Thrombosis Research 229 (2023) 15–25

Contents lists available at ScienceDirect

Thrombosis Research
journal homepage: www.elsevier.com/locate/thromres

Review Article

Management of anticoagulation in patients with infective endocarditis

Xiaogang Zhu a, Zhenhua Wang b, Markus W. Ferrari c, Katharina Ferrari-Kuehne d,
David H. Hsi e, Gary Tse f, Quanzhong Zhou g, Haifeng Liang a, Yuhui Zhang h, *, Jian Zhang h, *
a
Department of Cardiology, Fu Xing Hospital, Capital Medical University, China
b
Department of Cardiology, Second Affiliated Hospital of Fujian Medical University, China
c
Clinic of Internal Medicine 1, HSK, Clinic of the City of Wiesbaden and the HELIOS Group, Germany
d
University of Jena, Jena, Germany
e
Heart & Vascular Institute, Stamford Hospital, Stamford, CT, United States
f
Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
g
Department of Radiology, The Center for Medical Imaging of Guizhou Province, Affiliated Hospital of Zunyi Medical University, China
h
Heart Failure Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical
Sciences and Peking Union Medical College, China

A R T I C L E I N F O A B S T R A C T

Keywords: Infective endocarditis (IE) carries a high risk of vascular complications (e.g., cerebral embolism, intracerebral
Infective endocarditis hemorrhage, and renal infarction), which are correlated with increased early and late mortality. Although
Thromboembolism anticoagulation is the cornerstone for management of thromboembolic complications, it remains controversial
Stroke
and challenging in patients with IE. An appropriate anticoagulation strategy is crucial to improving outcomes
Intracerebral hemorrhage
Vitamin K antagonist
and requires a good understanding of the indication, timing, and regimen of anticoagulation in the setting of IE.
Oral anticoagulants Observational studies have shown that anticoagulant treatment failed to reduce the risk of ischemic stroke in
patents with IE, supporting that IE alone is not an indication for anticoagulation. In the absence of randomized
controlled trials and high-quality meta-analyses, however, current guidelines on IE were based largely on
observational data and expert opinion, providing few specific recommendations on anticoagulation. A multi­
disciplinary approach and patient engagement are required to determine the timing and regimen of anti­
coagulation in patients with IE, especially in specific situations (e.g., receiving warfarin anticoagulation at the
time of IE diagnosis, cerebral embolism or ischemic stroke, intracerebral hemorrhage, or urgent surgery).
Collectively, individualized strategies on anticoagulation management of IE should be based on clinical evalu­
ation, available evidence, and patient engagement, and ultimately be developed by the multidisciplinary team.

Abbreviations: ACC, American College of Cardiology; AF, atrial fibrillation; AHA, American Heart Association; APS, antiphospholipid syndrome; APTT, activated
partial thromboplastin time; ARVC, arrhythmogenic right ventricular cardiomyopathy; CM, cardiac amyloidosis; CMBs, cerebral microbleeds; COR, class of
recommendation; CT, computed tomography; CTA, computed tomography angiography; DSA, digital subtraction angiography; DVT, deep vein thrombosis; EACTS,
European Association for Cardio-Thoracic Surgery; EEs, embolic events; ERS, European Respiratory Society; ESC, European Society of Cardiology; EULAR, European
League Against Rheumatism; HCM, hypertrophic cardiomyopathy; HES, hypereosinophilic syndrome; HRS, Heart Rhythm Society; ICH, intracerebral hemorrhage; IE,
infective endocarditis; INR, international normalized ratio; ISHLT, International Society for Heart and Lung Transplantation; LA, left atrium (left atrial); LMWH, low
molecular weight heparin; LOE, level of evidence; LV, left ventricle (left ventricular); LVAD, left ventricular assist device; LVOT, left ventricular outflow tract; MDT,
multidisciplinary team; MHV, mechanical heart valve; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; MS, mitral stenosis; MSCT, multi-
slice computed tomography; MT, mechanical thrombectomy; NBTE, non-bacterial thrombotic endocarditis; NOACs, non-vitamin K oral anticoagulants; NR, not
reported; NVE, native valve endocarditis; OAC, oral anticoagulants; PCC, prothrombin complex concentrate; PE, pulmonary embolism; PET/CT, positron emission
tomography/computed tomography; PPCM, peripartum cardiomyopathy; PT, prothrombin time; PVE, prosthetic valve endocarditis; RCM, restrictive cardiomyop­
athy; RCTs, randomized controlled trials; S aureus, Staphylococcus aureus; TE, thromboembolism; TEE, transesophageal echocardiography; TIA, transient ischemic
attack; TTE, transthoracic echocardiography; TTS, Takotsubo syndrome; UFH, unfractionated heparin; VHD, valvular heart disease; VKA, vitamin K antagonist; VTE,
venous thromboembolism.
* Corresponding authors at: Heart Failure Center, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases,
Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Rd, Beijing 100037, China.
E-mail addresses: yuhuizhangjoy@163.com (Y. Zhang), fwzhangjian62@126.com (J. Zhang).

https://doi.org/10.1016/j.thromres.2023.06.010
Received 19 October 2022; Received in revised form 5 June 2023; Accepted 9 June 2023
Available online 10 June 2023
0049-3848/© 2023 Published by Elsevier Ltd.
X. Zhu et al. Thrombosis Research 229 (2023) 15–25

