Download Update in 2015: Novel Oral Anticoagulant (NOAC

Darlene J. Elias M.D. CTS Update NOAC Treatment VTE 032212015 Update in 2015: Novel Oral Anticoagulant (NOAC) Drugs for Treatment of Venous Thromboembolism (VTE) Darlene J. Elias, M.D. Director, Anticoagulation Services Division of Pulmonary and Critical Care Medicine Scripps Clinic and Scripps Green Hospital, La Jolla, California *There are 4 novel oral anticoagulants (NOACs) that include apixaban (Eliquis®), dabigatran (Pradaxa®), edoxaban (Savaysa®), and rivaroxaban (Xarelto®) that are FDA approved for treatment of (VTE). Each has demonstrated efficacy in the prevention of recurrence in the treatment of acute VTE compared to warfarin therapy, in randomized clinical trials. Major bleeding rates are the same or less compared to warfarin. Dabigatran and edoxaban require 5 days of pre-­‐treatment with low molecular weight heparin (LMWH) before the oral agent is started. Apixaban and rivaroxaban do not require pre-­‐treatment with LMWH. Each agent has unique dosing and dose adjustment. Apixaban, dabigatran and rivaroxaban are approved for long term prevention of recurrent VTE. *Patient selection for NOAC therapy in VTE includes assessment of renal and liver function and review of medications. Dosing is unique for each NOAC. Apixaban is not dose adjusted for renal insufficiency in VTE. Edoxaban is dose adjusted when Cr Cl is 15-­‐
50 ml/min or if weight < 60 kg. Dabigatran and rivaroxaban are not recommended in patients with Cr Cl <30 ml/min. NOACs undergo some hepatic metabolism and patients with moderate to severe liver dysfunction were excluded from the trials. There are infrequent drug-­‐drug interactions which may require a dose adjustment or may prevent use of a NOAC: phenytoin, carbamazepine, rifampin, clarithromycin, itraconozole, and HIV medications. Check the package insert guidelines or when in doubt consult with your pharmacist. *Interruption of NOAC anticoagulation for a surgical procedure is usually 24 or 48 hours. There are no antidotes for reversal of NOAC anticoagulation. Discontinue the NOAC at least 24 hours prior to surgery with low risk of bleeding or where bleeding would be in a non-­‐critical location and controllable. Discontinue the NOAC at least 48 hours prior to surgery with a moderate or high risk of bleeding. Some interventions may require longer holds such as for neurosurgical or epidural procedures. Antidotes for reversal of NOAC anticoagulation are under study and are not in clinical use. *These agents have advantages over conventional warfarin therapy due to fixed doses, predictable pharmacokinetics, minimal food and drug interactions and lack of requirement for blood test monitoring. The choice of therapy between warfarin and NOAC must be individualized. Warfarin is less expensive than the NOACs, even after the costs associated with blood test monitoring are considered. Journal of Thrombosis and Haemostasis, 12: 320–328
DOI: 10.1111/jth.12485
ORIGINAL ARTICLE
Effectiveness and safety of novel oral anticoagulants as
compared with vitamin K antagonists in the treatment of
acute symptomatic venous thromboembolism: a systematic
review and meta-analysis
T. VAN DER HULLE,* J. KOOIMAN,* P. L. DEN EXTER,* O. M. DEKKERS,† F. A. KLOK*
and M . V . H U I S M A N *
*Department of Thrombosis and Hemostasis, Leiden University Medical Center; and †Departments of Clinical Epidemiology and
Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands
To cite this article: van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA, Huisman MV. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and
meta-analysis. J Thromb Haemost 2014; 12: 320–8.
Summary. Introduction: New direct oral anticoagulants
(NOACs) constitute a novel treatment option for acute
venous thromboembolism (VTE), with practical advantages. Individual studies have demonstrated comparable
efficacy to that of vitamin K antagonists (VKAs) and
have suggested a more favorable safety profile . We performed a meta-analysis to determine the efficacy and
safety of NOACs as compared with those of VKAs in
patients with acute VTE. Methods: We searched MEDLINE, EMBASE, the Cochrane Database of Systematic
Reviews and the Clinical Trials Registry up to October
2013. Eligible studies included phase 3 trials comparing
NOACs with VKAs in patients with acute VTE. Relative
risks (RRs), absolute risk differences and numbers needed
to treat (NNTs) to prevent one event were calculated for
recurrent VTE, fatal pulmonary embolism (PE), overall
mortality, major bleeding, and other bleeding complications, with random-effects models. Results: Five studies
were included, investigating four NOACs (rivaroxaban,
dabigatran, apixaban, and edoxaban) in 24 455 patients
with acute VTE. RRs for recurrent VTE, fatal PE and
overall mortality for NOACs vs. VKAs were 0.88 (95%
confidence interval [CI] 0.74–1.05), 1.02 (95% CI 0.39–
5.96), and 0.97 (95% CI 0.83–1.14), respectively. The RR
for major bleeding was 0.60 (95% CI 0.41–0.88). The
Correspondence: Tom van der Hulle, Department of Thrombosis
and Hemostasis, Leiden University Medical Center, Albinusdreef 2,
PO Box 9600, 2300 RC, Leiden, the Netherlands.
Tel.: +31 71 526 8132; fax: +31 71 526 6868.
E-mail: [email protected]
Received 28 September 2013
Manuscript handled by: M. Cushman
Final decision: M. Cushman, 6 December 2013
NNT with NOACs instead of VKA to prevent one major
bleed was 149. The RR and NNT for fatal bleeding were
0.36 (95% CI 0.15–0.87) and 1111. A fixed-effect network
analysis did not demonstrate significant differences
between individual NOACs and rivaroxaban. Conclusions: NOACs have comparable efficacy to that of VKAs,
and are associated with a significantly lower risk of bleeding complications, although the NNT to prevent one
major bleed was relatively high.
Keywords: anticoagulants; hemorrhage; safety; treatment
outcome; venous thromboembolism.
Introduction
Vitamin K antagonists (VKAs) constitute the standard
treatment for venous thromboembolism (VTE), which
includes acute pulmonary embolism (PE) and deep vein
thrombosis (DVT). VKAs are highly effective for the prevention of recurrent VTE, with a relative risk (RR) reduction of ~ 85% as compared with placebo, resulting in a
recurrence risk of ~ 3% while patients are on treatment
[1]. Two important limitations of VKA treatment are the
need for tailored dosing based on frequent International
Normalized Ratio monitoring, and the rate of major
bleeding complications of ~ 2.1% during the first
6 months of treatment, with a case-fatality rate of 11%
[2]. Intracranial bleeding account for 8.7% of major
bleeds, and is associated with a mortality risk of ~ 46%
[3]. Most major bleeds occur during the first weeks of
VKA treatment, presumably because of an underlying
bleeding predisposition [3,4].
In recent years, new direct oral anticoagulants
(NOACs) have been developed, including factor IIa
© 2013 International Society on Thrombosis and Haemostasis
Effectiveness and safety of novel oral anticoagulants 321
(thrombin) and FXa inhibitors, which lack some of the
limitations of VKA treatment. The relatively stable pharmacokinetics and pharmacodynamics of these agents
obviate the need for routine laboratory monitoring [5].
Several trials in patients with acute VTE have demonstrated comparable efficacy to that of VKAs in terms of
VTE recurrence rates, with lower risks of bleeding complications [6–10]. Nonetheless, the absolute risk of bleeding
was low, ranging from 0.6% for fatal bleeding to 10.6% for
a first major or clinically relevant non-major bleeding, most
differences being non-significant. However, detailed knowledge about bleeding complications is imperative for the use
of NOACs in patients with acute VTE. We therefore
performed a systematic review and meta-analysis to assess
the risks of recurrent VTE and bleeding complications in
patients with acute VTE during treatment with NOACs as
compared with VKAs.
Methods
Data sources and searches
We searched MEDLINE (via PubMed), EMBASE, the
Cochrane Database of Systematic Reviews and the Clinical Trials Registry for peer-reviewed publications comparing NOACs with standard VKA treatment from
inception to 25 October 2013. Our strategy included the
National Library of Medicine’s Medical Subject Headings
keyword nomenclature and text words for VTE and
NOACs, and validated search terms for randomized controlled trials. The complete search string is detailed in
Data S1. The electronic search was complemented with a
manual review of reference lists of included articles and
review articles. For unreported data, we additionally
searched the authorization documents available through
the European Medicines Agency (www.ema.europa.eu/
ema), and requested the manufacturer to provide unreported data.
Study selection and quality assessment
Search results were combined and duplicates were
removed. Studies were screened for relevance by two
independent reviewers, on the basis of title and abstract
(T.vdH. and P.L.dE.). Discrepancies were resolved by
consensus or by contacting a third reviewer (F.A.K.).
Full-text articles identified by either reviewer as potentially relevant were retrieved for further evaluation by the
two reviewers. Inclusion criteria for eligible studies were
as follows: (i) a phase 3 randomized controlled trial in
patients with acute VTE comparing an orally administered direct FIIa inhibitor (including but not limited to
dabigatran) or a direct FXa inhibitor (including but not
limited to edoxaban, rivaroxaban, and apixaban) with
VKA treatment; (ii) concerning a population with objectively diagnosed acute DVT, PE, or both; (iii) randomly
© 2013 International Society on Thrombosis and Haemostasis
allocating patients to the intervention groups; (iv) reporting outcomes after at least 3 months of follow-up, including the diagnosis of acute recurrent VTE based on
predefined objective criteria in accordance with current
international standards [11] and the rate of both major
and clinically relevant non-major bleeding events, and
adjudication of outcomes by an independent adjudication
committee; and (v) publication in a peer-reviewed journal.
Exclusion criteria were as follows: (i) studies concerning
ximelagatran, as its use was rejected by the Food and
Drug Administration, owing to concerns about potential
liver toxicity; and (ii) studies evaluating extended anticoagulant treatment, as a proportion of patients in these
studies were also included in the acute-phase studies, and
we were only interested in patients with acute VTE, as
most bleeding complications occur shortly after the initiation of anticoagulant treatment [3,4].
Risk of bias was evaluated in accordance with the
Cochrane Collaboration’s tool for assessing risk of bias
in randomized trials [12]. This tool evaluates the presence
of random sequence generation, allocation concealment,
blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective
reporting, and other risks of confounding.
