JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 83, NO.

3, 2024

ª 2024 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

THE PRESENT AND FUTURE

JACC STATE-OF-THE-ART REVIEW

When Direct Oral Anticoagulants

Should Not Be Standard Treatment
JACC State-of-the-Art Review

Antoine Bejjani, MD,a,b,c,* Candrika D. Khairani, MD, MMSC,a,b,* Ali Assi, MD, MBA,d Gregory Piazza, MD, MS,a,b,d
Parham Sadeghipour, MD,e,f Azita H. Talasaz, PHARMD,g,h John Fanikos, RPH, MBA,i Jean M. Connors, MD,j
Deborah M. Siegal, MD, MSC,k Geoffrey D. Barnes, MD, MSC,l Karlyn A. Martin, MD, MS,m
Dominick J. Angiolillo, MD, PHD,n Dawn Kleindorfer, MD,o Manuel Monreal, MD, PHD,p David Jimenez, MD, PHD,q
Saskia Middeldorp, MD, PHD,r Mitchell S.V. Elkind, MD, MS,s,t Christian T. Ruff, MD, MPH,b
Samuel Z. Goldhaber, MD,a,b Harlan M. Krumholz, MD, SM,u,v,w Roxana Mehran, MD,x Mary Cushman, MD, MSC,y,z
John W. Eikelboom, MBBS,aa Gregory Y.H. Lip, MD,bb,cc Jeffrey I. Weitz, MD,dd,ee Renato D. Lopes, MD, PHD,ff,gg
Behnood Bikdeli, MD, MSa,b,r,hh

ABSTRACT

For most patients, direct oral anticoagulants (DOACs) are preferred over vitamin K antagonists for stroke prevention in
atrial fibrillation and for venous thromboembolism treatment. However, randomized controlled trials suggest that DOACs
may not be as efficacious or as safe as the current standard of care in conditions such as mechanical heart valves,
thrombotic antiphospholipid syndrome, and atrial fibrillation associated with rheumatic heart disease. DOACs do not
provide a net benefit in conditions such as embolic stroke of undetermined source. Their efficacy is uncertain for con-
ditions such as left ventricular thrombus, catheter-associated deep vein thrombosis, cerebral venous sinus thrombosis,
and for patients with atrial fibrillation or venous thrombosis who have end-stage renal disease. This paper provides an
evidence-based review of randomized controlled trials on DOACs, detailing when they have demonstrated efficacy and
safety, when DOACs should not be the standard of care, where their safety and efficacy are uncertain, and areas requiring
further research. (J Am Coll Cardiol 2024;83:444–465) © 2024 by the American College of Cardiology Foundation.

From the aThrombosis Research Group, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA;
b
Cardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; cDe-
partment of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA; dDepartment of Medicine, Brigham
and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; eRajaie Cardiovascular, Medical, and Research
Center, Iran University of Medical Sciences, Tehran, Iran; fClinical Trial Center, Rajaie Cardiovascular, Medical, and Research
Center, Iran University of Medical Sciences, Tehran, Iran; gTehran Heart Center, Tehran University of Medical Sciences, Tehran,
Iran; hVirginia Commonwealth University, Richmond, Virginia, USA; iDepartment of Pharmacy, Brigham and Women’s Hospital,
Harvard Medical School, Boston, Massachusetts, USA; jHematology Division, Department of Medicine, Brigham and Women’s
Hospital, Harvard Medical School, Boston, Massachusetts, USA; kDivision of Hematology, Department of Medicine, University of
Ottawa, Ottawa, Ontario, Canada; lFrankel Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann
Listen to this manuscript’s
Arbor, Michigan, USA; mDivision of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of
audio summary by
Medicine, Chicago, Illinois, USA; nDivision of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, USA;
Editor-in-Chief
o
University of Cincinnati, Cincinnati, Ohio, USA; pCátedra de Enfermedad Tromboembólica, Universidad Católica San Antonio de
Dr Valentin Fuster on
Murcia, Spain; qRespiratory Department, Hospital Ramón y Cajal and Medicine Department, Universidad de Alcalá (Instituto de
www.jacc.org/journal/jacc.
Ramón y Cajal de Investigación Sanitaria), Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES),
Madrid, Spain; rDepartment of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; sDepartment of
Neurology, Vagelos College of Physicians and Surgeons, New York, New York, USA; tDepartment of Epidemiology, Mailman School
of Public Health, Columbia University, New York, New York, USA; uYale New Haven Hospital/Yale Center for Outcomes Research
and Evaluation, New Haven, Connecticut, USA; vDepartment of Health Policy and Management, Yale School of Public Health,
New Haven, Connecticut, USA; wSection of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine,

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2023.10.038

JACC VOL. 83, NO. 3, 2024 Bejjani et al 445
JANUARY 23, 2024:444–465 When to Consider Avoiding DOACs

prevention in rheumatic atrial fibrillation, 40 ABBREVIATIONS

HIGHLIGHTS AND ACRONYMS
and prevention of thromboembolism with

Target-specific (or direct) oral anticoag- mechanical heart valves. 41,42
In other cases,
AF = atrial fibrillation
ulants are preferred for prevention or DOACs have failed to add benefit, including
APS = antiphospholipid
treatment of thromboembolism in most in patients undergoing transcatheter aortic
syndrome
43-46
patients with atrial fibrillation or venous valve replacement (TAVR) or those with
CRNMB = clinically relevant
thromboembolism. embolic stroke of undetermined source nonmajor bleed
(ESUS).47-50 Uncertainties exist about the risks CVST = cerebral venous sinus

DOACs should not be the standard
and benefits of DOACs in other scenarios, thrombosis
treatment for patients with mechanical
such as catheter-associated VTE, 51-53 cerebral DAPT = dual antiplatelet
heart valves, atrial fibrillation with
venous sinus thrombosis (CVST), 54 left ven- therapy
rheumatic mitral stenosis, or anti-
tricular thrombus, or chronic thromboembolic DOAC = direct oral
phospholipid syndrome. anticoagulant
pulmonary hypertension, and specific patient
DVT = deep vein thrombosis

The efficacy and safety of DOACs remain subgroups requiring anticoagulation with
uncertain for several other clinical con- coexisting end-stage renal disease (ESRD), 55-57 ESRD = end-stage renal disease
58,59 60-63
ditions and subgroups, and future studies liver cirrhosis, or pregnancy. ESUS = embolic stroke of
undetermined source
should address those situations. This review aims to provide an evidence-

D
based summary of clinical evidence, particu- ISTH = International Society on
Thrombosis and Haemostasis
irect oral anticoagulants (DOACs), including larly from RCTs, concerning the efficacy and
MI = myocardial infarction
both oral factor Xa and thrombin inhibitors, safety of DOACs compared with standard
PE = pulmonary embolism
offer advantages over vitamin K antagonists treatment. It also discusses the potential
mechanisms behind the varying efficacy of RCT = randomized controlled
(VKAs), including a lower risk of intracranial
trial
bleeding, 1-3
fixed dosing without routine laboratory DOACs compared with other standard treat-
SPAF = stroke prevention in
monitoring or dietary restriction, and a faster drug ments, areas where the efficacy and safety of
atrial fibrillation
onset/offset, facilitating periprocedural planning. DOACs remain uncertain, and fields where
TAVR = transcatheter aortic
Based on data from large randomized controlled trials further research is required. For the purpose of valve replacement

(RCTs), DOACs have become the preferred anticoagu- this review, all DOACs (apixaban, dabigatran, VKA = vitamin K antagonist
lants for stroke prevention in atrial fibrillation edoxaban, and rivaroxaban) have been group-
VTE = venous
(SPAF) 2-8 and for acute treatment9-13 and extended- ed together in most cases, although in some thromboembolism

duration secondary prevention of venous thromboem- scenarios, there may be a class effect, while in
bolism (VTE) in most patients, 14-16
and are used for others distinct effects might exist (eg, poten-
other indications 17,18
including primary prevention tially because of different dosing or unique features of
of VTE. 19-30
DOACs have been recommended by each drug).
numerous professional societies for these condi- This work included 2 components: systematic
tions. 31-34 literature review of published data for
Despite their success, RCTs indicate that in certain evidence synthesis (see Supplemental Figure 1 and
scenarios, DOACs may not be as efficacious or as safe Supplemental Table 1 for Methods) and subsequently,
as the standard of care. Examples include throm- interpretation of synthesized evidence by the au-
botic antiphospholipid syndrome (APS), 35-39 stroke thors’ group. The recommendations in this paper are