1. Introduction among neurologically asymptomatic patients with left-sided IE [18].

Infective endocarditis (IE) is a life-threatening infection of the
endocardial surface that typically involves the heart valves (native or
prosthetic) or an indwelling intracardiac device. Owing to the vegeta­
tions (septic thrombi), IE can lead to a variety of vascular complications
(e.g., cerebral embolism, intracerebral hemorrhage, and renal infarc­
tion), which are correlated with increased early and late mortality
[1–3]. Although anticoagulation is the cornerstone for management of
thromboembolic complications [4], it remains controversial in IE pa­
tients, presumably because of the lack of randomized controlled trials
(RCTs) and high-quality meta-analyses, as well as a major concern sur­
rounding the hemorrhagic risk associated with anticoagulation. Physi­
cians are caught in a common conundrum where the benefit of treatment
or prophylaxis with anticoagulants in IE patients must be balanced
against the real or perceived risk of hemorrhage. Also, the intricate and
variable pathophysiological process encompassing embolic and hemor­
rhagic events in patients with IE remains to be fully elucidated. The
current guidelines consequently provide few specific recommendations
on anticoagulation in patients with IE [5–7], including the latest ACC/
AHA valvular disease guidelines [8]. In this setting, the following
questions are proposed: Should we consider anticoagulation in IE, and if
so, when and how? Can the existing antiplatelet therapy continue after
the diagnosis of IE? All these issues are undoubtedly enormous chal­
lenges for the physicians’ responsible managing IE cases.
The purpose of this review is to highlight contemporary knowledge
associated with embolic and hemorrhagic risks in IE patients that may
assist in the clinical evaluation of IE-related vascular complications, and
present an update on current anticoagulation management strategies in
patients with IE.
2. Epidemiology
IE carries a high risk of embolic events (EEs), with a reported inci­
dence ranging from 20 % to 74 % [9–14], peaking during the first 2
weeks of antibiotic therapy while dropping to only 6–21 % after
appropriate therapy [5,9,14,15]. Ischemic stroke is the most frequent
and severe embolic complication of left-sided IE, with an incidence be­
tween 6 % and 65 % that differs widely depending on the patient pop­
ulation, imaging modality, and treatment (Table 1)
[12,14,16–19,21–23]. For instance, when magnetic resonance imaging
(MRI) is routinely done, the ischemic stroke incidence can be up to 70 %
Studies have investigated the impact of anticoagulation on the
incidence of ischemic stroke in IE. One retrospective study shows that
the risk of ischemic stroke is similar in IE patients with or without
anticoagulation [23], which is compatible with most [17,22–25], but
not all studies (Table 2) [26]. Spleen infarction is the second most
frequent embolic complication of left-sided IE, occurring in 8 % to 26 %
of IE patients, followed by renal infarction (4 % to 9 %) [9,13,14]. Septic
pulmonary emboli are frequent complications of right-sided IE, occur­
ring in 4 % to 20 % of IE patients [9,14].
On the other hand, intracerebral hemorrhage (ICH) represents the
most feared hemorrhagic complication of IE [22], with a reported
incidence ranging from 2 % to 31 % (see Table 1) [12,16,19–23], mainly
resulting from hemorrhagic transformation (HT) of an embolic infarct
(Fig. 1). Compared to HT rates of 40 % to 50 % in older series [16,28],
more recent studies suggest rates of <20 % [22,23]. Moreover, some
investigators have looked at the impact of anticoagulation on the inci­
dence of ICH in IE (see Table 2). In one retrospective study of 56 patients
with Staphylococcus aureus (S aureus) IE, Tornos et al. noticed that ICH
occurred in roughly 30 % of those on anticoagulation versus 3 % of those
without this treatment [16], suggesting that anticoagulation was likely
to increase the risk of ICH in patients with S aureus IE, which was similar
to the findings of one multicenter observational study [22]. In this
observational study, the investigators reported that IE patients with
continued anticoagulation underwent a larger number of hemorrhagic
events, even following one week of antibiotic treatment [22]. However,
several other studies did not confirm these findings [25–27].
3. Pathophysiology
The normal cardiac endothelium is resistant to frequent bacteremia
caused by daily activities such as chewing and tooth brushing [29].
Therefore, the development of IE requires several independent factors to
occur at the same time. Firstly, valve sclerosis, rheumatic valvulitis or
direct bacterial activity (especially from S aureus) can lead to vascular
endothelial damage, producing a suitable location for bacterial attach­
ment and colonization [2,30]. Secondly, after endothelial injury, the
release of inflammatory cytokines and tissue factors with the expression
of related fibronectin results in the formation of platelet-fibrin
thrombus, thus facilitating bacterial adhesion [31]. Thirdly, bacterial
colonization activates additional cycles of endothelial injury and
thrombus deposition, finally forming an infected mass or ‘vegetation’ by

Table 1
Frequency of embolic events and ICH in infective endocarditis.
First author Year published (ref. Population Imaging Ischemic stroke Other EEs ICH
#) (%) (%)
All Symptomatic Asymptomatic
(%) (%) (%)

Tornos P 1999 [16] S aureus IE, N = 56, retrospective study 100 % CT 21 NR NR NR 13

