Research

JAMA Internal Medicine | Original Investigation

Association of Vegetation Size With Embolic Risk

in Patients With Infective Endocarditis
A Systematic Review and Meta-analysis
Divyanshu Mohananey, MD; Ashley Mohadjer, DO; Gosta Pettersson, MD, PhD; Jose Navia, MD;
Steven Gordon, MD; Nabin Shrestha, MD; Richard A. Grimm, MD; L. Leonardo Rodriguez, MD;
Brian P. Griffin, MD; Milind Y. Desai, MD

Supplemental content
IMPORTANCE Infective endocarditis is a life-threating condition with annual mortality of as
much as 40% and is associated with embolic events in as many as 80% of cases. These
embolic events have notable prognostic implications and have been linked to increased
length of stay in intensive care units and mortality. A vegetation size greater than 10 mm has
often been suggested as an optimal cutoff to estimate the risk of embolism, but the evidence
is based largely on small observational studies.

OBJECTIVE To study the association of vegetation size greater than 10 mm with embolic
events using meta-analytic techniques.

DATA SOURCES A computerized literature search of all publications in the PubMed and
EMBASE databases from inception to May 1, 2017, was performed with search terms including
varying combinations of infective endocarditis, emboli, vegetation size, pulmonary infarct,
stroke, splenic emboli, renal emboli, retinal emboli, and mesenteric emboli. This search was last
assessed as being up to date on May 1, 2017.

STUDY SELECTION Observational studies or randomized clinical trials that evaluated the
association of vegetation size greater than 10 mm with embolic events in adult patients with
infective endocarditis were included. Conference abstracts and non–English language
literature were excluded. The search was conducted by 2 independent reviewers blinded to
the other’s work.

DATA EXTRACTION AND SYNTHESIS Following PRISMA guidelines, the 2 reviewers

independently extracted data; disputes were resolved with consensus or by a third
investigator. Categorical dichotomous data were summarized across treatment arms using
Mantel-Haenszel odds ratios (ORs) with 95% CIs. Heterogeneity of effects was evaluated
using the Higgins I2 statistic.

RESULTS The search yielded 21 unique studies published from 1983 to 2016 with a total of
6646 unique patients with infective endocarditis and 5116 vegetations with available
dimensions. Patients with a vegetation size greater than 10 mm had increased odds of
embolic events (OR, 2.28; 95% CI, 1.71-3.05; P < .001) and mortality (OR, 1.63; 95% CI,
1.13-2.35; P = .009) compared with those with a vegetation size less than 10 mm.

CONCLUSIONS AND RELEVANCE In this meta-analysis of 21 studies, patients with vegetation

size greater than 10 mm had significantly increased odds of embolism and mortality. Author Affiliations: Heart and
Vascular Institute, Cleveland Clinic,
Understanding the risk of embolization will allow clinicians to adequately risk stratify patients
Cleveland, Ohio (Mohananey,
and will also help facilitate discussions regarding surgery in patients with a vegetation size Mohadjer, Pettersson, Navia, Grimm,
greater than 10 mm. Rodriguez, Griffin, Desai);
Department of Infectious Disease,
Cleveland Clinic, Cleveland, Ohio
(Gordon, Shrestha).
Corresponding Author: Milind Y.
Desai, MD, Heart and Vascular
Institute, Cleveland Clinic, 9500
JAMA Intern Med. doi:10.1001/jamainternmed.2017.8653 Euclid Ave, Desk J1-5, Cleveland, OH
Published online February 19, 2018. 44195 (desaim2@ccf.org).

(Reprinted) E1
© 2018 American Medical Association. All rights reserved.