Study outcomes and definitions
Efficacy outcomes were recurrent VTE, fatal PE, and
overall mortality. Safety outcomes were major bleeding,
non-fatal major bleeding at a critical site, clinically relevant non-major bleeding, non-fatal intracranial bleeding,
major gastrointestinal bleeding, and fatal bleeding during
anticoagulant treatment.
Recurrent symptomatic VTE included fatal and nonfatal PE and DVT. Recurrent VTE was considered as a
cause of death if there was objective documentation in
terms of autopsy, or if death could not be attributed to
another documented cause of death and PE could not be
ruled out.
The definition of major bleeding was similar for all
included studies: overt and associated with a decrease in
the hemoglobin level of ≥ 2 g dL 1, requiring transfusion of at least two units of blood, occurring in a critical site (intracranial, intraspinal, intraocular, pericardial,
intra-articular intramuscular with compartment syndrome, retroperitoneal), or contributing to death [13]. In
all included studies, except for the Re-Cover study, clinically relevant non-major bleeding was defined as overt
bleeding not meeting the criteria for major bleeding
complications, but associated with medical intervention,
contact with a physician, interruption of study drug, or
discomfort or impairment in carrying out activities in
daily life [14]. In the Re-Cover study, several criteria
were established for clinically relevant non-major bleeding that are comparable with the definition used in the
other trials.
322 T. van der Hulle et al
Data extraction
1483 references
1469 excluded after review of title and abstract
Data extraction was independently performed by two
reviewers. For each included study, we extracted the number of participants, follow-up period, number of patients
with DVT, PE, or both, unprovoked VTE, active malignancy, previous VTE, and the mean time spent in therapeutic range (TTR) during VKA therapy.
Data synthesis and analysis
Data were analyzed with the Mantel–Haenszel randomeffects model, by the use of Review Manager (V. 5.1;
The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen). RRs with corresponding 95% confidence intervals (CIs) were reported. Comparisons were
performed for all endpoints. Statistical heterogeneity
was assessed and quantified with the Cochrane Q-test
and the I2-statistic, respectively. Absolute risk differences with CIs and the number needed to treat (NNT)
with NOACs in order to prevent one outcome event
were calculated. The NNT calculation was based on the
point estimate of the absolute risk difference. The
presence of publication bias was evaluated with funnel
plots, with formal tests for funnel plot asymmetry
being used only in the case of inclusion of at least 10
studies.
In the absence of trials making direct comparisons
between NOACs, we performed a fixed-effect network
analysis based on inverse variance weighting. In this
analysis, dabigatran, apixaban and edoxaban were compared with rivaroxaban. Rivaroxaban was chosen as the
comparator, as this is the only drug currently registered
for the treatment of acute VTE.
Results
Study selection
The initial search identified 889 records in PubMed, 453
unique records in EMBASE, 67 unique records in the
Cochrane Database of Systematic Reviews, and 74
records from the Clinical Trials Registry, resulting in a
total of 1483 references. On the basis of screening of
titles and abstracts, 14 studies were selected for full text
review. Of these 14 studies, four were excluded because
they were not phase 3 trials [12,15–17], the Re-Cover II
study was excluded because this study had not yet been
published in a peer-reviewed journal [18], the
THRIVE II/V study was excluded because of the use of
ximelagatran (application rejected by the Food and Drug
Administration because of concerns about potential liver
toxicity) [19], and three references were excluded because
extended treatment of VTE was investigated [20–22].
Therefore, five studies were eligible for inclusion
(Fig. 1) [6–10].
14 references
5 studies
9 excluded after full text review
4 no phase 3 trial
3 extended treatment of VTE
1 investigating ximelagatran
1 not peer-reviewed (Re-Cover II study)
Fig. 1. Flow diagram of study selection. VTE, venous thromboembolism.
Characteristics of included randomized controlled trials
One study evaluated dabigatran in patients with PE and/
or DVT (Re-Cover I study) [6], one investigated rivaroxaban in patients with DVT (Einstein-DVT study) [7], one
investigated rivaroxaban in patients with PE (Einstein-PE
study) [8], one investigated apixaban in patients with
DVT and/or PE (Amplify study) [9], and one investigated
edoxaban in patients DVT and/or PE (Hokusai study)
[10]. In total, 24 455 patients were included, of whom
57% were male. The mean age ranged between 55 and
58 years. The percentage of patients with unprovoked
VTE varied from 62% to 90%. Overall, PE was present
in 10 796 patients (44%), and 13 607 (56%) had isolated
proximal DVT. Active malignancy was present in 1465
patients (6%), 4651 patients (19%) had experienced a previous VTE, and the TTR ranged from 58% to 64%
(Table 1). Dabigatran (150 mg twice daily) and edoxaban
(60 mg once daily, or 30 mg once daily in the case of a
creatinine clearance of 30–50 mL min 1 or a body weight
of < 60 kg) were combined with weight-adjusted therapeutic-dose low molecular weight heparin or unfractionated heparin as initial treatment for at least 5 days, whereas
rivaroxaban (15 mg twice daily for 3 weeks, followed by
20 mg once daily) and apixaban (10 mg twice daily for
7 days, followed by 5 mg twice daily) were used as singledrug regimens. In the Re-Cover study and the Amplify
study, patients were treated for 6 months; in the Einstein
studies and the Hokusai study, the treating physician
determined the treatment duration. In the Einstein-DVT
study, 63% of the patients were treated for 6 months,
25% for 12 months, and 12% for 3 months. In the
Einstein-PE study, 57% of the patients were treated for
6 months, 37% for 12 months, and 5% for 3 months. In
the Hokusai study, 12% of the patients were treated for
3 months, 26% for 3–6 months, and 61% for
> 6 months.
All included studies were of good quality as determined
by the Cochrane Collaboration’s tool for assessing risk of
bias in randomized trials (Fig. 2). Most important potential risks of bias were associated with the open label
design of the two Einstein studies [7,8], and all five studies were sponsored and managed by the pharmaceutical
industry. As our meta-analysis included only five studies,
© 2013 International Society on Thrombosis and Haemostasis
© 2013 International Society on Thrombosis and Haemostasis
2539
3449
4832
5395
8240
3/6/12*
3/6/12*
6
3/6/12*
Patients, n
6
Treatment
duration
(months)
4716 (57)
3167 (59)
2556 (53)
1960 (57)
1484 (58)
Men,
n (%)
56 (not provided)
57 (not provided)
58 (not provided)
56 (not provided)
55 (18–97)
Mean age
in years
(range)
3319 (40)
1836 (34)
4832 (100)
23 (1)
786 (31)
PE or PE and
DVT, n (%)
4921 (60)
3532 (65)
0 (0)
3405 (99)
1749 (69)
Isolated
DVT, n (%)
5410 (66)
4845 (90)
3117 (65)
2138 (62)
Not provided
Unprovoked,
n (%)
771 (9)
143 (3)
223 (5)
207 (6)
121 (5)
Cancer,
n (%)
1520 (18)
872 (16)
944 (20)
666 (19)
649 (26)
Previous
VTE, n (%)
64
61
63
58
60
TTR in
VKA group (%)
DTI, direct thrombin inhibitor; DVT, deep vein thrombosis; PE, pulmonary embolism; TTR, time in therapeutic range; VKA, vitamin K antagonist; VTE, venous thromboembolism. *Treatment duration defined by treating physician.
Re-Cover
2009
Dabigatran
DTI
Einstein-DVT
2010
Rivaroxaban
FXa inhibitor
Einstein-PE
2012
Rivaroxaban
FXa inhibitor
Amplify
2013
Apixaban
FXa inhibitor
Hokusai
2013
Edoxaban
FXa inhibitor
Study
Year
Drug
class
Table 1 Study characteristics
Effectiveness and safety of novel oral anticoagulants 323
Re-Cover
2009
Einstein-DVT
2010
Einstein-PE
2012
Amplify 2013
+
+
+
+
+
+
–
+
+
–
+
+
+
–
+
+
–
+
+
+
–
+
+
+
+
+
+
–
Hokusai 2013
+
+
+
+
+
+
–
Random sequence generation
Allocation concealment
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data
Selective reporting
Other bias
324 T. van der Hulle et al
we did not perform formal tests for funnel plot asymmetry (Data S2).
Meta-analysis: efficacy outcomes
During anticoagulant treatment, recurrent VTE occurred
in 241 of the 12 151 patients (2.0%) treated with NOACs
and in 273 of the 12 153 patients (2.2%) treated with
VKAs. In accordance with the results of the individual
studies, the combined RR for recurrent VTE did not
demonstrate a significant difference between these drug
classes: 0.88 (95% CI 0.74–1.05) (Table 2; Fig. 3). Fatal
PE occurred in nine of the 12 151 patients (0.07%) treated with NOACs and in nine of the 12 153 patients
(0.07%) treated with VKAs. In total, 290 of the 12 197
patients (2.4%) treated with NOACs and 298 of the
12 193 patients (2.4%) treated with VKAs died during
follow-up. The RR for all-cause mortality was 0.97
(95% CI 0.83–1.14). The I2 of all evaluated efficacy outcomes was 0%, indicating low heterogeneity.
Meta-analysis: safety outcomes
Fig. 2. Results of Cochrane Collaboration’s tool for assessing risk of
bias.
All combined RRs were significantly lower for the
patients treated with NOACs, except that for major gas-
Table 2 Efficacy and safety outcomes
Outcome
Recurrent VTE
Fatal PE
Overall mortality
Major bleeding
Non-fatal bleeding at a critical site
Clinically relevant non-major bleeding
Non-fatal intracranial bleeding
Major gastrointestinal bleeding
Fatal bleeding
NOACs n
% Range
VKAs n
% Range
241/12 151
2.0
1.6–2.4
9/12 151
0.07
0.04–0.10
290/12 197
2.4
1.5–3.2
131/12 197
1.1
0.6–1.6
28/12 179
0.23
0.08–0.32
806/12 179
6.6
3.9–9.5
11/12 179
0.09
0.00–0.12
28/8079
0.35
0.17–0.71
7/12 179
0.06
0.04–0.08
273/12 153
2.2
1.8–3.0
9/12 153
0.07
0.0–0.24
298/12 193
2.4
1.7–3.1
211/12 193
1.7
1.2–2.2
77/12 193
0.63
0.18–1.08
1024/12 193
8.4
6.9–9.8
31/12 193
0.25
0.00–0.42
43/8071
0.53 0.23–0.67
21/12 193
0.17
0.07–0.29
Pooled absolute risk
difference, % (95% CI)
NNT with NOACs to
prevent one event (95% CI)
0.24 (
0.60 to 0.11)
417 (167 to
909)
0.01 (
0.06 to 0.08)
10 000 (1667 to
0.10 (
0.47 to 0.28)
1000 (213 to
0.67 (
1.13 to
0.21)
149 (88–476)
0.38 (
0.65 to
0.10)
263 (153-1000)
1.77 (
3.40 to
0.15)
56 (29–667)
0.14 (
0.31 to 0.03)
714 (323 to
0.16 (
0.42 to 0.11)
625 (238–909)
0.09 (
0.17 to 0.00)
1111 (588–0)
1250)
357)
3333)
CI, confidence interval; NNT, number needed to treat; NOAC, new direct oral anticoagulant; PE, pulmonary embolism; VKA, vitamin K
antagonist; VTE, venous thromboembolism.