Heiro M 2000 [12] IE, N = 218, retrospective cohort study 100 % CT 6 NR NR 28 2
Thuny F 2005 [14] IE, N = 384, prospective study 95 % CT 16 NR NR 27 NR
Dickerman SA 2007 [17] Left-sided IE, N = 1437, prospective NR 15 NR NR NR NR
cohort study
Cooper HA 2009 [18] IE, N = 56, prospective cohort study 71 % MRI 59 25 34 NR NR
Duval X 2010 [19] IE, N = 130, prospective study 100% 52 NR NR NR 16a
MRI
10 % CT
Okazaki S 2011 [20] IE, N = 26, retrospective cohort study 100% NR NR NR NR 31
MRI
100 % CT
Hess A 2013 [21] IE, N = 109, prospective cohort study 100% 37 0 37 NR 10a
MRI
García-Cabrera 2013 [22] Left-sided IE, N = 1345, retrospective CT 14 NR NR NR 4
E study
Salaun E 2018 [23] Left-sided IE, N = 963, retrospective study MRI, CT 16 NR NR NR 7

Abbreviations: CT, computed tomography; EEs, embolic events; ICH, intracerebral hemorrhage; IE, infective endocarditis; MRI, magnetic resonance imaging; NR, not
reported; NVE, native valve endocarditis; PVE, prosthetic valve endocarditis; S aureus, Staphylococcus aureus.
a
Including patients with subarachnoidal hemorrhage.

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X. Zhu et al. Thrombosis Research 229 (2023) 15–25

Table 2
Frequency of ischemic stroke and intracerebral hemorrhage in IE patients with-versus-without anticoagulation.
First author Year published Population Imaging Follow-up in weeks On anticoagulation No anticoagulation
(ref. #) (mean or median)
Ischemic ICH Ischemic ICH
stroke (%) (%) stroke (%) (%)

Tornos P 1999 [16] Spain, S aureus IE, N = 56, retrospective 100 % NR 24a 29a 2a0 3a
observational study CT
Heiro M 2000 [12] Finland, IE, N = 218, retrospective cohort 100 % NR NR 2 NR 2
study CT
Dickerman SA 2007 [17] USA, left-sided IE, N = 1437, prospective NR NR 15 NR 13 NR
multicenter cohort study
Rasmussen 2009 [26] Denmark, Sweden, S aureus IE, N = 175, MRI, CT NR 15 †
3 34 †
3
RV prospective cohort study
Snygg-Martin 2011 [27] Sweden, Denmark, left-sided NVE, N = 587, MRI, CT NR 2 2 18 2
U prospective observational study
García- 2013 [22] Spain, left-sided IE, N = 1345, retrospective CT NR 18 9‡ 13 3‡
Cabrera E multicenter observational study
Lee SJ 2014 [25] Republic of Korea, IE, N = 150, retrospective MRI, CT NR 16 10 20 4
monocentric study
Salaun E 2018 [23] France, left-side IE, N = 963, retrospective M RI, CT 68 w 15 8 17 7
monocentric study
Davis KA 2019 [24] USA, left-side IE, N = 258, retrospective CT, MRI 10 w 34 6 35 11
cohort study
a
The data on 2 patients with biological protheses not available.
†
Including patients with intracerebral infection, P = 0.02.
‡
P < 0.001.

‘burying’ of proliferative organisms in the protective matrix of serum
molecules and platelets [2].
Similarly, the pathophysiological mechanisms underlying the
vascular complications of IE include the interactions among the above
factors and immune reactions from the host. These interactions lead to
the creation of vegetation that followed by the growth of vegetation due
to activated platelets and a coagulation cascade activated by cytokines,
and the migration of vegetation particles by detaching and dissemi­
nating. These detached particles travel with blood flow until lodging in a
vascular bed, thus resulting in vascular phenomena, such as major
arterial emboli (most often cerebral in location), ICH, and Janeway le­
sions [2]. Also, the immune reactions from the host cause the formation
and the deposition of circulating immune complexes, thereby resulting
in immunological phenomena (e.g., Osler nodes and Roth spots) (Fig. 2)
[32], which might also be septic microthrombi, or local immunologic
reaction caused by microthrombi [1,2,5,33].
Importantly, the cerebral emboli, of which nearly 40–70 % lodge in
the distribution of the middle cerebral artery (MCA) [12,34], are often
followed by HT [23]. A larger territorial infarction increases the risk of
HT, while the patients with smaller infarcts are at risk of HT as well,
especially when anticoagulation and S aureus IE concur [35]. Potential
mechanisms for ICH in IE patients also comprise rupture of a mycotic
aneurysm, infectious erosion of atherosclerotic vessels, and anti­
coagulation intervention [1,16,28].
4. Clinical evaluation
Reaching a rapid and accurate clinical evaluation is of critical
importance in IE patients with suspected vascular complications.
4.1. Clinical history and physical examination
In the initial evaluation, a focused medical history and physical ex­
amination, together with collection of vital signs, should be obtained, in
order to determine the attack time, location, and severity of vascular
complications, and whether they are ongoing. Physical examination
should include vascular and immunological phenomena, such as major
arterial emboli, ICH, Osler nodes, as noted above. Moreover, clinicians
should pay attention to the comorbidities and concomitant treatments
that may cause embolism/bleeding or change their treatment (e.g.,
atrial fibrillation [AF], valvular heart disease [VHD], mechanical heart
valve [MHV], cardiac devices, thrombocytopenia, uremia, liver disease,
antithrombotic therapy, and concurrent medications that can increase
or decrease anticoagulant drug levels) [4].
4.2. Laboratory assessment
With respect to embolic/hemorrhagic risks in IE, laboratory assess­
ment should comprise complete blood count, prothrombin time (PT)/
international normalized ratio (INR), activated partial thromboplastin
time (APTT), and evaluation of hepatic and renal function [4].
4.3. Imaging evaluation
Echocardiography, either transthoracic echocardiography (TTE) or
transesophageal echocardiography (TEE), plays an important role in the
measurement of the size and mobility of vegetations and thereby pre­
diction of embolic events in IE patients [9,14,17,22]. TTE and TEE can
supplement each other for the comprehensive assessment of anatomy
and hemodynamics in IE patients [5]. Of note, another potentially life-
threatening source of TE is non-bacterial thrombotic endocarditis
(NBTE), characterized by the presence of sterile vegetations on the heart
valves. Despite the difficulties in the diagnosis of NBTE, it is necessary to
differentiate NBTE from IE. Specifically, when NBTE is highly suspected,
TEE and comprehensive laboratory assessment should be performed [5].
Other imaging modalities are playing an increasing role in the
diagnosis and management of IE-related vascular complications, such as
multi-slice computed tomography (MSCT), positron emission tomogra­
phy/computed tomography (PET/CT), and MRI [5,6,13,18,19]. The
higher sensitivity of MRI facilitates better detection of cerebral lesions in
neurologically asymptomatic patients with IE [5]. Also, for IE cases with
ICH, computed tomography angiography (CTA) or magnetic resonance
angiography (MRA) is reasonable for detection of intracranial infectious
aneurysms [5], and digital subtraction angiography (DSA) should be
considered, if necessary [5,6].
A topic of controversy is whether surveillance imaging to detect
cerebral/systemic vascular complications should be done in all patients
with IE [5]. Given the unexpectedly high incidence of cerebrovascular
complications in neurologically asymptomatic patients with left-sided IE
[18,19], we currently advocate that brain MRI should be performed for
all left-sided IE patients [6], particularly those cases with indications for
anticoagulation, although there have been no studies investigating the