New Haven, Connecticut, USA; xZena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai,
New York, New York, USA; yDepartment of Medicine, Larner College of Medicine at the University of Vermont, Burlington,
Vermont, USA; zDepartment of Pathology and Laboratory Medicine, Larner College of Medicine at the University of Vermont,
aa
Burlington, Vermont, USA; Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton,
Ontario, Canada; bbLiverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and
cc
Liverpool Heart and Chest Hospital, Liverpool, United Kingdom; Danish Center for Clinical Health Services Research, Depart-
dd ee
ment of Clinical Medicine, Aalborg University, Aalborg, Denmark; McMaster University, Hamilton, Ontario, Canada; Th-
rombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada; ffDuke Clinical Research Institute, Duke University
Medical Center, Durham, North Carolina, USA; ggBrazilian Clinical Research Institute, São Paulo, Brazil; and the hhCardiovascular
Research Foundation, New York, New York, USA. *Drs Bejjani and Khairani contributed equally to this work.
Ph. Gabriel Steg, MD, served as Guest Associate Editor for this paper. Javed Butler, MD, MPH, MBA, served as Guest Editor-in-
Chief for this paper.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received September 12, 2023; revised manuscript received October 16, 2023, accepted October 19, 2023.
446 Bejjani et al
When to Consider Avoiding DOACs
not the result of a formal clinical practice guideline
process and are not meant to substitute for a clinical
practice guideline by any professional society.
SCENARIOS IN WHICH DOACs HAVE
DEMONSTRABLE EFFICACY AND SAFETY
Current guidelines recommend the use of DOACs for
SPAF,31,64 based on the results of landmark clinical
trials.4-7 These recommendations extend to the use of
DOACs in patients with atrial fibrillation and acute
coronary syndromes or recent percutaneous coronary
65-70
intervention. In accordance with the most recent
guidelines on chronic coronary disease and clinical
trials, the ideal regimen for stable patients who have
undergone percutaneous intervention or had a recent
acute coronary syndrome and have atrial fibrillation
is a DOAC with a single antiplatelet agent, preferably
a P2Y 12 inhibitor, for which clopidogrel is typically
chosen.71 The guidelines also suggest that in patients
with chronic coronary disease who require oral anti-
coagulation and have a low atherothrombotic risk,
discontinuation of aspirin with continuation of DOAC
alone can be considered 1 year after percutaneous
intervention. 71,72 In patients with atrial fibrillation
with many types of valvular heart disease, DOACs are
currently recommended. 73-75 Issues about rheumatic
heart disease and mechanical valves are discussed in
subsequent sections. The nonvalvular atrial fibrilla-
tion (AF) terminology has been largely eliminated
from guidelines. 76
For patients with VTE, guidelines recommend the
use of DOACs for acute management, 9-13 including for
cancer-associated thrombosis,77-81 as well as extended-
duration secondary prevention of VTE.82 The timing
to switch to oral anticoagulation after advanced
therapies, such as fibrinolysis, in patients with
intermediate-high risk pulmonary embolism (PE) is not
well established and requires further investigations.
In patients with stable atherosclerotic cardiovas-
cular disease 17 or after recent peripheral artery
revascularization,18 low-intensity rivaroxaban was
shown to play a role in the reduction of cardiovas-
cular events in combination with aspirin.71,83 The
other DOACs have not been studied yet in these
conditions. Further details can be found in other re-
views, and Supplemental Table 2.
WHERE DOACs ARE LESS EFFICACIOUS OR
SAFE, OR PROVIDE NO BENEFIT COMPARED
WITH STANDARD OF CARE
Results of several recent RCTs have shown that
DOACs may be less efficacious or safe, or not confer
net benefit compared with standard of care in
JACC VOL. 83, NO. 3, 2024
JANUARY 23, 2024:444–465
scenarios such as mechanical heart valves, rheumatic
AF, thrombotic APS, post-TAVR, and ESUS (Figure 1).
MECHANICAL HEART VALVES. The use of DOACs in
patients with mechanical heart valves has mostly
yielded unfavorable results (Table 1). In a phase 2 trial
of 252 patients with mechanical aortic or mitral
valves, dabigatran 150 to 300 mg twice daily was
compared with warfarin; the trial was stopped early
because of excess thrombotic (9 [5%] strokes vs 0)
and bleeding (7 major bleeds [4%] vs 2 [2%]) events in
the dabigatran group. 41 Most thromboembolic events
occurred in patients starting the study drug within a
week after valve replacement. An open-label RCT
compared apixaban 5 mg twice daily with warfarin
>3 months after mechanical On-X aortic heart valve
replacement (thought to be less thrombogenic
because of a flared inlet designed to reduce flow
turbulence) on the background of low-dose aspirin in
both arms. The trial was terminated early after
enrolling 863 participants because of high rates of a
composite of valve thrombosis or valve-related
thromboembolism in patients assigned to apixaban
compared with warfarin (20 vs 6 events; HR: 2.6;
95% CI: 1.0-6.7).42 There was no significant difference
in the rate of major bleeding between apixaban and
warfarin (17 vs 21; HR: 0.6; 95% CI: 0.3-1.3). An open-
label proof-of-concept trial of patients who under-
went mechanical aortic or mitral valve replacement
surgery >3 months prior, randomized 44 patients to
rivaroxaban 15 mg twice daily vs warfarin. Over a
median follow-up of 90 days, there was no significant
difference in thromboembolic events (1 vs 3; risk ra-
tio: 0.27; 95% CI: 0.02-2.85) or major bleeding (no
cases of major bleeding) between rivaroxaban and
warfarin.84 The open-label ongoing RENOVATE
(Long-term Anticoagulation With Oral Factor Xa In-
hibitor Versus Vitamin K Antagonist After Mechanical
Aortic Valve Replacement; NCT04258488) trial plans
to randomize 1,300 patients with mechanical aortic
valves to rivaroxaban (20 mg daily) or warfarin
>3 months after surgery. Overall, in patients with
mechanical aortic or mitral valves, DOACs are less
efficacious than warfarin, and should be avoided
outside the setting of a clinical trial. Current guide-
lines recommend VKAs as the standard of care in
patients with mechanical heart valves85 (Table 2).
RHEUMATIC ATRIAL FIBRILLATION. In an RCT of 4,531
patients with rheumatic AF, defined as AF plus rheu-
matic heart disease proven by echocardiography,
rivaroxaban (20 mg once daily) was associated with a
significantly increased rate of a composite of stroke,
systemic embolism, myocardial infarction (MI), or
death compared with VKAs (560 vs 446; HR: 1.25;
JACC VOL. 83, NO. 3, 2024 Bejjani et al 447
JANUARY 23, 2024:444–465 When to Consider Avoiding DOACs

F I G U R E 1 Where DOACs Are Preferred and Where They Fared Worse

Mechanical Rheumatic Thrombotic

AF* VTE ESUS TAVR‡ LVAD
Heart Valves AF APS
6 † 9,14 42 39 49,50 46
Apixaban
Apixaban

vs
9 9 8 8
Apixaban Apixaban Apixaban Apixaban Apixaban
vs
Warfarin
vs
Warfarin
vs
Warfarin
? vs
Warfarin
vs
Aspirin
Vitamin K
Antagonist
?
or
antiplatelet

5 † 10,13,15 40 36-38 47 44
Rivaroxaban

Rivaroxaban Rivaroxaban Rivaroxaban

9 9 8 8 8 8
Rivaroxaban Rivaroxaban Rivaroxaban
vs
Warfarin
vs
Warfarin,
Aspirin
? vs
Vitamin K
Antagonist
vs
Warfarin
vs
Aspirin
vs
Aspirin,
Clopidogrel
?

7 12 ‡ 43,45
Edoxaban
Edoxaban

vs
9 9
Edoxaban Edoxaban
vs
Warfarin
vs
Warfarin
? ? ? ? Aspirin and
Clopidogrel, ?
Vitamin K
Antagonist

4 † 11,16 41 48 92

Dabigatran
Dabigatran

9 9 8 8 8
Dabigatran Dabigatran Dabigatran Dabigatran vs
vs
Warfarin
vs
Warfarin
vs
Warfarin
? ? vs
Aspirin
? Phenpro-
coumon
and Aspirin

9 DOACs had demonstrable 8 DOACs lacked safety DOACs did not show ? No trial performed;
safety and efficacy and/or efficacy a net benefit compared unknown evidence
compared with standard compared with with standard treatment
treatment standard treatment§

*Excluding patients with mechanical heart valves or rheumatic atrial fibrillation (AF). †Apixaban, rivaroxaban, and dabigatran are also approved for extended-treatment
duration of venous thromboembolism (VTE). ‡The ENVISAGE-TAVI AF (Edoxaban Compared to Standard Care After Heart Valve Replacement Using a Catheter in Patients
With Atrial Fibrillation) trial compared edoxaban with vitamin K antagonists (VKAs) in patients post-transcatheter aortic valve replacement (TAVR) and AF. §In patients
with acute coronary syndromes and no indication for anticoagulation, direct oral anticoagulants (DOACs) are not approved by the U.S. Food and Drug Administration.
Apixaban failed to show benefit. Rivaroxaban reduced ischemic events but increased major and intracranial bleeds. Dabigatran and edoxaban were not studied. Numbers
in boxes indicate references. APS ¼ antiphospholipid syndrome; ESUS ¼ embolic stroke of undetermined source; LVAD ¼ left ventricular assist device.

95% CI: 1.10-1.41). There was no significant difference
in the rate of major bleeding (40 vs 56; HR: 0.76; 95% CI:
0.51-1.15)40 (Table 1). Data are scarce from this RCT or
elsewhere about patients with AF who have a history of
rheumatic heart disease with less severe mitral valve
disease. Nonetheless, these results suggest that DOACs
are less efficacious than VKAs for the management of
patients with rheumatic AF. Guidelines recommend
the use of VKAs for stroke prevention in patients with
rheumatic AF.31,64
448 Bejjani et al JACC VOL. 83, NO. 3, 2024

When to Consider Avoiding DOACs JANUARY 23, 2024:444–465

T A B L E 1 Trials of Patients With Rheumatic AF, Mechanical Heart Valves, and Post-TAVR Receiving DOACs vs SOC

First Author, Year Short Code DOAC Agent Standard of Care Follow-Up Duration Topline Trial Results