© 2013 International Society on Thrombosis and Haemostasis
Effectiveness and safety of novel oral anticoagulants 325
Outcome Study
Recurrent VTE
R R Lower limit Upper limit Weight (%)
Re-Cover (dabigatran)
Einstein-DVT (rivaroxaban)
Einstein-PE (rivaroxaban)
Amplify (apixaban)
Hokusai (edoxaban)
Subtotal (I2 = 0%, P = 0.46)
1.10
0.70
1.13
0.84
0.83
0.88
0.66
0.46
0.76
0.60
0.60
0.74
1.84
1.07
1.69
1.18
1.14
1.05
11.2
16.7
18.4
25.4
28.3
100
Re-Cover (dabigatran)
Einstein-DVT (rivaroxaban)
Einstein-PE (rivaroxaban)
Amplify (apixaban)
Hokusai (edoxaban)
Subtotal (I2 = 0%, P = 0.71)
0.33
2.98
2.00
0.50
1.33
1.02
0.03
0.12
0.18
0.05
0.30
0.39
3.18
73.04
21.99
5.57
5.96
5.96
18.0
9.0
16.0
16.0
41.1
100
0.99
0.77
1.16
0.79
1.05
0.97
0.55
0.51
0.80
0.53
0.82
0.83
1.81
1.17
1.68
1.19
1.33
1.14
7.1
14.6
18.3
15.6
44.4
100
Fatal PE
Overall mortality
Re-Cover (dabigatran)
Einstein-DVT (rivaroxaban)
Einstein-PE (rivaroxaban)
Amplify (apixaban)
Hokusai (edoxaban)
Subtotal (I2 = 0%, P = 0.50)
0.1
R R (95% CI)
Favors NOACs
1
Favors VKAs
10
Fig. 3. Efficacy outcomes. CI, confidence interval; NOACs, new direct oral anticoagulants; PE, pulmonary embolism; VKA, vitamin-K antagonist; VTE, venous thromboembolism.
Outcome Study
R R Lower limit Upper limit Weight (%)
Major bleeding
0.46
1.49
18.2
0.83
Re-Cover (dabigatran)
15.9
1.38
Einstein-DVT (rivaroxaban) 0.70
0.35
21.8
0.80
0.50
0.31
Einstein-PE (rivaroxaban)
0.55
18.6
Amplify (apixaban)
0.31
0.17
Hokusai (edoxaban)
1.21
25.5
0.85
0.60
2
Subtotal (I = 62%, P = 0.03) 0.60
0.41
0.88
100
Non-fatal bleeding at a critical site
Re-Cover (dabigatran)
0.11
0.01
5.5
0.87
0.20
9.0
4.93
Einstein-DVT (rivaroxaban) 1.00
0.27
Einstein-PE (rivaroxaban)
0.12
28.4
0.62
0.09
17.4
0.87
Amplify (apixaban)
0.29
Hokusai (edoxaban)
0.27
39.7
1.02
0.52
2
Subtotal (I = 13%, P = 0.33) 0.38
0.23
0.62
100
Clinically relevant non-major bleeding
0.58
0.42
0.82
17.1
Re-Cover (dabigatran)
0.83
1.34
19.7
Einstein-DVT (rivaroxaban) 1.05
Einstein-PE (rivaroxaban)
0.97
0.81
1.15
21.3
Amplify (apixaban)
0.48
0.38
0.61
20.0
0.81
Hokusai (edoxaban)
0.70
0.94
21.9
2
Subtotal (I = 88%, P < 0.01) 0.76
0.58
0.99
100
Non-fatal intracranial bleeding
0.14
0.01
2.75
8.0
Re-Cover (dabigatran)
0.24
103.65
7.7
Einstein-DVT (rivaroxaban) 4.98
0.01
0.10
0.78
15.3
Einstein-PE (rivaroxaban)
Amplify (apixaban)
0.13
0.50
2.01
28.3
0.15
0.42
1.18
40.8
Hokusai (edoxaban)
2
Subtotal (I = 20%, P = 0.29) 0.39
0.16
0.94
100
Major gastrointestinal bleeding
Re-Cover (dabigatran)
1.79
5.33
22.9
0.60
3.33
14.5
0.17
Einstein-DVT (rivaroxaban) 0.75
0.56
1.27
Einstein-PE (rivaroxaban)
32.4
0.25
Amplify (apixaban)
0.39
0.93
30.1
0.16
2
Subtotal (I = 37%, P = 0.19) 0.68
0.36
0.30
100
Fatal bleeding
10.3
15.88
0.06
Re-Cover (dabigatran)
0.99
17.1
1.70
0.02
Einstein-DVT (rivaroxaban) 0.20
24.7
3.97
0.11
0.66
Einstein-PE (rivaroxaban)
13.7
5.54
0.05
0.50
Amplify (apixaban)
34.2
Hokusai (edoxaban)
0.91
0.04
0.20
2
0.15
0.87
100
Subtotal (I = 0%, P = 0.75) 0.36
0.1
R R (95% CI)
Favors NOACs
1
Favors VKAs
10
Fig. 4. Safety outcomes. CI, confidence interval; NOACs, new direct oral anticoagulants; VKA, vitamin-K antagonists.
trointestinal bleeding (Table 2; Fig. 4). Major bleeding
occurred in 1.1% of the patients treated with NOACs
and in 1.7% of the patients treated with VKAs, with an
accompanying combined RR of 0.60 (95% CI 0.41–0.88)
and an I2 of 62%. The combined absolute risk difference
for major bleeding was
0.67% (95% CI
1.13 to
0.21), resulting in an NNT with NOACs instead of
VKAs of 149 (95% CI 88–476).
Non-fatal bleeding at a critical site occurred in 0.23%
of the patients treated with NOACs and in 0.63% of the
patients treated with VKAs. The combined RR was 0.38
(I2 = 13%; 95% CI 0.23–0.62) and the absolute risk
© 2013 International Society on Thrombosis and Haemostasis
difference was
0.38% (95% CI
0.65 to
0.10),
resulting in an NNT of 263 (95% CI 153–1000).
The combined RR for clinically relevant non-major
bleeding was 0.76 (95% CI 0.58–0.99). This risk varied
considerably between the individual studies (I2 of 88%).
In the studies investigating rivaroxaban (Einstein-DVT
and Einstein-PE), the RRs were very similar, whereas in
the studies investigating dabigatran, apixaban, and edoxaban, the RRs were in favor of NOACs.
Non-fatal intracranial bleeding occurred in 0.09% of
the patients treated with NOACs and in 0.25% of the
patients treated with VKAs, resulting in a combined RR
326 T. van der Hulle et al
of 0.39 (95% CI 0.16–0.94). Only in the Einstein-DVT
study was the incidence higher in patients treated with
rivaroxaban than in those treated with VKAs: two events
in 1718 patients vs. 0 in 1711 patients. In the EINSTEINPE study, which also evaluated rivaroxaban, the opposite
association was observed. Owing to the low incidence
rates of intracranial bleeding and the wide CIs, the I2 was
only 20%.
The incidence of major gastrointestinal bleeding was
not reported in the Hokusai study, and the combined RR
of the other four studies for NOACs was 0.68 (I2 = 37%;
95% CI 0.36–1.30); only the Re-Cover study, the only
study that investigated a direct thrombin inhibitor (dabigatran), reported a higher risk. In this study, the incidence
rates were 0.71% (9/1273) in patients treated with dabigatran and 0.39% (5/1266) in patients treated with VKAs, a
difference of 0.31% (95% CI
0.26 to 0.89).
Fatal bleeding occurred in seven of the 12 179 patients
(0.06%) treated with NOACs and in 21 of the 12 193
patients (0.17%) treated with VKAs, with a combined
RR of 0.36 (95% CI 0.15–0.87) and an NNT of 1111
(95% CI 588–0). All studies demonstrated RRs in favor
of NOACs, with wide CIs because of the low incidence
rates, resulting in an I2 of 0%.
Fixed-effect network analysis
In a fixed-network analysis, dabigatran, apixaban and
edoxaban were compared with rivaroxaban for the predefined efficacy and safety endpoints. No statistically significant differences were observed for all outcomes. For
recurrent VTE, P-values ranged from 0.74 to 0.85, and
for major bleeding they ranged from 0.48 to 0.60. The
results of the other evaluated outcomes are provided in
Data S3.
Discussion
For all of the evaluated efficacy outcomes, the pooled RRs
were comparable between patients treated with NOACs
and patients treated with VKAs. In contrast, statistically
significantly lower risks were observed for all evaluated
bleeding complications during treatment with NOACs
than during treatment with VKAs, except for the risk of
major gastrointestinal bleeding. This is probably attributable to a lack of power, as the Hokusai study did not
report major gastrointestinal bleeding separately, and
therefore could not be included in this specific analysis. We
asked for this information from the manufacturer in vain.
Despite the lower bleeding risk with the new agents,
our analyses indicate that the advantage of NOACs in
absolute terms is somewhat limited for patients with acute
VTE who need anticoagulant treatment for a relatively
short duration. This is reflected by the high NNT for
treatment with NOACs instead of VKA, ranging from 56
to prevent a clinically relevant non-major bleeding to
even 1111 to prevent one fatal bleeding. Although the
inclusion criteria of the trials ruled out patients with any
bleeding risks, the relatively high NNTs cannot be
explained by an overall low incidence of bleeding, as the
bleeding incidences from the pooled studies are very similar to those of other large VTE treatment studies [3].
