Introduction
Vitamin K antagonists (VKAs) were first introduced in the 1920s from studies on the
“hemorrhagic” effect of spoiled sweet clover consumption by cattle1 and have evolved
ever since to the cornerstone of oral anticoagulation therapy. The most commonly used
VKA in the United States is warfarin, while in some European countries acenocoumarol
and phenprocoumon are commonly used.2 VKAs exhibit their anticoagulant effect by inhibiting
the vitamin K epoxide reductase complex subunit 1 in the liver. This enzyme catalyzes
the post‐translational modification of vitamin K–dependent proteins. Inhibition of
vitamin K epoxide reductase complex subunit 1 results in impaired synthesis of coagulation
factors II (prothrombin), VII, IX, and X as well as of anticoagulant proteins C, S,
and Z.3 The primary indications for VKA use are prophylaxis and treatment of venous
thromboembolic disease (VTE, which includes deep vein thrombosis and pulmonary embolism)
and of thromboembolic complications associated with atrial fibrillation (AF) and/or
mechanical cardiac valves.
Although VKAs are efficacious in the prevention and treatment of VTE4 and AF‐related
thromboembolic complications,5 their use has some hindrances. First, the dose required
to provide therapeutic anticoagulation is highly variable between individuals. It
is influenced by various pharmacogenetic parameters, such as polymorphisms affecting
VKA pharmacokinetics (cytochrome CYP2C9 gene that regulates VKAs hepatic metabolism)6
and pharmacodynamics (VKORC1 gene).7 Second, co‐administration of other medications,
such as anti‐inflammatory, antibiotics, antiplatelets, statins, antidepressants, amiodarone,
antifungals, antiretrovirals, and over‐the‐counter dietary supplements, can interact
with VKAs.8 Third, changes in dietary patterns or alcohol consumption alter the efficacy
of VKAs, requiring adjustment of the maintenance dose.8 Last, given this variability
and the narrow therapeutic window of VKAs, frequent anticoagulation monitoring is
required to ensure appropriate dosing.9
The need to overcome these limitations resulted in the development of a new class
of oral anticoagulants, the non–vitamin K oral anticoagulants (NOACs), also known
as “direct oral anticoagulants.” Currently, there are 5 NOACs that have completed
phase III clinical trials and are approved for clinical use (dabigatran, rivaroxaban,
apixaban, edoxaban, and betrixaban). Contrary to VKAs that indirectly inhibit the
synthesis of coagulation factors, NOACs directly inhibit specific coagulation factors.
Dabigatran inhibits thrombin (factor IIa), whereas apixaban, betrixaban, edoxaban,
and rivaroxaban inhibit activated factor X (Xa).10 These agents have more predictable
pharmacokinetics and pharmacodynamics than VKAs and a wide therapeutic window, allowing
for a fixed oral dosing, without the need for monitoring their anticoagulation effect.
In addition, most have a short elimination half‐life compared with VKAs and rapid
onset of action, achieving therapeutic levels in the plasma within 1 to 2 hours.10
Betrixaban has distinct pharmacokinetic properties because it is minimally cleared
by the liver and the kidneys and has a prolonged half‐life.11 The terminal half‐life
of betrixaban is 37 hours. Table 1 summarizes the landmark phase III clinical trials
involving NOACs. These trials demonstrate noninferiority or superiority of NOACs compared
with VKAs in stroke prevention in patients with AF,12, 13, 14, 15, 16 and prevention17,
18, 19 and treatment20, 21, 22, 23, 24, 25 of VTE, with a better safety profile. The
results from phase III clinical trials on NOACs and the ease of their use have resulted
in their progressively increasing utilization. However, some areas of uncertainty
remain. First, their efficacy has not been validated in patients with severe mitral
stenosis or mechanical prosthetic valves. RE‐ALIGN (A Randomised, Phase II Study to
Evaluate the Safety and Pharmacokinetics of Oral DabIgatran Etexilate in Patients
After Heart Valve Replacement), a phase II clinical trial of dabigatran in patients
with mechanical heart valves, was discontinued prematurely because of an increased
rate of thromboembolic and bleeding events among patients in the dabigatran group.26
Second, there are limited data in patients with cancer‐associated VTE or other hypercoagulable
states, such as the anti‐phospholipid syndrome (APS), the nephrotic syndrome, and
congenital coagulopathies. Third, the efficacy of NOACs has not been evaluated in
patients with advanced renal insufficiency, end‐stage renal disease, or hepatic dysfunction.
Fourth, important patient subgroups, such as pediatric patients and pregnant women,
have not been adequately studied. Last, the prevalence and sequelae of physician underdosing
warrants study, as does patient adherence and long‐term medication persistence. This
review will expand on the treatment gaps in NOAC use and summarize indications where
anticoagulation with indirectly acting anticoagulants such as VKAs and heparins will
still be considered first‐line treatment pending further studies.
Table 1
Landmark Phase III Clinical Trials Demonstrating the Efficacy of NOACs in Thromboembolism
Prophylaxis in Patients With AF and Management of VTE
Study
Agent
Year
Design
Relevant Exclusion Criteria
Results
AF
RE‐LY12
Dabigatran
2009
Dabigatran (110 or 150 mg twice daily) vs dose‐adjusted warfarin
Severe valvular heart disease or prosthetic valve, severe stroke within 6 mo, increased
risk for hemorrhage, CrCl <30 mL/min, active liver disease and pregnancy
Dabigatran 110 mg: noninferior to warfarin with lower rate of ICH and other major
hemorrhage
Dabigatran 150 mg: superior to warfarin with lower rate of ICH, similar rate of other
major hemorrhage
ROCKET AF13
Rivaroxaban
2011
Rivaroxaban (20 mg/d) vs dose‐adjusted warfarin
Hemodynamically significant mitral stenosis, prosthetic heart valve, severe, disabling
stroke within 3 mo or any stroke within 14 d, active internal bleeding, major surgical
procedure or trauma within 30 d of randomization, CrCl <30, pregnancy, known liver
disease and severe comorbid condition with life expectancy ≤2 y
Rivaroxaban: noninferior to warfarin with lower rate of ICH, similar rate of other
major hemorrhage
AVERROIS14
Apixaban
2011
Apixaban (5 mg twice/d) vs aspirin (81–324 mg) in patients for whom VKA was unsuitable
Valvular disease requiring surgery, a serious bleeding event in the previous 6 mo
or high risk of bleeding, stroke within the previous 10 d, life expectancy of <1 y,
CrCl <25 mL/min and abnormal liver function
Apixaban: reduced risk of SSE without significantly increasing the risk of major bleeding
or ICH
ARISTOTLE15
Apixaban
2011
Apixaban (5 mg twice/d) vs dose‐adjusted warfarin
Moderate or severe mitral valve stenosis, prosthetic, mechanical valve, stroke within
7 d, CrCl <25 mL/min, abnormal liver function tests, pregnancy, severe comorbid condition
with life expectancy ≤1 y
Apixaban: superior to warfarin with lower rate of ICH and lower rate of other major
hemorrhage
ENGAGE AF—TIMI 4816
Edoxaban
2013
Edoxaban (30 or 60 mg daily) vs dose‐adjusted warfarin
Moderate‐to severe mitral stenosis, CrCl <30 mL/min, a high risk of bleeding, acute
coronary syndromes, coronary revascularization, or stroke within 30 d before randomization
Both once‐daily regimens of edoxaban were noninferior to warfarin with respect to
the prevention of stroke or systemic embolism and were associated with significantly