Mechanical heart valve

Eikelboom et al,41 RE-ALIGN Dabigatran Warfarin (low 144.3 da The trial was terminated early after enrolling 252 patients caused
2013 150/220/300 mg thromboembolic risk: by higher rates of thromboembolic events (9 strokes, 5%) and
twice daily INR 2.0-3.0; major bleeding (7 cases, 4%) in patients treated with
intermediate or high dabigatran compared with warfarin (no strokes and 2 major
thromboembolic risk: bleeding events). A composite of stroke, TIA, MI, systemic
INR 2.5-3.5) embolism, or death occurred in 15 patients with mechanical
aortic or mitral valves in the dabigatran group, compared with
only 4 (5%) in the warfarin group (HR: 1.94; 95% CI: 0.64-
5.86). Bleeding of any type occurred in 45 patients treated with
dabigatran compared with 10 patients in the warfarin group
(HR: 2.45; 95% CI: 1.23-4.86).
Wang et al,42 PROACT-Xa Apixaban Warfarin (INR 2.0-3.0) 13.4 mob The trial was terminated early after enrolling 863 patients with an
2023 5 mg twice daily On-X mechanical aortic valve at least 3 mo prior caused by an
excessive number of thromboembolic events in the apixaban
group compared with warfarin in patients (HR: 2.6; 95% CI:
1.0-6.7). No significant difference in the risk of major bleeding
(HR: 0.6; 95% CI: 0.3-1.3).
Ahn et alc, RENOVATE Rivaroxaban Warfarin (INR 2.0-3.0) Plan follow-up Still ongoing. The trial plans to enroll 1,300 patients who have
NCT04258488 20 mg daily of 1 y undergone mechanical aortic valve replacement at least 3 mo
prior. The primary outcome is a composite of cardiac death,
valve thrombosis, thromboembolic events, major bleeding, and
CRNMB.
Rheumatic AF
Connolly et al,40 INVICTUS Rivaroxaban VKAs (INR 2.0-3.0) 3.1 ya In a trial of 4,531 patients with rheumatic AF, rivaroxaban showed
2022 20 mg daily an increased rate of a composite of stroke, systemic embolism,
myocardial infarction, or death compared with VKAs (HR: 1.25;
95% CI: 1.10-1.41). No significant difference was noted in the
rate of major bleeding between the 2 groups (HR: 0.76; 95% CI:
0.51-1.15). Patients assigned to rivaroxaban had higher
mortality rates than those on VKA (HR: 1.23; 95% CI: 1.08-
1.40).
TAVR
Dangas et al,44 GALILEO Rivaroxaban Aspirin 17 mob The trial was terminated early after enrolling 1,644 patients caused
2020 10 mg daily (and 75 to 100 mg daily (and by a higher rate of death or first thromboembolic event
aspirin for 3 mo clopidogrel for 3 mo (HR: 1.35; 95% CI: 1.01-1.81) and a higher rate of major bleeding
post-TAVR) post-TAVR) (HR: 1.5; 95% CI: 0.95-2.37) in patients assigned to rivaroxaban
compared with aspirin.
Park et al,45 ADAPT-TAVR Edoxaban DAPT; 6 moa In a trial of 229 patients post-TAVR and with sinus rhythm, the risk
2022 60 mg daily Aspirin 100 mg daily and of leaflet thrombosis on 4-dimensional CT was numerically
clopidogrel 75 mg lower with edoxaban (10 vs 20; RR: 0.53; 95% CI: 0.26-1.09).
daily No significant difference was noted in the risk of new lesions on
brain MRI between the edoxaban and DAPT groups (RR: 1.24;
95% CI: 0.75-2.04). The rate of bleeding events was not
significantly different between the 2 arms.
Collet et al,46 ATLANTIS Apixaban VKAs or antiplatelet 1 ya In a trial of 1,500 patients post-TAVR, 751 patients were
2022 5 mg twice daily agents (aspirin, randomized to receive SOC, stratified by the need for chronic
clopidogrel, or both) AC (30.4% requiring AC vs 69.6% not requiring AC). The
composite rates of death, MI, stroke/TIA, systemic embolism,
intracardiac or bioprosthesis thrombosis, DVT or PE, or major
bleeding were not significantly different between apixaban and
SOC (HR: 0.92; 95% CI: 0.73-1.16).
Van Mieghem ENVISAGE-TAVI Edoxaban VKAs (INR 2.0 to 3.0; 542 db In a trial of patients with AF and post-TAVR, the rates of composite
et al,43 2021 AF 60 mg daily adjusted range for death, MI, stroke, systemic embolism, valve thrombosis, or
patients $70 y in major bleeding were not significantly different between
Japan: 1.6-2.6) edoxaban and VKAs (HR: 1.05; 95% CI: 0.85-1.31).

a
Mean follow-up duration. bMedian follow-up duration. cOngoing trial.
AC ¼ anticoagulation; ADAPT-TAVR ¼ Anticoagulant Versus Dual Antiplatelet Therapy for Preventing Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement;
AF ¼ atrial fibrillation; ATLANTIS ¼ Anti-Thrombotic Strategy After Trans-Aortic Valve Implantation for Aortic Stenosis; CRNMB ¼ clinically relevant nonmajor bleed; CT ¼ computed tomography;
DAPT ¼ dual antiplatelet therapy; DOAC ¼ direct oral anticoagulant; DVT ¼ deep vein thrombosis; ENVISAGE-TAVI AF ¼ Edoxaban Compared to Standard Care After Heart Valve Replacement Using a
Catheter in Patients With Atrial Fibrillation; GALILEO ¼ Global Study Comparing a rivAroxaban-based Antithrombotic Strategy to an antipLatelet-based Strategy After Transcatheter aortIc vaLve rEplacement
to Optimize Clinical Outcomes; INR ¼ international normalized ratio; INVICTUS ¼ INVestIgation of rheumatiC AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies, Non-Inferiority;
MI ¼ myocardial infarction; MRI ¼ magnetic resonance imaging; NCT ¼ National Clinical Trial; PE ¼ pulmonary embolism; PROACT-Xa ¼ A Trial to Determine if Participants With an On-X Aortic Valve Can be
Maintained Safely on Apixaban; RE-ALIGN ¼ Dabigatran Etexilate in Patients With Mechanical Heart Valves; RENOVATE ¼ Long-term Anticoagulation With Oral Factor Xa Inhibitor Versus Vitamin K
Antagonist After Mechanical Aortic Valve Replacement; RR ¼ risk ratio; SOC ¼ standard of care; TAVR ¼ transcatheter aortic valve replacement; TIA ¼ transient ischemic attack; VKA ¼ vitamin K antagonist.
JACC VOL. 83, NO. 3, 2024 Bejjani et al 449
JANUARY 23, 2024:444–465 When to Consider Avoiding DOACs

T A B L E 2 Current Recommendations for Conditions Where DOACs Are Not SOC, and Conditions Where Their Efficacy Is Uncertain

Standard of Care Based on

Clinical Condition Existing Evidence Professional Society Recommendations Comments

Where DOACs are less efficacious or safe, or provide no benefit compared with standard of care
Mechanical heart valves VKA Clinical practice guidelines recommend that patients with The results of the PROACT-Xa42 and RIWA84 trials are
mechanical heart valves should receive a VKA.85 consistent with but were released after the
publication of these guidelines.
Rheumatic AF VKA Clinical practice guidelines recommend VKAs for preventing The results of the INVICTUS trial are consistent with
stroke in patients with rheumatic AF.31,64 but were released after these guidelines were
published.40
Thrombotic VKA For patients with a history of VTE and thrombotic The ASTRO-APS trial and a meta-analysis of 4 studies
antiphospholipid antiphospholipid syndrome, clinical practice guidelines were published after these guidelines.35,39 The
syndrome recommend long-term VKA treatment.87 meta-analysis indicates that DOACs, compared
with VKAs, are associated with increased odds of
subsequent arterial thrombotic events,
irrespective of triple-positivity or the qualifying
thrombotic event.35
TAVR Aspirin and Clinical practice guidelines suggest that for patients post- Results of the ATLANTIS and ADAPT-TAVR trials were
clopidogrel TAVR without other indications for oral anticoagulants, released after the publication of these
the guidelines recommend aspirin combined with guidelines.45,46 A recently published trial suggests
clopidogrel for 3-6 months, followed by aspirin alone.91 that a single antiplatelet may be more suitable
than dual antiplatelet therapy, given the lower risk
of bleeding.131
Embolic stroke of Aspirin Clinical practice guidelines recommend the use of aspirin in The ATTICUS and ARCADIA trial results came out after
undetermined source patients with embolic stroke of undetermined source, the publication of these guidelines.49,50
because of a lack of demonstrated benefit with oral
anticoagulation.91
LVAD VKA and low-dose Clinical practice guidelines advise the use of VKAs for all
aspirin patients with LVAD, with an INR of 2.0-3.0, along with
low-dose aspirin.93,94
Heart failure with No anticoagulation Clinical practice guidelines advise that there is no evidence of
reduced left benefit for anticoagulation in heart failure with reduced
ventricular systolic left ventricular systolic function without AF.132
function without AF
Where the efficacy and safety of DOACs is uncertain
Left ventricular thrombus Prevention: not Routine prophylactic anticoagulation for left ventricular
recommended thrombus following acute MI is not typically
Treatment: DOACs or recommended. For the treatment of left ventricular
VKA thrombus after acute MI, an AHA Scientific Statement
suggests DOACs may be a reasonable alternative to
warfarin.97
Catheter-associated deep Low molecular Current guidance recommends treating cancer patients with This guidance is from 2014 and precedes the trials
vein thrombosis weight heparin or catheter-associated thrombosis using low-molecular- that show that DOACs can be used in cancer-
VKA weight heparin for 3 mo. VKAs are also an option.133 associated VTE. However, limited evidence exists
They do not comment on DOACs. for catheter-associated VTE.
Splanchnic vein Direct oral Current guidance recommends full-intensity DOACs for A trial was published after the publication of this
thrombosis anticoagulants noncirrhotic patients without active bleeding, including guidance.105
cancer-related symptomatic acute splanchnic vein
thrombosis for a minimum of 3-6 months.106
Cerebral venous sinus VKA Clinical practice guidelines and scientific statements VKAs use in cerebral venous sinus thrombosis had
thrombosis recommend the use of VKAs for cerebral venous sinus been largely based on limited data and expert
thrombosis, because of limited evidence for opinion.
DOACs.107,108
ESRD VKA or DOACs on Given the lack of strong evidence, clinical practice guidelines The results of the RENAL-AF,55 VALKYRIE,56 and
case by case suggest the decision to use a DOAC or VKAs in patients AXADIA-AFNET 857 came out after the guidelines
with ESRD or on dialysis and AF requires a high degree of were published. No RCTs for VTE and ESRD exist.
individualization.109

AXADIA-AFNET 8 ¼ Compare Apixaban and Vitamin-K Antagonists in Patients With Atrial Fibrillation (AF) and End-Stage Kidney Disease (ESKD); AF ¼ atrial fibrillation; AHA ¼ American Heart Association;
ARCADIA ¼ AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke; ASTRO-APS ¼ Apixaban for Secondary Prevention of Thromboembolism Among Patients With Anti-
phosPholipid Syndrome; ATLANTIS ¼ Anti-Thrombotic Strategy After Trans-Aortic Valve Implantation for Aortic Stenosis; DOACs ¼ direct oral anticoagulants; ESRD ¼ end-stage renal disease;
INR ¼ international normalized ratio; INVICTUS ¼ INVestIgation of rheumatiC AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies, Non-Inferiority; LVAD ¼ left ventricular assist device;
MI ¼ myocardial infarction; PROACT-Xa ¼ A Trial to Determine if Participants With an On-X Aortic Valve Can be Maintained Safely on Apixaban; RENAL-AF ¼ Trial to Evaluate Anticoagulation Therapy in
Hemodialysis Patients With Atrial Fibrillation; RIWA ¼ Rivaroxaban vs Warfarin in Patients With Metallic Prosthesis; SOC ¼ standard of care; TAVR ¼ transcatheter aortic valve replacement; VALKYRIE ¼ Effect
on Vascular Calcification of Replacing Warfarin by Rivaroxaban With or Without VitK2 in Hemodialysis Patients; VKA ¼ vitamin K antagonist; VTE ¼ venous thromboembolism.

