Keywords
anticoagulants - oral anticoagulants - apixaban - rivaroxaban - dabigatran
Three new oral anticoagulant drugs (apixaban, rivaroxaban, and dabigatran) have become
available for prophylaxis and treatment of acute venous thromboembolism (VTE), and,
since 2010, also for prevention of stroke and systemic embolism in patients with nonvalvular
atrial fibrillation (AF). This represents a significant change, because since the
introduction of warfarin half a century ago, there had been no significant changes
in drugs available for use in long-term anticoagulation. The favorable features of
the new oral agents (i.e., less complex drug-to-drug interaction profiles, the lack
of need for routine monitoring) make them an attractive option for managing anticoagulation
in the inpatient and outpatient settings. On the contrary, the new agents have important
limitations (e.g., contraindication in severe renal insufficiency, lack of an antidote
in case of bleeding, and higher cost than warfarin) that complicate clinical decisions
about when and how to use them. This review describes the landmark clinical trial
data as well as practical considerations that are relevant to treating patients with
the three new oral agents (apixaban, dabigatran, and rivaroxaban) that are now in
advanced stages of clinical development.
Pharmacology
All drug dosage recommendations in this article are for North America, unless otherwise
stated. The doses approved may differ in other regions.
Apixaban
Apixaban is a reversible, direct, and highly selective active site inhibitor of factor
Xa (FXa). It does not require antithrombin for its anticoagulant activity. Apixaban
inhibits free and clot-bound FXa, and prothrombinase activity. Apixaban has no direct
effects on platelet aggregation, but indirectly inhibits tissue factor–induced platelet
aggregation in vitro, presumably by inhibiting the production of thrombin.[1]
[2]
Apixaban is produced as a 2.5 mg film-coated tablet. The bioavailability of apixaban
is approximately 50%; it is rapidly absorbed, not affected by food, with maximum concentrations
appearing 3 to 4 hours after tablet intake and has a half-life of approximately 12
hours.[3] Apixaban is metabolized mainly via the cytochrome P450 (CYP) enzyme 3A4/5.[3] Renal excretion of apixaban accounts for approximately 27% of total clearance with
additional contributions from biliary and direct intestinal excretion.[3]
The recommended apixaban doses for most patients are 5 mg twice daily for stroke prevention
in AF and 2.5 mg twice daily for the prevention of VTE after orthopedic surgery. No
dose adjustment is necessary in patients with mild renal impairment. There is no clinical
experience in patients with creatinine clearance (CrCl) less than 15 mL/min, or in
patients undergoing dialysis.[4] No dose adjustment is required in patients with mild or moderate hepatic impairment
(Child Pugh A or B), but apixaban is contraindicated in patients with hepatic disease
associated with coagulopathy.[4]
No additional adjustment is necessary by body weight or age. There are no data available
from the use of apixaban in pregnant women, and apixaban is not recommended during
pregnancy. It is unknown whether apixaban or its metabolites are excreted in human
milk. Available data in animals have shown excretion of apixaban in milk.[5]
Rivaroxaban
Rivaroxaban is an oral FXa inhibitor that selectively blocks the active site of FXa
and, like apixaban, does not require antithrombin for its activity.
Rivaroxaban is manufactured as tablets: 10, 15, and 20 mg. The absolute bioavailability
is more than 50% and it is dose-dependent; at 10 mg dose, it is estimated to be 80
to 100% bioavailable. The bioavailability of rivaroxaban is not decreased by food
and it is not affected by drugs that alter gastric pH.[6]
[7]
The maximum concentrations of rivaroxaban appear 2 to 4 hours after oral intake and
the elimination half-life of rivaroxaban is 5 to 9 hours. Rivaroxaban is metabolized
mainly via oxidative degradation in the liver.[8] In humans, CYP3A4 and CYP2J2 are the two enzymes responsible for its oxidative metabolism.[8] Inhibitors and inducers of these CYP enzymes can result in changes in rivaroxaban
exposure.
Approximately 40% of the unchanged drug is excreted into the urine due to elimination
by active tubular secretion.[6] Rivaroxaban is a moderate substrate of the efflux transporter P-glycoprotein (P-gp).
Drugs that inhibit both the CYP3A4 enzymes and the P-gp include ketoconazole, ritonavir,
clarithromycin, fluconazole, and erythromycin.[9] The concomitant use of rivaroxaban and these medications could increase blood levels
of rivaroxaban and bleeding risk.[9]
The recommended postoperative thromboprophylaxis (knee and hip replacement) is 10 mg
once daily. The therapeutic dose ranges between 15 and 20 mg once daily, and needs
adjustment based on the estimated CrCl. For patients with CrCl > 50 mL/min, 20 mg
is the recommended daily dose; with CrCl < 50 mL/min, 15 mg is the recommended daily
dose. There is no clinical experience in patients with CrCl < 30 mL/min.[7] For the first 21 days of treatment for acute DVT or PE, rivaroxaban is given at
a dose of 15 mg orally twice daily.