lower rates of bleeding and death from cardiovascular causes
Treatment of venous thromboembolic disease
RE‐COVER20
Dabigatran
2009
Comparison of dabigatran (150 mg twice/d) vs dose‐adjusted warfarin in patients with
acute VTE after a therapy for a median of 9 da with parenteral anticoagulation with
the outcome or recurrent VTE and related mortality
Duration of symptoms longer than 14 d, pulmonary embolism with hemodynamic instability
or requiring thrombolytic therapy, a high risk of bleeding, liver disease, CrCl <30 mL/min,
life expectancy <6 mo, pregnancy
Dabigatran is as effective as warfarin in preventing VTE recurrence and mortality
and was associated with lower rates of any bleeding (but similar rates of major bleeding)
RE‐SONATE21
Dabigatran
2013
Comparison of dabigatran (150 mg twice/d) vs placebo in patients with VTE who previously
received anticoagulation for 6 to 18 mo, with the outcome of recurrent or fatal VTE
Active liver disease, CrCl <30 mL/min, acute bacterial endocarditis, active bleeding
or high risk for bleeding, uncontrolled hypertension, life expectancy <6 mo, pregnancy
Dabigatran reduced recurrent symptomatic or fatal VTE significantly more compared
with placebo but was associated with higher rates of major, clinically relevant or
any bleeding
RE‐MEDY21
Dabigatran
2013
Comparison of dabigatran vs dose‐adjusted warfarin in patients with VTE who had already
received at least 3 mo of anticoagulation, with the outcome of recurrent or fatal
VTE
Interruption of anticoagulant therapy for 2 or more wks during the 3 to 12 mo of treatment
for the prior VTE, patients with an excessive risk of bleeding, abnormal liver function
tests, CrCl <30 mL/min
Dabigatran reduced recurrent symptomatic or fatal VTEs at rates similar to warfarin
and was associated with lower rate of major, clinically relevant and any bleeding
EINSTEIN‐DVT22
Rivaroxaban
2010
Comparison of rivaroxaban alone (15 mg twice daily for 3 wks, followed by 20 mg once
daily) vs enoxaparin followed by dose‐adjusted VKA for 3, 6, or 12 mo in patients
with acute, symptomatic DVT with the outcome or recurrent VTE
Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat
the current episode of DVT and/or PE
Rivaroxaban had similar effect to enoxaparin‐warfarin in preventing recurrent VTE
and had similar rates of major, or clinically relevant bleeding
EINSTEIN‐PE23
Rivaroxaban
2012
Comparison of rivaroxaban alone (15 mg twice daily for 3 wks, followed by 20 mg once
daily) vs enoxaparin followed by dose‐adjusted VKA for 3, 6, or 12 mo in patients
with acute, symptomatic PE with the outcome or recurrent symptomatic VTE
Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat
the current episode of DVT and/or PE
Rivaroxaban alone had similar effect to enoxaparin‐warfarin in preventing recurrent
VTE both for the initial and long‐term treatment of pulmonary embolism and was associated
with lower major bleeding rates
AMPLIFY24
Apixaban
2013
Comparison of apixaban (10 mg twice daily for 7 d, followed by 5 mg twice daily for
6 mo) with enoxaparin, followed by warfarin in patients with acute VTE with the outcome
of recurrent symptomatic or fatal VTE
Hemoglobin level <9 mg/dL, platelet count <100 000/mm3, CrCl <25 mL/min, short life
expectancy, active bleeding or high risk for serious bleeding
Apixaban alone was noninferior to conventional therapy for the treatment of acute
VTE and was associated with significantly less major and clinically relevant bleeding
rates
Hokusai‐VTE25
Edoxaban
2013
Comparison of edoxaban (60 mg once daily, or 30 mg once daily if CrCl 30–50 mL/min)
vs dose‐adjusted warfarin for 3 to 12 mo in patients with acute VTE who had initially
received heparin, with the outcome of recurrent symptomatic VTE
Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat
the current episode of DVT and/or PE, CrCl <30 mL/min, significant liver disease,
patients with active cancer for whom long‐term treatment with low molecular weight
heparin is anticipated, active bleeding or high risk for bleeding, chronic treatment
with aspirin or nonsteroidal anti‐inflammatory drugs, concurrent treatment with potent
glycoprotein P inhibitors
Edoxaban administered once daily after initial treatment with heparin was noninferior
to standard therapy and was associated with lower major or clinically relevant bleeding
rates
Prophylaxis of venus thromboembolic disease
MAGELLAN17
Rivaroxaban
2013
Comparison of rivaroxaban (10 mg/d) vs enoxaparin (40 mg once/d) in patients who were
hospitalized for an acute medical illness with the outcome of asymptomatic proximal
or symptomatic VTE in 10 and 35 d
Conditions that may increase the risk of bleeding, including intracranial hemorrhage,
concomitant conditions or diseases that may increase the risk of study subjects or
interfere with the study outcome
Rivaroxaban was noninferior to enoxaparin for standard duration thromboprophylaxis.
Extended duration rivaroxaban reduced the risk of venous thromboembolism but was associated
with an increased risk of major or clinically relevant bleeding
ADOPT18
Apixaban
2011
Comparison of apixaban (2.5 mg twice daily for 30 d) vs enoxaparin (40 mg once daily
for 6–14 d) in patients who were hospitalized for an acute medical illness with the
outcome of VTE or death related to VTE
Patients with VTE, active bleeding or at high risk of bleeding, unable to take oral
medication, with diseases requiring ongoing treatment with anticoagulants or antiplatelets
other than aspirin at a dose ≤165 mg/d
Apixaban administration for 30 d did not provide superior thromboprophylaxis compared
with enoxaparin for 6– 14 d.
Apixaban was associated with significantly more major bleeding events than was enoxaparin
APEX19
Betrixaban
2016
Comparison of betrixaban (160 mg loading dose and then 80 mg twice daily for 35–42 d)
vs enoxaparin 40 mg once daily for 10±4 d in patients who were hospitalized for acute
medical illness and had an elevated D‐dimer level with the outcome of VTE
Life expectancy <8 wks. Anticipated need for prolonged anticoagulation during the
trial
In patients with acute medical illness and elevated D‐dimers, betrixaban was associated
with similar rates of VTE and major bleeding with enoxaparin.
In patients with acute medical illness and elevated D‐dimers or older than 75 y, betrixaban
was associated with a 24% risk reduction for VTE, and similar rates of bleeding compared
with enoxaparin
AF indicates atrial fibrillation; CrCl, creatinine clearance; DVT, deep venous thrombosis;
GI, gastrointestinal; ICH, intracerebral hemorrhage; NOACs, non–vitamin K oral anticoagulants;
PE, pulmonary embolism; SSE, stroke or systemic embolism; VKA, vitamin K antagonists;
VTE, venous thromboembolic disease.
Mechanical Prosthetic Valves and Rheumatic Mitral Valve Disease
Valvular heart disease has a prevalence of 2.5% (any valve) in the United States,
and is equally distributed between men and women.27 Prosthetic heart valve replacement
is recommended for many patients with severe valvular heart disease28 and on average
300 000 prosthetic heart valve replacements are performed every year worldwide, 100 000
of which are in North America.29 By 2050, the annual number of valve replacements
is projected to be 850 000.30 Mechanical valves are more durable than bioprosthetic
valves but typically require lifelong anticoagulation therapy.31 The use of VKAs provides
excellent protection against thromboembolic complications in patients with mechanical
heart valves,31 but its use is bound by the drawbacks previously described.