Therefore, when NOACs are introduced as a generally
accepted therapy for acute VTE, the relatively small net
benefit should be weighed against the financial consequences of using this costly drug class.
Last year, the first meta-analysis of the efficacy and
safety of NOACs for the treatment of acute VTE was
published, with partly overlapping patient cohorts [23].
The major difference between that meta-analysis and our
study is the inclusion of relatively small phase 2 trials
with shorter durations of follow-up and different NOAC
dosages, and studies on ximelagatran by Fox et al.
[12,19]. By including the recently published trials on
apixaban and edoxaban, we exceed their sample size while
restricting our analysis to robust data of high quality.
Regarding the extended treatment of VTE, i.e. beyond
the treatment during the first 3–6 months, the efficacy
and safety of NOACs as compared with VKAs are still
unclear. In only one study was dabigatran randomly compared with VKAs during extended treatment; hazard
ratios for recurrent VTE of 1.44 (95% CI 0.78–2.64) and
0.54 (95% CI 0.41–0.71) for major or clinically relevant
non-major bleeding were reported [21]. In two other studies, apixaban and rivaroxaban were randomly compared
with placebo and were included in a recently published
meta-analysis [24]. As expected, these drugs showed high
efficacy as compared with placebo, but their efficacy and
safety as compared with VKAs remain to be demonstrated.
Given the absence of the possibility of direct comparisons between the individual NOACs, we performed an
indirect comparison of dabigatran, apixaban and edoxaban with rivaroxaban. Although differences in efficacy
and safety outcomes between individual drugs can be reasonably expected, no significant differences in efficacy and
safety outcomes were observed. Owing to the relatively
low incidence rates of all outcomes, large randomized
controlled trials in > 20 000 patients would be required to
identify potentially relevant differences between the
NOACs. For practical reasons, it seems very unlikely that
such studies will be initiated in the (near) future. Therefore, pooling the results of all separate studies evaluating
different NOACs in comparison with VKAs provides the
best available evidence for deciding whether NOACs constitute a suitable alternative, or are even preferable, to
VKAs for the treatment of acute VTE.
Although not identified by the fixed-effect network
analysis, reasonably expected differences between the
individual drugs may be the reason for the high heterogeneity observed for major bleeding (I2 = 62%) and clinically
relevant
non-major
bleeding
(I2 = 88%).
© 2013 International Society on Thrombosis and Haemostasis
Effectiveness and safety of novel oral anticoagulants 327
Considering major bleeding, all studies demonstrated
RRs in favor of NOACs, but the effect size differed. For
clinically relevant non-major bleeding, in particular, the
RRs reported in the Einstein studies differed from the
other RRs. This might be explained by a specific effect
of rivaroxaban, or it could be a result of the PROBE
design of the Einstein studies, as the other studies were
double-blind studies. For major gastrointestinal bleeding,
the relatively high heterogeneity (I2 = 37%) seems to be
explained by the higher RR reported in the Re-Cover
study. This might be explained by an individual drug
effect or a difference between drug classes (FIIa inhibitors
and FXa inhibitors).
The more favorable safety profile of NOACs may be
ascribed to their more stable anticoagulant effect than
that of VKAs [5]. The lower risk of intracranial bleeding
may be a consequence of maintaining normal concentrations of FVII and the formation of FVIIa–tissue factor
complexes, which play an important role in cerebral vascular damage [25]. Other supposed mechanisms are the
reduced suppression of thrombin at the site of cerebral
injury, and the inability of rivaroxaban to substantially
penetrate the blood–brain barrier [26].
A concern regarding NOACs is the absence of specific
antidotes. On the basis of experimental studies, non-specific prohemostatic agents are recommended for direct
reversal of the anticoagulant effect [27,28]. It is of note
that patients with a major bleed while on dabigatran had
a better prognosis than patients with a major bleed while
on VKAs [29]. Furthermore, the lower bleeding risk and
the presumed introduction of specific antidotes in the
coming years put this concern in perspective.
Our study has limitations. First, because of the absence
of studies comparing the same drugs, we were unable to
perform a random-effects Bayesian network meta-analysis. Even so, the alternatively performed fixed-effect network analysis did not demonstrate significant differences
between the individual drugs. Second, we were unable to
perform subgroup analyses for patients with PE and
DVT. Third, we could not differentiate between early and
late bleeding occurrences, as detailed data were lacking.
Fourth, treatment durations were not identical throughout the studies, although most patients were subjected to
a 6-month anticoagulant course. Fifth, in the Hokusai
study, the safety outcomes of fatal PE and overall mortality were only reported for the total follow-up duration.
Sixth, the results of this meta-analysis should not be generalized to all patients with acute VTE, as specific populations, including the elderly, patients with cancer, patients
with renal insufficiency, patients with rare localizations of
VTE (e.g. distal DVT, splanchnic thrombosis, and cerebral vein thrombosis), and patients with morbid obesity,
were underrepresented or excluded. Finally, two studies
had a PROBE design, in which participants and researchers were aware of the treatment allocation, and only the
adjudication committee was blinded. It has been suggested
© 2013 International Society on Thrombosis and Haemostasis
that the open design of PROBE studies leads to a more
real-world study population, owing to the easier recruitment of patients, although the risk of reporting bias might
be increased. Furthermore, this design may influence
decisions regarding other medical treatments. Hence, it has
been suggested that the PROBE design could result in
overoptimistic results in favor of NOACs. Even so, recent
studies evaluating NOACs in patients with atrial fibrillation or VTE have not demonstrated such an effect [30,31].
In conclusion, NOACs show comparable efficacy to
VKAs in patients with acute VTE, as well as greater practical simplicity and a more favorable bleeding profile,
although the absolute benefit was somewhat limited,
owing to the high NNT.
Addendum
T. van der Hulle, J. Kooiman, P. L. den Exter, and O.
M. Dekkers performed the data extraction and performed
the analyses. T. van der Hulle and F. A. Klok drafted the
paper. M. V. Huisman critically revised the paper for
important intellectual content. All authors designed the
study and reviewed the manuscript.
Disclosure of conflict of interests
M. V. Huisman has received unrestricted grant support
from Boehringer Ingelheim and GSK for research projects. The other authors state that they have no conflict
of interest.
Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Data S1. Search strategy.
Data S2. Funnel plots.
Data S3. Results of fixed-effect network analysis.
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© 2013 International Society on Thrombosis and Haemostasis
ATVB in Focus
Clinical Experience With the Novel Oral Anticoagulants
Series Editor: Jeffrey I. Weitz
Overview of the New Oral Anticoagulants
Opportunities and Challenges
Calvin H. Yeh, Kerstin Hogg, Jeffrey I. Weitz
Abstract—The non-vitamin K oral anticoagulants (NOACs) are replacing warfarin for many indications. These agents
include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. All
the 4 agents are licensed in the United States for stroke prevention in atrial fibrillation and for treatment of venous
thromboembolism and rivaroxaban and apixaban are approved for thromboprophylaxis after elective hip or knee
arthroplasty. The NOACs are at least as effective as warfarin, but are not only more convenient to administer because
they can be given in fixed doses without routine coagulation monitoring but also are safer because they are associated
with less intracranial bleeding. As part of a theme series on the NOACs, this article (1) compares the pharmacological
profiles of the NOACs with that of warfarin, (2) identifies the doses of the NOACs for each approved indication, (3)
provides an overview of the completed phase III trials with the NOACs, (4) briefly discusses the ongoing studies with the
NOACs for new indications, (5) reviews the emerging real-world data with the NOACs, and (6) highlights the potential
opportunities for the NOACs and identifies the remaining challenges. (Arterioscler Thromb Vasc Biol. 2015;35:00-00.
DOI: 10.1161/ATVBAHA.115.303397.)
Key Words: anticoagulant drugs ◼ warfarin
O
ral anticoagulants are widely used for long-term prevention and treatment of venous and arterial thromboembolism. Until recently, vitamin K antagonists, such as warfarin,
were the only available oral anticoagulants. This situation
changed with the recent introduction of the non-vitamin K
oral anticoagulants (NOACs), which include dabigatran, rivaroxaban, apixaban, and edoxaban. Designed to overcome the
limitations of warfarin, the NOACs have revolutionized oral
anticoagulation because they are at least as effective as warfarin, but are more convenient to administer because the NOACs
can be given in fixed doses without routine coagulation monitoring. Moreover, as a class, the NOACs are associated with
significantly less intracranial bleeding than warfarin. This is
an important advantage because bleeding into the brain is the
most feared complication of anticoagulation therapy.
In the United States, rivaroxaban and apixaban are licensed
for prevention of venous thromboembolism (VTE) after elective hip or knee replacement surgery and dabigatran, rivaroxaban, apixaban, and edoxaban are approved for treatment of
VTE and for stroke prevention in patients with atrial fibrillation (AF). Although not approved in the United States for this
indication, rivaroxaban is licensed in Europe for prevention of
recurrent ischemia in stabilized patients with acute coronary
syndrome (ACS). In this theme series, the role of NOACs for
the prevention and treatment of VTE is reviewed by Friedman
and Schulman et al, respectively, whereas the evidence supporting their use for stroke prevention in AF is covered by
Sharma et al. Carreras and Mega discuss the potential role of
the NOACs as adjuncts to antiplatelet therapy in patients with
ACS and Crowther et al provide an update on the status of
antidotes for the NOACs. On the backdrop of these reviews,
the purpose of this introductory article is to (1) compare the
pharmacological profiles of the NOACs with that of warfarin,
(2) identify the doses of the NOACs for each approved indication, (3) provide an overview of the phase III trials performed,
to date, with the NOACs, (4) briefly discuss the ongoing studies with the NOACs, (5) review the emerging real-world data
with the NOACs, and (6) highlight the potential opportunities
for the NOACs and identify the remaining challenges.
Comparison of the Pharmacological Properties
of the NOACs With Those of Warfarin
As outlined in Table 1, warfarin inhibits vitamin K epoxide
reductase, thereby attenuating the reduction of oxidized vitamin K in the liver. Without reduced vitamin K as a cofactor
for hepatic γ-carboxylase, functional levels of the vitamin
K–dependent clotting proteins, factors II, VII, IX, and X
decrease. This results in attenuated thrombin generation
regardless of whether clotting is triggered via the extrinsic,
Received on: January 29, 2015; final version accepted on: March 5, 2015.