Rivaroxaban has not been studied in patients with severe hepatic impairment (Child
Pugh C). For patients with moderate hepatic impairment (Child Pugh B), the mean rivaroxaban
exposure is increased by 2.3-fold.[7]
The safety and effectiveness of rivaroxaban during labor and delivery have not been
studied in clinical trials; it is not known if rivaroxaban is excreted in human milk.
Dabigatran Etexilate
Dabigatran etexilate is a pro-drug that is converted by tissue esterases to dabigatran,
a competitive, direct thrombin inhibitor.[10] There is an evidence from in vitro experiments that both free and clot-bound thrombin
are inhibited by dabigatran.[2] Also, there is evidence of inhibition of tissue factor–induced platelet aggregation
by this medication.[2]
Dabigatran is available in the United States as 75 and 150 mg capsules. In many other
jurisdictions, dabigatran is available as 110 and 150 mg capsules. The absolute bioavailability
of dabigatran following oral administration is approximately 3 to 7%. The absorption
is influenced by the intestinal efflux transporter P-gp. The maximum concentration
occurs at 1 hour postadministration in the fasted state; and can be delayed by approximately
2 hours if administered with meals, but the presence of food does not change the ultimate
bioavailability of dabigatran. The half-life of dabigatran etexilate is 12 to 17 hours.[10]
Dabigatran is not a substrate, inhibitor, or inducer of CYP450 enzymes and is eliminated
primarily in the urine.[11] In adults with moderate hepatic impairment (Child Pugh B), there is no evidence
of a consistent change in exposure or pharmacodynamics.[12]
The recommended dose of dabigatran is 150 mg taken orally, twice daily; a dose reduction
to 75 mg twice daily is indicated (in the United States) for patients with CrCl < 30
mL/min.[12] There is no clinical trial experience in patients with a CrCl < 30 mL/min (the 75 mg
dose was approved based on pharmacokinetic modeling) and the manufacturer recommends
that dabigatran should not be used in patients with a CrCl < 15 mL/min or in patients
who require renal replacement therapy.
The concomitant use of dabigatran etexilate with P-gp inducers (e.g., rifampicin)
reduces exposure to dabigatran and should generally be avoided[13]; although concomitant P-gp inhibitors may increase exposure to dabigatran,[14] the prescribing information approved by the U.S. Food and Drug Administration (FDA)
does not require a dose adjustments in such situations. There are no well-controlled
studies in pregnant women, and it is not known whether dabigatran is excreted in human
milk.
Clinical Trial Evidence
Apixaban
Available phase III clinical trial data support the use of apixaban for VTE prophylaxis
after orthopedic surgery and for cardioembolic prophylaxis in AF ([Tables 1]
[2]
[3]). Phase II studies indicate that apixaban may be a safe and effective option for
the treatment of VTE but data from pivotal phase III trials are pending.
Table 1
Summary of the efficacy and safety data for apixaban, rivaroxaban, and dabigatran
in the prevention of venous thromboembolism after major orthopedic surgery
|
Agent
(where approved for postoperative VTE prevention)
|
Trial name
|
Dose, frequency
|
Comparator
(enoxaparin)
|
VTE[a] (%)
(vs. LMWH %)
|
Relative Risk for VTE (95% CI)
|
Major bleeding (%)
(vs. LMWH %)
|
Relative risk for major bleeding (95% CI)
|
Number of patients
randomized
|
|
Apixaban
(Europe)
|
ADVANCE-1: knee
ADVANCE-2: knee
ADVANCE-3: hip
|
2.5 mg b.i.d.
2.5 mg b.i.d.
2.5 mg b.i.d.
|
30 mg b.i.d.
40 mg o.d.
40 mg o.d.
|
9.0 (vs. 8.8)
15.1 (vs. 24.4)
1.4 (vs. 3.9)
|
1.02 (0.78–1.32)
0.62 (0.51–0.74)
0.36 (0.23–0.56)
|
0.7 (vs. 1.4)
0.6 (vs. 0.9)
0.8 (vs. 0.7)
|
0.5 (0.24–1.02)
0.65 (0.28–1.49)
1.22 (0.65–2.26)
|
3,195
3,057
5,407
|
|
Rivaroxaban
(Europe, Canada, United States)
|
RECORD-1: hip
RECORD-2: hip
RECORD-3: knee
RECORD-4: knee
|
10 mg o.d.
