Updatein2015:’Novel’Oral’Anticoagulant’(NOAC…multibriefs.com/briefs/cts/noca.pdf · Updatein2015:’Novel’Oral’Anticoagulant’(NOAC)’Drugs’for’Treatment’of’Venous’’

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.

ORIGINAL ARTICLE

Effectiveness and safety of novel oral anticoagulants ascompared with vitamin K antagonists in the treatment ofacute symptomatic venous thromboembolism: a systematicreview and meta-analysis

T . VAN DER HULLE ,* J . KOOIMAN,* P . L . DEN EXTER ,* O. M. DEKKERS ,† F . A . KLOK*

and M. V . HU ISMAN**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 anti-

coagulants 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 advanta-

ges. Individual studies have demonstrated comparable

efficacy to that of vitamin K antagonists (VKAs) and

have suggested a more favorable safety profile . We per-

formed 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 MED-

LINE, 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 complica-

tions, 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

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. Conclu-

sions: NOACs have comparable efficacy to that of VKAs,

and are associated with a significantly lower risk of bleed-

ing 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 pre-

vention of recurrent VTE, with a relative risk (RR) reduc-

tion 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

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

© 2013 International Society on Thrombosis and Haemostasis

Journal of Thrombosis and Haemostasis, 12: 320–328 DOI: 10.1111/jth.12485

(thrombin) and FXa inhibitors, which lack some of the

limitations of VKA treatment. The relatively stable phar-

macokinetics and pharmacodynamics of these agents

obviate the need for routine laboratory monitoring [5].

Several trials in patients with acute VTE have demon-

strated comparable efficacy to that of VKAs in terms of

VTE recurrence rates, with lower risks of bleeding compli-

cations [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 knowl-

edge 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 Clini-

cal Trials Registry for peer-reviewed publications compar-

ing 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 con-

trolled 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 unre-

ported 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 poten-

tially 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 adminis-

tered 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 objec-

tively diagnosed acute DVT, PE, or both; (iii) randomly

allocating patients to the intervention groups; (iv) report-

ing outcomes after at least 3 months of follow-up, includ-

ing 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 antico-

agulant 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 initia-

tion 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 out-

come 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 rele-

vant non-major bleeding, non-fatal intracranial bleeding,

major gastrointestinal bleeding, and fatal bleeding during

anticoagulant treatment.

Recurrent symptomatic VTE included fatal and non-

fatal 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 transfu-

sion of at least two units of blood, occurring in a criti-

cal site (intracranial, intraspinal, intraocular, pericardial,

intra-articular intramuscular with compartment syn-

drome, retroperitoneal), or contributing to death [13]. In

all included studies, except for the Re-Cover study, clini-

cally 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 bleed-

ing that are comparable with the definition used in the

other trials.


Effectiveness and safety of novel oral anticoagulants 321

Data extraction

Data extraction was independently performed by two

reviewers. For each included study, we extracted the num-

ber of participants, follow-up period, number of patients

with DVT, PE, or both, unprovoked VTE, active malig-

nancy, previous VTE, and the mean time spent in thera-

peutic range (TTR) during VKA therapy.

Data synthesis and analysis

Data were analyzed with the Mantel–Haenszel random-

effects model, by the use of Review Manager (V. 5.1;

The Nordic Cochrane Centre, The Cochrane Collabora-

tion, Copenhagen). RRs with corresponding 95% confi-

dence 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 differ-

ences 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 com-

pared 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].

Characteristics of included randomized controlled trials

One study evaluated dabigatran in patients with PE and/

or DVT (Re-Cover I study) [6], one investigated rivarox-

aban 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 pre-

vious 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 thera-

peutic-dose low molecular weight heparin or unfractionat-

ed 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 single-

drug 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 poten-

tial risks of bias were associated with the open label

design of the two Einstein studies [7,8], and all five stud-

ies were sponsored and managed by the pharmaceutical

industry. As our meta-analysis included only five studies,

1469 excluded after review of title and abstract

9 excluded after full text review4 no phase 3 trial3 extended treatment of VTE1 investigating ximelagatran1 not peer-reviewed (Re-Cover II study)

1483 references

14 references

5 studies

Fig. 1. Flow diagram of study selection. VTE, venous thromboem-

bolism.