From the Thrombosis and Atherosclerosis Research Institute and Departments of Medicine and of Biochemistry and Biomedical Sciences, McMaster
University, Hamilton, Ontario, Canada.
Correspondence to Jeffrey I. Weitz, Thrombosis and Atherosclerosis Research Institute, 237 Barton St E, Hamilton, Ontario, Canada L8L 2X2. E-mail
[email protected]
© 2015 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org
DOI: 10.1161/ATVBAHA.115.303397
Downloaded from http://atvb.ahajournals.org/ 1at Scripps Res. Inst./Kresge on March 23, 2015
2 Arterioscler Thromb Vasc Biol May 2015
Nonstandard Abbreviations and Acronyms
Table 1. Comparison of the Pharmacological Properties of
Warfarin, Rivaroxaban, Apixaban, and Edoxaban
APPRAISE-2
Apixaban with Antiplatelet Therapy after Acute
Coronary Syndrome
ATLAS ACS 2–TIMI-51 Rivaroxaban in Patients with a Recent Acute
Coronary Syndrome
AVERT
Apixaban for the prevention of venous thromboembolism in cancer patients
COMMANDER HF
A study to assess the effectiveness and safety of
rivaroxaban in reducing the risk of death, myocardial infarction or stroke in participants with heart
failure and coronary artery disease after an episode of decompensated heart failure
COMPASS
Rivaroxaban for the prevention of major cardiovascular events in coronary or peripheral artery
disease
EINSTEIN CHOICE
Reduced-dose rivaroxaban in the long-term
prevention of recurrent symptomatic venous
thromboembolism
GARFIELD-AF
global anticoagulant registry in the field in patients with atrial fibrillation
GARFIELD-VTE
Global anticoagulant registry in the field observing
treatment and outcomes in patients with treated
acute venous thromboembolic events in the real
world
GLORIA-AF
Global registry on long-term oral antithrombotic
treatment in patients with atrial fibrillation
INR
international normalized ratio
LMWH
low-molecular-weight heparin
MARINER
A study of rivaroxaban (JNJ39039039) on the
venous thromboembolic risk in posthospital discharge patients
MI
myocardial infarction
NAVIGATE ESUS
Rivaroxaban versus aspirin in secondary prevention of stroke and prevention of systemic embolism in patients with recent embolic stroke of
undetermined source
NOAC
non-vitamin K oral anticoagulant
prothrombin complex concentrate
PCC
percutaneous coronary intervention
PCI
A study exploring two strategies of rivaroxaban
PIONEER AF-PCI
(JNJ39039039)
Evaluation of dual therapy with dabigatran versus
REDUAL PCI
triple therapy with warfarin in patients with atrial
fibrillation that undergo a PCI with Stenting
RE-LY
Randomized evaluation of long term anticoagulant therapy with dabigatran etexilate
RE-SPECT ESUS
Dabigatran etexilate for secondary stroke prevention in patients with embolic stroke of undetermined source
ROCKET-AF
An efficacy and safety study of rivaroxaban with
warfarin for the prevention of stroke and noncentral nervous system systemic embolism in
patients with nonvalvular atrial fibrillation
intrinsic, or common pathway of coagulation. Because of its
indirect mechanism of action, the onset and offset of action
of warfarin are delayed for several days, a phenomenon that
often necessitates bridging with a rapidly acting parenteral
anticoagulant when initiating warfarin therapy, and complicates periprocedural management (Figure).
In contrast to warfarin, the NOACs directly inhibit a single
clotting enzyme; dabigatran inhibits thrombin, whereas rivaroxaban, apixaban, and edoxaban inhibit factor Xa. As direct
Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban
Target
VKORC1 Thrombin
Bioavailability, %
100
7
80
60
62
Dosing
OD
BID
OD (BID)
BID
OD
Half-life, h
Renal clearance as
unchanged drug, %
Interactions
4–5 d
No
Factor Xa Factor Xa
No
Time-to-peak effect
Yes
Factor Xa
Prodrug
No
No
1–3 h
2–4 h
1–2 h
1–2 h
40
14–17
7–11
8–14
5–11
None
80
33
27
50
Multiple
P-gp
3A4/P-gp
3A4/P-gp
P-gp
3A4 indicates cytochrome P450 3A4 isoenzyme; BID, twice daily; OD, once
daily; P-gp, P-glycoprotein; and VKORC1, C1 subunit of the vitamin K epoxide
reductase enzyme.
inhibitors, these agents have a rapid onset of action such that
peak plasma levels are achieved 1 to 4 hours after oral administration. With half-lives of ≈12 hours, the NOACs also have a
rapid offset of action.
Although warfarin is predominantly cleared through nonrenal mechanisms, the NOACs are excreted, at least in part,
via the kidneys. The extent of renal clearance varies; ≈80%
of absorbed dabigatran is cleared unchanged by the kidneys,
whereas 50%, 33%, and 27% of absorbed edoxaban, rivaroxaban, and apixaban, respectively, are cleared unchanged
via the renal route. Consequently, the drugs can accumulate
in patients with renal impairment, thereby potentially placing
them at risk for bleeding. To avoid this complication, NOACs
should be used with caution in patients with a creatinine
clearance <30 mL/min, and they should not be used if the creatinine clearance is <15 mL/min. Although apixaban dosage
recommendations for patients with end-stage renal disease
on chronic hemodialysis are provided in the United States
product monograph, it is important to point out that these
recommendations are based on pharmacokinetic and pharmacodynamic data collected in <20 patients. Because there are
no efficacy or safety data with apixaban in such patients, we
think that the drug should not be used in this setting.
The dose of warfarin varies between patients reflecting
differences in dietary vitamin K intake, multiple drug–drug
interactions, and common polymorphisms that affect warfarin metabolism or pharmacodynamics. Warfarin has a narrow
therapeutic window; thus, under anticoagulation can lead to
recurrent thrombosis, whereas excessive anticoagulation can
cause bleeding. Consequently, frequent coagulation monitoring and dose adjustments are necessary to ensure that the
international normalized ratio (INR) remains within the therapeutic range. In contrast, because the NOACs produce a more
predictable anticoagulant response, they can be given in fixed
doses without routine monitoring, thereby simplifying therapy. Although there are few clinically important drug–drug
interactions with the NOACs, potent inhibitors or inducers of
CYP 3A4 and p-glycoprotein can be problematic with rivaroxaban and apixaban, whereas potent inhibitors of p-glycoprotein may increase exposure with dabigatran and edoxaban.
Dietary vitamin K intake does not influence the NOACs and
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Yeh et al New Oral Anticoagulants 3
Contact
baseline levels, but this can take ≤24 hours. Rapid warfarin reversal can be achieved with 4-factor prothrombin complex concentrate (PCC). Fresh frozen plasma is an alternative to PCC, but it
produces incomplete restoration of the INR to baseline levels, its
infusion takes longer than administration of PCC and large volumes of plasma are often needed, which can be problematic for
patients with compromised cardiopulmonary function. For these
reasons, guidelines recommend PCC over fresh frozen plasma
for patients who require urgent warfarin reversal.
There are no specific antidotes for the NOACs, but as
outlined by Crowther et al, these are under development.
Although nonactivated or activated PCC may be effective for
reversal of the anticoagulant effects of the NOACs, clinical
data in patients with serious bleeding are limited.
TF/VIIa
IX
Platelet
Surface
VIIIa
Warfarin
Xa
Va
Rivaroxaban
Apixaban
Edoxaban
Thrombin
Fibrinogen
Dabigatran
Overview of Phase III Clinical Trial Results
With the NOACs
Fibrin
Figure. Sites of action of warfarin and the non-vitamin K oral
anticoagulants.
there are no dietary restrictions except that therapeutic doses
of rivaroxaban should be administered with a meal to maximize its absorption.
The recommended doses for the NOACs for each approved
indication are provided in Table 2. In general, the doses used
for thromboprophylaxis are half those used for VTE treatment or for stroke prevention in AF. When used for stroke
prevention, the doses of the NOACs are reduced based on
important patient characteristics to maximize the benefit-torisk profile.
Vitamin K is the antidote for warfarin. When given orally
or by slow intravenous infusion, vitamin K restores the INR to
The NOACs were compared with enoxaparin for VTE prevention in patients undergoing hip or knee arthroplasty and in the
medically ill patients. For acute VTE treatment, the NOACs
were compared with conventional treatment, which consists
of a parenteral anticoagulant, such as enoxaparin, for a minimum of 5 days followed by warfarin. The NOACs were compared with warfarin for stroke prevention in AF, whereas in
patients with stabilized ACS, rivaroxaban and apixaban were
compared with placebo on a background of antiplatelet therapy mostly with aspirin plus clopidogrel. Finally, in a phase II
dose validation study, dabigatran was compared with warfarin
in patients with mechanical heart valves. Each of these indications will briefly be discussed.
Thromboprophylaxis
Patients undergoing elective hip or knee arthroplasty require
extended thromboprophylaxis for at least 2 to 4 weeks after
Table 2. Approved Indications and Doses for the NOACs
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Atrial fibrillation
150 mg BID; 110 mg
BID (EU and Canada) in
patients aged >80 y,
CrCl=30–50 mL/min, or
high risk for bleeding;
75 mg BID (US) when
CrCl=15–30 mL/min
20 mg OD; 15 mg OD
when CrCl=30–50 mL/
min (EU and Canada)
and 15–50 mL/min (US)
5 mg BID; 2.5 mg BID
in patients with 2 of
the following: age >80
y, weight ˂60 kg, or
creatinine >1.5 mg/dL
(133 μmol/L)
60 mg OD; 30 mg OD
when CrCl=15–50 mL/
min; edoxaban should
not be used when CrCl
>95 mL/min (US)
Venous thromboembolism
treatment
150 mg BID (after at
least 5 days of heparin)
15 mg BID for 21 days,
then 20 mg OD
10 mg BID for 7 days,
then 5 mg BID
60 mg OD (after 5–10
days of heparin); 30 mg
OD if CrCl=15–50 mL/
min, weight ≤60 kg or
if taking potent P-gp
inhibitors
Thromboprophylaxis after
hip or knee arthroplasy
220 mg OD (EU and
Canada); 150 mg OD
in patients aged ≥75
y, CrCl=30–50 mL/
min, concomitant
verapamil, amiodarone,
or quinidine
10 mg OD
2.5 mg BID
Not licensed in EU or
North America
BID indicates twice daily; EU, Europe; NOAC, non-vitamin K oral anticoagulant; OD, once daily; P-gp, P-glycoprotein; and US, United
States.
