Abstract

The direct oral anticoagulants (DOACs) have transformed the management of thrombotic disorders. Large clinical trials have demonstrated that DOACs can replace vitamin K antagonists (VKAs) in the 2 existing major indications for anticoagulation: the prevention of stroke in atrial fibrillation and the acute treatment and secondary prevention of venous thromboembolism (VTE); this literature is widely known. In this article, we will concentrate on the less well-discussed benefits of the use of DOACs—using low doses as primary and secondary prophylaxis in both venous and arterial thromboprophylaxis. The attractiveness of using a low-dose DOAC is that the bleeding risk seems to be slightly lower than with the standard dose and significantly lower than with VKAs so that they can be used safely for long periods, where previously, VKAs had risk/benefit ratios that did not permit this. We discuss in detail the extended use of low-dose DOACs in secondary VTE prevention. We also cover the utility of low-dose DOACs in the evolving fields of prevention of hospital-associated VTE in acutely ill medical patients, after total hip and knee replacement, and in cancer patients. To complete the indications, we briefly discuss the role of low-dose DOACs in the secondary prevention of arterial vascular events.

References

References
1.
Heit
JA
.
The epidemiology of venous thromboembolism in the community
.
Arterioscler Thromb Vasc Biol
.
2008
;
28
(
3
):
370
-
372
.
2.
Martinez
C
,
Cohen
AT
,
Bamber
L
,
Rietbrock
S
.
Epidemiology of first and recurrent venous thromboembolism: a population-based cohort study in patients without active cancer
.
Thromb Haemost
.
2014
;
112
(
2
):
255
-
263
.
3.
Cohen
AT
,
Katholing
A
,
Rietbrock
S
,
Bamber
L
,
Martinez
C
.
Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study
.
Thromb Haemost
.
2017
;
117
(
1
):
57
-
65
.
4.
Jha
AK
,
Larizgoitia
I
,
Audera-Lopez
C
,
Prasopa-Plaizier
N
,
Waters
H
,
Bates
DW
.
The global burden of unsafe medical care: analytic modelling of observational studies
.
BMJ Qual Saf
.
2013
;
22
(
10
):
809
-
815
.
5.
Catterick
D
,
Hunt
BJ
.
Impact of the national venous thromboembolism risk assessment tool in secondary care in England: retrospective population-based database study
.
Blood Coagul Fibrinolysis
.
2014
;
25
(
6
):
571
-
576
.
6.
Kearon
C
,
Akl
EA
,
Ornelas
J
, et al
.
Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report [published correction appears in Chest. 2016;150(4):988]
.
Chest
.
2016
;
149
(
2
):
315
-
352
.
7.
Agnelli
G
,
Buller
HR
,
Cohen
A
, et al
;
AMPLIFY-EXT Investigators
.
Apixaban for extended treatment of venous thromboembolism
.
N Engl J Med
.
2013
;
368
(
8
):
699
-
708
.
8.
Weitz
JI
,
Bauersachs
R
,
Beyer-Westendorf
J
, et al
;
EINSTEIN CHOICE Investigators
.
Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism. Rationale for and design of the EINSTEIN CHOICE study
.
Thromb Haemost
.
2015
;
114
(
3
):
645
-
650
.
9.
van Es
N
,
Coppens
M
,
Schulman
S
,
Middeldorp
S
,
Büller
HR
.
Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials
.
Blood
.
2014
;
124
(
12
):
1968
-
1975
.
10.
Fisher
WD
.
Impact of venous thromboembolism on clinical management and therapy after hip and knee arthroplasty
.
Can J Surg
.
2011
;
54
(
5
):
344
-
351
.
11.
Geerts
WH
,
Bergqvist
D
,
Pineo
GF
, et al
.
Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
.
Chest
.
2008
;
133
(
6 suppl
):
381S
-
453S
.
12.
Januel
JM
,
Chen
G
,
Ruffieux
C
, et al
;
IMECCHI Group
.
Symptomatic in-hospital deep vein thrombosis and pulmonary embolism following hip and knee arthroplasty among patients receiving recommended prophylaxis: a systematic review
.
JAMA
.
2012
;
307
(
3
):
294
-
303
.
13.
Falck-Ytter
Y
,
Francis
CW
,
Johanson
NA
, et al
.
Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
.
Chest
.
2012
;
141
(
2 suppl
):
e278S
-
325S
.
14.
Anderson
DR
,
Dunbar
M
,
Murnaghan
J
, et al
.
Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty
.
N Engl J Med
.
2018
;
378
(
8
):
699
-
707
.
15.
Dawoud
DM
,
Wonderling
D
,
Glen
J
, et al
.
Cost-utility analysis of venous thromboembolism prophylaxis strategies for people undergoing elective total hip and total knee replacement surgeries in the English National Health Service
.
Front Pharmacol
.
2018
;
9
:
1370
.
16.
Xu
K
,
Chan
NC
,
Ibrahim
Q
, et al
.
Reduction in mortality following elective major hip and knee surgery: a systematic review and meta-analysis
.
Thromb Haemost
.
2019
;
119
(
4
):
668
-
674
.
17.
Dentali
F
,
Douketis
JD
,
Gianni
M
,
Lim
W
,
Crowther
MA
.
Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients
.
Ann Intern Med
.
2007
;
146
(
4
):
278
-
288
.
18.
Amin
AN
,
Varker
H
,
Princic
N
,
Lin
J
,
Thompson
S
,
Johnston
S
.
Duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients
.
J Hosp Med
.
2012
;
7
(
3
):
231
-
238
.
19.
Kahn
SR
,
Lim
W
,
Dunn
AS
, et al
.
Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
.
Chest
.
2012
;
141
(
2 suppl
):
e195S
-
226S
.
20.
Schünemann
HJ
,
Cushman
M
,
Burnett
AE
, et al
.
American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients
.
Blood Adv
.
2018
;
2
(
22
):
3198
-
3225
.
21.
Cohen
AT
,
Harrington
RA
,
Goldhaber
SZ
, et al
;
APEX Investigators
.
Extended thromboprophylaxis with betrixaban in acutely ill medical patients
.
N Engl J Med
.
2016
;
375
(
6
):
534
-
544
.
22.
Goldhaber
SZ
,
Leizorovicz
A
,
Kakkar
AK
, et al
;
ADOPT Trial Investigators
.
Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients
.
N Engl J Med
.
2011
;
365
(
23
):
2167
-
2177
.
23.
Hull
RD
,
Schellong
SM
,
Tapson
VF
, et al
;
EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study
.
Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial
.
Ann Intern Med
.
2010
;
153
(
1
):
8
-
18
.
24.
Cohen
AT
,
Spiro
TE
,
Büller
HR
, et al
;
MAGELLAN Investigators
.
Rivaroxaban for thromboprophylaxis in acutely ill medical patients
.
N Engl J Med
.
2013
;
368
(
6
):
513
-
523
.
25.
Spyropoulos
AC
,
Ageno
W
,
Albers
GW
, et al
;
MARINER Investigators
.
Rivaroxaban for thromboprophylaxis after hospitalization for medical illness
.
N Engl J Med
.
2018
;
379
(
12
):
1118
-
1127
.
26.
Gibson
CM
,
Nafee
T
,
Yee
MK
, et al
.
Symptomatic event reduction with extended-duration betrixaban in acute medically ill hospitalized patients
.
Am Heart J
.
2018
;
198
:
84
-
90
.
27.
Chi
G
,
Yee
MK
,
Amin
AN
, et al
.
Extended-duration betrixaban reduces the risk of rehospitalization associated with venous thromboembolism among acutely ill hospitalized medical patients: findings from the APEX Trial (Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban Trial)
.
Circulation
.
2018
;
137
(
1
):
91
-
94
.
28.
Gibson
CM
,
Chi
G
,
Halaby
R
, et al
;
APEX Investigators
.
Extended-duration betrixaban reduces the risk of stroke versus standard-dose enoxaparin among hospitalized medically ill patients: an APEX Trial substudy (Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban)
.
Circulation
.
2017
;
135
(
7
):
648
-
655
.
29.
Lyman
GH
,
Bohlke
K
,
Khorana
AA
, et al
;
American Society of Clinical Oncology
.
Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update 2014
.
J Clin Oncol
.
2015
;
33
(
6
):
654
-
656
.
30.
Streiff
MB
,
Holmstrom
B
,
Ashrani
A
, et al
.
Cancer-associated venous thromboembolic disease, version 1.2015
.
J Natl Compr Canc Netw
.
2015
;
13
(
9
):
1079
-
1095
.
31.
Carrier
M
,
Abou-Nassar
K
,
Mallick
R
, et al
;
AVERT Investigators
.
Apixaban to prevent venous thromboembolism in patients with cancer
.
N Engl J Med
.
2019
;
380
(
8
):
711
-
719
.
32.
Khorana
AA
,
Soff
GA
,
Kakkar
AK
, et al
;
CASSINI Investigators
.
Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer
.
N Engl J Med
.
2019
;
380
(
8
):
720
-
728
.
33.
Levine
MN
,
Gu
C
,
Liebman
HA
, et al
.
A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer
.
J Thromb Haemost
.
2012
;
10
(
5
):
807
-
814
.
34.
Parker
A
,
Peterson
E
,
Lee
AYY
, et al
.
Risk stratification for the development of venous thromboembolism in hospitalized patients with cancer
.
J Thromb Haemost
.
2018
;
16
(
7
):
1321
-
1326
.
35.
Khorana
AA
,
Noble
S
,
Lee
AYY
, et al
.
Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH
.
J Thromb Haemost
.
2018
;
16
(
9
):
1891
-
1894
.
36.
Baglin
T
,
Luddington
R
,
Brown
K
,
Baglin
C
.
Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study
.
Lancet
.
2003
;
362
(
9383
):
523
-
526
.
37.
Kearon
C
,
Ginsberg
JS
,
Kovacs
MJ
, et al
;
Extended Low-Intensity Anticoagulation for Thrombo-Embolism Investigators
.
Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism
.
N Engl J Med
.
2003
;
349
(
7
):
631
-
639
.
38.
Anand
SS
,
Bosch
J
,
Eikelboom
JW
, et al
;
COMPASS Investigators
.
Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial
.
Lancet
.
2018
;
391
(
10117
):
219
-
229
.
39.
Connolly
SJ
,
Eikelboom
JW
,
Bosch
J
, et al
;
COMPASS investigators
.
Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial
.
Lancet
.
2018
;
391
(
10117
):
205
-
218
.
40.
Eikelboom
JW
,
Connolly
SJ
,
Bosch
J
, et al
;
COMPASS Investigators
.
Rivaroxaban with or without aspirin in stable cardiovascular disease
.
N Engl J Med
.
2017
;
377
(
14
):
1319
-
1330
.
You do not currently have access to this content.