322 T. van der Hulle et al

Table

1Studycharacteristics

Study

Year

Drug

class

Treatm

ent

duration

(months)

Patients,n

Men,

n(%

)

Meanage

inyears

(range)

PEorPEand

DVT,n(%

)

Isolated

DVT,n(%

)

Unprovoked,

n(%

)

Cancer,

n(%

)

Previous

VTE,n(%

)

TTR

in

VKA

group(%

)

Re-Cover

2009

Dabigatran

DTI

62539

1484(58)

55(18–97)

786(31)

1749(69)

Notprovided

121(5)

649(26)

60

Einstein-D

VT

2010

Rivaroxaban

FXainhibitor

3/6/12*

3449

1960(57)

56(notprovided)

23(1)

3405(99)

2138(62)

207(6)

666(19)

58

Einstein-PE

2012

Rivaroxaban

FXainhibitor

3/6/12*

4832

2556(53)

58(notprovided)

4832(100)

0(0)

3117(65)

223(5)

944(20)

63

Amplify

2013

Apixaban

FXainhibitor

65395

3167(59)

57(notprovided)

1836(34)

3532(65)

4845(90)

143(3)

872(16)

61

Hokusai

2013

Edoxaban

FXainhibitor

3/6/12*

8240

4716(57)

56(notprovided)

3319(40)

4921(60)

5410(66)

771(9)

1520(18)

64

DTI,

directthrombin

inhibitor;

DVT,deepveinthrombosis;

PE,pulm

onary

embolism

;TTR,timein

therapeuticrange;

VKA,vitamin

Kantagonist;VTE,venousthromboem

bolism

.*T

reat-

mentdurationdefined

bytreatingphysician.



we did not perform formal tests for funnel plot asymme-

try (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%) trea-

ted 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 out-

comes was 0%, indicating low heterogeneity.

Meta-analysis: safety outcomes

All combined RRs were significantly lower for the

patients treated with NOACs, except that for major gas-

Re-Cover

Einstein-DVT

+

Einstein-PE

Amplify 2013

Hokusai 2013

2009

2010

2012

+

+

+

+R

ando

m s

eque

nce

gene

ratio

n

Allo

catio

n co

ncea

lmen

t

Blin

ding

of p

artic

ipan

ts a

nd p

erso

nnel

Blin

ding

of o

utco

me

asse

ssm

ent

Inco

mpl

ete

outc

ome

data

Sel

ectiv

e re

port

ing

Oth

er b

ias

+

+

+

+

+

+

+

+

+

+

+

–

–

–

–

–

–

–

+

+

+

+

+

+

+

+

+

+

+

+

Fig. 2. Results of Cochrane Collaboration’s tool for assessing risk of

bias.

Table 2 Efficacy and safety outcomes

Outcome

NOACs n

% Range

VKAs n

% Range

Pooled absolute risk

difference, % (95% CI)

NNT with NOACs to

prevent one event (95% CI)

Recurrent VTE 241/12 151

2.0

1.6–2.4

273/12 153

2.2

1.8–3.0

� 0.24 (� 0.60 to 0.11) 417 (167 to � 909)

Fatal PE 9/12 151

0.07

0.04–0.10

9/12 153

0.07

0.0–0.24

0.01 (� 0.06 to 0.08) 10 000 (1667 to � 1250)

Overall mortality 290/12 197

2.4

1.5–3.2

298/12 193

2.4

1.7–3.1

� 0.10 (� 0.47 to 0.28) 1000 (213 to � 357)

Major bleeding 131/12 197

1.1

0.6–1.6

211/12 193

1.7

1.2–2.2

� 0.67 (� 1.13 to � 0.21) 149 (88–476)