10 mg o.d.
10 mg o.d.
10 mg o.d.
|
40 mg o.d.
40 mg o.d.
40 mg o.d.
30 mg b.i.d.
|
1.1 (vs. 3.7)
2.0 (vs. 9.3)
9.6 (vs. 18.9)
6.9 (vs. 10.1)
|
0.30 (0.18–0.51)
0.21 (0.13–0.35)
0.51 (0.39–0.65)
0.69 (0.51–0.92)
|
0.3 (vs. 0.1)
0.1 (vs. 0.1)
0.6 (vs. 0.5)
0.7 (vs. 0.3)
|
3.02 (0.61–14.95)
1.00 (0.06–15.98)
1.19 (0.40–3.53)
2.47 (0.78–7.86)
|
5,541
2,509
2,531
3,148
|
|
Dabigatran
(Europe, Canada)
|
RE-NOVATE: hip
RE-MODEL: knee
RE-MOBILIZE: knee
|
220 mg o.d.
150 mg o.d.
220 mg o.d.
150 mg o.d.
220 mg o.d.
150 mg o.d.
|
40 mg o.d.
40 mg o.d.
30 mg b.i.d.
30 mg b.i.d.
30 mg b.i.d.
30 mg b.i.d.
|
6.0 (vs. 6.7)
8.6 (vs. 6.7)
36.4 (vs. 37.7)
40.5 (vs. 37.7)
31.1 (vs. 25.3)
33.7 (vs. 25.3)
|
0.90 (0.63–1.29)
1.28 (0.93–1.78)
0.97 (0.82–1.13)
1.07 (0.92–1.25)
1.23 (1.03–1.47)
1.33 (1.12–1.58)
|
2.0 (vs. 1.6)
1.3 (vs. 1.6)
1.5 (vs. 1.3)
1.3 (vs. 1.3)
0.6 (vs. 1.4)
0.6 (vs. 1.4)
|
1.29 (0.70–2.37)
0.83 (0.42–1.63)
1.14 (0.46–2.78)
0.99 (0.39–2.47)
0.42 (0.15–1.19)
0.42 (0.15–1.17)
|
3,493
2,101
2,615
|
Abbreviations: b.i.d., twice daily; CI, confidence interval; LMWH, low-molecular-weight
heparin; o.d., once daily; vs., versus; VTE, venous thromboembolism.
a VTE numbers included asymptomatic events detected by surveillance venography.
Table 2
Summary of efficacy and safety data for rivaroxaban and dabigatran in the treatment
of acute venous thromboembolism
|
Agent
|
Trial name
|
Dose, frequency
|
Comparator
(INR indicated if VKA)
|
Recurrent VTE[a] (%)
(vs. VKA %)
|
Relative risk for recurrent VTE
(95% CI)
|
Major bleeding (%)
(vs. comparator %)
|
Relative risk for major bleeding
(95% CI)
|
Number of patients
randomized
|
|
Rivaroxaban
|
EINSTEIN-DVT
EINSTEIN-extension
EINSTEIN-PE
|
15 mg b.i.d. then 20 mg o.d.
20 mg o.d.
15 mg b.i.d. then 20 mg o.d.
|
INR 2.0–3.0
placebo
INR 2.0–3.0
|
2.1 (vs. 3.0)
1.3 (vs. 7.1)
2.1 (vs. 1.8)
|
0.70 (0.46–1.07)
0.19 (0.09–0.40)
1.13 (0.76–1.69)
|
0.8 (vs. 1.2)
0.7 (vs. 0.1)
1.1 (vs. 2.2)
|
0.70 (0.35–1.38)
7.89 (0.42–148.99)
0.50 (0.31–0.80)
|
3,449
1,197
4,832
|
|
Dabigatran
|
RE-COVER
RE-COVER II
RE-SONATE
RE-MEDY
|
150 mg b.i.d.
150 mg b.i.d.
150 mg b.i.d.
150 mg b.i.d.
|
INR 2.0–3.0
INR 2.0–3.0
placebo
INR 2.0–3.0
|
2.4 (vs. 2.1)
2.4 (vs. 2.2)
0.4 (vs. 5.6)
1.8 (vs. 1.3)
|
1.10 (0.66–1.84)
1.09 (0.65–1.81)
0.08 (0.02–0.25)
1.44 (0.79–2.62)
|
1.6 (vs. 1.9)
1.2 (vs. 1.7)
0.3 (vs. 0.1)
19.4 (vs. 26.2)
|
0.83 (0.46–1.49)
0.69 (0.36–1.33)
3.89 (0.18–86.07)
0.74 (0.65–0.85)
|
2,539
2,568
1,343
2,856
|
Abbreviations: b.i.d., twice daily; CI, confidence interval; INR, international normalized
ratio; o.d., once daily; VKA, vitamin K antagonist; vs., versus; VTE, venous thromboembolism.
a Recurrent VTE was taken as the composite of deep venous thrombosis or nonfatal or
fatal pulmonary embolism.