THROMBOTIC ANTIPHOSPHOLIPID SYNDROME. rivaroxaban, 36-38 while apixaban was investigated in 1

Four RCTs investigated the safety and efficacy of RCT.39 In a meta-analysis of these RCTs, which
DOACs in patients with thrombotic antiphospholipid included a total of 472 patients, the odds of subse-
syndrome (APS). 36-39 Of these, 3 investigated quent arterial thrombotic events (MI, stroke, and
450 Bejjani et al JACC VOL. 83, NO. 3, 2024

When to Consider Avoiding DOACs JANUARY 23, 2024:444–465

T A B L E 3 Summary of Trials and Meta-Analysis of Patients With Thrombotic Antiphospholipid Syndrome Receiving DOACs vs VKAs

Follow-Up
First Author, Year Short Code DOAC Agent Standard of Care Duration Topline Trial Results

Cohen et al,36 RAPS Rivaroxaban VKAs (INR 2.0-3.0) 7 moa In a trial of 110 patients with thrombotic APS and a history of
2016 20 mg daily venous thrombosis, the endogenous thrombin potential for
rivaroxaban was significantly higher than for VKAs. No clinical
events occurred during short-term follow-up.
Pengo et al,37 TRAPS Rivaroxaban VKAs (INR 2.0-3.0) 20 moa The trial was terminated early after enrolling 120 patients with
2018 20 mg daily thrombotic triple-positive APS caused by excess
thromboembolic events in the rivaroxaban arm. Of 120 patients
enrolled, 7 patients experienced thromboembolic events in the
rivaroxaban arm, whereas no events were recorded in the group
randomized to VKAs.
Ordi-Ros et al,38 Not applicable Rivaroxaban VKAs (INR 2.0-3.0)b 35 moa In a trial of 190 patients with thrombotic APS, the rate of stroke
2019 20 mg daily was significantly higher among patients assigned to rivaroxaban
vs VKAs (HR: 20.01; 95% CI: 1.12-431.8).
Woller et al,39 ASTRO-APS Apixaban VKAs (INR 2.0-3.0) 12 moa The trial was terminated early after enrolling 48 patients caused by
2022 2.5 then 5 mg excessive risk of stroke in the apixaban arm. Of the 23 patients
twice dailyc randomized to apixaban, 6 experienced a stroke, while none of
the 25 patients randomized to VKAs had a stroke.
Khairani et al,35 Meta-analysis of the above trials, including pooled analyses of 19 moa Use of DOACs compared with VKAs was associated with increased
2023 published and unpublished subgroup results arterial thrombotic events (OR: 5.43; 95% CI: 1.87-15.75),
especially strokes (OR: 10.74; 95% CI: 2.29-50.38). No
significant difference in the odds of VTE or major bleeding were
observed. Results were consistent within 3 key subgroups:
women vs men, triple-positive thrombotic APS vs single/
double-positive thrombotic APS, and patients with a history of
arterial thrombosis vs no history of arterial thrombosis.

a
Mean follow-up duration. bPatients with a history of recurrent thrombosis were assigned to an INR of 3.1 to 4 in the VKAs arm. cInitially, patients were receiving apixaban 2.5 mg twice daily, but after
3 strokes occurred, the data safety and monitoring board required all currently and newly randomized patients to the apixaban arm to receive apixaban 5 mg twice daily.
APS ¼ antiphospholipid syndrome; RAPS ¼ Rivaroxaban in Antiphospholipid Syndrome; TRAPS ¼ Rivaroxaban in Thrombotic Antiphospholipid Syndrome; other abbreviations as in Tables 1 and 2.

major acute limb events) were found to be higher in
patients assigned to DOACs compared with warfarin
(24 vs 3; OR: 5.43; 95% CI: 1.87-15.75), primarily
driven by an excess risk of stroke (20 vs 0; OR: 10.74;
95% CI: 2.29-50.38).35 No significant differences in the
odds of subsequent VTE or major bleeding were
observed (Table 3). There was no effect modification
by sex, type of APS (triple-positive vs any others), or
history of arterial thrombosis (vs no history of arterial
thrombosis). Although many patients in these trials
had a positive lupus anticoagulant, known to be
strongly associated with thrombosis, 86 in the apix-
aban trial, only 3 of the 6 patients who developed a
stroke while assigned to apixaban had a positive
lupus anticoagulant.39 Overall, DOACs should not be
used as first-line therapy in patients with thrombotic
APS because of a significantly increased risk of arte-
rial thrombosis. For patients with a history of VTE
and thrombotic APS, the guidelines recommend long-
term VKA treatment. 87
TRANSCATHETER AORTIC VALVE REPLACEMENT.
The potential use of DOACs for preventing thrombo-
embolic events in patients who have undergone TAVR
has recently been extensively studied (Table 1). A 3-
month course of rivaroxaban (10 mg once daily) com-
bined with aspirin (n ¼ 826) was compared with aspirin
combined with clopidogrel (n ¼ 818) post-TAVR.
Rivaroxaban was associated with
increase in the rate of death or first thromboembolic
event (105 vs 78; HR: 1.35; 95% CI: 1.01-1.81). The rate of
major bleeding was also increased with rivaroxaban
(46 vs 31; HR: 1.50; 95% CI: 0.95-2.37), safety concerns
that led to the early termination of the trial. 44
In an RCT of 1,500 patients post-TAVR, apixaban
(5 mg twice daily) was compared with standard of
care (VKAs for patients with an indication for AC
[30.4%] and dual antiplatelet therapy [DAPT] for pa-
tients with no indication for AC [69.6%]) for a dura-
tion of 1 year.46 The rate of a composite of death, MI,
stroke/transient ischemic attack, systemic embolism,
intracardiac or bioprosthetic thrombosis, deep vein
thrombosis (DVT) or PE, or major bleeding were not
significantly different between apixaban and stan-
dard of care (138 vs 151; HR: 0.92; 95% CI: 0.73-1.16).
Likewise, the rate of major bleeding or life-
threatening bleeding was not significantly different
between apixaban and standard of care (64 vs 64; HR:
1.02; 95% CI: 0.72-1.44). Results were consistent
across strata of the control group.
Two RCTs investigated the use of edoxaban in pa-
tients after TAVR: The first trial (n ¼ 229) compared
edoxaban (60 mg daily) with DAPT in post-TAVR pa-
tients with sinus rhythm. There were no significant
difference in the risk of leaflet thrombosis on 4-
dimensional computed tomography (10 vs 20; risk
a significant ratio: 0.53; 95% CI: 0.26-1.09), in the risk of new
JACC VOL. 83, NO. 3, 2024 Bejjani et al 451
JANUARY 23, 2024:444–465 When to Consider Avoiding DOACs

T A B L E 4 Summary of Trials of Patients With Embolic Stroke of Undetermined Source Receiving DOACs vs Aspirin

Standard of Follow-Up
First Author, Year Short Code DOAC Agent Care Duration Topline Trial Results

Hart et al,47 NAVIGATE-ESUS Rivaroxaban Aspirin 11 moa The trial was terminated early after enrolling 7,213 patients because of
2018 15 mg daily 100 mg daily a lack of benefit with regard to stroke risk and because of excess
bleeding associated with rivaroxaban. Rates of a composite of any
recurrent stroke or systemic embolism were not significantly
different between patients assigned to rivaroxaban and those
assigned to aspirin (HR: 1.07; 95% CI: 0.87-1.33). Rates of major
bleeding were higher in the rivaroxaban arm (HR: 2.72; 95% CI:
1.68-4.39).
Diener et al,48 RE-SPECT ESUS Dabigatran Aspirin 19 moa In a trial of 5,390 patients with ESUS and no AF, rates of recurrent
2019 150 mg twice daily 100 mg daily stroke were not significantly different between patients assigned
to dabigatran and those assigned to aspirin (HR: 0.85; 95% CI:
0.69-1.03). No significant difference in the rates of major bleeding
between dabigatran and aspirin (HR: 1.19; 95% CI: 0.85-1.66). The
rate of CRNMB was significantly higher among patients assigned to
dabigatran compared with aspirin (HR: 1.73; 95% CI: 1.17-2.54).
Poli et alb,49,50 ATTICUS Apixaban Aspirin Plan follow-up of The trial was terminated early after enrolling 352 patients because of
NCT02427126 5 mg twice daily 100 mg daily 12 mo futility.c 13.6% of patients randomized to rivaroxaban and 16.0%
of those randomized to aspirin were found to have new ischemic
lesions (P ¼ 0.57). No significant difference in major bleeding
between the 2 groups. AF was detected in 25.6% of the enrolled
patients.d Full-text results are awaited.
Kamel et ale,89,90 ARCADIA Apixaban Aspirin 1.8 y The trial was terminated early after enrolling 1,015 patients with ESUS
NCT03192215 5 mg twice daily 81 mg daily and atrial cardiopathy, defined as at least 1 of the following:
P-wave terminal force >5000 mV  ms in ECG lead V1, serum
NT-proBNP >250 pg/mL, and left atrial diameter index $3 cm/m2
on echocardiogram, but no known AF. No significant differences in
the rate of recurrent stroke (4.4% vs 4.4%; HR: 1.00; 95% CI:
0.64-1.66) or major bleeding (0.7% vs 0.8%; HR: 1.02; 95% CI
0.29-3.51) were noted between apixaban and aspirin. CRNMB was
not yet reported. Full-text results are awaited.

a
Median follow-up duration. bFull results have not been published yet. cEnrollees had a risk profile for cardiac thromboembolism defined as left atrium size >45 mm, spontaneous echocardiogram contrast in
left atrial appendage, left atrial appendage flow velocity #0.2 cm/s, atrial high-rate episodes, CHA2DS2-VASc score $4, or patent foramen ovale. dRemote cardiac monitoring was mandatory during the trial.
e
Ongoing trial.
ARCADIA ¼ AtRial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke; ATTICUS ¼ Apixaban for Treatment of Embolic Stroke of Undetermined Source; NAVIGATE-
ESUS ¼ Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source; NT-proBNP ¼ N-terminal pro–B-
type natriuretic peptide; RESPECT-ESUS ¼ Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source; other abbreviations as in Tables 1 and 2.