Although preclinical studies showed a potential role of NOACs in the presence of a
mechanical valve, in the RE‐ALIGN trial, dabigatran was associated with increased
thromboembolic risk. Patients with severe mitral stenosis or mechanical valves were
excluded from the major NOAC trials, and thus their results cannot be generalized
in this distinct patient population. In vitro studies have demonstrated that dabigatran
(1 μmol/L)32 and high‐dose rivaroxaban (300 ng/mL)33 were as effective as unfractionated
heparin and low molecular weight heparin (LMWH) in preventing thrombus formation on
mechanical heart valves. In porcine models of heterotopic mechanical valve implantation,
dabigatran34 and rivaroxaban35 have been equally effective as enoxaparin in preventing
valvular thrombus formation. Dabigatran provides a mortality benefit when compared
with warfarin after mechanical mitral valve replacement in pigs.36 However, these
results have not been translated in humans. Several case reports demonstrated severe
valvular thrombosis when dabigatran was used in the setting of mechanical mitral valve,37,
38 mechanical aortic valve,39 or rheumatic mitral stenosis.40 In the RE‐ALIGN phase
II clinical trial, patients with mechanical heart valves were randomized to receive
either dabigatran (150, 220, or 300 mg twice daily, to achieve serum dabigatran trough
concentrations >50 ng/mL) or dose‐adjusted warfarin with a target international normalized
ratio (INR) of 2 to 3 or 2.5 to 3.5, depending on their thromboembolic risk. The trial
was terminated prematurely because of significantly increased thromboembolic and bleeding
rates in the dabigatran arm.26 As a result, research for this indication has been
stopped, and use of these agents is contraindicated in patients with mechanical prosthetic
valves.
There are several potential reasons why dabigatran failed to provide adequate thromboprophylaxis
in RE‐ALIGN. The dose of dabigatran that was used (trough levels >50 ng/mL) was selected
based on studies in AF.12 The pathophysiology of thrombosis in the setting of mechanical
valve implantation is different from that in AF and thus the optimal dabigatran dose
in the setting of AF might be higher. In AF, thromboembolic events are thought to
occur primarily because of low flow and blood pooling in the left atrium, pro‐thrombotic
changes in vessel walls, and an imbalance between coagulation and fibrinolysis resulting
in a hypercoagulable state.41 Mechanical valves are associated with abnormal flow
and high shearing stress.42 A significant release of pro‐thrombotic particles and
thrombin that occur during cardiopulmonary bypass might predispose patients to thrombotic
events.43 Tissue factor released at the site of tissue destruction has been thought
to be a major contributor to postoperative thrombosis through activation of the extrinsic
coagulation pathway.44 In addition, there is activation of the contact coagulation
pathway because of the interface of blood with the mechanical valve sewing ring45
and valvular disks.46 In vitro, dabigatran fails to normalize the increased endogenous
thrombin potential of serum exposed to mechanical valves, while warfarin is able to
normalize it.47 Furthermore, during surgery DNA and RNA are released from destroyed
tissues and inorganic polyphosphate residues are released from activated platelets.
Extracellular RNA, released from tissue damage, can bind to factors XII and XI, leading
to activation of the contact coagulation pathway.48 Inorganic polyphosphate residues,
released from activated platelets, directly bind and activate factor XII.49 Recent
studies suggest that factor XI and the intrinsic coagulation pathway might be central
to the mechanism of postoperative thrombosis, since selective inhibition of factor
XI with anti‐sense oligonucleotides reduces the rates of thrombosis.50
In RE‐ALIGN, most valvular thrombosis occurred in the immediate postoperative period,26
suggesting that the increased release of pro‐thrombotic substances after surgery overwhelms
the capacity of dabigatran to antagonize thrombin. Anticoagulation in this setting
should occur with frequent and individualized dose adjustments that match the unpredictably
released pro‐coagulant factors and maintain a net anticoagulant effect.51 Although
by study design dabigatran was dosed up to twice the Food and Drug Administration
approved dose for AF, to achieve circulating levels >50 ng/mL, this might not reflect
the true anticoagulation effect of dabigatran, at the valve level, in the setting
of unpredictable bursts of pro‐thrombotic factors after surgery. However, patients
receiving dabigatran had a higher risk of bleeding compared with those receiving VKA.
Contrary to this, INR measurements reflect the net anticoagulation effect of VKAs
and enable individualized dose adjustment to achieve the desired level of anticoagulation.
Given their short half‐lives, monitoring the net anticoagulation effect of NOACs in
this dynamic setting would be challenging. Furthermore, dabigatran is a competitive
inhibitor of a single coagulation factor while VKAs are noncompetitive irreversible
inhibitors of multiple coagulation factors of both the intrinsic and extrinsic coagulation
pathways, as well as of factor X and thrombin in the common pathway.52
VKAs remain the anticoagulation modality of choice in patients with mechanical valves.31
In a meta‐analysis of 46 anticoagulation studies and 53 647 patients with mechanical
valves, a mechanical valve in the mitral position was associated with a 2‐fold higher
thromboembolic risk compared with the aortic position. Anticoagulation with warfarin
was an effective approach for the reduction of thromboembolic events.53 High INR variability
is independently associated with reduced survival after a mechanical valve implantation.54
There is limited experience on the safety and efficacy of NOACs in patients with AF
and biological prosthesis or mitral valve repair.55
Regarding patients with rheumatic mitral valve disease, the American College of Chest
Physicians guidelines recommend anticoagulation with VKAs in the presence of left
atrial enlargement (>55 mm), left atrial thrombus, AF, or history of systemic embolism.31
There are no randomized controlled clinical trials assessing the benefit of VKAs in
patients with rheumatic valve disease, and these recommendations are primarily based
on observational studies.56, 57 Patients with rheumatic mitral valve disease were
excluded from all major NOAC trials and their use should be avoided until further
studies become available.
Cancer‐Associated Thrombosis
Venous thromboembolism is an increasingly common complication in patients with cancer.
Patients with cancer have on average 4 to 7 times higher risk of developing VTEs compared
with noncancer patients, and 20% to 30% of first episodes of VTE are associated with
cancer.58 The prognosis of cancer patients who develop a VTE is poor, and VTE is the
second leading cause of death in these patients.59 Management of cancer‐associated
VTE is particularly challenging as the annual VTE recurrence rate approaches 21% to
27%, which is 2‐ to 6‐fold higher than noncancer patients.60, 61 In addition, bleeding
complications associated with treatment are 2 to 3 times higher than in noncancer
patients, with an incidence rate of 12% to 13% per year.60, 61 The management of cancer‐associated
thrombosis occurs in 3 different settings: treatment of acute VTE, prevention of VTE
in hospitalized medical or surgical patients, and primary prevention of VTE in ambulatory
cancer patients receiving chemotherapy.
There are several concerns related to the use of NOACs for VTE prophylaxis or treatment
in patients with cancer. First, the exact mechanism of cancer‐associated VTE is not
entirely understood, but it is likely multifactorial (eg, increased expression of
tissue factor, apoptosis, formation of microparticles, and deleterious effects of
chemotherapy on vascular endothelium). NOACs target single coagulation factors and
may not be able to adequately block the upregulation of the coagulation system that
occurs in many types of cancer. A post hoc analysis of the subgroup of cancer patients
enrolled in MATISSE‐DVT (Mondial Assessment of Thromboembolism Treatment Initiated
by Synthetic Pentasaccharide with Symptomatic Endpoints) demonstrated a trend toward
higher VTE recurrence rates in the fondaparinux group, an indirect factor Xa inhibitor,
compared with the LMWH group.62 Second, cancer cells may alter the efficacy of the
antithrombotic agents. In an in vitro study, the type of cancer cells affected the
antithrombotic efficacy of specific factor Xa inhibitors but not the potency of enoxaparin.63
Third, NOACs interfere with the CYP3A4 (rivaroxaban and apixaban) and the P‐glycoprotein
system (dabigatran, rivaroxaban, apixaban, edoxaban, and betrixaban), which play an
integral role in the metabolism of several chemotherapeutic agents.64 Potent inhibitors
or inducers of the CYP3A4 and P‐glycoprotein systems will cause clinically significant
interactions, and co‐administration of these drugs with NOACs should be contraindicated.65
Fourth, overexpression of P‐glycoprotein on the surface of cancer cells has been associated
with multidrug resistance, since P‐glycoprotein functions as an efflux pump and its
inhibition has been proposed as a therapeutic strategy to overcome resistance to chemotherapy
drugs.66 It is unknown whether NOACs, through their interference with the P‐glycoprotein
pathway, affect the efflux‐mediated chemotherapy resistance. Fifth, nausea and vomiting
are highly prevalent in patients with cancer, reaching 20% to 30% in patients with
advanced cancer,67 and this might result in inadequate adherence to oral medication
administration. Given the short half‐life of NOACs,10 medication nonadherence and
missed doses are expected to expose patients to a high risk of VTE. Last, renal dysfunction
is highly prevalent in patients with cancer, and many chemotherapy regimens are also
nephrotoxic.68 NOACs are renally excreted and might accumulate in patients with renal
failure. All NOAC studies excluded patients with severe renal insufficiency.