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X. Zhu et al.
cost-effectiveness of routine brain MRI in IE patients without neuro­
logical symptoms. In addition, follow-up MRI may be considered in IE
patients with cerebral microbleeds (CMBs), despite the controversies in
the association between CMBs and ICH [1,5,20,21,36].
However, prediction of vascular events and thus development of risk
stratification in the individual IE patient remain tremendously difficult,
although they are of importance in optimizing management. Table 3
summarizes the predictors of EEs or ICH for IE patients in the published
literature, which might provide valuable clinical information. Notably, S
aureus or fungal etiology is associated with a higher risk of intracerebral
hemorrhage in patients with IE [16,22,23].
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Thrombosis Research 229 (2023) 15–25
Fig. 1. Ischemic stroke and hemorrhagic trans­
formation in infective endocarditis: (A to B) Ischemic
infarcts on brain CT scan at the stroke symptom onset
in one patient with IE (white arrow). (C to D) Hem­
orrhagic transformation on non-contrast CT scan at
Day 5 in the same patient (double red arrows). (E to
F) Hemorrhagic lesions becoming smaller on follow-
up CT scan at Day 12 (red arrow). (For interpreta­
tion of the references to colour in this figure legend,
the reader is referred to the web version of this
article.)
5. Management
Management of anticoagulation in IE patients presents substantial
controversies and challenges. Until recently, guidelines on IE were based
largely on observational data and expert opinion, providing few specific
recommendations on anticoagulation, because of the low incidence of
this disease, the lack of RCTs and the limited number of meta-analyses
[5]. Acknowledging these limitations, anticoagulation management in
IE should be individualized using clinical evaluation in conjunction with
available evidence and patient engagement, and ultimately be directed
by an endocarditis multidisciplinary team (MDT), including cardiolo­
gists, cardiac surgeons, infectious disease specialists, neurologists,
X. Zhu et al. Thrombosis Research 229 (2023) 15–25

Fig. 2. Mechanisms and organ manifestations of vascular complications in IE: (A to B) Continuous bacteremia triggers the interactions among bacteria, damaged
valvular endothelium, platelets, proteins, subendothelial matrix, cytokines, coagulation system, and immune reaction from the host, leading to the creation of
vegetations and circulating immune complexes (stage 1). Further interactions cause progressive growth of vegetation, followed by the detachment of vegetation
particles (stage 2). (C) These detached particles travel with blood flow until lodging in a vascular bed (stage 3), thus resulting in vascular phenomena. When the
septic particles are large enough (stage 4), they can result in embolic complications, particularly cerebral emboli (white arrow) often followed by hemorrhagic
transformation (red arrow). The immune complexes deposition, or septic microthrombi can cause local immunological phenomena, such as Osler nodes (painful,
erythematous nodules on the tips of the fingers), and Roth spots (retina hemorrhages with pale centers). (For interpretation of the references to colour in this figure
legend, the reader is referred to the web version of this article.)