Table 3
Summary of the efficacy and safety data for apixaban, rivaroxaban, and dabigatran
in the prevention of embolism in atrial fibrillation
|
Agent
(where approved for stroke prevention in AF)
|
Trial name
|
Dose, frequency
|
Comparator[a]
(INR indicated if VKA)
|
All stroke or systemic embolism
|
Relative risk for embolism
(95% CI)
|
Major bleeding (%)
ICH (%)
(vs. VKA %)
|
Relative risk for major bleeding/ICH
(95% CI)
|
Number of patients
randomized
|
|
Apixaban
(Europe, Canada, United States of America)
|
ARISTOTLE
AVERROES
|
5 mg b.i.d.
5 mg b.i.d.
|
INR 2.0–3.0
aspirin
|
2.3 (vs. 2.9)
1.8 (vs. 4.0)
|
0.80 (0.67–0.95)
0.45 (0.32–0.62)
|
3.6 (vs. 5.1)
0.6 (vs. 1.3)
1.6 (vs. 1.4)
0.4 (vs. 0.5)
|
0.70 (0.61–0.81)
0.42 (0.31–0.59)
1.12 (0.73–1.72)
0.84 (0.38–1.87)
|
18,201
5,599
|
|
Rivaroxaban
(Europe, Canada, United States of America)
|
ROCKET-AF
|
20 mg o.d.
|
INR 2.0–3.0
|
3.8 (vs. 4.3)
|
0.88 (0.75–1.03)
|
5.6 (vs. 5.4)
0.8 (vs. 1.2)
|
1.03 (0.89–1.18)
0.66 (0.47–0.92)
|
14,264
|
|
Dabigatran
(Europe, Canada, United States of America)
|
RE-LY
|
110 mg b.i.d.
150 mg b.i.d.
|
INR 2.0–3.0
|
3.0 (vs. 3.3)
2.2 (vs. 3.3)
|
0.92 (0.75–1.12)
0.67 (0.54–0.83)
|
5.4 (vs. 6.6)
0.4 (vs. 1.4)
6.2 (vs. 6.6)
0.6 (vs. 1.4)
|
0.81 (0.70–0.94)
0.31 (0.20–0.48)
0.94 (0.82–1.07)
0.41 (0.28–0.60)
|
18,113
|
Abbreviations: b.i.d., twice daily; CI, confidence interval; ICH, intracranial hemorrhage;
INR, international normalized ratio; o.d., once daily; VKA, vitamin K antagonist;
VTE, venous thromboembolism.
a All embolism was defined as the composite of stroke and noncentral nervous system
systemic embolism.
Taken together, the clinical trial data for apixaban as prophylaxis against VTE after
orthopedic surgery, demonstrate that apixaban is as effective as low-molecular-weight
heparin (LMWH), with a trend toward lower rates of major hemorrhagic complications[15]
[16]
[17] ([Table 1]).
For thromboprophylaxis in nonsurgical patients, the ADOPT trial randomly assigned
acutely ill patients who had congestive heart failure, respiratory failure, or other
medical disorders and at least one additional risk factor for deep vein thrombosis
(DVT) to 6 days of LMWH or 30 days of apixaban.[18] All included patients were hospitalized with an expected stay of at least 3 days.
The primary efficacy outcome was the 30-day composite of death related to pulmonary
embolism (PE), symptomatic DVT, or asymptomatic proximal-leg DVT, as detected with
the use of systematic bilateral compression ultrasonography on day 30. Apixaban was
not superior to enoxaparin for the primary efficacy outcome; however, the patients
randomized to apixaban had a trend toward higher rate of major bleeding during treatment
(relative risk [RR], 2.53; 95% confidence interval [CI], 0.98 to 6.50).[18]
In the VTE treatment setting, a phase II study evaluated apixaban versus LMWH followed
by a vitamin K antagonist (VKA) in patients with symptomatic DVT. Although not powered
to yield definitive conclusions, the results of this trial[19] were sufficiently promising that two additional phase III trials (AMPLIFY, AMPLIFY-EXT)
evaluating the efficacy of apixaban in this setting are now near completion.