Treatment of Acute Venous Thromboembolism
LMWH is the standard of care for treatment of cancer‐associated VTEs.4, 69, 70 LMWH
is superior to VKA in reducing recurrent thromboembolic events in patients with cancer‐associated
acute VTE.71, 72 A Cochrane meta‐analysis of 7 randomized‐controlled trials comparing
LMWH with VKA in patients with cancer and VTE found that patients treated with LMWH
had up to 50% lower VTE recurrence rates with similar bleeding rates. However, there
was no statistically significant survival benefit.73 A different meta‐analysis of
16 randomized controlled trials comparing LMWH with unfractionated heparin for the
treatment of cancer‐associated VTE found a 30% reduction in mortality at 3 months
of follow‐up with LMWH compared with unfractionated heparin.74 In the most recent
CATCH trial (Tinzaparin versus Warfarin for Treatment of Acute Venous Thromboembolism
in Patients With Active Cancer), treatment for 6 months with the LMWH tinzaparin was
not associated with lower mortality, VTE recurrence, or major bleeding compared with
warfarin (goal INR: 2.0–3.0).75 In a contemporary network meta‐analysis of 10 randomized
controlled trials and 3242 patients with cancer, which includes the CATCH trial, LMWH
was superior to VKA in preventing recurrent VTE (relative risk [RR]=0.60, 95% confidence
interval, 0.45–0.79), and LMWH had similar rates of major bleeding with VKA.76
There are no randomized clinical trials to date comparing the efficacy and safety
of NOACs to LMWH in patients with cancer and VTE. Of completed VTE studies, patients
with cancer represent only 2% to 9% of the total participants (Table 1). Hokusai‐VTE
compared edoxaban with warfarin in patients with VTE and had the highest enrollment
of patients with cancer (n=771).25 In prespecified and post hoc subgroup analysis
of Hokusai‐VTE in patients with cancer, edoxaban failed to meet the noninferiority
margin in preventing recurrent VTE.77 However, patients with cancer where use of LMWH
was anticipated were excluded from the trial. In a subgroup analysis of 169 participants
of AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep‐Vein
Thrombosis as First‐Line Therapy) with cancer, apixaban had an efficacy and safety
profile similar to that of enoxaparin followed by warfarin.78 In a pooled analysis
of 335 participants of RE‐COVER and RE‐COVER II (Dabigatran versus warfarin in the
treatment of acute venous thromboembolism) with cancer, dabigatran had similar clinical
benefits and rates of bleeding compared with warfarin.79 Similar results were reported
for rivaroxaban in a pooled analysis of 353 participants of EINSTEIN‐DVT (Oral Direct
Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep Vein Thrombosis)
and EINSTEIN‐PE (Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute
Symptomatic Pulmonary Embolism) with cancer.80 In a meta‐analysis of 6 studies and
1132 patients with cancer and VTE, the rate of recurrence of VTE and the rate of major
bleeding were similar between patients treated with a NOAC and warfarin.81 The results
of these studies should be interpreted with caution. First, current trials assessing
the efficacy of NOACs in VTE were not designed specifically for patients with cancer.
Limited life expectancy was an exclusion criterion and thus the sample of patients
with cancer that were enrolled likely represents the healthiest individuals. Second,
patients with increased risk of bleeding and advanced renal disease, which is highly
prevalent in patients with cancer,68 were excluded from these studies. Last, current
studies compare NOACs with VKA but not LMWH, which is the standard of care for the
treatment of cancer‐associated VTEs.
There is limited evidence of NOAC use in these patients. In 3 single‐center, single‐arm,
nonrandomized, open‐label cohorts of 200 to 400 patients with cancer‐associated VTE,
treatment with rivaroxaban for 3 to 6 months was associated with VTE recurrence in
3.3% to 4.4%, and major bleeding occurred in 2.2% to 2.5% of the participants.82,
83, 84 There are currently several ongoing trials evaluating NOACs in the treatment
of VTE in patients with cancer (Table 2). Before these trials conclude, LMWH will
remain the standard treatment of cancer‐associated VTEs.
Table 2
PICO Model for Planned and Ongoing Clinical Trials Assessing NOACs in Management of
Cancer‐Associated VTE
Trial
Design
Patient Population
Intervention
Comparison
Primary Outcome
Clinical Trial Registration
Study Start Date
Estimated Completion Date
Treatment of VTE
Direct oral anticoagulants (DOACs) vs LMWH+/−warfarin for VTE in cancer: a randomized
effectiveness trial (CANVAS Trial)
Randomized, parallel assignment, open label trial
Patients with cancer and VTE (within 30 d of enrollment)
Dabigatran
Rivaroxaban
Apixaban
Edoxaban (details not provided)
LMWH alone or with warfarin
Cumulative VTE recurrence
NCT02744092
April 2016
September 2019
Rivaroxaban in the treatment of VTE in cancer patients—a randomized phase III study
Randomized, parallel assignment, open label trial
Patients with active cancer, newly diagnosed VTE, and good performance status
Rivaroxaban (15 mg twice daily for 21 d, followed by 20 mg once daily over a period
of 3 mo)
Enoxaparin (1 mg/kg BW twice daily
Tinzaparin 175 IE/kg BW once daily
Dalteparin 200 IE/kg BW once daily)
Patient‐reported treatment satisfaction
Secondary: Rate of symptomatic VTE recurrence
NCT02583191
October 2015
March 2018
Efficacy and safety of oral rivaroxaban for the treatment of venous thromboembolism
in patients with active cancer. A pilot study (CASTE‐DIVA)
Randomized, single‐blind clinical trial
Active solid cancer or myeloma treated with immunomodulatory drugs and symptomatic
VTE
Rivaroxaban, (15 mg twice/d for 3 wks followed by 20 mg once daily for 9 wks)
Dalteparin, (200 IU/kg once daily for 4 wks followed by 150 IU/kg once daily for 8 wks)
Symptomatic recurrent VTE or worsening of pulmonary vascular or venous obstruction
NCT02746185
December 2015
May 2017
A phase III, randomized, open label study evaluating the safety of apixaban in subjects
with cancer‐related venous thromboembolism
Randomized, parallel assignment, open‐label study
Active cancer (except nonmelanoma skin cancer), and confirmed acute VTE
Apixaban 10 mg twice daily on d 1–7 and 5 mg apixaban twice daily on d 8–180
Dalteparin (200 IU/kg/d on d 1–30 and 150 IU/kg/d on d 31–180)
Any episode of major bleeding including fatal bleeding
NCT02585713
October 2015
December 2020
Apixaban as treatment of venous thrombosis in patients with cancer: the CAP study
Single‐group, open‐label, study
Active cancer other than basal‐cell or squamous‐cell carcinoma of the skin and confirmed
VTE
Apixaban (10 mg 2 times daily for 1 wk, then apixaban 5 mg 2 times daily for 6 mo,
then apixaban 2.5 mg 2 times daily for as long as the treating physician finds it
necessary)
N/A
Recurrent confirmed VTE or VTE‐related death
Major or clinically relevant nonmajor bleeding
NCT02581176
October 2015
April 2016
Rivaroxaban for the prevention of venous thromboembolism in Asian patients with cancer
Single‐arm study
Asian patients with cancer‐associated VTE
Rivaroxaban (15 mg twice/d for the first 3 wks, followed by 20 mg once daily)