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 Research Original Investigation
I
nfective endocarditis is a rare but potentially life-
threating condition with annual mortality of as much as
40%.1,2 Infective endocarditis is often accompanied by sev-
eral complications that contribute to morbidity and mortal-
ity, prime among them being systemic embolic events.
Embolic events have notable prognostic implications and have
been linked to increased length of intensive care unit stay and
mortality.3,4 A vegetation size greater than 10 mm has often
been suggested as an optimal cutoff to estimate the risk of
embolic events. This cutoff is used by the American Heart
Association guidelines on infective endocarditis as an impor-
tant part of their recommendations for early surgery and also
forms an integral part of protocols for large prospective clini-
cal trials.5,6 However, the evidence behind this seemingly ar-
bitrary cutoff is based largely on observational data from small
studies with varied methods and periods of observation and
the significant potential for selection bias. Previous literature
on embolic risk in patients with large vegetations has yielded
varied results. Some studies have suggested that the risk
of embolic events is not increased with larger vegetation
sizes,7,8 whereas others have noted significantly increased odds
of systemic embolization with a vegetation size greater than
10 mm.9,10 A meta-analysis11 published in 1997 aimed to fill this
gap in the literature and reported a significantly increased risk
of systemic embolization and a borderline increased risk of
death with large vegetations. However, this analysis had
several design flaws, such as inclusion of no vegetation in the
group with a vegetation size less than 10 mm, limitation of the
search to MEDLINE, no formal assessment of study quality, and
no quantification of heterogeneity.11 Moreover, several large
studies have been published on this topic since 1997, and an
updated meta-analysis is needed. Therefore, we conducted a
systematic review of literature and meta-analysis to study
the association of a vegetation size greater than 10 mm with
embolic events. Within our selected pool of studies, we also
evaluated the association of a vegetation size greater than
10 mm with all-cause mortality. We further used meta-
regression techniques to evaluate the association of age, sex,
and type of involved valve with the overall risk of emboliza-
tion with a vegetation size greater than 10 mm.
Methods
Data Sources and Searches
We performed a computerized literature search of all publica-
tions in the PubMed and EMBASE databases from inception to
May 1, 2017. We then manually searched the reference lists of
included articles. This search was last assessed as being up to
date on May 1, 2017 (Figure 1). Our aim was to include all ran-
domized and nonrandomized studies conducted on patients
hospitalized for infective endocarditis with a comparison be-
tween those with and without a vegetation size greater than
10 mm with regard to the outcome of embolic events. Inclu-
sion of vegetation size equal to 10 mm varied, with some stud-
ies including it in the group with vegetation sizes greater than
10 mm and others including it in the group with vegetation sizes
less than 10 mm (Table). Search terms included varying com-
E2 JAMA Internal Medicine Published online February 19, 2018 (Reprinted)
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Association of Vegetation Size With Embolic Risk in Infective Endocarditis
Key Points
Question What is the association of vegetation size greater than
10 mm with embolic events in patients with infective endocarditis?
Findings In this systematic review and meta-analysis of 21 unique
studies that included 6646 unique patients with infective
endocarditis and 5116 measured vegetations, patients with a
vegetation size greater than 10 mm had significantly increased
odds of embolic events and mortality.
Meaning Large vegetations (>10 mm) may be associated with
an increased risk of embolization.
Figure 1. PRISMA Diagram of Search Strategy for Meta-analysis
4576 References identified using
PubMed and EMBASE
3832 References after duplicates
removed
3549 Excluded
372 Non-English language
1757 Case reports, case series, or abstracts
1087 Did not meet inclusion criteria
54 Studies on prosthetic valves, devices,
no echocardiographic imaging modalities,
or nonquantitative assessment
279 Reviews articles, letters, and 1
meta-analysis
283 Full texts reviewed
264 Excluded
202 Studies did not meet inclusion criteria
48 Studies with not enough information to
abstract data
12 Studies on devices and prosthetic valves
2 Studies on 3D TTE
21 Studies included in qualitative
analysisa
21 Studies included in quantitative
analysis
The search was last assessed as being up to date on May 1, 2017. TTE indicates
2-dimensional transthoracic echocardiography.
a
Two studies were added after manual review.
binations of the following keywords: infective endocarditis,
emboli, vegetation size, pulmonary infarct, stroke, splenic
emboli, renal emboli, retinal emboli, and mesenteric emboli.
Study Selection
We applied the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses statement (PRISMA) to the meth-
ods for this study.29 We used the following inclusion criteria:
(1) studies of adult patients with native valve infective endo-
carditis due to any organism, (2) studies that provided the in-
formation on embolic events in patients with a vegetation size
less than 10 mm and a vegetation size greater than 10 mm, and
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 Table. Description of Studies Included in the Meta-analysis
Patients With Inclusion Patients With
Patients Measured Cutoff Above Staphylococcus
Years of With IE, Vegetation or Below aureus Bacteremia,
Source Study Study Type No. Sizes, No. Valves Involved Type of EE 10 mm Criteria for IE No. (%)
12
Wong et al, 1978-1981 Prospective 34 27 Aortic, mitral, Splenic, bone, >10 3 of the Following present: fever, 16/34 Patients (47.1)
1983 tricuspid cerebral, pulmonary, regurgitant murmur, EE, or bacteremia
renal