Non-fatal bleeding at a critical site 28/12 179

0.23

0.08–0.32

77/12 193

0.63

0.18–1.08

� 0.38 (� 0.65 to � 0.10) 263 (153-1000)

Clinically relevant non-major bleeding 806/12 179

6.6

3.9–9.5

1024/12 193

8.4

6.9–9.8

� 1.77 (� 3.40 to � 0.15) 56 (29–667)

Non-fatal intracranial bleeding 11/12 179

0.09

0.00–0.12

31/12 193

0.25

0.00–0.42

� 0.14 (� 0.31 to 0.03) 714 (323 to � 3333)

Major gastrointestinal bleeding 28/8079

0.35

0.17–0.71

43/8071

0.53 0.23–0.67� 0.16 (� 0.42 to 0.11) 625 (238–909)

Fatal bleeding 7/12 179

0.06

0.04–0.08

21/12 193

0.17

0.07–0.29

� 0.09 (� 0.17 to 0.00) 1111 (588–0)

CI, confidence interval; NNT, number needed to treat; NOAC, new direct oral anticoagulant; PE, pulmonary embolism; VKA, vitamin K

antagonist; VTE, venous thromboembolism.



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

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 edox-

aban, 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

Outcome Study R R Lower limit Upper limit Weight (%) R R (95% CI)Recurrent VTE

Fatal PE

Overall mortality

Re-Cover (dabigatran) 1.10 0.66 1.84 11.216.718.425.428.3100

18.09.0

16.016.041.1100

7.114.618.315.644.4100

0.1 1Favors NOACs Favors VKAs

10

1.071.691.181.141.05

3.1873.0421.995.575.965.96

1.811.171.681.191.331.14

0.460.760.600.600.74

0.030.120.180.050.300.39

0.550.510.800.530.820.83

0.701.130.840.830.88

0.332.982.000.501.331.02

0.990.771.160.791.050.97

Einstein-DVT (rivaroxaban)Einstein-PE (rivaroxaban)Amplify (apixaban)

Amplify (apixaban)

Amplify (apixaban)

Hokusai (edoxaban)

Hokusai (edoxaban)

Hokusai (edoxaban)

Subtotal (I2 = 0%, P = 0.46)

Subtotal (I2 = 0%, P = 0.71)

Subtotal (I2 = 0%, P = 0.50)

Re-Cover (dabigatran)


Einstein-DVT (rivaroxaban)


Einstein-PE (rivaroxaban)


Fig. 3. Efficacy outcomes. CI, confidence interval; NOACs, new direct oral anticoagulants; PE, pulmonary embolism; VKA, vitamin-K antago-

nist; VTE, venous thromboembolism.

Outcome Study R R Lower limit Upper limit Weight (%)Major bleeding

Non-fatal bleeding at a critical site

Clinically relevant non-major bleeding

Non-fatal intracranial bleeding

Major gastrointestinal bleeding

Fatal bleeding

Re-Cover (dabigatran) 0.83

0.11 0.010.200.120.090.27

5.59.0

28.417.439.7

0.874.930.620.871.02

1.000.270.290.52

0.420.830.810.380.70

0.821.341.150.610.94

17.119.721.320.021.9

0.581.050.970.480.81

0.144.980.100.500.42

1.790.750.560.39

0.990.200.660.500.20

0.060.020.110.050.04

15.881.703.975.540.91

10.317.124.713.734.2

5.333.331.270.93

22.914.532.430.1

0.600.170.250.16

2.75103.650.782.011.18

8.07.7

15.328.340.8

0.010.240.010.130.15

0.46 1.49 18.215.921.818.625.5

1.380.800.551.21

0.350.310.170.60

0.700.500.310.850.60 0.41 0.88 100

0.38 0.23 0.62 100

0.76 0.58 0.99 100

0.39 0.16 0.94 100

0.68 0.36 0.30 100

0.36 0.15 0.87 100

0.1 1 10


















Amplify (apixaban)