None
Recurrence of VTE
NCT01989845
October 2013
February 2017
SELECT‐D: anticoagulation therapy in SELECTeD cancer patients at risk of recurrence
of venous thromboembolism
Randomized, open label, multicenter pilot study
Patients with cancer and acute VTE
Rivaroxaban (details not provided)
Dalteparin
Recurrence of VTE
ISRCTN86712308
January 2013
December 2018
Cancer VTE
Randomized controlled, clinical trial
Patients with cancer and acute VTE
Edoxaban (details not provided)
Dalteparin
Recurrence of VTE
NCT02073682
March 2015
December 2017
Prevention of VTE
Efficacy and safety of rivaroxaban prophylaxis compared with placebo in ambulatory
cancer patients initiating systemic cancer therapy and at high risk for venous thromboembolism
Randomized, double‐blind, placebo‐controlled clinical trial
Patients with active malignancy and good performance status who plan to initiate systemic
chemotherapy within ±1 wk of receiving the first study drug dose
Rivaroxaban (10 mg daily for 180 d)
Placebo
First confirmed VTE or VTE‐related death
NCT02555878
September 2015
January 2018
The safety of oral apixaban (Eliquis) vs subcutaneous enoxaparin (Lovenox) for thromboprophylaxis
in women with suspected pelvic malignancy; a prospective randomized open blinded end
point (PROBE) design
Randomized, single‐blind, safety study
Women with pelvic malignancy undergoing surgical debulking
Apixaban (2.5 mg twice daily for 28 d postsurgery)
Enoxaparin (40 mg daily for 28 d postsurgery)
Incidence of major bleeding
NCT02366871
February 2015
March 2018
A phase III randomized, open label, multicenter study of the safety and efficacy of
apixaban for thromboembolism prevention vs no systemic anticoagulant prophylaxis during
induction chemotherapy in children with newly diagnosed acute lymphoblastic leukemia
(ALL) or lymphoma (T or B cell) treated with pegylated l‐asparaginase
Randomized, open‐label, placebo‐controlled clinical trial
Children with new diagnosis of de novo acute lymphocytic leukemia or lymphomas and
planned induction chemotherapy with a corticosteroid, vincristine, and PEG l‐asparaginase,
with or without daunorubicin
Apixaban (if <35 kg of 0.07 mg/kg twice a day 25–28 d, if ≥35 kg either 2.5 mg tablet
twice a day or 6.2 mL of the 0.4 mg/mL solution twice a day for 25–28 d)
Placebo
Composite of nonfatal VTE and VTE‐related death
major bleeding
NCT02369653
April 2015
May 2020
Apixaban for the prevention of venous thromboembolism in cancer patients (AVERT)
Randomized controlled, double‐blind placebo‐controlled clinical trial
Patients with cancer, undergoing surgery
Apixaban (2.5 mg twice/ d)
Placebo
First episode of VTE
NCT02048865
January 2014
January 2017
Apixaban for primary prevention of venous thromboembolism in patients with multiple
myeloma receiving immunomodulatory therapy
Randomized, double‐blind, placebo‐controlled clinical trial
Current or prior diagnosis of symptomatic multiple myeloma that will be starting or
already receiving immunomodulatory therapy (thalidomide, lenalidomide, or pornalidomide)
Apixaban (2.5 mg orally twice daily for primary prevention of VTE for a duration of
6 mo)
Placebo
Symptomatic VTE
Major and clinically relevant nonmajor bleeding
NCT02958969
January 2017
December 2019
Evaluation of the use of apixaban in prevention of thromboembolic disease in patients
with myeloma treated with iMiDs (MYELAXAT)
Single‐arm study
Patients with myeloma who are treated with melphalan, prednisone, thalidomide, lenalidomide,
or dexamethasone
Apixaban (2.5 mg twice/d)
None
VTE and VTE‐related death
Major and clinically relevant nonmajor bleeding
NCT02066454
April 2014
July 2017
BW indicates body weight; IU, International Unit; LMWH, low molecular weight heparin;
NOACs, non–vitamin K oral anticoagulants; VTE, venous thromboembolic disease.
Prevention of Venous Thromboembolism in the Hospital Setting
Routine pharmacological VTE prophylaxis is recommended in all patients with cancer
who are hospitalized for medical or surgical reasons, both by the European Society
of Medical Oncology69 and the American Society of Clinical Oncology.70 There is little
evidence on the use of NOACs for the prevention of VTE in patients with cancer who
are hospitalized because of acute medical or surgical illness. The MAGELLAN (Venous
Thromboembolic Event [VTE] Prophylaxis in Medically Ill Patients) trial compared rivaroxaban
with enoxaparin in patients who were hospitalized for an acute medical illness and
demonstrated that rivaroxaban was noninferior to enoxaparin for standard duration
thromboprophylaxis (10 days). Extended duration of rivaroxaban treatment (35 days)
reduced the risk of venous thromboembolism but was associated with an increased risk
of bleeding.17 The ADOPT (Study of Apixaban for the Prevention of Thrombosis‐related
Events in Patients With Acute Medical Illness) trial compared administration of apixaban
for 30 days to enoxaparin for 6 to 14 days in patients hospitalized for an acute medical
illness and demonstrated that an extended course of apixaban was not superior to a
short course of enoxaparin in preventing thrombotic events, while it was associated
with a significantly higher rate of major bleeding.18 The recent APEX (Prevention
with Extended Duration Betrixaban) trial demonstrated that extended duration betrixaban
(35–42 days) was similar to enoxaparin (for 10±4 days) for prevention of VTE in patients
with acute medical illness.19 None of these trials was specific to cancer patients,
and only 7.3% to 10.4% of the total participants had cancer. Both trials demonstrated
higher bleeding rates with NOACs compared with enoxaparin, suggesting that these agents
might not be safe for VTE prophylaxis in patients with cancer because of the patients'
higher risk of bleeding.60, 61 There are no studies to date assessing the use of NOACs
in patients with cancer hospitalized for a surgical condition. Currently, there are
few ongoing clinical trials assessing apixaban for VTE prophylaxis in patients with
cancer undergoing surgery (Table 2).
Primary Prevention of Venous Thromboembolism in the Ambulatory Setting
Thromboprophylaxis in ambulatory patients with cancer is not routinely recommended
but it may be considered in selected high‐risk individuals, such as patients with
multiple myeloma receiving anti‐angiogenic agents and/or dexamethasone.70 There is
only 1 phase II trial evaluating the role of apixaban in primary VTE prophylaxis in
ambulatory patients with cancer. In this trial, 125 patients with advanced or metastatic
lung, breast, gastrointestinal, bladder, ovarian, or prostate cancer, cancer of unknown
origin, myeloma, or selected lymphomas receiving chemotherapy were randomized to receive
placebo or apixaban (2.5, 5, or 10 mg twice daily). The rate of major bleeding in
the apixaban group was 2.2% and the authors concluded that apixaban was well tolerated,
but future studies are warranted to determine a safe regimen for VTE prophylaxis in
ambulatory patients receiving chemotherapy.85 There are several ongoing clinical trials
assessing apixaban for VTE prophylaxis in ambulatory patients with cancer who undergo
chemotherapy (Table 2).