interventional neuroradiologists, and other specialists if needed [5].
5.1. Indication for anticoagulation
Although one might expect that the incidence of TE will be reduced
by anticoagulation in IE patients, there is no convincing evidence to
support this. In an analysis of one prospective cohort of IE patients, the
authors found no significant difference in stroke incidence between
patients with-and-without vitamin K antagonist (VKA) [17], in keeping
with the results of most studies [22–25], and supporting that IE itself is
not an indication for anticoagulation [37]. However, IE patients with
high thrombotic risk are more likely to benefit from anticoagulation,
even if the bleeding risk is high. Table 4 provides indications for anti­
coagulant treatment with high risk of thromboembolism (TE)
[4,8,38–42]. Moreover, compelling indications for anticoagulation with
VKA are summarized in Table 5 [8,38–41,43,44].
Despite the richness of platelets in vegetations and the promising
results in previous studies [2,45,46], the only published RCT comparing
oral aspirin 325 mg/d with placebo in IE patients, not only found no
significant benefit in terms of embolic events, but observed more
bleeding events in the oral aspirin group [47]. Therefore, routine initi­
ation of antiplatelet therapy is currently not recommended for IE pa­
tients, although continuation of long-term antiplatelet therapy in IE
patients without hemorrhagic complications, may be reasonable [6].
5.2. Timing of anticoagulation
When an indication for anticoagulant therapy is met in patients with
IE, the next more challenging issue becomes the timing of anti­
coagulation, which is an important consideration and encompasses
initiation, continuation, discontinuation, and reintroduction of anti­
coagulation. Determining the appropriate timing for anticoagulation has

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X. Zhu et al. Thrombosis Research 229 (2023) 15–25

Table 3 Table 4
The Predictors of Embolic Events or Intracerebral Hemorrhage for Patients with Primary indications for anticoagulant therapy with high risk of TE.
IE. Indication for anticoagulation Clinical features that may further
Factors Predictive of EEs Predictive of ICH increase the risk of TE

Mildly Strongly Mildly Strongly MHV Presence of any of the following: 1)

mitral or tricuspid MHV; 2) older-
S aureus pathogen Yes Yes [16,22] generation MHV (eg, ball-in-cage); 3)
[10,14,17,18,22] MHV and additional risk factors for TE
Fungal pathogen Yes [6,15] Yes [22,23] (e.g., AF, previous TE, LV dysfunction,
Vegetation size >10 Yes [9,14] or hypercoagulable state) [8]
mm Left ventricular assist device [38]
Vegetation size ≥30 Yes [22] Yes* Valvular AF with moderate-to-severe MS
mm [22] [39]
Mobility of the Yes [9,14] Rheumatic MS and presence of any of the
vegetation following: 1) AF; 2) a prior embolic
Increasing vegetation Yes† event; or 3) an LA thrombus [8]
size during therapy [15] Nonvalvular AF and presence of any of Presence of one and more of the
Mitral valve Yes‡ Yes [17] the following: 1) CHA2DS2-VASc score following factors: 1) CHA2DS2-VASc
involvement [22] of ≥2 in men or ≥ 3 in women; 2) RCM; score ≥ 4; 2) ischemic stroke/TIA within
Previous embolism Yes [15] 3) ARVC; 4) cardiac amyloidosis; 5) 3 months; or 3) stroke risk ≥10 % per
Acute ischemic stroke Yes LVNC; or 6) PPCM [40] year [4]
[22,23,28] HCM and presence of any of the
Anticoagulant therapy Yes [16,22] following: 1) AF, 2) left ventricular
CMBs on MRI Yes [20] apical aneurysm, or 3) LVOT
Abbreviations: CMBs, cerebral microbleeds; EEs, embolic events; ICH, intrace­ obstruction with LA dimension (≥48
mm) [40]
rebral hemorrhage; MRI, magnetic resonance imaging.
* Venous thromboembolism (VTE) [4], Presence of any of the following: 1) VTE
Adjusted hazard ratio (HR): 2.93; 95 % confidence interval (CI): 0.91–9.49;
including DVT and/or PE within 3 months; 2) history of
P = 0.073. unprovoked or recurrent VTE; 3) active
†
Relative risk (RR): 3.77; CI: 0.97–12.57, P = 0.007. cancer and history of cancer-associated
‡
HR: 1.33; 95 % CI: 0.98–1.80; P = 0.069. VTE [4]
Prior thromboembolic events with
discontinuation of anticoagulation [4]
the dual therapeutic purpose of preventing embolic events while mini­
Left atrial/ventricular thrombus [4] Presence of any of the following: 1)
mizing hemorrhagic risk. Therefore, the clinician should assess the net ARVC; 2) HES; 3) TTS; or 4) PPCM [40]
clinical benefit of anticoagulation in the context of real or perceived Antiphospholipid syndrome (APS) with Presence of triple antiphospholipid