lesions on brain cardiac magnetic resonance (26 vs 22;
risk ratio: 1.24; 95% CI: 0.75-2.04), and in the risk of
major bleeding (6 vs 4) between the 2 groups.45 The
other trial compared edoxaban (60 mg daily) with
VKAs in 1,426 post-TAVR patients with AF. Edoxaban
was noninferior to warfarin for the prevention of a
composite of death, MI, stroke, systemic embolism,
valve thrombosis, or major bleeding (170 vs 157; HR:
1.05; 95% CI: 0.85-1.31; P ¼ 0.01 for noninferiority). 43
Edoxaban, however, was associated with a signifi-
cantly higher risk of major bleeds compared with
warfarin (98 vs 68; HR: 1.40; 95% CI: 1.03-1.91),
largely related to excess gastrointestinal bleeding.
In summary, DOACs do not seem to confer a benefit
in patients post-TAVR who are in sinus rhythm. There
are no RCT data with apixaban, dabigatran, or rivar-
oxaban for patients with AF undergoing TAVR. For
patients post-TAVR and no other indications for oral
anticoagulants, the guidelines recommend aspirin
combined with clopidogrel for 3 to 6 months, fol-
lowed by aspirin alone. 85 Emerging data suggest that
single antiplatelet therapy may be reasonable in
many patients.
EMBOLIC STROKE OF UNDETERMINED SOURCE.
Several RCTs have investigated the role of DOACs in
patients with ESUS (Table 4).47-50,88 Dabigatran
(150 mg twice daily) did not significantly reduce the
rate of recurrent stroke compared with aspirin
(100 mg daily) in a trial of 5,390 patients with ESUS
(177 vs 207; HR: 0.85; 95% CI: 0.69-1.03). The rates of
major bleeding were not significantly different, but
dabigatran was associated with a significantly higher
risk of clinically relevant nonmajor bleed (CRNMB)
(70 vs 41; HR: 1.73; 95% CI: 1.17-2.54).48
In another RCT, 7,213 patients with ESUS were
randomized to rivaroxaban (15 mg daily) or aspirin
(100 mg daily). There was no significantly difference
in the rate of subsequent stroke (171 vs 158; HR: 1.08;
95% CI: 0.87-1.34) but there was a higher risk of major
bleeding with rivaroxaban (62 vs 23; HR: 2.72; 95% CI:
1.68-4.39).47 Similarly, apixaban (5 mg twice daily)
was compared with aspirin in an RCT of 352 patients
with ESUS and increased risk for AF/systemic embo-
lism. The rates of new ischemic lesions on brain car-
diac magnetic resonance were not significantly
different between the 2 arms (13.6% for apixaban vs
452 Bejjani et al
When to Consider Avoiding DOACs
16.0% for aspirin). 49,50 Both the rivaroxaban and
apixaban trials were terminated early caused by a lack
of benefit in reducing stroke risk.
The ARCADIA (AtRial Cardiopathy and Antith-
rombotic Drugs In Prevention After Cryptogenic
Stroke) trial, which investigated the safety and effi-
cacy of apixaban compared with aspirin for prevent-
ing recurrent stroke in patients with ESUS and atrial
cardiopathy, was stopped for futility. 89
The trial
found no significant difference in the rate of recurrent
stroke (4.4% vs 4.4%; HR: 1.00; 95% CI: 0.64-1.66) or
major bleeding (0.7% vs 0.8%; HR: 1.02; 95% CI: 0.29-
3.51) between apixaban and aspirin, and CRNMB has
not yet been reported. 90
In summary, in patients with ESUS, DOACs do not
offer significant benefits over aspirin and are associ-
ated with an increased risk of bleeding. Therefore, the
use of DOACs is not advised. Current guidelines do
not recommend oral anticoagulation for patients with
ESUS because of the lack of demonstrable benefit,
compared with aspirin. 91
LEFT VENTRICULAR ASSIST DEVICE. Only 1 trial
investigated the safety and efficacy of dabigatran plus
aspirin compared with phenprocoumon plus aspirin
for the prevention of thromboembolism in patients
with a left ventricular assist device (n ¼ 16).92 The trial
was stopped early because of a higher rate of throm-
boembolic events (4 vs 1) in patients who received
dabigatran plus aspirin. No major bleeding events
were reported. Although the number of patients was
small, the results were concerning, and we are un-
aware of other ongoing trials for DOACs in patients
with left ventricular assist devices. Guidelines advise
the use of VKAs combined with low-dose aspirin for all
patients with left ventricular assist device. 93,94
HEART FAILURE WITH REDUCED LEFT VENTRICULAR
SYSTOLIC FUNCTION WITHOUT AF. Among 5,022 pa-
tients with worsening chronic heart failure, reduced
left ventricular ejection fraction, and coronary artery
disease without AF, rivaroxaban (2.5 mg twice daily)
compared with placebo did not significantly reduce
the rate of a composite of death from any cause,
myocardial infarction, or stroke (626 vs 658; HR: 0.94;
95% CI: 0.84-1.05), but significantly reduced the rate
of stroke (2.0% vs 3.0%; HR: 0.66; 95% CI: 0.47-
0.95).95 In an on-treatment analysis, patients taking
rivaroxaban had a higher rate of major bleeding than
those taking placebo (3.3% vs 2.0%; HR: 1.68; 95% CI:
1.18-2.39). Thus, in patients with heart failure with
reduced left ventricular systolic function without AF,
low-intensity rivaroxaban did not confer a net benefit
to warrant a change in practice. Guidelines do not
suggest the routine use of anticoagulation in patients
JACC VOL. 83, NO. 3, 2024
JANUARY 23, 2024:444–465
with heart failure with reduced left ventricular sys-
tolic function and without AF.
WHERE THE SAFETY/EFFICACY OF DOACs
IS UNCERTAIN
UNCERTAIN INDICATIONS. Left ventricular thrombus. An
RCT with 279 patients compared the efficacy of rivar-
oxaban (2.5mg twice daily) plus DAPT to DAPT alone
in preventing left ventricular thrombus formation
postanterior MI (Figure 2).96 Rivaroxaban plus DAPT
was associated with lower incidence of left
ventricular thrombus formation within 30 days
postanterior MI compared with DAPT alone (1 vs 12;
HR: 0.08; 95% CI: 0.01-0.62). Rates of systemic
embolism (1 vs 4; HR: 0.49; 95% CI: 0.09-2.69) and of
major bleeding (1 vs 0) showed no significant
difference between groups. The ongoing APERITIF
(Direct Oral Anticoagulants for Prevention of lEft
ventRIcular Thrombus After Anterior Acute
Myocardial InFarction; NCT05077683) trial aims to
enroll 560 patients, comparing the efficacy of
rivaroxaban (2.5 mg twice daily) combined with DAPT
vs only DAPT in preventing left ventricular thrombus
after an anterior acute MI. Routine prophylactic
anticoagulation for left ventricular thrombus
following acute MI is not typically recommended. 97
A recent American Heart Association Scientific
Statement suggested that, in patients with left ven-
tricular thrombus, DOACs seem to be a reasonable
alternative to warfarin, based on 3 insufficiently pow-
ered RCTs.97-100 Pooled results of the meta-analysis of
these trials (n ¼ 139) were underpowered and showed
no significant differences in stroke (OR: 0.14; 95% CI:
0.01-1.27) or all-cause mortality (OR: 0.68; 95% CI:
0.10-4.43) rates. 98-101 A fourth trial (NCT05705089)
recently completed enrollment and follow-up, with
results forthcoming. The choice of anticoagulants for
patients with intracardiac thrombus regardless of
thrombus localization and any underlying heart dis-
ease has not been well-established yet: The ongoing
ARGONAUT (Anticoagulation Therapy in Non-device-
related Intra-cardiac Thrombus; NCT05825573) trial is
planning to enroll 340 patients randomized to a VKA or
a DOAC (apixaban, dabigatran, or rivaroxaban) to
answer this question.
C a t h e t e r - a s s o c i a t e d d e e p v e i n t h r o m b o s i s . Most
evidence on this topic is from studies of primary
prevention. Animal studies suggest that only high
levels of dabigatran attenuate catheter occlusion.51
In vitro data showed that apixaban and rivaroxaban
are less potent than enoxaparin for prevention of
catheter-induced thrombosis.53 However, clinical
data to corroborate this finding are lacking. In a
JACC VOL. 83, NO. 3, 2024 Bejjani et al 453
JANUARY 23, 2024:444–465 When to Consider Avoiding DOACs

F I G U R E 2 Indications for Which the Tradeoffs of Using DOACs Are Uncertain

Study Key Knowledge

Study Topline Study Results
Design Gaps

Subgroup Apixaban 2.5 mg twice daily, when compared

analysis of with placebo, was associated with lower rates of
Brandt et al52 VTE (HR: 0.26; 95% CI: 0.14-0.47) and no
2022 AVERT
RCT103 difference in major bleeding (HR: 0.69;
95% CI: 0.20-2.35). Limited evidence,
RCTs urgently
Thromboprophylaxis with rivaroxaban 10 mg needed.
daily, when compared with placebo, resulted in Pivotal VTE trials
TRIM-Line104 no significant different rate of VTE in patients should present
Pilot RCT
2021 with cancer and central venous catheters breakdown of
(HR: 0.66; 95% CI: 0.11-3.90). One major bleeding results according
Catheter- in rivaroxaban arm. to presence
Associated
Ongoing trial, planning to enroll 1,828 patients, of CVCs.
DVT
is comparing rivaroxaban 10 mg daily with
TRIM-Line
RCT placebo for primary thromboprophylaxis in
Ongoing
cancer patients with central venous catheters
(CVCs).

Dabigatran 150 mg twice daily, when compared Small sample size

RE-SPECT with warfarin with an INR of 2 to 3, resulted in no and low event
CVT54 RCT recurrent VTE in both groups, with 1 major rates. Other DOACs
2022 bleeding event recorded in the dabigatran arm need to be
Cerebral Venous
and 2 in the warfarin arm at 25 weeks. studied.
Sinus Thrombosis

Rivaroxaban 15 mg daily, when compared with Small sample size.

placebo, resulted in a significantly lower rate of Need to study
RIPORT106 recurrent VTE (0 per 100 person-years vs 19.71 rates of
RCT
2022 per 100 person-years; 95% CI: 7.49-31.92) in recurrent VTE.
patients with noncirrhotic chronic portal vein Further RCTs
Splanchnic Vein thrombosis. needed.
Thrombosis

For prevention of LV thrombus following

anterior MI, combination of rivaroxaban 2.5 mg More RCTs with
Zhang et al96 twice daily and DAPT, when compared with DAPT larger sample sizes
RCT
2022 alone, was associated with lower rates of LVT are needed and
formation at 30 days (HR: 0.08; 95% other agents tested.
CI: 0.01-0.62).
For treatment of LV thrombus post-MI, a pooled
analysis of 3 small trials suggested no
Sayed et al101 Meta- difference in stroke (OR: 0.14; 95% CI: 0.01-1.27) Trials were
2021 analysis or LVT resolution (OR: 1.17; 95% CI: 0.37-3.45) underpowered.
between DOACs and warfarin, but major bleeding Further RCTs are
Left Ventricular was lower in DOACs (OR: 0.16; 95% CI: 0.02-0.82).
Thrombus needed, including
Ongoing trial, aiming to enroll 50 patients, is for LV thrombus
REWARF- other than post-MI.
comparing rivaroxaban 15 mg daily vs
STEMI RCT
warfarin in patients with LV thrombus follow
Ongoing
acute ST-segment elevation myocardial infarction.

