarin revealed a slightly higher
risk of myocardial infarction or ACS in patients taking dabigatran.22
It is not known whether this is because dabigatran actually increases
the risk or because it is less beneficial than warfarin for lowering
risk. However, it may be reasonable to select either warfarin or another
TSOA over dabigatran in patients with a high risk or past history of
coronary artery disease.
In NVAF, apixaban and dabigatran are superior to warfarin for
preventing TEEs; apixaban may be the appropriate agent if the patient is
at high risk for GI bleeding. Rivaroxaban, which is noninferior to
warfarin, may be an option in patients who would benefit from once-daily
In addition, TSOAs may be reasonable alternatives to warfarin for the
acute treatment and prophylaxis of recurrent DVT or PE in patients with
a CrCl >30 mL/min. Rivaroxaban, which is FDA-approved for this
indication, may be an option for patients who require once-daily dosing
but have difficulty with the monitoring requirements for warfarin.
Apixaban is an attractive alternative because of its potentially lower
bleeding risk compared with warfarin; however, it requires twice-daily
dosing. While dabigatran also has shown a lower bleeding risk versus
warfarin, the extended trial demonstrated a potential risk of ACS, so
this agent may not be the best choice for patients with recent ACS or
with a high risk of cardiovascular disease.
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