Amplify (apixaban)

Amplify (apixaban)

Amplify (apixaban)

Amplify (apixaban)

Amplify (apixaban)

Hokusai (edoxaban)

Hokusai (edoxaban)

Hokusai (edoxaban)

Hokusai (edoxaban)

Hokusai (edoxaban)

Subtotal (I2 = 62%, P = 0.03)

Subtotal (I2 = 13%, P = 0.33)

Subtotal (I2 = 88%, P < 0.01)

Subtotal (I2 = 20%, P = 0.29)

Subtotal (I2 = 37%, P = 0.19)

Subtotal (I2 = 0%, P = 0.75)

R R (95% CI)

Favors NOACs Favors VKAs

Fig. 4. Safety outcomes. CI, confidence interval; NOACs, new direct oral anticoagulants; VKA, vitamin-K antagonists.



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 EINSTEIN-

PE 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 (dabig-

atran), reported a higher risk. In this study, the incidence

rates were 0.71% (9/1273) in patients treated with dabiga-

tran 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 prede-

fined efficacy and safety endpoints. No statistically signifi-

cant 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 attribut-

able 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 simi-

lar 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 conse-

quences 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 com-

pared with VKAs during extended treatment; hazard

ratios for recurrent VTE of 1.44 (95% CI 0.78–2.64) and0.54 (95% CI 0.41–0.71) for major or clinically relevant

non-major bleeding were reported [21]. In two other stud-

ies, 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 demon-

strated.

Given the absence of the possibility of direct compari-

sons between the individual NOACs, we performed an

indirect comparison of dabigatran, apixaban and edox-

aban with rivaroxaban. Although differences in efficacy

and safety outcomes between individual drugs can be rea-

sonably 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. There-

fore, pooling the results of all separate studies evaluating

different NOACs in comparison with VKAs provides the

best available evidence for deciding whether NOACs con-

stitute 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 hetero-

geneity observed for major bleeding (I2 = 62%) and clin-

ically relevant non-major bleeding (I2 = 88%).



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 concentra-

tions of FVII and the formation of FVIIa–tissue factor

complexes, which play an important role in cerebral vas-

cular 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-spe-

cific 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-analy-

sis. Even so, the alternatively performed fixed-effect net-

work 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 through-

out 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 mortal-

ity were only reported for the total follow-up duration.

Sixth, the results of this meta-analysis should not be gen-

eralized to all patients with acute VTE, as specific popula-

tions, including the elderly, patients with cancer, patients

with renal insufficiency, patients with rare localizations of

VTE (e.g. distal DVT, splanchnic thrombosis, and cere-

bral vein thrombosis), and patients with morbid obesity,

were underrepresented or excluded. Finally, two studies

had a PROBE design, in which participants and research-

ers were aware of the treatment allocation, and only the

adjudication committee was blinded. It has been suggested

that the open design of PROBE studies leads to a more

real-world study population, owing to the easier recruit-

ment 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 fibrilla-

tion 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 prac-

tical 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 pro-

jects. 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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1

Oral anticoagulants are widely used for long-term preven-tion and treatment of venous and arterial thromboembo-

lism. 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, riva-roxaban, apixaban, and edoxaban. Designed to overcome the limitations of warfarin, the NOACs have revolutionized oral anticoagulation because they are at least as effective as warfa-rin, but are more convenient to administer because the NOACs can be given in fixed doses without routine coagulation moni-toring. 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 elec-tive hip or knee replacement surgery and dabigatran, rivaroxa-ban, apixaban, and edoxaban are approved for treatment of VTE and for stroke prevention in patients with atrial fibrilla-tion (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 sup-porting 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 indica-tion, (3) provide an overview of the phase III trials performed, to date, with the NOACs, (4) briefly discuss the ongoing stud-ies 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 vita-min 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,

© 2015 American Heart Association, Inc.

Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.115.303397

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

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]

Overview of the New Oral AnticoagulantsOpportunities and Challenges

Calvin H. Yeh, Kerstin Hogg, Jeffrey I. Weitz

Series Editor: Jeffrey I. Weitz

ATVB in Focus Clinical Experience With the Novel Oral Anticoagulants

at Scripps Res. Inst./Kresge on March 23, 2015http://atvb.ahajournals.org/Downloaded from

mailto:[email protected]

http://atvb.ahajournals.org/

2 Arterioscler Thromb Vasc Biol May 2015

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 compli-cates periprocedural management (Figure).

In contrast to warfarin, the NOACs directly inhibit a single clotting enzyme; dabigatran inhibits thrombin, whereas riva-roxaban, apixaban, and edoxaban inhibit factor Xa. As direct

inhibitors, these agents have a rapid onset of action such that peak plasma levels are achieved 1 to 4 hours after oral admin-istration. With half-lives of ≈12 hours, the NOACs also have a rapid offset of action.

Although warfarin is predominantly cleared through non-renal 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, rivar-oxaban, 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 cre-atinine 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 pharma-codynamic 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 warfa-rin 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 moni-toring and dose adjustments are necessary to ensure that the international normalized ratio (INR) remains within the thera-peutic range. In contrast, because the NOACs produce a more predictable anticoagulant response, they can be given in fixed doses without routine monitoring, thereby simplifying ther-apy. 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 rivar-oxaban and apixaban, whereas potent inhibitors of p-glyco-protein may increase exposure with dabigatran and edoxaban. Dietary vitamin K intake does not influence the NOACs and

Nonstandard Abbreviations and Acronyms

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 thrombo-embolism in cancer patients

COMMANDER HF A study to assess the effectiveness and safety of rivaroxaban in reducing the risk of death, myocar-dial infarction or stroke in participants with heart failure and coronary artery disease after an epi-sode of decompensated heart failure

COMPASS Rivaroxaban for the prevention of major cardio-vascular 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 pa-tients 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 dis-charge patients

MI myocardial infarction

NAVIGATE ESUS Rivaroxaban versus aspirin in secondary preven-tion of stroke and prevention of systemic em-bolism in patients with recent embolic stroke of undetermined source

NOAC non-vitamin K oral anticoagulant

PCC prothrombin complex concentrate

PCI percutaneous coronary intervention

PIONEER AF-PCI A study exploring two strategies of rivaroxaban (JNJ39039039)

REDUAL PCI Evaluation of dual therapy with dabigatran versus triple therapy with warfarin in patients with atrial fibrillation that undergo a PCI with Stenting

RE-LY Randomized evaluation of long term anticoagu-lant therapy with dabigatran etexilate

RE-SPECT ESUS Dabigatran etexilate for secondary stroke preven-tion in patients with embolic stroke of undeter-mined source

ROCKET-AF An efficacy and safety study of rivaroxaban with warfarin for the prevention of stroke and non-central nervous system systemic embolism in patients with nonvalvular atrial fibrillation

Table 1. Comparison of the Pharmacological Properties of Warfarin, Rivaroxaban, Apixaban, and Edoxaban

Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban

Target VKORC1 Thrombin Factor Xa Factor Xa Factor Xa

Prodrug No Yes No No No

Bioavailability, % 100 7 80 60 62

Dosing OD BID OD (BID) BID OD

Time-to-peak effect 4–5 d 1–3 h 2–4 h 1–2 h 1–2 h

Half-life, h 40 14–17 7–11 8–14 5–11

Renal clearance as unchanged drug, %

None 80 33 27 50

Interactions 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.



Yeh et al New Oral Anticoagulants 3

there are no dietary restrictions except that therapeutic doses of rivaroxaban should be administered with a meal to maxi-mize 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 treat-ment 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-to-risk profile.

Vitamin K is the antidote for warfarin. When given orally or by slow intravenous infusion, vitamin K restores the INR to

baseline levels, but this can take ≤24 hours. Rapid warfarin rever-sal can be achieved with 4-factor prothrombin complex concen-trate (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 vol-umes 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.