The efficacy and safety of DOACs in catheter-associated deep vein thrombosis (DVT), cerebral venous sinus thrombosis, splanchnic vein thrombosis, and the prevention
and treatment of LV thrombus remain uncertain. DVT ¼ deep vein thrombosis; INR ¼ international normalized ratio; LV ¼ left ventricular; MI ¼ myocardial infarction;
RCT ¼ randomized controlled trial; other abbreviations as in Figure 1.
454 Bejjani et al
When to Consider Avoiding DOACs
prospective cohort study of 70 cancer patients
treated with apixaban for catheter-associated upper
extremity DVT, all catheters remained functional
without removal, with only 1 recurrent DVT, but
major bleeding occurred in 2.9% of patients, and
CRNMB in 5.7%.102 In an RCT comparing apixaban
(2.5 mg twice daily) with placebo for primary pre-
103
vention of VTE in patients with cancer, a sub-
group analysis of 217 patients with a central venous
catheter found that the rate of VTE was significantly
lower among patients assigned to apixaban (4 vs 17;
HR: 0.26; 95% CI: 0.14-0.47).52 An open-label pilot
trial of 105 patients with cancer and central venous
catheters showed no significant difference in the
rate of VTE between patients assigned to rivarox-
aban (10 mg daily) or placebo (2 vs 3; HR: 0.66;
95% CI: 0.11-3.90).104 One major bleeding event
occurred in the rivaroxaban arm. TRIM-Line (Pri-
mary Thromboprophylaxis in Patients With Malig-
nancy and Central Venous Catheters), an ongoing
RCT aiming to enroll 1,828 cancer patients with
central venous catheters, will compare rivaroxaban
(10 mg daily) with placebo for primary thrombopro-
phylaxis (NCT05029063). As for the treatment of
VTE, pivotal RCTs have not reported results for
subgroups of line-related DVT.
S p l a n c h n i c v e i n t h r o m b o s i s . In an open-label RCT
of 111 patients with noncirrhotic chronic portal vein
thrombosis, rivaroxaban (15 mg daily) was associated
with a significantly lower rate of recurrent VTE
compared with placebo (0 per 100 person-years vs
19.71 per 100 person-years; 95% CI: 7.49-31.92) after a
median follow-up of 11.8 months, findings which led
to early termination of the trial. 105 Major bleeding
occurred in 2 patients assigned to rivaroxaban and 1
patient assigned to placebo. In the setting of limited
high-quality data, expert consensus from the Inter-
national Society on Thrombosis and Haemostasis
(ISTH) advises full-dose DOACs for noncirrhotic
patients without active bleeding, including cancer-
related symptomatic acute splanchnic vein throm-
bosis. ISTH guidance also advises a minimum of 3 to
6 months of anticoagulant therapy for these patients,
irrespective of thrombosis extension and risk
factors. 106
C e r e b r a l v e n o u s s i n u s t h r o m b o s i s . In an RCT that
compared dabigatran (150 mg twice daily) with
warfarin (INR target of 2.0-3.0) for 24 weeks in 120
patients with CVST, there were no recurrent VTEs in
either group.54 There were 1 and 2 cases of major
bleeding in the dabigatran and warfarin arms,
respectively. With the small sample size, the trial was
underpowered for both efficacy and safety. Previous
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JANUARY 23, 2024:444–465
guidelines and scientific statements recommend the
use of VKAs for CVST, because of limited evidence
about DOACs.107,108
SUBGROUPS WITH UNCERTAIN EVIDENCE. E n d - s t a g e
r e n a l d i s e a s e . Current guidelines emphasize the
lack of clear evidence of efficacy for both VKAs and
DOACs in patients with ESRD.109 Pivotal RCTs for
acute or extended VTE treatment excluded patients
with serum creatinine levels >2.5 mg/dL or creatinine
clearance <25 to 30 mL/min.110 Similarly, pivotal tri-
als of patients with AF excluded those with advanced
renal disease or ESRD.4-16 Despite this, the U.S.
Food and Drug Administration labels for apixaban
and rivaroxaban have not excluded their use in
ESRD, largely based on pharmacokinetic and phar-
macodynamic studies. The other DOACs are not
currently approved in patients with severe renal
impairment (creatinine clearance <15 mL/min) or
those on dialysis.
Although there is currently no RCT evidence sup-
porting the use of DOACs for VTE treatment in pa-
tients with ESRD, some smaller RCTs have compared
DOACs vs VKAs in ESRD patients with AF. In a trial of
132 patients with AF who were on hemodialysis, the
rate of a composite of fatal cardiovascular disease,
nonfatal stroke, cardiac events, and other vascular
events was lower among patients assigned to rivar-
oxaban (10 mg once daily) than with VKAs (23 vs 35;
HR: 0.41; 95% CI: 0.25-0.68) (Figure 3).56 The rate of
major bleeding was also lower with rivaroxaban (8 vs
17; HR: 0.39; 95% CI: 0.17-0.90) than with VKAs. An
RCT comparing apixaban (5 mg twice daily) with
warfarin in hemodialysis patients with AF was
stopped early due to enrollment challenges but
showed that the 1-year rate of stroke or systemic
embolism was not significantly different with apix-
aban (3.0%; 95% CI: 0.5-9.7) vs warfarin (3.3%;
95% CI: 0.6-10.5). The rate of a composite of major
bleeding or CRNMB was not significantly different in
the apixaban and warfarin groups (31.5% vs 25.5%;
HR: 1.20; 95% CI: 0.63-2.30) at 1 year.55 In a third RCT
that compared apixaban (2.5 mg twice daily) with
phenprocoumon in AF patients on chronic hemodi-
alysis, the rate of a composite of major bleeding,
CRNMB and all-cause death was not significantly
different (22 vs 25; HR: 0.93; 95% CI: 0.53-1.65). 57 The
study could not establish the noninferiority of apix-
aban. In summary, dose-reduced DOACs have shown
some promise in patients with AF and ESRD. How-
ever, larger-size RCTs are needed, and until then, as
is the case with VKAs in ESRD, 111 the limitations of
evidence should be kept in mind. Shared-decision
making between patients and physicians is essential.
JACC VOL. 83, NO. 3, 2024 Bejjani et al 455
JANUARY 23, 2024:444–465 When to Consider Avoiding DOACs

F I G U R E 3 Subgroups in Whom the Effects of DOACs Are Uncertain

Study Key Knowledge

Study Topline Study Results
Design Gaps

Rivaroxaban 10 mg daily, when compared

with VKAs with an INR of 2 to 3, was associated
VALKYRIE56 RCT with lower rates of cardiovascular events
2021 (HR: 0.41; 95% CI: 0.25-0.68) and major
bleeding (HR: 0.39; 95% CI: 0.17-0.90)
at 18 months. RCTs either had
small sample
Apixaban 5 mg twice daily, when compared with sizes or failed
warfarin with an INR of 2 to 3, showed no to reach
difference in the rate of a composite of major predefined non-
RENAL-AF55 RCT bleeding and CRNMB at 1 year (HR: 1.20; inferiority
2022 95% CI: 0.63-2.30). One-year rates of stroke or criteria.
systematic embolism were 3.0% vs 3.3% in the RCTs with larger
apixaban and warfarin groups. sample sizes are
End-Stage
needed.
Renal Disease Apixaban 2.5 mg twice daily, when compared
and AF* AXADIA- with phenprocoumon with an INR 2 to 3,
AFNET 857 RCT demonstrated no difference in the rate of a
2023 composite of major bleeding, CRNMB and all-
cause death (HR: 0.93; 95% CI: 0.53-1.65)

Bapat et al60,61,63 Ex vivo

human During pregnancy, apixaban, dabigatran, and
2014, 2015, and rivaroxaban are transferred across the placenta.
2016 models Until further data
suggest otherwise,
DOACs should be
Among 336 reported DOAC-exposed avoided in
Beyer-
pregnancies with known outcomes, 21 fetal pregnancy.
Pregnancy Westendorf Retrospective
abnormalities were reported, of which 12 were
et al62 cohort
major birth defects (4.0%; 95% CI: 2.0%-6.0%).
2020
Miscarriage rate was 22.0% (95% CI: 17.7%-26.8%).

Clinical evidence
Ayuk et al112 for safety is lacking.
2020 Milk: plasma ratio is low for dabigatran and Encourage careful
Single-arm rivaroxaban (0.1 and 0.2, respectively) while the protocols for
trial milk: plasma ratio is greater than acceptable for breastfeeding
Zhao et al113 apixaban (2.61). women receiving
Breastfeeding 2020 rivaroxaban or
dabigatran.

In 766 patients receiving DOACs for atrial

arrhythmias, annual rates of thromboembolic
Stalikas et al117 Meta-
events and major bleeding events were low: RCTs are urgently
2020 analysis
0.98% (95% CI: 0.51%-1.86%) and 1.74% needed as the
(95% CI: 0.86%-3.49%), respectively. population of
An ongoing study is assessing the outcomes of patients with
apixaban in 250 patients with adult congenital adult congenital
PROTECT-AR Prospective heart disease and atrial arrhythmias. The primary heart disease is
Adult Congenital growing.
Heart Disease Ongoing cohort outcomes are: 1) a composite of stroke, systemic
or pulmonary embolism, and intracardiac
thrombosis; and 2) major bleeding.