risks of hemorrhage and TE. For example, in IE patients who are at prior VTE [41] (aPL) positivity [42]
relatively low thrombotic risk (e.g., nonvalvular AF with CHA2DS2-VASc Abbreviations: AF, atrial fibrillation; ARVC, arrhythmogenic right ventricular
score <2 in men or <3 in women) [4,43], it may be reasonble to delay cardiomyopathy; CM, cardiac amyloidosis; DVT, deep vein thrombosis; HCM,
anticoagulation for a short duration and reassess the need for anti­ hypertrophic cardiomyopathy; HES, hypereosinophilic syndrome; LA, left
coagulation after consideration of patient values/preferences. atrium (left atrial); LV, left ventricle (left ventricular); LVOT, left ventricular
The following paragraphs will address how to determine the timing outflow tract; MHV, mechanical heart valve; MS, mitral stenosis; PE, pulmonary
of anticoagulation in IE patients with specific situations. embolism; PPCM, peripartum cardiomyopathy; RCM, restrictive cardiomyopa­
thy; TE, thromboembolism; TIA, transient ischemic attack; TTS, Takotsubo
syndrome; VTE, venous thromboembolism.
5.2.1. Receiving VKA anticoagulation at the time of IE diagnosis
For patients who are already receiving VKA anticoagulation at the
time of IE diagnosis, whether to continue anticoagulation remains 5.2.2. Intracerebral hemorrhage
controversial. In an observational study of 587 patients with native ICH indicates primary hemorrhage, or HT of an ischemic stroke. Not
valve endocarditis (NVE), the investigators found no increased risk of surprisingly, the presence of ICH was related to a poorer outcome in
hemorrhagic complications in patients who continue warfarin therapy, patients with IE [22,48]. Nevertheless, a unique challenge is deter­
thus suggesting cautious continuation of anticoagulation with warfarin mining the timing of reintroduction of anticoagulation after ICH in IE
in NVE patients without ICH [27], despite the potential for selection bias patients with MHV. The European Society of Cardiology (ESC) suggests
in the study. However, the latest American College of Cardiology/ interruption of all anticoagulation once ICH is diagnosed, and reintro­
American Heart Association (ACC/AHA) guideline suggests that tem­ duction of parenteral anticoagulants in IE patients with MHV as soon as
porary interruption of VKA anticoagulation may be considered in pa­ possible following multidisciplinary discussion [5]. It is important to
tients receiving anticoagulation with VKA at the time of IE diagnosis stress, however, that the recurrence of ICH in these patients can result in
(Class 2b recommendation), probably because of the combined risk of further discontinuation of anticoagulation and higher risk of thrombosis
bleeding from emergency surgeries and risk of ICH, and a high likeli­ [4]. In general, risk factors associated with the recurrence of ICH
hood of requiring early valve surgery (roughly 50 %) in prosthetic valve comprise the mechanism of ICH (namely, spontaneous vs. secondary),
endocarditis (PVE) patients [8]. Of note, PVE accounts for 10 % to 30 % the location of the initial hemorrhage, the presence and number of ce­
of all patients with IE and involves bioprosthetic and mechanical valves rebral CMBs on MRI, and receiving anticoagulant therapy [4,49].
equally [5], whereas there is no evidence that embolic vegetations can Therefore, the risk-benefit evaluation of restarting anticoagulation
be controlled by VKA in patients with PVE. It is important to emphasize, should consider the cause and severity of the ICH and whether the cause
however, that interruption of anticoagulation without weighty reasons is correctable, and indication for anticoagulation must be reassessed in
should not be considered when convincingly indicated for anti­ this setting as well.
coagulation. Accordingly, in high-thrombotic-risk patients receiving However, for IE patients with MHV and ICH, no prospective studies
VKA therapy at the time of IE diagnosis, replacement of VKA by have investigated the benefits or risks of restarting anticoagulation after
parenteral anticoagulants for 1–2 weeks, then transitioning carefully to ICH. In a nationwide observational study, the investigators suggested
appropriate oral anticoagulants (OAC), may be considered, especially that anticoagulation may be started 7–8 weeks after ICH in patients with
for S aureus IE [1,5], although the impact of S aureus IE together with AF [50], while this timeframe does not seem to meet the special needs of
anticoagulation on the risk of ICH is mixed [16,22,25,26]. patients with MHV [51]. In a recent multicenter retrospective study of