Overview of Phase III Clinical Trial Results With the NOACs

The NOACs were compared with enoxaparin for VTE preven-tion 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 mini-mum of 5 days followed by warfarin. The NOACs were com-pared 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 ther-apy 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 indica-tions will briefly be discussed.

ThromboprophylaxisPatients undergoing elective hip or knee arthroplasty require extended thromboprophylaxis for at least 2 to 4 weeks after

IX

TF/VIIa

VIIIa

Xa

Thrombin

Fibrin

PlateletSurface

Contact

Fibrinogen

RivaroxabanApixabanEdoxaban

Dabigatran

Va

Warfarin

Figure. Sites of action of warfarin and the non-vitamin K oral anticoagulants.

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.




surgery. With hospital stays shortening, prophylaxis is mainly provided in the outpatient setting. Although guidelines recom-mend warfarin, a low-molecular-weight heparin (LMWH), such as enoxaparin or fondaparinux for these patients, war-farin requires monitoring and dose adjustment, whereas enoxaparin and fondaparinux need daily subcutaneous injec-tions. These limitations can compromise adherence to out-of-hospital thromboprophylaxis. In contrast, with fixed-dose oral administration and no monitoring, the NOACs simplify extended thromboprophylaxis.

When compared with enoxaparin for postoperative throm-boprophylaxis in patients undergoing elective hip or knee arthroplasty, pooled data suggest that rivaroxaban reduces the rate of VTE, including symptomatic VTE, but is associ-ated with a small increase in the risk of major bleeding.1 The efficacy and safety of dabigatran in this setting are compa-rable 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 bleed-ing.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 effec-tive 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 riva-roxaban nor apixaban is licensed for thromboprophylaxis in medically ill patients.

VTE TreatmentConventional treatment for VTE starts with a parenteral anti-coagulant, 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 rivaroxa-ban or apixaban were compared with conventional treatment consisting of enoxaparin for at least 5 days followed by war-farin. In contrast, because there were no phase II data support-ing 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 meta-analysis 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 rivaroxa-ban 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 AFCompared 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 limita-tions highlight the need for alternative anticoagulants.

In phase III trials, the NOACs were compared with warfa-rin 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 prefer-ence 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




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 fre-quently 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 SyndromeMost cases of ACS are triggered by thrombosis after rup-ture 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 plate-let 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 war-farin 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 com-pared 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 signifi-cantly 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 throm-bosis from 2.9% to 2.3% (P=0.02); a finding that challenges the concept that stent thrombosis is a platelet-driven phenom-enon. 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 rivar-oxaban regimen received regulatory approval in the European Union for secondary prevention in patients with elevated car-diac 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 prasug-rel because it was not tested in combination with these more potent ADP receptor antagonists.

New Opportunities for the NOACsThe convenience of treatment with NOACs coupled with their favorable benefit-to-risk profiles have prompted their evalu-ation 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 coro-nary intervention (PCI), out-of-hospital thromboprophylaxis in medically ill and cancer patients, and extended VTE treat-ment (Table 3). The rationale for use of the NOACs in each of these setting is provided.

Mechanical Heart ValvesIn 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 bio-prosthetic heart valves.

Heart FailureAlmost 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 hos-pitalization, which renders this disease costly for the healthcare system. Because most patients with heart failure have underlying




coronary artery disease and because addition of low-dose rivar-oxaban 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 DiseasePatients 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 con-tributes 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 atherosclero-sis, the findings will provide further support for the role of thrombin in the pathogenesis of atherothrombosis.