Evidence is limited for the use of DOACs in patients with AF and end-stage renal disease as well as patients with adult congenital heart disease, and their use
should be avoided in pregnant and breastfeeding patients, pending further studies. *Patients with serum creatinine levels >2.5 mg/dL or creatinine clearance
of <25 to 30 mL/min were excluded from landmark RCTs for acute or extended-duration secondary prevention of VTE and for stroke prevention in AF. Abbreviations as in
Figures 1 and 2.
456 Bejjani et al
When to Consider Avoiding DOACs
BREASTFEEDING AND PREGNANCY. Limited data
show that the milk to plasma ratios (average milk
concentration of drug/average maternal plasma con-
centration of drug) for dabigatran112 and rivarox-
aban 113 are low (0.1 and 0.2, respectively). Drugs with
extremely low milk to plasma ratios (eg, 0.1) are likely
112
to be safe during breastfeeding. Estimated
maximum plasma dabigatran concentration in the
neonate were 100,000 times below the concentrations
that would have a significant effect on coagulation
indexes.112 Nevertheless, clinical evidence about the
safety of these 2 agents during breastfeeding is lack-
ing. Apixaban 113 has a greater-than-acceptable milk to
plasma ratio (2.61), and its use is not recommended.
Ex vivo human models indicated transplacental
transfer for apixaban, 60 dabigatran, 61 and rivarox-
aban 63 during pregnancy, with levels that may carry
effective anticoagulant properties. Therefore,
pending further studies, DOACs should not be used for
anticoagulation in pregnancy because of the potential
risk to the fetus. If a patient becomes pregnant while
taking DOACs, she should be switched to alternative
anticoagulants as soon as possible, although many
experts do not recommend pregnancy termination.62
With respect to nonhemorrhagic issues, in a study of
DOAC-exposed pregnancies derived from pharmaco-
vigilance analyses, 336 DOAC-exposed pregnancies
had available outcomes: The miscarriage rate was
22.0% (95% CI: 17.7%-26.8%) and 21 fetal abnormal-
ities were reported, of which 12 (4%; 95% CI: 2.0%-
6.0%) were adjudicated as major birth defects.62 In the
general population, the rate of miscarriage is 15.3%
(95% CI: 12.5%-18.7%) 114 and the rate of major birth
defects is 2.76% (95% CI: 2.73%-2.79%).115
Adult congenital heart disease. Despite the guideline
recommendations for using warfarin in patients with
adult congenital heart disease and AF or atrial flutter,
116
DOACs are often used in clinical practice. Pooled
data from limited retrospective studies suggest that
patients given DOACs may have low thromboembolic
117
and bleeding rates. However, DOACs have not yet
been evaluated in RCTs in this subgroup.
Chronic thromboembolic pulmonary hypertension. No pub-
lished RCTs have evaluated the safety and efficacy of
DOACs in patients with chronic thromboembolic
pulmonary hypertension. Pooled results from 3
limited retrospective studies (n ¼ 2,427) suggest the
use of DOACs was associated with a low mortality rate
and low rates of recurrent VTE and bleeding events in
patients with chronic thromboembolic pulmonary
hypertension. 118 An ongoing RCT comparing edox-
aban with warfarin plans to enroll 74 patients to
evaluate the improvement in pulmonary vascular
resistance at 1 year compared with baseline resting
JACC VOL. 83, NO. 3, 2024
JANUARY 23, 2024:444–465
pulmonary vascular resistance in patients with
chronic thromboembolic pulmonary hypertension. 119
O t h e r p a t i e n t s u b g r o u p s . The safety and efficacy
of DOACs remain poorly studied among patients with
a body mass index >45 kg/m2 and those postbariatric
surgery. 120 In patients with heparin-induced throm-
bocytopenia and thrombosis, DOACs have occasion-
ally been used based on limited retrospective cohort
data.121,122 Given that they are not heparin-based
drugs, they are likely to work in this subgroup of
patients. However, high-quality evidence is still
needed, and DOACs are not widely recommended for
this indication as of now.
OTHER CONSIDERATIONS
SAFETY CONCERNS ASSOCIATED WITH THE USE OF
DOACs. Most pivotal VTE and SPAF trials excluded
patients on medications known to cause serious in-
teractions with DOACs because of an increased risk of
thrombosis or hemorrhage. DOACs are metabolized
via cytochrome P450 3A4 and P-glycoproteins, 123 and
are therefore contraindicated alongside strong in-
ducers or inhibitors of these pathways.110 Low-
intensity DOACs are sometimes used off-label in
scenarios requiring full-dose therapy or in areas of
uncertainty, such as those involving frail patients. 110
DOACs are also contraindicated in patients with
advanced liver disease (Child-Pugh stage C), because
of their partial hepatic clearance (apixaban 75%,
rivaroxaban 65%, edoxaban 50%, and dabigatran
20%) and increased serum concentration and elimi-
nation time. 58,59
LIMITATIONS OF DOACs DRUG MONITORING. Labo-
ratory tests to measure true DOACs plasma levels
(such as chromogenic antifactor X assays) are
becoming increasingly available but their role in
monitoring drug levels is uncertain. In addition, the
correlation of DOAC levels with clinical outcomes
such as stroke or bleeding is poorly understood. This
contrasts with the familiarity with INR for monitoring
VKAs. These limitations of DOAC monitoring become
important in situations such as suspected non-
adherence to DOACs (eg, precardioversion), anti-
coagulation failure, unexpected major bleeding, or
forensic medicine.
POSSIBLE MECHANISMS FOR DOAC VARIED
EFFICACY AND SAFETY ACROSS INDICATIONS
The reduced efficacy of DOACs in certain conditions is
likely multifactorial (Figure 4). The distinct, focused
mechanism of action compared with other agents
could be 1 possible explanation. Unlike VKAs, which
inhibit the synthesis of multiple clotting factors,
JACC VOL. 83, NO. 3, 2024 Bejjani et al 457
JANUARY 23, 2024:444–465 When to Consider Avoiding DOACs

F I G U R E 4 Putative Mechanisms of Direct Oral Anticoagulants’ Reduced Efficacy in Some Indications

Left Ventricular Central Venous

Assist Device Catheter

Transcatheter Aortic Mechanical

Valve Replacement Heart Valves

Medical devices trigger clotting via

the intrinsic pathway

Reduced synthesis by
Activating Vitamin K Antagonists
surface Vessel injury
or endothelial
cell activation
XII XIIa
Contact Tissue Factor
Activation (Extrinsic)
XI XIa TF
(Intrinsic) Pathway)
Pathway
IX IXa VIIa VII Factor Xa
inhibitors
• Apixaban
X Xa • Edoxaban
• Rivaroxaban
Common
II IIa Factor IIa
Pathway
inhibitors
• Dabigatran
I Ia

Fibrin clot
formation

Alternative Classical
Pathway Pathway

Neutrophil extracellular
Complement activation
traps (NET) trigger clotting
via intrinsic pathway

NET and complement activation contribute to

clotting in thrombotic antiphospholipid syndrome

Compared with vitamin K antagonists, direct oral anticoagulants only inhibit a single factor in the coagulation pathway, a distinction that may
be essential given that medical devices such as mechanical valves result in contact activation and thrombosis through the intrinsic pathway.
This also applies to neutrophil extracellular traps and complement activation that trigger clotting via the intrinsic pathway in patients with
thrombotic antiphospholipid syndrome.
458 Bejjani et al JACC VOL. 83, NO. 3, 2024

When to Consider Avoiding DOACs JANUARY 23, 2024:444–465

C E N T RA L I LL U STRA T I ON Important Considerations for Direct Oral Anticoagulant Use

Bejjani A, et al. J Am Coll Cardiol. 2024;83(3):444–465.

Continued on the next page

JACC VOL. 83, NO. 3, 2024 Bejjani et al 459
JANUARY 23, 2024:444–465 When to Consider Avoiding DOACs

DOACs specifically target factor Xa or thrombin to
prevent blood clot formation. This distinction be-
comes significant as medical devices like catheters,
stents, TAVR prostheses, mechanical heart valves,
and left atrial appendage occlusion devices trigger
clotting via the intrinsic pathway.124-126 In vitro
models have demonstrated that dabigatran, rivarox-
aban, and apixaban are less effective than warfarin
in suppressing mechanical heart
thrombin generation. 124,127
Moreover, DOACs may be ineffective in thrombotic
APS because of clotting involving neutrophil extra-
cellular traps and complement activation via the
alternative and classical pathways. 128 Neutrophil
extracellular traps trigger clotting
intrinsic pathway. VKAs may be more efficacious than
DOACs for attenuating clotting induced by NETs
because VKAs reduce the synthesis of several clotting
factors in the intrinsic and common pathway, not just
factor Xa or thrombin.
In the INVICTUS (INVestIgation of rheumatiC AF
Treatment Using Vitamin K Antagonists, Rivaroxaban
or Aspirin Studies, Non-Inferiority) trial involving
patients with AF and rheumatic heart disease, the
VKAs group had more interactions with physicians
than the rivaroxaban group, caused by monthly
monitoring of INR.40 These frequent interactions may
have facilitated addressing a broader range of health
issues, which could potentially explain why patients
on VKAs experienced better efficacy outcomes.
Except for apixaban, DOACs are associated with
higher rates of gastrointestinal bleeding than VKAs.
The risk of gastrointestinal bleeding with edoxaban
and dabigatran appears to be dose-related (there
was significantly less gastrointestinal bleeding with
the 30 mg daily edoxaban regimen than with
warfarin in the ENGAGE AF-TIMI 48 [Global Study
to Assess the Safety and Effectiveness of Edoxaban
(DU-176b) vs Standard Practice of Dosing With
Warfarin in Patients With Atrial Fibrillation] trial7
and no increase in gastrointestinal bleeding with
the 110 mg twice daily dosing regimen of dabigatran
in the RE-LY [Randomized Evaluation of Long Term
Anticoagulant Therapy With Dabigatran Etexilate]
trial).4 Bleeding may reflect active drug in the gut;
there would be more active drug in the gut with
once-daily dosing of rivaroxaban or edoxaban than
with twice-daily dosing of apixaban. Apixaban is the
only DOAC to not significantly increase the risk of
valve-induced gastrointestinal bleeding compared with warfarin.
KNOWLEDGE GAPS AND FUTURE DIRECTIONS
Recent RCTs shed light on important considerations
for the use of DOACs (Central Illustration). Neverthe-
through the less, there is a critical need to further elucidate why
DOACs are less efficacious or safe than the standard of
care in certain scenarios, such as thrombotic APS,
ESUS, mechanical heart valves, and post-TAVR. There
is an urgent need to conduct subgroup analyses from
pivotal VTE and SPAF trials; eg, subgroup analyses
stratified by the presence of a catheter in VTE trials
would be informative and may drive future RCTs. The
role of DOACs in special subgroups, such as those
with ESRD and pregnant or breastfeeding patients,
where the evidence is still uncertain, requires further
investigation.
Another key area of research involves the potential
role of factor XIa inhibitors. The ongoing trials with
factor XIa inhibitors are plentiful, as addressed else-
where,129,130 and beyond the scope of this review.
These trials will bring evidence to several areas of
uncertainty regarding DOAC use, such as in patients
with ESRD where the benefits of DOACs, or even
VKAs,111 are uncertain. For instance, the CONVERT
(Study to Investigate the Safety of a Drug Called
Osocimab at Low and High Doses in Adult Patients
With Kidney Failure Requiring Regular Hemodialysis;
NCT04523220) trial enrolled 686 patients randomized
to different doses of osocimab (which binds activated
factor XI and prevents activation of factor IX) vs
placebo in patients requiring hemodialysis, with a