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X. Zhu et al. Thrombosis Research 229 (2023) 15–25

Table 5 interruption of anticoagulation carries a higher risk of TE or valve

Current guidelines for recommendations on compelling indications for anti­ dysfunction in patients with PVE [53]. In an observational study by
coagulation with a VKA. Delahaye et al., the investigators have suggested that heparin anti­
Guideline Year Recommendations COR LOE coagulation should be sustained in PVE patients whenever there is a
published cerebral infarction, unless it is hemorrhagic and/or large [54]. Hence,
(ref. #) for IE patients with ischemic stroke and without hemorrhage, the 2015
ESC/ 2016 [41] Vitamin K antagonist therapy (INR I B ESC guidelines suggest replacement of VKA by parenteral anticoagulants
EACTS 2.0–3.0 or higher) is recommended for 1–2 weeks under close monitoring (Class IIa recommendation) [5].
for stroke prevention in AF patients
Conversely, the most recent ACC/AHA guideline suggests temporary
with moderate-to-severe MS or
MHVs discontinuation of all forms of anticoagulation in IE patients with evi­
AHA/ 2019 [43] For patients with AF who have I B dence of cerebral embolism or stroke, irrespective of the other in­
ACC/ MHVs, warfarin is recommended dications for anticoagulant therapy (Class 2a recommendation) [8],
HRS providing no specific recommendations on the timing of restarting
ESC/ERS 2019 [41] Oral anticoagulant treatment with I B
a VKA for an indefinite period is
anticoagulation. Also, some investigators have pointed out that anti­
recommended for patients with coagulation is highly perilous in IE patients with acute ischemic stroke
APS after PE until infection is fully controlled and the evidence of no mycotic aneu­
ACC/AHA 2020 [8] In patients with MHV, 1 A rysms or other pathology related to high risk of ICH is confirmed [55].
anticoagulation with VKA is
To some degree, however, we agree that the hemorrhagic risk associated
recommended
In patients with rheumatic MS and 1 C- with anticoagulation after ischemic stroke may be overestimated in
1) AF, 2) a prior embolic event, or LD patients with IE [26,35], but it is not nil. For these reasons, in IE patients
3) an LA thrombus, anticoagulation with a convincing indication for anticoagulation who develop ischemic
with a VKA is indicated stroke, temporary discontinuation of all forms of anticoagulation and
For patients with AF and rheumatic 1 C-
prompt initiation of appropriate antibiotic therapy for 1–2 weeks fol­
MS, long-term VKA oral EO
anticoagulation is recommended lowed by reassessing HT risk and recurrence of cerebral embolism as
AATS/ 2020 [38] Initiation of anticoagulation and I B well as starting anticoagulation with great caution in the absence of
ISHLT antiplatelet agents and INR targets contraindications and neurologic complications, may be a reasonable
for anticoagulant therapy with VKA
strategy to balance hemorrhagic and embolic risk [56]. In addition,
should follow the Instructions for
Use from the LVAD manufacturer mechanical thrombectomy (MT) could be an option in selected patients
ESC/ 2021 [44] OAC using a VKA is recommended I B with large-vessel embolic stroke associated with IE [5,57], especially for
EACTS lifelong for all patients with MHV patients with high risk of hemorrhage.
In patients with MHVs, it is I C
recommended to (re)-initiate VKAs
5.2.4. Urgent surgical or invasive procedure
on the first postoperative day
The management of IE patients receiving long-term OAC in whom
Abbreviations: ACC, American College of Cardiology; AHA, American Heart interruption of anticoagulation is needed for urgent surgical or invasive
Association; APS, antiphospholipid syndrome; COR, Class of Recommendation; procedures should consider the type of procedure, thromboembolic risk
EACTS, European Association for Cardio-Thoracic Surgery; ERS, European
factors, the length of time to interrupt oral anticoagulation, and bleeding
Respiratory Society; ESC, European Society of Cardiology; EULAR, European
risk [8]. However, there are no RCTs evaluating a strategy of
League Against Rheumatism; HRS, Heart Rhythm Society; INR, international
normalized ratio; ISHLT, International Society for Heart and Lung Trans­ continuation-versus-discontinuation of OAC in IE patients receiving
plantation; LA, left atrium (left atrial); LOE, Level of Evidence; LVAD, left ven­ long-term OAC who require urgent surgical or invasive procedures, thus
tricular assist device; MHV, mechanical heart valve; MS, mitral stenosis; OAC, decisions about anticoagulation in these patients should be individual­
oral anticoagulant; PE, pulmonary embolism; VKA, vitamin K antagonist. ized and take the trade-offs between TE and hemorrhage into account,
especially for patients with MHVs.
MHV-patients with anticoagulation-associated ICH, the authors suggest For MHV-patients who require minor invasive procedures (e.g.,
that therapeutic anticoagulation should not be routinely reinitiated cataract removal, or dental extraction) where blood loss is commonly
within 14 days after ICH to balance between least hemorrhagic and small and easily controlled, current guidelines recommend continued
embolic complications, and that restarting anticoagulation at day 6 after therapeutic anticoagulation with VKA [8,44]. However, for MHV-
initial ICH may be considered only in high-risk patients with MHV [52]. patients who require emergency major surgeries, temporary interrup­
Nevertheless, we favor a more conservative approach, because of the tion of VKA and administration of intravenous prothrombin complex
potentially high risk of hemorrhage in IE patients. Therefore, for IE concentrate (PCC) are reasonable [8,44,58], the latter aiming for a rapid
patients with MHV and ICH, it might be reasonable to reassess hemor­ and predictable reversal of VKA [58]. Furthermore, for MHV-patients
rhage risk carefully and restart anticoagulation with extreme caution 2 with high-thrombotic-risk factors (e.g., mitral MHV, see Table 4), cur­
weeks after ICH, if patients are clinically stable without contraindica­ rent guidelines suggest therapeutic bridging with either unfractionated
tions. Of note, the strength of this evidence is very low for IE patients, heparin (UFH) or low molecular weight heparin (LMWH) in the preop­
thus decision on the timing of anticoagulation after ICH, should be erative period when the INR is subtherapeutic [8,44]. Also, (re)initiation
individualized and ultimately be made by the multidisciplinary team. of VKA on the first postoperative day is recommended for patients with
MHVs [44]. Of note, for patients with an aortic bileaflet MHV and no
5.2.3. Cerebral embolism or ischemic stroke other risk factors for TE who are undergoing major surgical or invasive
Embolic stroke in IE may represent disseminated vegetation parti­ procedures, temporary discontinuation of VKA therapy and avoiding
cles, or real TE unrelated to the valve infection instead, particularly for bridging anticoagulation when the INR is subtherapeutic are recom­
PVE patients. In this setting, the evidence base for the timing of anti­ mended, due to the low risk of TE after stopping VKA anticoagulation for
coagulation is quite mixed. The 2015 AHA scientific statement advises only a few days in these patients [8]. However, caution is needed in
that it is reasonable to interrupt all forms of anticoagulation for at least generalizing the foregoing recommendations in IE patients, because of
2 weeks in IE patients with MHV and embolic stroke. This time frame the lack of high-quality evidence in the setting of IE.
may permit thrombus organization and hold back the acute hemorrhagic
transformation of embolic stroke [6]. On the other hand, a longer

21
X. Zhu et al. Thrombosis Research 229 (2023) 15–25

5.3. Anticoagulant options and bridging therapy
Current recommendations on oral or parenteral anticoagulants in IE,
are based on observational evidence and expert opinions. Hence, the
importance of tailored anticoagulants to the best-suited patients with IE
can never be over-emphasized.
5.3.1. Vitamin K antagonist
To date, the VKA remains the cornerstone of therapy for patients
with high thrombotic risk (e.g., MHVs, moderate-to-severe mitral
stenosis [MS] with AF, see Table 5), although concern has been raised
about the hemorrhagic risk associated with VKA in IE [16,22]. However,
routine VKA anticoagulation is not recommended for patients with NVE
unless an evidence-based indication for VKA exists [7,8]. On the other
hand, current guidelines provide no specific recommendations on target
INR for MHV-patients with IE [8,44], but until new controlled trials offer
additional information, it might be reasonable to implement the same
target INR (e.g., 2.5 or 3.0, depending on the clinical context) in MHV-
patients with IE as in MHV-patients without IE. Similarly, for MHV-
patients with IE, it is also important to maintain a low INR variability

Fig. 3. Algorithm for the anticoagulation management of IE.