Until the safety and efficacy of NOACs are compared with LMWH in randomized clinical
trials of patients with cancer, conventional treatment with LMWH will remain the standard
of care for the management of thromboembolic disease in these patients. Unfortunately,
contemporary analysis of practice patterns in the United States and Germany demonstrates
that LMWH is underutilized for treatment and prevention of cancer‐related VTE, and
VKA is the preferred anticoagulant, despite guideline recommendations. More patients
remained on oral versus injectable agents, which may be related to self‐injection
burden and costs.86, 87
Antiphospholipid Syndrome
APS is defined by the occurrence of venous and/or arterial thrombosis and/or pregnancy
morbidity, in the setting of persistent circulating antiphospholipid antibodies (aPLs).88
There are 3 types of aPLs used in the Sydney criteria to diagnose APS: anti‐beta2‐glycoprotein
I, anticardiolipin, and antibodies detected by lupus‐anticoagulant assays (anti‐beta2‐glycoprotein
I or antiprothrombin).88 Additional antibodies directed against phospholipid/phospholipid‐protein
have been causally linked to APS (IgA and IgM anticardiolipin, IgA and IgM beta‐2
glycoprotein I, anti‐phosphatidylserine antibodies, anti‐phosphatidylethanolamine
antibodies, anti‐prothrombin antibodies, and antibodies against the phosphatidylserine‐prothrombin
complex). Presence of aPLs in the serum does not necessarily translate to APS, but
it is associated with a broad spectrum of clinical manifestations ranging from asymptomatic
seropositivity to thrombotic microangiopathy with multiorgan involvement and failure.88
The exact mechanisms of APS remain largely unknown but a “2‐hit” model has been proposed
where the first hit is the presence of aPLs and the second hit is frequently related
to activation of the innate immune system.89
The 14th International Congress on Antiphospholipid Antibodies Task Force Report on
Antiphospholipid Syndrome Treatment Trends recommends that VKAs should be the first‐line
anticoagulation in patients with thrombotic APS.90 Although there is some controversy
on the therapeutic goals of anticoagulation in patients with APS, evidence suggests
that the target INR should be between 2.0 and 3.0, since patients treated to a higher
INR goal (3.0–4.0) have the same rate of thrombotic recurrence but higher incidence
of bleeding.91, 92 Management of anticoagulation with VKAs in patients with APS is
particularly challenging. In addition to the issues inherent to VKA use, monitoring
of anticoagulation may be complicated by the variable responsiveness of thromboplastin
reagents to aPLs, which may potentially influence the validity of INR measurement.93
The pathophysiology of thrombosis in APS is complex and incompletely understood. APS
is governed by massive release of thrombin94, 95 and tissue factor,96, 97 as well
as augmented activation of multiple coagulation factors.98, 99 NOACs that selectively
inhibit 1 coagulation factor might provide inadequate protection in this setting.
In a murine model of obstetric APS, hirudin (direct thrombin inhibitor) and fondaparinux
(indirect factor Xa inhibitor) were ineffective in preventing pregnancy loss. Both
unfractionated heparin and LMWH (indirect inhibitors of multiple factors) prevented
miscarriages, suggesting that selective factor inhibition might not be an adequate
anticoagulation strategy in APS.100 However, there is conflicting evidence on the
clinical use of anticoagulation for prevention of pregnancy loss in patients with
APS, and this discussion is beyond the scope of this review.
There are limited clinical data on the safety and efficacy of NOACs in patients with
APS. The rivaroxaban trials (EINSTEIN‐DVT and EINSTEIN‐PE) included a small subset
of patients with known thrombophilic conditions (5–7%) including some patients with
aPLs. The sample size of those patients is limited and details on the antibody profile
or APS status are not available. The results of these studies cannot be generalized
to patients with APS.101 In small case series, dabigatran and rivaroxaban have failed
to prevent thrombosis in patients with APS.101, 102 In RAPS (Rivaroxaban in Anti‐Phospholipid
Syndrome), patients with APS and a history of VTE who had been on warfarin (INR range
between 2.0 and 3.0) for at least 6 months were randomized to receive rivaroxaban
20 mg once daily (or 15 mg once daily if creatinine clearance is 30–49 mL/min, n=116)
or continue warfarin with a target INR of 2.5 (n=54). The primary outcome was percentage
change in endogenous thrombin potential from randomization to day 42. Rivaroxaban
failed to reach the noninferiority threshold in reducing endogenous thrombin potential.
There was no increase in thrombotic risk in patients treated with rivaroxaban compared
with standard‐intensity warfarin, although this small study was not powered for efficacy.103
There are 3 ongoing clinical trials currently evaluating NOACs in patients with APS.
TRAPS (Trial on Rivaroxaban in AntiPhospholipid Syndrome, NCT02157272) is a multicenter,
randomized, open‐label study that evaluates whether rivaroxaban 20 mg once daily (or
15 mg in patients with moderate renal insufficiency) is noninferior to warfarin (INR
target 2.5), for the prevention of thromboembolic events, major bleeding, and death
in high‐risk patients with antiphospholipid syndrome.104 Rivaroxaban for Patients
With Antiphospholipid Syndrome (NCT02926170) is a randomized open‐label clinical trial
comparing the efficacy and safety of rivaroxaban (20 mg daily) with dose‐adjusted
acenocoumarol in patients with thrombotic antiphospholipid syndrome who are treated
with VKA for at least 6 months. ASTRO‐APS (Apixaban for the Secondary Prevention of
Thrombosis among Patients with Antiphospholipid Syndrome, NCT02295475) is a prospective,
randomized, open‐label, blinded event pilot study. In this study, patients with antiphospholipid
syndrome who have been on anticoagulation for secondary prevention of thrombosis are
randomized to receive apixaban 5 mg twice a day or adjusted‐dose warfarin and the
safety and efficacy of the 2 strategies will be compared.105 Until the results of
these trials provide evidence of efficacy and safety of NOACs in patients with APS,
according to the task force report on antiphospholipid syndrome treatment trends,
NOACs should be considered in APS patients with VTE only when there is known VKA allergy,
intolerance, or poor anticoagulant control.90
Other Hypercoagulable States
Very limited data exist on the role of NOACs in other hypercoagulable states such
as inherited coagulopathies (homozygous factor V Leiden mutation, protein C or S deficiency,
elevated levels of factors VII–XII), or the nephrotic syndrome. Individuals with these
conditions were significantly underrepresented in the current trials. Dabigatran was
prescribed in a 21‐year‐old woman with recurrent VTEs caused by protein C deficiency,
complicated by warfarin‐induced skin necrosis, and inability to maintain anticoagulation
on LMWH. The patient did not experience any VTE recurrence in 6 months of follow‐up.106
Rivaroxaban was prescribed to a 30‐year‐old woman who had homozygosity of factor V
Leiden mutation and who sustained an ovarian vein thrombosis with proximal extension
to the renal vein. The patient remained free of symptoms without recurrence of thrombi
or bleeding complications.107 Dabigatran108 and rivaroxaban109 have been used for
secondary prophylaxis in a few patients with nephrotic syndrome. Anticoagulation in
these patients has been traditionally achieved with VKAs or heparins.110, 111
Other Considerations
End‐Stage Renal Disease
Currently available NOACs are primarily renally excreted. Dabigatran is 80% renally
excreted, while the renal excretion of factor Xa inhibitors ranges between 6% and
13% (betrixaban) and 50% (edoxaban).112 Clinical trials included patients with mild
to moderate renal disease with assigned lower study dose in most of these trials.