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4 Arterioscler Thromb Vasc Biol May 2015
surgery. With hospital stays shortening, prophylaxis is mainly
provided in the outpatient setting. Although guidelines recommend warfarin, a low-molecular-weight heparin (LMWH),
such as enoxaparin or fondaparinux for these patients, warfarin requires monitoring and dose adjustment, whereas
enoxaparin and fondaparinux need daily subcutaneous injections. These limitations can compromise adherence to outof-hospital thromboprophylaxis. In contrast, with fixed-dose
oral administration and no monitoring, the NOACs simplify
extended thromboprophylaxis.
When compared with enoxaparin for postoperative thromboprophylaxis in patients undergoing elective hip or knee
arthroplasty, pooled data suggest that rivaroxaban reduces
the rate of VTE, including symptomatic VTE, but is associated with a small increase in the risk of major bleeding.1 The
efficacy and safety of dabigatran in this setting are comparable with those of enoxaparin, whereas apixaban is more
effective than once daily enoxaparin and equally effective
as twice daily enoxaparin with a similar risk of major bleeding.2,3 Therefore, the NOACs offer a convenient alternative
to enoxaparin in elective hip or knee arthroplasty patients.
Observational data also suggest that rivaroxaban is as effective and safe as LMWH in patients undergoing surgery for
hip fracture.4
For thromboprophylaxis in medically ill patients, a
30-day course of rivaroxaban or apixaban was compared
with a minimum 10-day course of enoxaparin followed by
placebo.5,6 During 10 days, the efficacy of rivaroxaban and
apixaban was similar to that of enoxaparin. Although the
rates of major bleeding were low, there was significantly
more bleeding with rivaroxaban and apixaban than with
enoxaparin. In the extended phase, the rates of VTE were
similar with apixaban and placebo, whereas rivaroxaban
reduced the rate of VTE from 5.7% to 4.2% (relative risk,
0.77; 95% confidence interval [CI], 0.62–0.97; P=0.02).
However, the rates of bleeding were higher with apixaban
and rivaroxaban than with placebo. Therefore, neither rivaroxaban nor apixaban is licensed for thromboprophylaxis in
medically ill patients.
VTE Treatment
Conventional treatment for VTE starts with a parenteral anticoagulant, such as LMWH, which is administered for at least
5 days, as patients are transitioned to warfarin. The parenteral
anticoagulant is stopped when the INR is therapeutic, and
patients are then continued on warfarin for at least 3 months.
Although effective, such treatment is cumbersome because
LMWH requires daily subcutaneous injection, which can be
problematic for some patients, and warfarin requires frequent
coagulation monitoring and dose adjustment. The limitation
of conventional treatment prompted evaluation of the NOACs
for this indication.
In patients with acute VTE, all-oral regimens of rivaroxaban or apixaban were compared with conventional treatment
consisting of enoxaparin for at least 5 days followed by warfarin. In contrast, because there were no phase II data supporting the safety or efficacy of all-oral regimens of dabigatran or
edoxaban, treatment started with a parenteral anticoagulant,
which was given for at least 5 days, and patients were then
transitioned to dabigatran or edoxaban or to warfarin. A metaanalysis of the phase III trials comparing the NOACs with
conventional therapy in patients with acute VTE suggests that
the NOACs reduce the rates of recurrent VTE, fatal PE, and
all-cause mortality to a similar extent, but are associated with
a lower risk of major bleeding.7 Therefore, the NOACs are
at least as effective as warfarin for VTE treatment, but are
more convenient to administer and are associated with less
bleeding.
Rivaroxaban, apixaban, and dabigatran were compared with
placebo for secondary prevention in patients who completed
at least 6 months of anticoagulant therapy for their index VTE
event. Although treatment doses of dabigatran and rivaroxaban were used in these trials, apixaban was evaluated at both
the treatment and the prophylactic dose of 5- and 2.5-mg BID,
respectively. Dabigatran was also compared with warfarin for
this indication.
Compared with placebo, all the NOACs significantly
reduced the risk of recurrent VTE by at least 80%. Rates of
major bleeding with the NOACs were low, and in the case
of apixaban, the 5- and 2.5-mg BID dose regimens were
associated with rates of major bleeding similar to that with
placebo.8 Compared with warfarin, the rate of recurrent VTE
with dabigatran was similar, but the rate of major bleeding
was 50% lower with dabigatran than with warfarin (0.9% and
1.8%, respectively; hazard ratio, 0.52; 95% CI, 0.27–1.02).9
Therefore, the NOACs are a convenient choice for extended
treatment of patients with VTE who are at risk of recurrence
should anticoagulation therapy stop.
Stroke Prevention in AF
Compared with control in patients with AF, warfarin reduces
the risk of stroke by ≈65%. Despite its efficacy, however, it
is estimated that ≤50% of eligible patients with AF fail to
receive warfarin prophylaxis, and in those who are treated, the
INR is frequently outside the therapeutic range. These limitations highlight the need for alternative anticoagulants.
In phase III trials, the NOACs were compared with warfarin in >71 000 patients with AF. Therefore, the clinical trial
database with the NOACs in patients with AF is robust. By
comparison, warfarin was compared with aspirin or placebo
for stroke prevention in patients with AF in clinical trials
conducted in the 1980s and early 1990s that included <3000
patients.
Compared with warfarin, a meta-analysis of the phase III
clinical trial data reveal that the NOACs are noninferior for
prevention of stroke and systemic embolism and as a class, are
associated with ≈10% reduction in all-cause mortality and a
similar reduction in cardiovascular mortality.10 Rates of major
bleeding are similar or lower than those with warfarin and all
the NOACs produce less intracranial bleeding than warfarin,
but with the exception of apixaban, are associated with more
gastrointestinal bleeding. Because of their more favorable
benefit-to-risk profile relative, several guidelines give preference to NOACs over warfarin in eligible patients with AF.
Apixaban was compared with aspirin in 5559 patients with
AF who were deemed unsuitable for warfarin or were unable
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Yeh et al New Oral Anticoagulants 5
to tolerate it.11 Compared with aspirin, apixaban significantly
reduced the annual rate of stroke or systemic embolism
from 3.7% to 1.6% (hazard ratio, 0.45; 95% CI, 0.32–062;
P<0.001) without significantly increasing the annual rate of
major bleeding (1.4% and 1.2%, respectively). Furthermore,
apixaban was well tolerated and was discontinued less frequently than aspirin. These findings support the concept that
there is little or no role for aspirin for stroke prevention in
patients with AF.
Acute Coronary Syndrome
Most cases of ACS are triggered by thrombosis after rupture of an atherosclerotic plaque in a coronary artery. Key
to thrombus formation is the generation of thrombin, which
not only converts fibrinogen to fibrin but also induces platelet activation and aggregation at the site of vascular injury.
Although dual antiplatelet therapy is more effective for
the prevention of recurrent events than aspirin alone after
ACS, there remains an ≈10% risk of recurrent ischemic
events at 1 year. The value of anticoagulants in this setting
is highlighted by studies with warfarin. A meta-analysis of
10 such trials revealed that, compared with aspirin alone,
the combination of warfarin plus aspirin reduces the annual
rate of recurrent myocardial infarction (MI) by 44% and
the annual rates of stroke and revascularization by 54%
and 20%, respectively.12 However, these benefits are offset
by a 2.5-fold increase in major bleeding. The results of an
indirect meta-analysis also suggest that the combination of
warfarin plus aspirin has similar benefits over aspirin plus
clopidogrel, but at the expense of a 2-fold increase in major
bleeding.13 Although the studies with warfarin provided
proof-of-principle that attenuation of thrombin generation
is of benefit in patients with ACS, the complexity of warfarin management and the increased risk of bleeding have
restricted its use in this setting.
With fixed dosing and no monitoring, the NOACs are more
convenient to administer than warfarin and they have a more
favorable safety profile. These observations prompted their
evaluation in patients with ACS. Thus, the phase III Apixaban
with Antiplatelet Therapy after Acute Coronary Syndrome
(APPRAISE-2)14 and ATLAS ACS 2–TIMI 5115 trials compared apixaban (5 mg BID) and rivaroxaban (2.5 or 5 mg
BID), respectively, with placebo in patients with stabilized
ACS. The APPRAISE-2 trial was stopped after recruitment
of 7392 of the planned 10 800 patients because of excessive
bleeding with apixaban that was not offset by a reduction
in ischemic events. In contrast, the ATLAS ACS 2–TIMI 51
trial went to completion and enrolled 15 526 patients. After
a mean treatment duration of 13 months, rivaroxaban significantly reduced the primary efficacy outcome—a composite
of cardiovascular death, MI or stroke—from 10.7% to 8.9%
(hazard ratio 0.84; 95% CI, 0.74–0.96; P=0.008). In patients
given the 5- and 2.5-mg BID regimens, the rates were 8.8%
(P=0.03) and 9.1% (P=0.02), respectively.15 Compared with
placebo, rivaroxaban increased the rates of major bleeding
from 0.6% to 2.1% (P<0.001) and intracranial hemorrhage
from 0.2% to 0.6% (P=0.009) without a significant increase
in the rate of fatal bleeding (0.2% and 0.3%, respectively;
P=0.66).15 Rivaroxaban also reduced the rate of stent thrombosis from 2.9% to 2.3% (P=0.02); a finding that challenges
the concept that stent thrombosis is a platelet-driven phenomenon. Although both the doses of rivaroxaban reduced the rate
of the primary efficacy end point, the 2.5-mg BID regimen
produced less fatal bleeding than the 5-mg BID dose (0.1%
and 0.4%, respectively; P=0.04) and compared with placebo,
reduced the rate of cardiovascular death from 4.1% to 2.7%
(P=0.002). On the basis of these results, the lower dose rivaroxaban regimen received regulatory approval in the European
Union for secondary prevention in patients with elevated cardiac biomarkers after an ACS event. Although approved for
use in conjunction with aspirin or clopidogrel, rivaroxaban is
not licensed for use in conjunction with ticagrelor or prasugrel because it was not tested in combination with these more
potent ADP receptor antagonists.