Apixaban has been evaluated for the treatment of recent acute coronary syndrome (ACS)
in the APPRAISE trials. Both of these studies were terminated prematurely because
of an increased rate of major bleeding events in the apixaban arm in the absence of
a clinically significant reduction in recurrent ischemic events. Nearly all patients
in these trials received concurrent standard antiplatelet therapy.[20]
[21]
For the prevention of stroke in patients with AF, the ARISTOTLE trial showed that
apixaban was superior to warfarin for efficacy (all stroke plus systemic embolism),
safety (major bleeding), and all-cause death[22] ([Table 3]). Moreover, the AVERROES trial (aspirin vs. apixaban in patients who were not suitable
for warfarin) was stopped early because of a lower rate of stroke in the apixaban-treated
patients with AF. Although no difference in clinically significant bleeding was observed,
the safety results must be interpreted with caution because the number of bleeding
events was low[23] ([Table 3]).
Rivaroxaban
This direct FXa inhibitor has supporting clinical trial data for its use in VTE prophylaxis
and treatment, and cardioembolic prevention in AF ([Tables 1]
[2]
[3]). Robust clinical trial evidence indicates that rivaroxaban is a very effective
medication for VTE prevention following joint replacement surgery. Four separate trials,
involving more than 13,000 patients in total, demonstrated that rivaroxaban-treated
patients had a lower rate of total (symptomatic and asymptomatic) VTE than did patients
who received enoxaparin.[24]
[25]
[26]
[27] A trend toward excess bleeding in the rivaroxaban-treated patients has been noted;
however, a prespecified pooled analysis highlights the very low overall rate of serious
hemorrhagic events[28 ]([Table 1]).
The MAGELLAN study, a multicenter randomized controlled trial (RCT), evaluated the
efficacy of rivaroxaban for 35 days versus enoxaparin for 10 days in patients hospitalized
for various acute medical illnesses with risk factors for VTE. The primary efficacy
outcome was the composite of asymptomatic proximal DVT, symptomatic DVT, symptomatic
nonfatal PE, and VTE-related death. The primary safety outcome was the composite of
major bleeding and clinically relevant nonmajor bleeding.[29] The modified intent-to-treat analysis showed comparable rates for the primary efficacy
outcome (3.0% in the rivaroxaban group vs. 3.1% in the enoxaparin group; RR, 0.99;
95% CI, 0.75 to 1.30; p = 0.95), but the safety outcome favored enoxaparin, with a higher rate of bleeding
in the rivaroxaban group (4.1 vs. 1.7%; RR, 2.5; 95% CI, 1.85 to 3.25; p < 0.0001).[30]
In the DVT treatment setting, the EINSTEIN-DVT study and the EINSTEIN-extension trial[31] have demonstrated that the efficacy of rivaroxaban for acute treatment and secondary
prevention of DVT is comparable to that provided by traditional therapy with LMWH
followed by long-term VKA. Furthermore, recent data from the EINSTEIN-PE trial that
rivaroxaban is noninferior to standard therapy in patients with symptomatic PE with
or without concurrent DVT[32] ([Table 2]).
The ATLAS ACS-TIMI 51 study assessed the efficacy of rivaroxaban in the treatment
of ACS.[33] This randomized, double-blind, placebo-controlled trial compared one of two twice-daily
doses (2.5 or 5 mg) of rivaroxaban to placebo. All patients received other standard
therapy for ACS (e.g., antiplatelet medications) at the discretion of the treating
physician. The primary efficacy end point, a composite of death due to cardiovascular
causes, myocardial infarction, or stroke, occurred less frequently in the rivaroxaban-treated
patients for both 2.5 mg (hazard ratio [HR], 0.84; 95% CI, 0.72 to 0.97; p = 0.02) and 5 mg doses (HR, 0.85; 95% CI, 0.73 to 0.98; p = 0.03). Moreover, the twice-daily 2.5 mg dose of rivaroxaban reduced the rates of
death from cardiovascular causes (2.7 vs. 4.1%; HR, 0.66; 95% CI, 0.51 to 0.86; p = 0.002) and death from any cause (2.9 vs. 4.5%; HR, 0.68; 95% CI, 0.53 to 0.87;
p = 0.002); this survival benefit was not seen with the twice-daily 5 mg dose, perhaps
because it caused more major bleeding.