Rivaroxaban 15 mg once per day13, 15 and edoxaban 30 mg once per day16 were used in
patients with creatinine clearance between 30 and 49 mL/min. The dose of apixaban
was reduced to 2.5 mg twice daily in the presence of 2 of 3 factors (age >80 years,
weight <60 kg, creatinine 1.5 mg/dL or greater). The proportion of patients with moderate
renal disease (creatinine clearance of 30–49 mL/min) that enrolled in these trials
ranged between 15% and 21%. In a study of 14 264 patients with nonvalvular AF and
creatinine clearance of 30 to 49 mL/min, rivaroxaban 15 mg per day had similar efficacy
and safety compared with dose‐adjusted warfarin.113 A meta‐analysis of 10 trials and
40 693 patients with creatinine clearance of 30 to 49 mL/min suggested that NOACs
are noninferior to standard anticoagulation, and they are associated with less bleeding.114
However, clinical trials excluded patients with severe renal insufficiency (creatinine
clearance <30 mL/min for dabigatran, rivaroxaban, and edoxaban and <25 mL/min for
apixaban) and those on dialysis. There are limited data on the efficacy and safety
of NOACs in these patient populations. Despite the dearth of data, there is a reported
increase in the number of NOAC prescriptions in patients on dialysis.115 In pharmacokinetic
and pharmacodynamic simulation studies, most NOAC administration in patients on dialysis
could potentially result in higher levels compared with those without renal impairment.116,
117, 118 In a small pharmacokinetic, pharmacodynamic, and safety study, patients with
end‐stage renal disease on dialysis (n=8) had a modest increase (36%) in apixaban
area under the curve and no increase in apixaban maximal concentration compared with
subjects with normal renal function (n=8). Hemodialysis had a limited impact on apixaban
clearance.119 These data resulted in the Food and Drug Administration revising the
label of apixaban and recommending that 5 mg twice daily can be used in patients with
end‐stage renal disease on hemodialysis, while 2.5 mg twice daily should be used in
patients who are older than 80 years of age or weigh <60 kg. Until clinical data on
the safety and efficacy of other NOACs in patients with end‐stage renal disease or
on dialysis become available, apixaban could be used with caution while other NOACs
should not be used in these patients. VKAs have been the standard anticoagulation
treatment, although a clear benefit over risk has not been demonstrated, and more
data are needed for this challenging group of patients.120
Another area of uncertainty is the use of NOACs in patients whose renal function fluctuates
widely over time or who are at heightened risk for acute kidney injury, such as patients
with advanced heart failure. Patients with AF and a ≥25% relative decrease in their
estimated glomerular filtration rate had a 2‐fold higher risk of ischemic stroke.121
Acute and chronic renal dysfunction is common among individuals requiring long‐term
anticoagulant therapy.122 Patients with impaired renal function represent a distinct
high‐risk group and there are limited data on what the optimal strategy of anticoagulation
should be.
Pediatric Patients
The efficacy and safety of NOACs in pediatric patients is not established. Pediatric
VTE is uncommon; however, its incidence has been increasing over the past 2 decades.123
Heparin and VKAs have been traditionally used in this population, mostly by extrapolation
of results of studies in adults. The hemostatic system undergoes significant changes
in neonatal life and, especially during the first year of life, levels of pro‐ and
anticoagulant factors are low compared with adults.124 For this reason, the net anticoagulant
effect of selective factor inhibition with NOACs in neonates and children might be
different from adults. There are limited data on the safety and efficacy of NOACs
in neonates and children. In in vitro studies of plasma spiked with dabigatran125
and rivaroxaban,126 the changes in hemostatic parameters were similar in children
and adults. However, clotting time was longer in neonatal plasma spiked with dabigatran127
and rivaroxaban128 compared with adult serum, suggesting that neonatal plasma may
be more sensitive to those agents compared with adults. There is only 1 phase II clinical
trial available evaluating dabigatran in adolescents. In this trial (n=9, age: 12–18 years
old), dabigatran doses of initially 1.71 (±10%) mg/kg for 3 days, followed by 2.14
(±10 %) mg/kg (target adult dose adjusted for patient's weight) was well tolerated
over the 3‐day treatment period, with the exception of occurrence of dyspepsia in
2 patients. The observed dabigatran pharmacokinetics and pharmacodynamics were similar
to that of adults.129 There are no available studies assessing the efficacy and safety
of apixaban and edoxaban in pediatric patients. However, there are several ongoing
clinical trials evaluating the safety and efficacy of NOACs in pediatric patients
(Table 3). Until the results of these studies are available, heparin and VKA should
remain the standard of care in pediatric patients.
Table 3
PICO Model for Planned and Ongoing Clinical Trials Assessing NOACs in Pediatric Patients
Trial
Design
Patient Population
Intervention
Comparison
Primary Outcome
Clinical Trial Registration
Study Start Date
Estimated Completion Date
Open label study comparing efficacy and safety of dabigatran etexilate to standard
of care in pediatric patients with venous thromboembolism (VTE)
Open‐label, randomized, parallel‐group clinical trial
Children <18 y old with VTE
Age and weight appropriate dabigatran twice/d dosing
VKA or LMWH
Combined: complete thrombus resolution, recurrent VTE, and mortality related to VTE
NCT01895777
September 2013
June 2018
Safety of dabigatran etexilate in blood clot prevention in children
Open‐label, single‐arm prospective cohort study
Children <18 y old with history of VTE and at least 1 risk factor for continuation
of anticoagulation therapy
Age and weight appropriate dabigatran twice/ d dosing
None
Recurrence of VTE at 6 and 12 mo, major and minor bleeding
NCT02197416
September 2014
November 2018
EINSTEIN Junior Phase II: oral rivaroxaban in young children with venous thrombosis
Open‐label, single‐arm study
Children 6 mo to <6 y old who have been treated for at least 2 mo with LMWH and/or
VKA for VTE
Age and weight appropriate rivaroxaban once per day dosing
None
Incidence of major bleeding and clinically relevant nonmajor bleeding
NCT02309411
January 2015
April 2017 (results pending)
Rivaroxaban for treatment in venous or arterial thrombosis in neonates
Open‐label, single‐arm study
Neonates and infants <6 mo who have been treated for at least 5 d with heparin and/or
VKA for arterial or venous thrombosis
Weight‐adjusted rivaroxaban oral suspension (0.1%) for 7 d
None
Plasma concentration of rivaroxaban, anti‐Xa activity
NCT02564718
November 2015
December 2017
EINSTEIN Junior Phase III: oral rivaroxaban in children with venous thrombosis
Multicenter, open‐label, active‐controlled, randomized clinical trial
Children aged 6 mo to 18 y old with confirmed VTE who receive initial treatment with
heparin and require anticoagulation for at least 90 d
Age‐ and weight‐appropriate rivaroxaban once per day dosing
LMWH or VKA
Symptomatic recurrent venous thromboembolism, major and clinically relevant nonmajor
bleeding
NCT02234843
November 2014
July 2019
Phase I study on rivaroxaban granules for oral suspension formulation in children
Open‐label, single‐arm pharmacokinetics study
Children 2 mo to 12 y old with previous VTE
Rivaroxaban granules for oral suspension
None
Area under the curve and maximum observed drug concentration
NCT02497716
November 2015
December 2017
Study to evaluate a single dose of apixaban in pediatric subjects at risk for a thrombotic
disorder
Open‐label, single‐arm study
Neonates to <18 y old and any stable disease that are at risk for venous or arterial
thrombus
Apixaban solution
None
Area under the curve, maximum observed drug concentration, and estimated time at which
maximum plasma concentration occurs
NCT01707394
January 2013
October 2017
A study of the safety and effectiveness of apixaban in preventing blood clots in children
with leukemia who have a central venous catheter and are treated with pegylated (PEG)
l‐asparaginase
Randomized, open label, multicenter clinical trial
Children 1–18 y old with new diagnosis of acute leukemias or lymphomas and planned
induction chemotherapy with corticosteroid, vincristine, and PEG l‐asparaginase
Weight‐adjusted apixaban solution for 25– 28 d
Placebo
Composite of nonfatal VTE and VTE‐related death, major bleeding
NCT02369653
April 2015
May 2020
Apixaban for the acute treatment of venous thromboembolism in children
Randomized, open‐label, active controlled clinical trial
Children 12– 18 y old who present with VTE and requiring anticoagulation for >12 wks
Age and weight appropriate apixaban twice per day dosing
Standard of care anticoagulation according to local practices
Composite of any VTE and VTE‐related mortality, major and clinically relevant nonmajor
bleeding
NCT02464969
November 2015
October 2020
Phase 1 pediatric pharmacokinetics/pharmacodynamics (PK/PD) study
Open‐label, single‐dose, nonrandomized study
Children <18 y old who continue to require anticoagulation therapy and will abstain
from the use of nonsteroidal anti‐inflammatory medications
Age and weight appropriate edoxaban once per day dosing
None
Pharmacokinetics and pharmacodynamics parameters of edoxaban
NCT02303431
August 2014
December 2017
Hokusai study in pediatric patients with confirmed VTE
Open‐label, randomized, multicenter, controlled clinical trial
Children <18 y old with VTE requiring anticoagulation for >90 d who have received
at least 5 d of heparin
Age‐ and weight‐appropriate edoxaban once per day dosing
VKA or heparin
Composite of symptomatic and recurrent VTE, VTE‐related death and no change or extension
of thrombotic burden
NCT02303431
April 2017
December 2021
LMWH indicates low molecular weight heparin; NOACs, non–vitamin K oral anticoagulants;
VKA, vitamin K antagonists; VTE, venous thrombolic disease.