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Robbins et al,13 1979-1982 Prospective 21 17 Tricuspid, pulmonary, Pulmonary >10 Major: echocardiographic evidence of 11/23 Patients (47.8)
1986 prosthetic vegetations, fever; minor: bacteremia, EE,
murmur (need 2 major or 1 major +3 minor)
Lutas et al,14 1979-1982 Retrospective 77 42 Aortic, mitral, NA <10 Not clear, mentions bacteremia and 22/76 Patients with
1986 tricuspid, prosthetic vegetations blood cultures (28.9)
Buda et al,7 NA Prospective 50 18 Aortic, mitral, Cerebral, peripheral NA Presence of murmur with ≥2 positive blood 21/50 Patients (42.0)
1986 tricuspid culture results obtained at separate times
yielding the same organism and ≥1 of the
following: a new or changed murmur,
peripheral stigmata of IE, or laboratory
evidence of IE
Erbel et al,15 NA Prospective 96 51 Aortic, mitral, NA <10 ≥1 of the Following: fever, chills, night 16/39 Patients with
1988 tricuspid, mural left sweats, arthralgia, murmur, EE, bacteremia, blood cultures (41.0)
ventricle/right anemia, or elevated ESR (all staphylococcus)
ventricle

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Association of Vegetation Size With Embolic Risk in Infective Endocarditis

Mügge et al,16 1984-1987 Prospective 105 96 Aortic, mitral, Cerebral, lung, spleen, >10 Fever, regurgitant murmur, or anemia 24/97 Patients with
1989 tricuspid, prosthetic kidney associated with bacteremia blood cultures (24.7)
Hwang et al,17 1989-1992 Prospective 41 41 Aortic, mitral, Cerebral, extremity, >10 Histologic findings of IE or clinical diagnosis 7/50 Patients with
1993 tricuspid, pulmonic spleen, kidney, retinal of probable or possible IE by the Von Reyn blood cultures (14.0)
artery criteria
Jung et al,18 1983-1993 Retrospective 80 37 Aortic, mitral, Cerebral, extremity, >10 ≥1 of the Following: direct evidence of IE 12/51 Patients with
1994 tricuspid, pulmonic, kidney, lung, spleen, at time of surgery or culture of embolus; blood cultures (23.5)
prosthetic coronary vessel ≥2 positive blood culture results with ≥3 of
fever, underlying heart disease, new murmur,
vegetations, or EE; positive blood culture
result with underlying heart disease or new
regurgitant murmur; negative blood culture
result with fever, heart disease, vegetations,
or EE
De Castro et al,19 1993-1995 Retrospective 57 54 Aortic, mitral, Peripheral artery, NA Duke criteria 16/57 Patients with
1997 tricuspid, pulmonic cerebral, lung, blood cultures (28.1)

© 2018 American Medical Association. All rights reserved.

coronary artery (all staphylococcus)
Di Salvo et al,20 1993-2000 Prospective 178 133 Aortic, mitral, Cerebral, lung, spleen, >10 Duke criteria 43/178 Patients
2001 tricuspid, pulmonic, kidney, peripheral (24.2)
prosthetic arteries, eye
coronaries
Vilacosta et al,21 1996-2000 Prospective 211 169 Aortic, mitral Cerebral, upper >10 Duke criteria 38/211 Patients
2002 extremity, lower (18.0)
extremity, kidney,
spleen
Deprèle et al,22 1995-2001 Retrospective 80 80 Aortic, mitral, Cerebral, skin, spleen, NA Duke criteria 6/80 Patients (7.5)
2004 tricuspid kidney, lung,
coronaries

(continued)

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Original Investigation Research

E3
 E4
Table. Description of Studies Included in the Meta-analysis (continued)
Patients With Inclusion Patients With
Patients Measured Cutoff Above Staphylococcus
Years of With IE, Vegetation or Below aureus Bacteremia,
Source Study Study Type No. Sizes, No. Valves Involved Type of EE 10 mm Criteria for IE No. (%)
Thuny et al,10 1993-2003 Prospective 384 384 Aortic, mitral, Cerebral, spleen, <10 Duke criteria NA for cohort of new
2005 tricuspid, pulmonic kidney, peripheral EE; 82/384 patients
arteries, eye (21.4) for cohort
coronaries, lung of all EE
Gotsman et al,23 1991-2000 Retrospective 100 50 Aortic, mitral, Arterial emboli, >10 Duke criteria 16/96 Patients (16.7)
Research Original Investigation