Embolic Stroke of Unknown SourceStrokes 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 append-age in those with subclinical AF but also from the deep veins

Table 3. Ongoing Clinical Trials With the NOACs

IndicationTrial Name NCT

no. Design Treatment ComparatorTreatment Duration

Primary Efficacy Outcome

Primary Safety Outcome No. of Patients

Medically ill MARINER NCT02111564

Double blind Rivaroxaban 7.5 or 10 mg OD

Placebo 45 d VTE in month after treatment

Major bleeding 8000

Cancer Houkusai-VTE-Cancer

NCT02073682

Open label Edoxaban Dalteparin 6 mo VTE CRNB 1000

AVERT NCT02048865

Double blind Apixaban 2.5 mg BID

Placebo 6 mo VTE Major and CRNB 574

ESUS NAVIGATE ESUS NCT02313909

Double blind Rivaroxaban 15 mg OD or aspirin 100 mg OD

Placebo 3 y Stroke or SEE Major bleeding 7000

RE-SPECT ESUS NCT02239120

Double blind Dabigatran 110 or 150 mg BID or aspirin 100 mg OD

Placebo 3 mo Stroke Major bleeding 6000

VTE EINSTEIN CHOICE Double blind Rivaroxaban 10 or 20 mg OD

Aspirin 100 mg OD

12 mo Recurrent VTE Major bleeding 2850

ACS PIONEER AF-PCI NCT01830543

Open label Rivaroxaban 15 mg OD+ADP receptor antagonist or Rivaroxaban 2.5 mg BID+DAPT

Warfarin+DAPT 1, 6, or 12 mo Time to first cardiovascular

event

Clinically significant bleeding

2100

REDUAL-PCI NCT02164864

Open label Dabigatran 110 mg BID+clopidogrel or ticagrelor or dabigatran 150 mg BID+clopidogrel or ticagrelor

Warfarin+DAPT 30 mo Time to first cardiovascular

event

Major bleeding 8520

Heart failure COMMANDER HF NCT01877915

Double blind Rivaroxaban 2.5 mg BID

Placebo 30 mo Time to first cardiovascular

event

Major bleeding 5000

CAD or PAD COMPASS NCT01776424

Double blind Rivaroxaban 2.5 mg BID and aspirin 100 mg OD or rivaroxaban 5 mg BID+placebo

Aspirin 100 mg OD+placebo

5 y Time-to-first cardiovascular

event

Major bleeding 21 400

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.




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 PCIThe 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 regi-mens will be compared with warfarin in patients with AF undergoing PCI and coronary stent placement. The rivaroxa-ban treatments include a double antithrombotic regimen con-sisting 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 (clopido-grel, prasugrel, or ticagrelor). All treatment regimens will be administered for 12 months and the primary outcome mea-sure 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), clopido-grel 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 ThromboembolismOngoing studies are evaluating NOACs for thromboprophy-laxis 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 clear-ance of 30–49 mL/min) with placebo on the risk of symptom-atic 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 warfa-rin 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 bleed-ing.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 indi-cated that the rate of recurrent VTE was lower in patients with cancer treated with NOACs than in those who received war-farin (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 com-pare edoxaban with dalteparin in 1000 patients with cancer-associated VTE.

Real-World DataLarge 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 prac-tice 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 warfa-rin. 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.




Using national Veterans Affairs administrative encounter and pharmacy data, Vaughan et al20 compared the risk of bleed-ing events in patients with AF who were switched to dabiga-tran 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 warfa-rin.22 The divergent results may reflect the age differences in the 2 patient populations and ongoing analyses are address-ing 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 expe-rienced 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 regis-tries 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 NOACsAlthough the NOACs represent a major advance in oral anti-coagulation, 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 con-cern 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 warfa-rin 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 thera-peutic 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 war-farin although the difference did not reach statistical sig-nificance.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, mortal-ity 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 moni-toring 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 char-acteristics 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




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 pharma-codynamics 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.

AcknowledgmentsC.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.

DisclosuresJ.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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Non-vitamin K antagonist oral anticoagulants were developed to overcome the limitations of warfarin. These agents, which include dabi-gatran, 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 low-molecular-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.

Significance



Calvin H. Yeh, Kerstin Hogg and Jeffrey I. WeitzOverview of the New Oral Anticoagulants: Opportunities and Challenges

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