The risk of clinically significant bleeding with rivaroxaban increased among patients
with ACS in a dose-dependent manner.[33] As compared with placebo, rivaroxaban increased the rates of major bleeding not
related to coronary artery bypass grafting (2.1 vs. 0.6%; HR, 3.96; 95% CI, 2.46 to
6.38; p < 0.001) and the rates of intracranial hemorrhage (ICH) (0.6 vs. 0.2%; p = 0.009). The twice-daily 2.5 mg dose resulted in fewer fatal bleeding events than
the twice-daily 5 mg dose (0.1 vs. 0.4%; p = 0.04). The ACS population that will derive a clear-cut net clinical benefit from
adding rivaroxaban to other antithrombotic therapies has yet to be defined.
The ROCKET AF trial[34] showed that rivaroxaban was not inferior to warfarin for the prevention of stroke
or systemic embolism in patients with high-risk nonvalvular AF; rivaroxaban-treated
patients exhibited a statistically significant reduction in the risk of intracranial
bleeding ([Table 3]).
Dabigatran Etexilate
The RE-NOVATE, the RE-MODEL, and the RE-MOBILIZE trials have explored the efficacy
of dabigatran as VTE prophylaxis following elective hip, elective knee replacement
surgery, respectively.[35]
[36]
[37] Taken together, the results of these trials suggest that dabigatran is an effective
and safe VTE prevention option following total joint replacement; however, the RE-MOBILIZE
trial, which demonstrated superiority for twice-daily enoxaparin over dabigatran,
suggests that the optimal VTE prophylaxis dose of this drug is not yet established[35]
[36]
[37] ([Table 1]).
For treatment of acute VTE, dabigatran has been compared with standard therapy in
the RE-COVER and RE-COVER II trials.[38]
[39] The primary outcome in both studies was the 6 month incidence of recurrent symptomatic
VTE and related deaths ([Table 2]). In both trials, the patients assigned to dabigatran were treated with LMWH or
unfractionated heparin for 5 to 11 days prior to the initiation of dabigatran. In
the control arm of both studies, parenteral therapy was overlapped with VKA treatment
until a therapeutic international normalized ratio (INR) was achieved. These studies
showed that dabigatran is as effective as LMWH followed by VKA for secondary VTE prevention,
without an increase in the bleeding rate when compared to more traditional pharmacologic
measures.[38]
[40] Furthermore, the data from the RE-SONATE and RE-MEDY studies have demonstrated the
safety and efficacy of continuing dabigatran for at least 6 more months beyond the
initial treatment for VTE[39]
[41] ([Table 2]). There was a slightly higher rate of treatment discontinuation in the dabigatran
group related to nonhemorrhagic adverse events, mainly dyspeptic symptoms.[38] In the RE-MEDY study, a higher rate of ACS was observed in the dabigatran arm. The
extent to which this difference may be explained by an imbalance in the baseline diabetes
and hypertension between the groups assigned to the different treatment arms is not
known.[41]
In patients with recent ACS, dabigatran has been evaluated for the prevention of recurrent
cardiovascular ischemic events in a placebo-controlled multicenter phase II dose escalation
RCT.[42] The overall rate of the efficacy outcome was low, with minor differences between
the treatment groups. The rate of clinically relevant bleeding was dose-dependent,
with 93% of the events occurring within the first 3 days of therapy; most of the patients
who experienced bleeding were receiving concomitant dual antiplatelet therapy (aspirin
and clopidogrel or ticlopidine) as part of the standard medical management of ACS
at randomization.[42] Even at the lowest dose of dabigatran, the 1.3% absolute increase in the 6-month
bleeding rate could not be justified by any off-setting benefit from this drug.
For stroke prevention in patients with AF, the RE-LY trial[43] evaluated patients with nonvalvular AF with an increased risk of stroke, who were
randomized to one of two fixed doses of dabigatran, or open-label use of warfarin
([Table 3]). Concomitant use of antiplatelet agents was discouraged but low-dose aspirin was
permitted in this study, and the median duration of follow-up was 2 years. Dabigatran
150 mg twice daily was superior to warfarin, and dabigatran 110 mg twice daily was
noninferior to warfarin for the prevention of stroke or systemic embolism.
The rates of major and intracranial bleeding were higher with warfarin than with either
the 110 mg dose of dabigatran or the 150 mg dose of dabigatran ([Table 3]). Not surprisingly, when compared with the 110 mg twice-daily dose, the 150 mg twice-daily
dose of dabigatran was associated with a higher rate of overall major bleeding (3.31%
per year vs. 2.87% per year; RR, 1.16; 95% CI, 1.00 to 1.34; p = 0.04), mainly from the gastrointestinal tract, and a nonsignificant trend toward
more intracranial bleeding (0.19% per year vs. 0.10% per year; RR, 1.90; 95% CI, 0.94
to 3.81; p = 0.07). In a subgroup analysis, the treatment effect of dabigatran appeared to change
based on age; dabigatran-associated major bleeding was more common than warfarin-associated
bleeding in patients older than 75 years.[44] Dyspeptic symptoms were significantly more common with dabigatran than with warfarin
(5.8% in the warfarin group; 11.8 and 11.3% in the 110 and 150 mg dabigatran groups,
respectively; p < 0.001 for both comparisons).