2007 tricuspid, prosthetic intracranial

hemorrhage,
pulmonary infarcts,
mycotic aneurysms,
splinter hemorrhage,
Janeway lesions,
conjunctival
hemorrhage
Pepin et al,24 1991-2006 Retrospective 241 101 Aortic, mitral, Cerebral, coronary >10 Modified Duke criteria 118/241 Patients
2009 prosthetic (49.0)
Leitman et al,25 1998-2010 Retrospective 146 102 Aortic, mitral, Brain, kidney, >10 Duke criteria 39% (All
2012 tricuspid, prosthetic, extremities, lung, staphylococcus)a
pacemaker, right subarachnoid
atrial wall hemorrhage

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Hajihossainlou 1995-2010 Retrospective 286 286 Aortic, mitral, NA >10 Duke criteria 87/286 Patients

JAMA Internal Medicine Published online February 19, 2018 (Reprinted)

et al,26 2013 tricuspid, prosthetic (30.4)
García-Cabrera 1984-2009 Prospective 1345 1116 Aortic, mitral, Ischemic stroke >10 Modified Duke criteria 263/1345 Patients
et al,27 2013 prosthetic (19.6)
Misfeld et al,9 1995-2012 Retrospective 1571 1516 Aortic, mitral, Cerebral embolism >10 Modified Duke criteria 143/375 Patients with
2014 tricuspid, pulmonic, embolism (38.1)
prosthetic
Rizzi et al,3 2004-2011 Retrospective 1456 710 Aortic, mitral, Cerebral, pulmonary, >10 Modified Duke criteria 283/1456 Patients
2014 prosthetic, right splenic, limbs (19.4)
sided
Aherrera et al,28 2013-2016 Prospective 87 86 Aortic, mitral, Arterial emboli, >10 Modified Duke criteria 13/87 Patients (14.9)
2016 tricuspid, pulmonic, intracranial
prosthetic hemorrhage,
pulmonary infarcts,
mycotic aneurysms

© 2018 American Medical Association. All rights reserved.

Abbreviations: CXR, chest x-ray; EE, embolic events; ESR, erythrocyte sedimentation rate; IE, infective endocarditis; NA, not available.
a
Numbers of patients or cases were not available in this study.