Abbreviations: INR, international normalized ratio; LMWH, low molecular weight heparin; MDT, multidisciplinary team; MHV, mechanical heart valve; NOACs, non-
vitamin K oral anticoagulants; OAC, oral anticoagulants; PCC, prothrombin complex concentrate; S aureus, Staphylococcus aureus; UFH, unfractionated heparin; VKA,
vitamin K antagonist.

22
X. Zhu et al.
[8,44]. In addition, attention should be paid to the paradoxical transient
procoagulant effect of VKA, especially when anticoagulation with VKA
is (re)initiated in MHV-patients with IE [59].
5.3.2. Non-vitamin K antagonist oral anticoagulants
Most non-vitamin K antagonist oral anticoagulants (NOACs) repre­
sent an advance in therapeutic safety when compared with VKA for
reducing the risk of thromboembolism in AF patients [43], and specific
NOACs, such as apixaban, may have lower risk of ICH than warfarin
[60], whereas the efficacy and safety of NOACs in IE have not been
systematically investigated. Notwithstanding, in patients receiving
NOACs for separate indication at the time of IE diagnosis, switching to
parenteral anticoagulants for 1–2 weeks in the absence of contraindi­
cations should be considered, especially for S aureus IE [1,5]. Addi­
tionally, for NOAC-eligible patients with high thrombotic risk (e.g.,
Nonvalvular AF with CHA2DS2-VASc score ≥ 4, see Table 4), initial
anticoagulation in IE patients should be individualized and be directed
by multidisciplinary team, due to the lack of evidence in this setting.
5.3.3. Bridging therapy
For bridging therapy with parenteral anticoagulants, there are no
controlled trials studying its role in IE patients while they are off OAC,
whereas some observational studies disclose an increased risk of hem­
orrhagic stroke in patients receiving anticoagulation with heparin dur­
ing the acute phase of IE [22,61]. However, bridging therapy might have
rational benefits in specific conditions (e.g., in unstable patients) [5].
Also, temporary bridging therapy with either UFH or LMWH may pro­
vide a rapid anticoagulant effect with an acceptable safety in patients
MHVs until therapeutic INR is achieved, but conclusions are mostly
based on a low level of evidence [62,63]. Notwithstanding, in IE patients
for whom the risk of TE is unacceptably high and discontinuation of OAC
is deemed necessary, temporary bridging therapy with UFH or LMWH
may be reasonable under close monitoring [4,5]. Among the recom­
mended heparins, however, UFH should be preferred in IE patients with
cerebrovascular complications, because it has short half-life and can be
completely reversed by protamine sulfate [4]. For example, for MHV-
patients with IE and cerebrovascular complication, when the timing of
(re)initiation of anticoagulation is appropriate, it may be reasonable to
begin cautiously with intravenous UFH titrated to an APTT range of 50
to 70 s for limited periods, followed by transitioning carefully to dose-
adjusted warfarin [6]. It is worth noting that, based on current guide­
lines, available evidence, and our experience, we propose an unvali­
dated algorithm for the anticoagulation management in IE patients
(Fig. 3), and recommend the management team to apply local expertise
to fill in the uncertainties.
6. Conclusions
Infective endocarditis carries a high risk of vascular complications,
and anticoagulation during this time period is challenging. Important
gaps in knowledge remain, such as cerebrovascular risk prediction,
timing of anticoagulation, anticoagulant options, and bridging therapy.
Collaboration among multiple centers is needed to resolve these ques­
tions, because of the overall rarity of IE. In the absence of RCTs and high-
quality meta-analyses, current guidelines on IE were based largely on
observational data and expert opinion, providing few specific recom­
mendations on anticoagulation. Importantly, the benefit of treatment or
prophylaxis with anticoagulants in IE patients must be balanced against
the real or perceived risk of hemorrhage. Therefore, individualized
strategies on anticoagulation management of IE should be based on
clinical evaluation, available evidence, and patient engagement, and
ultimately be developed by the multidisciplinary team.
Declaration of competing interest
The authors declare the following financial interests/personal
23
Thrombosis Research 229 (2023) 15–25
relationships which may be considered as potential competing interests:
This work was supported by the Key Projects in the National Science and
Technology Pillar Program of the 13th Five-Year Plan Period [grant
number 2017YFC1308300] for the design and conduct of the study, and
the National Natural Science Foundation of China [grant number
81873472] for the preparation and review of the manuscript.
Acknowledgments
The authors would like to credit Yuanyuan Bei and Sitong Liu for
assistance with graphic design.
Declaration of patient consent
The authors prove that informed consent was obtained from patient.
The patient has given consent for his/her images and other clinical in­
formation to be reported in the journal. The patient understands that
his/her name will not be published and due efforts will be made to
conceal his/her identity.
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