C ENTR AL I LL U STRA T I O N Continued

DOACs are strongly contraindicated in patients with thrombotic APS, mechanical heart valves, rheumatic AF, or LVAD. They do not offer
significant benefits and may increase harm in ESUS and TAVR patients. DOACs should not be used in pregnant or breastfeeding patients, as
well as in ESRD. Limited evidence exists for their use in LV thrombus prevention and treatment, CVST, splanchnic vein thrombosis, catheter-
associated DVT, and adult congenital heart disease. *Refer to Figure 2. ‡Although DOACs are the standard treatment for acute VTE, the
timing to switch to oral anticoagulation after initial fibrinolysis in patients with intermediate-high risk PE is not well established. AF ¼ atrial
fibrillation; APS ¼ antiphospholipid syndrome; CVST ¼ cerebral venous sinus thrombosis; DOACs ¼ direct oral anticoagulants; DVT ¼ deep-
vein thrombosis; ESRD ¼ end-stage renal disease; ESUS ¼ embolic stroke of undetermined source; LV ¼ left ventricular; LVAD ¼ left
ventricular assist device; SPAF ¼ stroke prevention in atrial fibrillation; TAVR ¼ transcatheter aortic valve replacement; VTE ¼ venous
thromboembolism.
460 Bejjani et al
When to Consider Avoiding DOACs
primary safety outcome of a composite of major
bleeding and CRNMB.
CONCLUSIONS
DOACs have emerged as the cornerstone of therapy
for SPAF and VTE treatment; however, recent RCTs
have suggested that they may be less effective or safe
than the standard of care in certain conditions such as
thrombotic APS, mechanical heart valves, and rheu-
matic AF. Further research is required to understand
the potential mechanisms behind their variable effi-
cacy and safety. Research gaps include RCTs of less
common conditions such as cerebral vein thrombosis
and splanchnic vein thrombosis, or subgroups such as
those with ESRD. Results reviewed here have signifi-
cant implications for optimizing anticoagulation
therapy and improving patient outcomes in clinical
practice. In some conditions, the safety and efficacy of
DOACs remain uncertain caused by the lack or flaws of
RCTs, necessitating immediate definitive trials.
ACKNOWLEDGMENT The schematic diagram of
included randomized clinical trials in Figure 1,
Figure 4, and the Central Illustration were created
using BioRender.com.
FUNDING SUPPORT AND AUTHOR DISCLOSURES
Dr Piazza has received research support paid to his institution from
Bristol Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen,
and Boston Scientific Corporation; and has received consulting fees
from Pfizer, Boston Scientific Corporation, Janssen, and Amgen. Dr
Fanikos has served as a consultant to AstraZeneca, Mallinckrodt, and
Pfizer. Dr Connors has received research funding to her institution
from CSL Behring; has received consulting fees from Abbott; has
received honoraria for lectures from Bristol Myers Squibb, Roche, and
Sanofi; and has participated on the advisory board of Abbott, Alny-
lam, Anthos, Bristol Myers Squibb, Sanofi, and Takeda, outside of the
submitted work. Dr Siegal is supported by a Tier 2 Canada Research
Chair in Anticoagulant Management of Cardiovascular Disease; de-
clares that she has received honoraria paid indirectly to her research
institute from AstraZeneca, Bristol Myers Squibb-Pfizer, Roche, and
Servier. Dr Barnes has served as a consultant for Pfizer, Bristol Myers
Squibb, Janssen, Bayer, AstraZeneca, Sanofi, Anthos, Boston Scienti-
fic, and Abbott Vascular; and has received grant funding from Boston
Scientific. Dr Martin is supported by National Institutes of Health
K23HL157758; and has received research support paid to her institu-
tion from Janssen Scientific Affairs. Dr Angiolillo has received
consulting fees or honoraria from Abbott, Amgen, AstraZeneca,
Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb,
Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen,
Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura;
and his institution has received research grants from Amgen, Astra-
Zeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo,
Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical In-
dustry Co, Merck, Novartis, and the Scott R. MacKenzie Foundation.
Dr Kleindorfer has received other support from the University of
Michigan College of Medicine. Dr Monreal has received unrestricted
grants for research from Sanofi, Leo and Rovi; and has participated in
advisory meetings sponsored by Sanofi. Dr Jimenez has served as an
advisor or consultant for Pfizer and Sanofi; and has served as a
JACC VOL. 83, NO. 3, 2024
JANUARY 23, 2024:444–465
speaker or a member of a Speakers Bureau for Bristol Myers Squibb,
Pfizer and Sanofi. Dr Middeldorp has received grants and personal
fees from Daiichi-Sankyo, Bayer, Pfizer, and Boehringer Ingelheim;
and has received personal fees from Portola/Alexion, Abbvie, Pfizer/
Bristol Myers Squibb, Norgine, Viatris, and Sanofi, all paid to her
institution and outside of the submitted work. Dr Elkind has received
study drug in kind from the Bristol Myers Squibb-Pfizer Alliance; has
received ancillary research funding from Roche for a National In-
stitutes of Health-funded trial of stroke prevention; and has received
royalties from UpToDate for chapters on stroke. Dr Elkind has
received study drug in kind from the Bristol Myers Squibb-Pfizer
Alliance and ancillary research funding from Roche for a National
Institutes of Health-funded trial of stroke prevention, and royalties
from UpToDate for chapters on stroke. Dr Ruff is a member of the
TIMI Study Group, which has received institutional research grant
support through Brigham and Women’s Hospital from Abbott,
Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca,
Bayer HealthCare Pharmaceuticals, Inc, Daiichi-Sankyo, Eisai, Intar-
cia, Ionis Pharmaceuticals, Inc, Janssen Research and Development,
LLC, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals,
Regeneron Pharmaceuticals, Inc, Roche, Siemens Healthcare Di-
agnostics, Inc, Softcell Medical Limited, The Medicines Company, and
Zora Biosciences. Dr Goldhaber has received research support from
Bayer, Bristol Myers Squibb, Boston Scientific BTG EKOS, Janssen,
National Heart, Lung, and Blood Institute, and Pfizer; and has
received consulting fees from Agile, Bayer, and Pfizer, outside of the
submitted work. In the past 3 years, Dr Krumholz has received ex-
penses and/or personal fees from UnitedHealth, Element Science,
Eyedentifeye, and F-Prime; is a co-founder of Refactor Health and
HugoHealth; and is associated with contracts, through Yale New
Haven Hospital, from the Centers for Medicare and Medicaid Services
and through Yale University from Janssen, Google, and Pfizer. Dr
Mehran has received institutional research payments from Abbott,
Abiomed, Alleviant Medical, Amgen, AM-Pharma, Arena, AstraZe-
neca, AtriCure Inc, Biosensors, Biotronik, Boston Scientific, Bristol
Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical,
Cytosorbents, Daiichi-Sankyo, Element Science, Faraday, Humacyte,
Idorsia Pharmaceuticals, Janssen, Magenta, MedAlliance, Media-
sphere, Medtelligence, Medtronic, MJH Healthcare, Novartis, Orbus-
Neich, Penumbra, PhaseBio, Philips, Pi-Cardia, PLx Pharma,
Protembis, RenalPro, RM Global, Shockwave, Vivasure, Zoll; has
received personal fees from Ionis Pharmaceuticals, J-CalC, Novartis,
NovoNordisk, Vectura, VoxMedia, WebMD, IQVIA, McVeigh Global,
Overcome, Primer Healthcare of New Jersey, Radcliffe, SL Solutions,
TARSUS Cardiology, and Esperion Science/Innovative Biopharma; has
received honoraria from JAMA Cardiology (Associate Editor) and the
ACC (BOT Member, SC Member CTR Program); and has equity <1% in
Applied Therapeutics, Elixir Medical, Stel, ControlRad (spouse). Dr
Eikelboom has received fees, honoraria and/or research support from
Anthos, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers
Squibb, DSI, Janssen, Pfizer, Servier, and Takeda. Dr Lip is a consul-
tant and speaker for Bristol Myers Squibb/Pfizer, Boehringer Ingel-
heim, Daiichi-Sankyo, and Anthos, no fees are received personally;
and is coprincipal investigator of the AFFIRMO project on multi-
morbidity in AF, which has received funding from the European
Union’s Horizon 2020 research and innovation program under grant
agreement #899871. Dr Weitz has served as a consultant and has
received honoraria from Alnylam, Anthos, Bayer, Bristol Myers
Squibb, Ionis, Janssen, Merck, Pfizer, Regeneron, and Servier. Dr
Lopes reports research grants or contracts from Amgen, Bristol Myers
Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi; funding for
educational activities or lectures from Pfizer, Bristol Myers Squibb,
Novo Nordisk, and AstraZeneca; and has received funding for
consulting from Bayer, Boehringer Ingelheim, Bristol Myers Squibb,
NovoNordisk, and AstraZeneca. Dr Bikdeli is supported by a Career
Development Award from the American Heart Association and VIVA
Physicians (#938814); was supported by the Scott Schoen and Nancy
Adams IGNITE Award; is supported by the Mary Ann Tynan Research
JACC VOL. 83, NO. 3, 2024
JANUARY 23, 2024:444–465
Scientist award from the Mary Horrigan Connors Center for Women’s
Health and Gender Biology at Brigham and Women’s Hospital, and
the Heart and Vascular Center Junior Faculty Award from Brigham
and Women’s Hospital; is a consulting expert, on behalf of the
plaintiff, for litigation related to 2 specific brand models of IVC filters;
has not been involved in the litigation in 2022 or 2023 nor has he
received any compensation in 2022 or 2023; is a member of the
Medical Advisory Board for the North American Thrombosis Forum;
and serves in the Data Safety and Monitory Board of the NAIL-IT trial
funded by the National Heart, Lung, and Blood Institute, and
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ADDRESS FOR
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