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Association of Vegetation Size With Embolic Risk in Infective Endocarditis
 Association of Vegetation Size With Embolic Risk in Infective Endocarditis
(3) studies in which vegetation size was estimated by
2-dimensional transthoracic echocardiography (TTE) and/or
transesophageal echocardiography (TEE). We used the follow-
ing exclusion criteria: (1) studies on prosthetic valve infective
endocarditis and device-associated infective endocarditis
unless data for native valve infective endocarditis were also
present, (2) studies in which vegetation size was not quanti-
fied but rather qualitatively assessed (such as small vs large),
(3) studies in which data for no vegetation were included with
vegetation size less than 10 mm and separate estimates of em-
bolic events for vegetation size less than 10 mm could not be
extracted from available information, (4) studies in which a
hazard ratio or an adjusted odds ratio (OR) was available but
enough data were not present to extract or calculate an unad-
justed OR, (5) studies in which multiple prognostic markers
were tested and data for a complete cohort of patients with a
vegetation size less than 10 mm or greater than 10 mm were
unavailable, (6) studies in which vegetation size was mea-
sured with modalities other than 2-dimensional TTE or TEE,
(7) conference abstracts, (8) case reports and case series, and
(9) non–English language literature.
Study End Points
The primary aim of this meta-analysis was to study the asso-
ciation of a vegetation size greater than 10 mm with embolic
events in patients with infective endocarditis. As a secondary
analysis, we also compared the odds of all-cause mortality in
patients with vegetation sizes less than and greater than 10 mm.
Data Extraction and Study Quality Appraisal
Two of us (D.M. and A.M.) abstracted data from all included
studies on a standardized worksheet. The following data were
collected: name of the author(s), study title, year of publica-
tion, years of study, type of study (retrospective vs prospec-
tive), type of echocardiography used, percentage of male pa-
tients, percentage of type of valve involved (aortic, mitral,
tricuspid, or prosthetic), percentage of patients undergoing
surgery, percentage of patients with Staphylococcus aureus
bacteremia, and mean age. Data used to calculate the OR for
systemic embolization among different vegetation sizes were
also obtained. For the study by Thuny et al,10 data on embolic
events were available before and after antibiotic administra-
tion. We used the postadministration data to calculate em-
bolic events. For the study by Leitman et al,25 data on short-
and long-term mortality were available. Herein we used the
data on short-term mortality to maintain uniformity with other
studies and to avoid incorporation of effect from other con-
founding factors that may influence long-term mortality in
these patients. Wherever separate values for TTE and TEE were
provided, the values with the maximum number of patients
were incorporated into our analysis.
Two of us (D.M. and A.M.) independently assessed the risk
of bias among the included studies using the standardized
Newcastle-Ottawa Scale. This validated instrument for
appraising observational studies measures risk of bias in
8 categories: representativeness of the exposed cohort, selec-
tion of the nonexposed cohort, ascertainment of exposure,
demonstration that the outcome of interest was not present
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Original Investigation Research
at the start of the study, comparability, assessment of out-
come, follow-up long enough for outcomes to occur, and ad-
equacy of follow-up of cohorts (eTable 1 in the Supplement).
All discrepancies in data abstraction or quality appraisal were
resolved by discussion or adjudication by another of us (M.Y.D.).
eTable 2 in the Supplement provides the PRISMA checklist
for the meta-analysis.
Data Synthesis and Analysis
We summarized categorical dichotomous data across treat-
ment arms using the Mantel-Haenszel OR with 95% CI.
We evaluated heterogeneity of effects using the Higgins I2
statistic. We also used Mantel-Haenszel risk difference to cal-
culate summary effects for the primary and secondary out-
comes. Random effects were used for all our analyses. We also
performed meta-regression analyses for the primary out-
come to assess whether the association of vegegation size with
embolic risk is modulated by prespecified study-level factors
such as age, male sex, type of valve involved, and prosthetic
valve involvement. This analysis was not possible for the sec-
ondary outcome owing to the smaller number of included stud-
ies for that analysis. We also performed a sensitivity analysis
to evaluate how removal of each study affected the overall out-
come and a prespecified subgroup analysis stratifying the
primary outcome by type of study (prospective vs retrospec-
tive), years of publication (1980-1999 vs 2000-2016), and use
of Duke (or modified Duke) criteria.30,31 To address publica-
tion bias, we used visual inspection of funnel plots and the
Egger test. Comprehensive Meta-analysis software (version
3.3.070; https://www.meta-analysis.com) was used for meta-
analysis and meta-regression. A 2-tailed P = .05 was consid-
ered to be significant for all our analyses.
Results
Our search yielded 21 unique studies published from 1983 to
2016,3,7,9,10,12-28 including a total of 6646 unique patients with
infective endocarditis and a total of 5116 vegetation speci-
mens with available dimensions. Characteristics of the stud-
ies are listed in the Table.
Association of Vegetation Size Greater Than 10 mm
With Embolic Events
We observed that patients with a vegetation size greater than
10 mm had increased odds of embolic events compared with
patients with a vegetation size less than 10 mm (OR, 2.28; 95%
CI, 1.71-3.05; P < .001) (Figure 2). The risk difference was 0.13
(95% CI, 0.09-0.18; P < .001). We further explored the hetero-
geneity among the included studies by performing subgroup
analysis by period and study method. We observed that the
odds of embolic events were comparable between patients with
and without a vegetation size greater than 10 mm when stud-
ies in the subgroup of studies published from 1983 to 1999 (OR,
1.41; 95 CI, 0.79-2.53; P = .24) were considered. However, we
found a markedly increased likelihood of embolic events with
a vegetation size greater than 10 mm in the studies published
from 2000 to 2016 (OR, 2.70; 95% CI, 1.91-3.81; P < .001), but
(Reprinted) JAMA Internal Medicine Published online February 19, 2018 E5
 Research Original Investigation Association of Vegetation Size With Embolic Risk in Infective Endocarditis