Although there was an almost statistically significant trend toward a higher rate
of myocardial infarction with dabigatran at both doses versus warfarin, a strong trend
toward less all-cause mortality was observed in the 150 mg twice-daily dabigatran
group compared with the warfarin group.
The FDA has not approved the 110 mg dose of dabigatran because their analyses failed
to identify a population where the “net benefit” would be greater at the lower dose.[45] In other jurisdictions such as Europe and Canada, the 110 mg dose has been approved
by the applicable regulatory agencies.
Clinical Application
The novel oral anticoagulants have a role in the management of acute VTE, stroke prophylaxis
in patients with AF, and in the primary prevention of VTE after joint replacement
surgery. An effectiveness overview and meta-analysis of the available data has been
recently published for the novel anticoagulants in the management of VTE and AF.[46] For these indications, the target-specific oral agents have demonstrated efficacy
and safety that are comparable to more traditional alternatives, such as LMWH or warfarin
([Figs. 1] and [2]).[46] In the case of VTE prevention after orthopedic surgery, the new agents will be less
costly overall than the parenteral alternative (LMWH or fondaparinux) currently used
in many institutions. This cost savings, in light of the oral route of administration
and the favorable clinical data, make the novel drugs especially attractive for this
indication. In other settings (such as AF or VTE), the new agents will offer additional
convenience at higher cost, but the degree to which they reduce clinically important
events such as thrombosis or bleeding will be limited, especially for patients on
optimally controlled warfarin. We suggest that, pending further evidence, the new
oral agents be avoided or used with caution in patients who have highly pro-thrombotic
conditions (e.g., patients with cancer-associated VTE or patients with bona fide antiphospholipid syndrome). Patients who, despite adhering to recommendations from
their provider, have INR values frequently outside the therapeutic range while on
warfarin may stand to gain the most from these newer drugs. That notwithstanding,
warfarin-treated patients with low time-in-therapeutic range because of poor compliance
are probably not good candidates for the novel oral agents. The short half-lives of
the newer medicines and the infrequent need for outpatient follow-up would make drugs
such as apixaban, dabigatran, and rivaroxaban especially problematic for a patient
who did not follow instructions on warfarin. Furthermore, the inability to easily
measure the anticoagulant effect of the novel agents and the lack of an available
antidote or evidence-based reversal strategy are disadvantages to consider.
Fig. 1 Comparison of outcomes for the treatment of venous thromboembolism with the new oral
anticoagulants compared with warfarin. Panels compare the key outcomes of venous thromboembolism
including (A) overall death, (B) recurrent deep venous thrombosis and pulmonary embolism,
and (C) thromboembolism-related death.
Fig. 2 Comparison of outcomes of treatment to prevent cardioembolism from atrial fibrillation
with the new oral anticoagulants compared with warfarin. Panels show outcomes of (A)
overall death, (B) hemorrhagic stroke, and (C) ischemic stroke.
As patients with severe renal failure or hemodialysis were excluded from the clinical
trials on the new oral anticoagulants, they should not be started on these medications.
Although the U.S. prescribing information for dabigatran includes a dose recommendation
for patients with CrCl between 15 and 30 mL/min, the dose (75 mg twice daily) is based
on pharmacokinetic modeling and has not been tested in a large clinical trial. Finally,
warfarin and other VKA remain the only anticoagulant options for patients with mechanical
heart valve replacement because the efficacy of the novel agents has not been evaluated
in this setting.
Measuring the Anticoagulant Effect and Managing Hemorrhagic Complications
Apixaban
As a result of FXa inhibition, apixaban can prolong prothrombin time (PT), and the
activated partial thromboplastin time (APTT). However, changes observed in these clotting
tests at the expected therapeutic dose are often very small and vary significantly
depending, in part, on the reagent used in the assay. A properly calibrated anti-FXa
chromogenic assay (using an apixaban standard) can exhibit a close direct linear relationship
with apixaban plasma concentration.[3]
Rivaroxaban
Rivaroxaban causes a dose-dependent prolongation of the PT with most reagents.[6] A normal PT measurement can reassure the clinician that little or no rivaroxaban
is present, especially if neoplastin is used as the reagent.[6] As with apixaban, the anticoagulant effect of rivaroxaban can be assessed with a
properly calibrated chromogenic anti-FXa activity measurement (using a rivaroxaban
standard).[47]
Dabigatran
Dabigatran etexilate prolongs the APTT and the thrombin time (TT). The PT/INR is relatively
insensitive to dabigatran, but the APTT can, if it is entirely normal, suggest that
very little anticoagulant effect is present.[48] The degree of anticoagulant activity can also be assessed by the ecarin clotting
time (ECT). This test is a more specific measure of the effect of dabigatran than
the APTT.[10] The TT assay provides a linear response to dabigatran[10]
[49]; modified TT assays to measure dabigatran levels are available in some countries.