New Opportunities for the NOACs
The convenience of treatment with NOACs coupled with their
favorable benefit-to-risk profiles have prompted their evaluation in new areas, including mechanical heart valves, heart
failure, coronary or peripheral artery disease, and embolic
stroke of unknown source. In addition, ongoing studies are
addressing patients with AF undergoing percutaneous coronary intervention (PCI), out-of-hospital thromboprophylaxis
in medically ill and cancer patients, and extended VTE treatment (Table 3). The rationale for use of the NOACs in each of
these setting is provided.
Mechanical Heart Valves
In a phase II dose evaluation study, dabigatran was compared
with warfarin in patients with newly implanted mechanical
heart valves or valves that were implanted at least 3 months
previously.16 Dabigatran was started at a dose of 150 mg BID
but the dose could be increased ≤300 mg BID to maintain the
trough dabigatran level >50 ng/mL. The study was stopped
early after enrolment of 252 patients because of an excess of
ischemic strokes and bleeding events in the dabigatran group.
These results reveal the limitations of dabigatran in patients
with mechanical heart valves. Although studies with the other
agents have yet to be done in this patient population, until
there is more information, NOACs are contraindicated in
patients with mechanical heart valves.
Small numbers of AF patients with bioprosthetic heart
valves were enrolled in some of the trials, but the efficacy
and safety of NOACs in such patients remain uncertain.
Although further studies of the NOACs in patients with
bioprosthetic heart valves are warranted, to our knowledge,
none are underway. Therefore, at least for now, warfarin is
the treatment of choice for patients with mechanical or bioprosthetic heart valves.
Heart Failure
Almost 6 million people in the United States have heart failure,
and despite recent advances in therapy, about half die within 4
years of diagnosis. Patients with heart failure require frequent hospitalization, which renders this disease costly for the healthcare
system. Because most patients with heart failure have underlying
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6 Arterioscler Thromb Vasc Biol May 2015
Table 3. Ongoing Clinical Trials With the NOACs
Design
Treatment
Comparator
Treatment
Duration
Primary Efficacy
Outcome
Primary Safety
Outcome
No. of Patients
MARINER
NCT02111564
HoukusaiVTE-Cancer
NCT02073682
AVERT
NCT02048865
NAVIGATE ESUS
NCT02313909
Double blind
Rivaroxaban 7.5
or 10 mg OD
Edoxaban
Placebo
45 d
Major bleeding
8000
Dalteparin
6 mo
VTE in month
after treatment
VTE
CRNB
1000
6 mo
VTE
Major and CRNB
574
3y
Stroke or SEE
Major bleeding
7000
RE-SPECT ESUS
NCT02239120
Double blind
3 mo
Stroke
Major bleeding
6000
VTE
EINSTEIN CHOICE
Double blind
12 mo
Recurrent VTE
Major bleeding
2850
ACS
PIONEER AF-PCI
NCT01830543
Open label
1, 6, or 12 mo
Time to first
cardiovascular
event
Clinically
significant
bleeding
2100
REDUAL-PCI
NCT02164864
Open label
30 mo
Time to first
cardiovascular
event
Major bleeding
8520
Heart failure
COMMANDER HF
NCT01877915
Double blind
30 mo
Major bleeding
5000
CAD or PAD
COMPASS
NCT01776424
Double blind
Time to first
cardiovascular
event
Time-to-first
cardiovascular
event
Indication
Medically ill
Cancer
ESUS
Trial Name NCT
no.
Open label
Double blind
Double blind
Apixaban 2.5
Placebo
mg BID
Rivaroxaban 15
Placebo
mg OD or aspirin
100 mg OD
Dabigatran 110
Placebo
or 150 mg BID
or aspirin 100
mg OD
Rivaroxaban 10 Aspirin 100 mg
or 20 mg OD
OD
Rivaroxaban
Warfarin+DAPT
15 mg OD+ADP
receptor
antagonist or
Rivaroxaban 2.5
mg BID+DAPT
Dabigatran
Warfarin+DAPT
110 mg
BID+clopidogrel
or ticagrelor
or dabigatran
150 mg
BID+clopidogrel
or ticagrelor
Rivaroxaban
Placebo
2.5 mg BID
Rivaroxaban
Aspirin 100 mg
5y
Major bleeding
21 400
2.5 mg BID
OD+placebo
and aspirin
100 mg OD or
rivaroxaban 5 mg
BID+placebo
ACS indicates acute coronary syndrome; BID, twice daily; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; ESUS, embolic stroke of undetermined
source; NOAC, non-vitamin K oral anticoagulant; OD, once daily; PAD, peripheral artery disease; and VTE, venous thromboembolism.
coronary artery disease and because addition of low-dose rivaroxaban to antiplatelet therapy reduced the risk of cardiovascular
death, MI, and stroke in patients with ACS in the ATLAS ACS
2–TIMI 51,15 the placebo-controlled COMMANDER HF trial
(NCT01877915) will determine whether low-dose rivaroxaban
also reduces cardiovascular events in patients with heart failure.
Coronary or Peripheral Artery Disease
Patients with coronary or peripheral artery disease are at risk
of cardiovascular events. Aspirin, the current standard of care
in most such patients, reduces the risk by ≈25%. Therefore,
there is an unmet need for more effective therapy. Antiplatelet
drugs and anticoagulants have complementary mechanisms
of action and there is mounting evidence that thrombin contributes to recurrent ischemic events in patients with ACS.
The ongoing COMPASS trial (NCT01776424) is evaluating
whether rivaroxaban has a role for secondary prevention of
cardiovascular death, MI, and stroke in patients with known
coronary artery disease or peripheral arterial disease. This
3-arm study is comparing aspirin alone (at a dose of 100 mg
once daily), rivaroxaban alone (at a dose of 5 mg BID), and
the combination of aspirin plus rivaroxaban (at a dose of 2.5
mg BIB). If rivaroxaban reduces the risk of recurrent ischemic
events in this broad population of patients with atherosclerosis, the findings will provide further support for the role of
thrombin in the pathogenesis of atherothrombosis.
Embolic Stroke of Unknown Source
Strokes of unknown source represent ≈25% of all ischemic
strokes and most are embolic in origin. Thrombi in such
patients may not only originate from the left atrial appendage in those with subclinical AF but also from the deep veins
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Yeh et al New Oral Anticoagulants 7
of the leg via paradoxical embolism, or from atherosclerotic
plaques in the aortic arch or the carotid or cerebral arteries.
The optimal management of patients with embolic stroke of
unknown source is uncertain, and most patients are currently
treated with aspirin. The RE-SPECT ESUS and NAVIGATE
ESUS trials will determine whether compared with aspirin,
dabigatran, or rivaroxaban, respectively, reduces the risk of
recurrent stroke in such patients.
NOACs After PCI
The optimal management of NOACs in patients with AF
undergoing PCI is uncertain. Such patients are traditionally
treated with dual antiplatelet therapy with aspirin and an ADP
receptor antagonist plus warfarin. In the ongoing PIONEER
AF-PCI study (NCT01830543), 2 different rivaroxaban regimens will be compared with warfarin in patients with AF
undergoing PCI and coronary stent placement. The rivaroxaban treatments include a double antithrombotic regimen consisting of rivaroxaban (15 mg once daily or 10 mg once daily
for those with a creatinine clearance between 30 and 50 mL/
min) plus an ADP receptor antagonist (clopidogrel, prasugrel,
or ticagrelor) or a triple antithrombotic regimen consisting of
rivaroxaban (2.5 mg BID) plus dual antiplatelet therapy with
aspirin (75–100 mg daily) and an ADP receptor antagonist
(clopidogrel, prasugrel, or ticagrelor). The control is a triple
antithrombotic regimen consisting of warfarin (dose-adjusted
to an INR of 2–3) plus dual antiplatelet therapy with aspirin
(75–200 mg daily) and an ADP receptor antagonist (clopidogrel, prasugrel, or ticagrelor). All treatment regimens will be
administered for 12 months and the primary outcome measure is the composite of major bleeding, minor bleeding, and
bleeding requiring medical attention.
Studies are also underway with dabigatran in patients with
PCI. The 3-arm REDUAL-PCI study (NCT02164864) will
compare dual antithrombotic therapy with dabigatran at a dose
of 110 or 150 mg BID plus clopidogrel or ticagrelor, with triple
antithrombotic therapy with aspirin (≤100 mg daily), clopidogrel or ticagrelor and warfarin in patients with AF who have
undergone PCI with coronary stent implantation. Efficacy will
be determined by comparing the rate of the composite of death,
MI, stroke, or systemic embolism, and comparison of the rate
of clinically relevant bleeding will be used to assess safety.
Venous Thromboembolism
Ongoing studies are evaluating NOACs for thromboprophylaxis in medically ill patients and for secondary prevention
in patients who have completed a 6- to 12-month course of
anticoagulant therapy for acute VTE. The ongoing phase
III, placebo-controlled MARINER study (NCT02111564) is
comparing a 45-day course of treatment with rivaroxaban (10
mg once daily for those with a creatinine clearance >50 mL/
min and 7.5 mg once daily for those with a creatinine clearance of 30–49 mL/min) with placebo on the risk of symptomatic VTE in medically ill patients recently discharged from
hospital. The AVERT study (NCT02040865) is comparing a
6-month course of apixaban (2.5 mg BID) with placebo for
thromboprophylaxis in ambulatory cancer patients who are at
high risk for VTE.
The optimal antithrombotic regimen for extended VTE
treatment is uncertain. Because of the complexities of warfarin management, many patients stop anticoagulant treatment
after 6 to 12 months. Compared with placebo, aspirin, at a
dose of 100 mg once daily, reduces the risk of recurrence by
≈32% without significantly increasing the risk of major bleeding.17 The EINSTEN CHOICE study (NCT02064439) will
compare rivaroxaban (at doses of 20 or 10 mg once daily)
with aspirin for secondary prevention in patients with VTE
who have completed a 6- to 12-month course of anticoagulant
therapy for their index event. The hypotheses being tested are
that both the doses of rivaroxaban will be more effective than
aspirin for VTE prevention and that the 2 doses of rivaroxaban
will have similar efficacy but that the lower dose will produce
less bleeding than the higher dose.