Pregnancy
There are very limited data on the safety of NOAC use during pregnancy.130 All major
NOAC trials excluded patients who were pregnant. In ex vivo studies of perfused placentas,
unbound dabigatran,131 unbound rivaroxaban,132 and unbound apixaban133 can cross the
placenta with transfer ratios of 33%, 69%, and 77%, respectively. Apixaban levels
in cord blood are predicted to be 35% to 90% of the corresponding maternal levels.133
This evidence suggests that NOACs can reach the fetus and potentially have adverse
effects on fetal and neonatal coagulation. Dabigatran, rivaroxaban, and edoxaban are
classified by the Food and Drug Administration as a pregnancy class C: “risk cannot
be ruled out.” Apixaban is classified as a pregnancy class B: “animal reproduction
studies have failed to demonstrate a risk to the fetus and there are no adequate and
well‐controlled studies in pregnant women.” Betrixaban was not associated with adverse
developmental fetal outcomes, but maternal hemorrhage was observed, in preclinical
animal studies.134 There are no clinical trials of NOACs in pregnancy. In an analysis
of 137 cases of women who were exposed to NOACs during pregnancy, fetal abnormalities
were present in 7 (5.1%) patients of which 3 (2.2%) could potentially be interpreted
as embryopathy.135 In a pharmacovigilance case‐series from Germany, 37 pregnancies
were prospectively ascertained and resulted in 6 spontaneous abortions, 8 elective
terminations of pregnancy, and 23 live births. There was 1 major malformation (conotruncal
cardiac defect) in a woman with a previous fetus with cardiac malformation without
exposure to rivaroxaban. All women had discontinued rivaroxaban after recognition
of pregnancy, mostly in the first trimester, but in 1 woman treatment continued until
gestational week 26.136 LMWH does not cross the placenta, is efficacious during pregnancy,
and is currently the recommended anticoagulant during pregnancy.137 Until evidence
on the safety of NOACs in pregnancy is available, LMWH should be the anticoagulant
of choice in pregnancy. It is uncertain whether NOACs are excreted in breast milk
and thus all NOACs should be avoided during lactation.
Drug Adherence and Physician Underdosing
The effect of medication adherence among patients prescribed NOACs has not been adequately
assessed to date. Medication nonadherence is a very common and perplexing issue. Approximately
50% of patients fail to comply with their prescribed medication regimen, independently
of sex, age, and medical condition.138 Most NOACs have a short half‐life, ranging
from 6 to 8 (apixaban and edoxaban) to 12 to 17 hours (dabigatran and rivaroxaban).112
The half‐life of betrixaban is 37 hours. Warfarin has an average half‐life of 40 to
60 hours. For this reason, medication nonadherence will be less tolerated with NOACs
as compared with warfarin. In a small cohort of 347 patients studied over a year,
36% of out‐of‐range INRs were caused by nonadherence.139 Warfarin nonadherence is
associated with increased health‐related costs.140 In a recent real‐world analysis
of >36 000 patients with nonvalvular AF, there was a concerningly low adherence to
NOAC therapy with proportion of days covered ranging between 69.2% and 80% over 6 months
of follow‐up.141, 142 The cost of treatment is directly associated with medication
nonadherence.143 NOACs are significantly more expensive compared with VKAs; the annual
cost for NOACs is estimated to be around $3000 to $3500, compared with warfarin, which
is around $50.144 In clinical trials, given the strict protocols and close follow‐up,
medication nonadherence is infrequently an issue, but adherence outside of this structured
setting can be problematic.
Last, there is emerging evidence of a concerning prevalence of NOAC underdosing in
routine clinical practice. One out of 8 patients participating in the ORBIT‐II (Outcomes
Registry for Better Informed Treatment of Atrial Fibrillation) registry (5738 patients,
242 community sites) was taking a NOAC dose inconsistent with labeling.145 Older age,
female sex, higher CHA2DS2‐VASc score, and higher bleeding risk were associated with
higher risk for underdosing. NOAC underdosing is associated with a 26% increase in
cardiovascular hospitalizations. In a large, international, prospective registry from
Europe, 15% of patients with creatinine clearance ≥50 mL/min inappropriately received
the lower rivaroxaban dose of 15 mg daily.146 In the nationwide RAMSES study (Real‐life
Multicenter Survey Evaluating Stroke Prevention Strategies in Turkey), off‐label use
of NOACs occurred in 40.2% of the patients, with 30.4% being underdosed.147 Single‐center
reports from around the world reveal rates of underdosing as high as 48% to 71% (Australia148)
and 12.4% to 36.9% (United States148, 149). Data from clinical practice need to be
analyzed to better understand the efficacy and safety of NOACs in the setting of medication
nonadherence and off‐label use of lower doses.
Conclusions and Future Directions
The non–vitamin K oral anticoagulants constitute a major breakthrough in the management
of thromboembolic disease. The ease of their use, the wide therapeutic window, and
the fact that they do not require monitoring will help to overcome the significant
obstacles encountered with VKAs. The studies conducted to date justify their use in
patients with nonvalvular AF, and for VTE prophylaxis and treatment. However, there
are specific conditions, such as valvular heart disease, cancer‐associated VTE, APS,
and other hypercoagulable states, severe renal and hepatic dysfunction, pediatric
patients, and pregnancy, where the efficacy and safety of NOACs have yet to be demonstrated.
From a translational science perspective, it is essential to elucidate the mechanisms
of thrombosis in these conditions. Determining the factors that have a nodal role
in these diseases would lay the theoretical ground for developing anticoagulation
strategies, specific for each disease, that achieve the maximal antithrombotic effect
while minimizing hemorrhagic complications. From a clinical perspective, given the
complexity and the challenges inherent to the management of these diseases, well‐designed
randomized clinical trials should be performed specifically in patients with these
medical conditions. Until such data become available, traditional anticoagulation
with VKAs or heparins will remain the mainstay of anticoagulation therapy.
Sources of Funding
This work was funded by the National Institutes of Health: 1RO1NS070307 (Hylek), 5T32HL007227‐42
(Aronis).
Disclosures
Dr Hylek has served as a consultant for Bayer, Boehringer Ingelheim, Bristol Myers
Squibb, Daiichi Sankyo, Janssen, Medtronic, Pfizer, and Portola Pharmaceuticals. Dr
Aronis has no conflict of interest to disclose. The National Institutes of Health
has not been involved, directly or indirectly, in the collection, management, analysis,
and interpretation of the data; preparation, review, or approval of the article; or
decision to submit the article for publication.