The HEMOCLOT (HYPHEN BioMed, France) direct thrombin inhibitor assay is a sensitive
assay that involves highly purified human thrombin to initiate coagulation and has
demonstrated a good correlation with plasma levels of dabigatran.[50] The HEMOCLOT assay, which is already registered in the European Union and Canada,
could be useful to evaluate for excessive dabigatran activity in patients presenting
with bleeding, or in patients undergoing elective surgery.[50]
The management of clinically significant hemorrhagic complications should include
supportive measures: immediately begin resuscitation (e.g., red blood cell transfusions,
if required), discontinue the anticoagulant medication, and consider investigations
to identify and treat the local source of bleeding. Unfortunately, there is no specific
antidote for acute reversal of the effect of these agents. Invasive procedures (e.g.,
endoscopy) are typically avoided until the anticoagulant effect has worn off.
On the basis of preclinical data, such as animal bleeding models and in vitro coagulation
testing, some authors have recommended considering high-dose prothrombin complex concentrates
or recombinant factor VIIa in cases of severe, life-threatening bleeding in patients
receiving a novel oral anticoagulant. While the rationale for and possible merits
of these interventions are discussed in detail elsewhere,[51] we remind clinicians that powerful procoagulant agents carry a risk of causing thrombosis
and, in patients with normal renal function, the anticoagulant effect of these new
oral agents will dissipate quickly.
Hemodialysis should be considered for dabigatran-associated bleeding, since it is
only 35% bound to plasma proteins.[52] However, dialysis is not a suitable option for removing rivaroxaban or apixaban
given their high degree of protein binding (> 95%).[6]
Other Novel Oral Anticoagulants under Clinical Investigation
The vast majority of the new oral anticoagulants in clinical development are direct
FXa inhibitors, many of them with completed phase II clinical trials for prevention
of VTE in the orthopedics surgery setting, and one of them (darexaban) in the ACS
treatment and AF cardioembolic prevention scenarios. However, the development of darexaban
was discontinued in September 2011 ([Table 4]). In addition to FXa and direct thrombin inhibitors, factor IXa and factor XIa[53] are among the suitable targets under current clinical investigation.[54]
Table 4
Oral anticoagulants under clinical development
|
Drug
|
Mechanism of action
|
Phase of development
|
|
TTP889
|
FIXa inhibitor
|
Phase II trials in VTE prophylaxis for hip replacement
|
|
Betrixaban
|
FXa inhibitor
|
Phase II trials in VTE prophylaxis for knee replacement, AF
|
|
Darexaban
|
FXa inhibitor
|
Phase II/III trials in VTE prophylaxis for hip and knee replacement, phase II for
ACS and AF
|
|
Edoxaban
|
FXa inhibitor
|
Phase II/III trials in VTE prophylaxis for hip and knee replacement, phase II/III
for AF
|
|
Eribaxaban
|
FXa inhibitor
|
Phase II trials in VTE prophylaxis for hip and knee replacement
|
|
Letaxaban
|
FXa inhibitor
|
Phase II trials in VTE prophylaxis for knee replacement, and treatment in ACS
|
|
LY517717
|
FXa inhibitor
|
Phase II trial in VTE prophylaxis for knee replacement
|
|
AZD0837
|
Direct thrombin inhibitor
|
Phase II trials in cardioembolic prophylaxis for AF
|
Abbreviations: ACS, acute coronary syndromes; AF, atrial fibrillation; FIXa, activated
factor IX; FXa, activated factor X; VTE, venous thromboembolism.
Adapted from Ahrens et al (2012).[54]
Conclusion
Three new anticoagulants have now become available for prophylaxis and treatment of
acute VTE and the prevention of cardioembolism in patients with AF. For these indications,
these agents have demonstrated efficacy and safety that are comparable to more traditional
alternatives, such as LMWH or well-controlled warfarin. The inability to easily measure
the anticoagulant effect of the novel agents and the lack of an available antidote
or evidence-based reversal strategy are disadvantages that will no doubt be addressed
in future research. In some instances, the cost of these newer agents will likely
be a barrier to their widespread use.