Patients with VTE in the setting of cancer are difficult to
manage because they are at higher risk of recurrence and
bleeding than those without cancer. Although patients with
active cancer were included in the phase III trials comparing
NOACs with warfarin for patients with VTE, the numbers
were small. Nonetheless, the results of a meta-analysis indicated that the rate of recurrent VTE was lower in patients with
cancer treated with NOACs than in those who received warfarin (4.1% and 6.1%, respectively; relative risk, 0.66; 95%
CI, 0.38–1.2), whereas the rates of the composite of major
and clinically relevant nonmajor bleeding were 15% and 16%,
respectively.18 Many patients with cancer-associated VTE are
treated with LMWH, and these results provide the basis for
a comparison of the NOACs with LMWH in such patients.
The Hokusai VTE Cancer study (NCT02073682) will compare edoxaban with dalteparin in 1000 patients with cancerassociated VTE.
Real-World Data
Large phase III trials have consistently demonstrated that
benefit-to-risk profile of the NOACs for treatment of VTE
and for stroke prevention in AF is more favorable than that
of warfarin. Because of the stringent inclusion and exclusion
criteria inherent to such trials, however, it remains uncertain
whether the findings apply to real-world patient populations.
Consequently, observational studies are needed to determine
the effectiveness and safety of the NOACs in everyday practice outside the confines of closely monitored clinical trials.
Many real-world studies with the NOACS are ongoing, but the
data published, to date, reveal outcomes similar to those in the
phase III trials, including reduced rates of ICH and increased
or similar rates of GI bleeding events.
Using Danish registry data, Larsen et al19 compared the
efficacy and safety of dabigatran in 4978 anticoagulant-naive
patients with AF with the results in 8936 patients taking warfarin. Rates of stroke and systemic embolism were in dabigatran
and warfarin-treated patients were similar. Both the 110- and
the 150-mg BID dabigatran doses were associated with lower
rates of ICH than warfarin. The rate of GI bleeding was lower
with the 110-mg BID dose of dabigatran than with warfarin,
a finding not found with the 150-mg BID dose. Therefore, the
results in every day practice were similar to those reported in
the RE-LY trial.
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8 Arterioscler Thromb Vasc Biol May 2015
Using national Veterans Affairs administrative encounter
and pharmacy data, Vaughan et al20 compared the risk of bleeding events in patients with AF who were switched to dabigatran after at least 6 months of warfarin therapy with the risk
in those who continued taking warfarin. Of the 85 344 patients
who had been on warfarin for at least 6 months, 1394 (1.6%)
were switched to dabigatran (150 mg BID). The risk-adjusted
rate of any bleeding in patients switched to dabigatran was
higher than that in patients who continued on warfarin (odds
ratio [OR], 1.27; 95% CI, 1.20–1.56); a difference mainly
driven by an increased risk of GI bleeding in patients treated
with dabigatran (OR, 1.54; 95% CI, 1.20–1.97). Rates of ICH
were similar in the 2 groups (OR, 0.86; 95% CI, 0.21–3.53),
as were the rates of other bleeding events (OR, 0.97; 95% CI,
0.68–1.23).
Using Medicare claims data, the Food and Drug
Administration (FDA) compared the rates of ischemic
stroke, ICH, major GI bleeding, MI, and death in >134 000
patients who were prescribed dabigatran or warfarin for AF.
Compared with warfarin, dabigatran was associated with
a lower risk of ischemic stroke, ICH, and death. The risk
of major GI bleeding was higher with dabigatran than with
warfarin, whereas the risk of MI was similar.21 The results
for major GI bleeding in this study differed from those of
the previous FDA Mini Sentinel Modular Program analysis,
which reported lower rates of GI bleeding and ICH among
new users of dabigatran compared with new users of warfarin.22 The divergent results may reflect the age differences in
the 2 patient populations and ongoing analyses are addressing this possibility.
A retrospective analysis in 2579 patients with AF receiving
rivaroxaban or dabigatran for stroke prevention in the United
States between October 2010 and November 2012 showed
that, during the 2-year time period, the rates of major bleeding
and ICH were 0.5% and 0.2%, respectively, and the rate of
fatal bleeding was only 0.08%.23 Of the 13 patients who experienced a major bleeding event, 8 would have been excluded
from phase III trials for this indication. Collectively, therefore,
the evidence from real-world observational studies confirms
the results of the phase III randomized trials and highlights the
favorable safety profile of the NOACs. Several ongoing registries are assessing the safety and effectiveness of the NOACs
in patients with AF or VTE, including GARFIELD-AF
(NCT01090362), GLORIA-AF (NCT01468701), and
GARFIELD-VTE (NCT02155491).
Challenges for the NOACs
Although the NOACs represent a major advance in oral anticoagulation, there are remaining challenges that need to be
overcome. These include higher drug acquisition costs, the
fear of bleeding in the absence of specific antidotes, the concern that adherence will be compromised with unmonitored
anticoagulant therapy, and the perception that monitoring
of the NOACs may help to optimize dosing, particularly in
vulnerable patient populations, such as the elderly or those
with compromised renal function. Each of these will briefly
be addressed.
Drug acquisition costs are higher for the NOACs than for
warfarin, which limits access in many healthcare systems.
Many payers maintain that NOACs should be restricted to
patients whose INR is poorly controlled with warfarin. The
NOACs are at least as effective as warfarin, but are more
convenient to administer. Although convenience alone is not
a sufficient reason to use the NOACs as first-line therapy,
≈50% reduction in ICH with the NOACs relative to warfarin is more compelling. This benefit over warfarin persists
regardless of how well warfarin is managed; a finding that
probably reflects the fact that in about two thirds of cases,
ICH with warfarin occurs when the INR is within the therapeutic range.
The safety of the NOACs has been questioned because
of the lack of specific antidotes. However, the outcome of
patients with major bleeds is no worse with the NOACs
than with warfarin. Thus, with dabigatran, in analysis of the
results of 5 phase III trials, 30-day mortality after a major
bleeding event was lower with dabigatran than with warfarin although the difference did not reach statistical significance.24 Likewise, major bleeding events with apixaban
were associated with a significant 50% lower risk of death
within 30 days than with warfarin in the ARISTOTLE trial.
Furthermore, in the RE-LY and ROCKET-AF trials, mortality in patients with ICH was similar in those treated with
dabigatran and rivaroxaban, respectively, as it was in those
given warfarin. Even in patients requiring urgent surgery or
interventions, the incidence of major bleeding in the RE-LY
trial was lower with dabigatran than with warfarin in those
who went to the procedure within 48 hours of taking their
last dose of study drug. Therefore, there is no evidence to
support the belief that the lack of specific antidotes renders
bleeding events with the NOACs more dangerous than those
with warfarin. The introduction of specific antidotes for the
NOACs will further allay concerns about bleeding or rapid
reversal.
With shorter half-lives than warfarin, adherence to the
NOACs is essential. Patients require follow-up to ensure that
they are taking their medications. Persistence with warfarin
and the NOACs is suboptimal and ongoing efforts are needed
to enhance compliance.
A recent report of a correlation between dabigatran levels
and bleeding and stroke outcomes in patients in the RE-LY
trial25 has prompted some clinicians to recommend monitoring to optimize dosing of the NOACs. However, tests
to measure drug levels are not widely available, the within
patient variability in drug levels is sufficiently wide that single
measurements may provide misleading information,26 and
the correlation between drug levels and clinical outcomes is
confounded by important clinical characteristics, such as age,
renal function, and concomitant medications. Therefore, until
there is evidence that dose adjustment based on drug levels
improves the efficacy or safety of treatment with the NOACs,
dose adjustment should be made according to the patient characteristics outlined in the product monograph for each agent.
Finally, more information is needed about dosing of the
NOACs in patients at extremes of body weight. Although the
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Yeh et al New Oral Anticoagulants 9
doses of apixaban and edoxaban are reduced in patients with
low body weight, those of dabigatran and rivaroxaban are not.
Whether dose adjustment is needed for patients with body
weight >150 kg is unknown because few such patients were
included in the clinical trials. Studies comparing the pharmacodynamics and pharmacokinetics of the NOACs in patients
with body weight <60 kg or >150 kg with those in patients
with body weight between these values would provide this
information.
In summary, the NOACs simplify oral anticoagulation and
have the potential to increase the uptake of anticoagulation
for long-term prevention of thromboembolic events in patients
with AF or in patients with VTE at high risk for recurrence.
With increasing familiarity, promising results of real-world
studies and expanding indications, the NOACs will replace
warfarin for more and more indications. However, the unmet
needs persist for patients with severe renal impairment or for
those with mechanical heart valves. Anticoagulant strategies
that target factor XII or factor XI are promising. Whether
agents targeting these coagulation factors will have a better
benefit-to-risk profile than the NOACs is unknown.
Acknowledgments
C.H. Yeh is supported by a Doctoral Scholarship from the Canadian
Institutes of Health Research. J.I. Weitz holds the Canada Research
Chair (Tier I) in Thrombosis and the Heart and Stroke Foundation
J. Fraser Mustard Chair in Cardiovascular Research at McMaster
University.
Disclosures
J.I. Weitz has served as a consultant and received honoraria from
Bristol-Myers Squibb, Pfizer, Daiichi Sankyo, Bayer, Janssen,
Boehringer-Ingelheim, ISIS Pharmaceuticals, and Portola. The other
authors report no conflicts.
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Significance
Non-vitamin K antagonist oral anticoagulants were developed to overcome the limitations of warfarin. These agents, which include dabigatran, rivaroxaban, apixaban, and edoxaban, can be administered in fixed doses without routine coagulation monitoring, and are at least
as effective as warfarin but produce less serious bleeding. The non-vitamin K antagonist oral anticoagulants are already replacing lowmolecular-weight heparin for thromboprophylaxis in patients undergoing elective hip or knee arthroplasty and replacing warfarin for stroke
prevention in patients with atrial fibrillation and treatment of venous thromboembolism. This article describes how these agents streamline
extended thromboprophylaxis and long-term anticoagulant therapy, and highlights their future potential.
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Overview of the New Oral Anticoagulants: Opportunities and Challenges
Calvin H. Yeh, Kerstin Hogg and Jeffrey I. Weitz
Arterioscler Thromb Vasc Biol. published online March 19, 2015;
Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272
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