Figure 2. Forest Plot for Comparative Odds of Embolic Events

No. of Embolic Events/

Total No.
Favors Favors
Vegetation Vegetation Relative Vegetation Vegetation
Source OR (95% CI) Size >10 mm Size <10 mm Weight, % Size >10 mm Size <10 mm
Wong et al,12 1983 0.72 (0.15-3.43) 6/16 5/11 2.73
Robbins et al,13 1986 0.19 (0.01-4.29) 8/11 6/6 0.82
Lutas et al,14 1986 3.71 (0.69-20.04) 9/26 2/16 2.42
Buda et al,7 1986 0.90 (0.13-6.08) 6/11 4/7 1.97
Erbel et al,15 1988 0.99 (0.22-4.42) 3/14 8/37 2.91
Mϋgge et al,16 1989 4.51 (1.74-11.66) 22/47 8/49 5.31
Hwang et al,17 1993 1.17 (0.20-6.80) 7/31 2/10 2.25
Jung et al,18 1994 1.50 (0.40-5.66) 11/17 11/20 3.47
De Castro et al,19 1997 0.73 (0.23-2.35) 16/38 8/16 4.11
Di Salvo et al,20 2001 4.27 (2.04-8.92) 40/67 17/66 6.82
Vilacosta et al,21 2002 4.64 (1.04-20.59) 22/124 2/45 2.93
Deprèle et al,22 2004 4.67 (1.77-12.32) 20/35 10/45 5.18
Thuny et al,10 2005 15.22 (3.56-65.09) 26/190 2/194 3.04
Gotsman et al,23 2007 3.48 (0.66-18.25) 9/31 2/19 2.49
Pepin et al,24 2009 1.36 (0.61-3.05) 24/56 16/45 6.27
Leitman et al,25 2012 1.84 (0.70-4.86) 12/46 9/56 5.18
Hajihossainlou et al,26 2013 4.90 (2.03-11.81) 17/96 8/190 5.76
García-Cabrera et al,27 2013 1.29 (0.93-1.81) 74/447 89/669 10.33
Misfeld et al,9 2014 1.65 (1.28-2.12) 261/940 109/576 10.96 Data are stratified by vegetation size
3 less than and greater than 10 mm.
Rizzi et al, 2014 2.17 (1.54-3.06) 228/492 62/218 10.26
Squares represent odds ratios (ORs),
Aherrera et al,28 2016 6.66 (2.36-18.77) 18/35 7/51 4.80
with their size proportional to the
Overall 2.28 (1.70-3.05) weight of the study using the Mantel
Test for heterogeneity: I 2 = 57.56%; Q = 47.13, P = .001 0.01 0.10 1 10 100 Haenszel test; horizontal lines, 95%
Test for overal effect: Z = 5.49, P <.001 OR (95% CI) CIs; diamond overall OR and 95% CI;
Q, Cochrane Q statistic.

the difference between the 2 subgroups was not significant
(Q = 3.49; P = .06) (eFigure 1 in the Supplement). A meta-
analysis of prospective (OR, 2.44; 95% CI, 1.31-4.53) and ret-
rospective (OR, 2.05; 95% CI, 1.53-2.75) studies showed in-
creased odds of embolic events with a vegetation size greater
than 10 mm, with no differences between the subgroups
(Q = 0.24; P = .62) (eFigure 2 in the Supplement). We also
observed no difference in the subgroup of studies that used
Duke or modified Duke criteria (OR, 2.52; 95% CI, 1.81-3.52;
P < .001) compared with studies that did not (OR, 1.61; 95% CI,
0.86-3.01; P = .13) (Q = 1.53; P = .21). When the primary out-
come was stratified by left- and right-sided vegetation speci-
mens, in the 5 studies that allowed for calculation of primary
outcome for left-sided vegetation specimens, the association
was not significant (OR, 1.37; 95% CI, 1.02-1.83; P = .06). Only
2 studies had isolated data for right-sided vegetation speci-
mens available. The association did not reach significance for
these studies, and the CIs were large (OR, 1.42; 95% CI, 0.17-
11.49) (eFigure 3 in the Supplement).
Use of meta-regression revealed that odds of embolic
events with a vegetation size greater than 10 mm were not sig-
nificantly associated with the mean age of the study popula-
tion, percentage of prosthetic valve involvement, percentage
of aortic valve involvement, percentage of mitral valve
involvement, or percentage of male patients. Although meta-
regression by percentage of tricuspid valve involvement
seemed to show nonsignificant lower odds with greater tri-
cuspid valve involvement, visual inspection of the scatter-
plot revealed that this result was owing to a single study by
Robbins et al13 that included patients with only right-sided
endocarditis. Removal of this study resulted in loss of this find-
ing. Details of meta-regression analyses are shown in eTable
3 in the Supplement, and meta-regression scatterplots are
presented in eFigure 4 in the Supplement.
Cumulative meta-analysis showed that with serial addi-
tion of studies by publication year, overall effect was statisti-
cally significant only after the 2001 publication (Di Salvo
et al20). Sensitivity analysis using the 1-study-removal method
failed to show that removal of any 1 study significantly influ-
enced the overall effect (eFigures 5 and 6 in the Supplement).
Considering only high-quality (Newcastle-Ottawa Scale score
≥7) studies did not change the effect significantly (OR, 2.54;
95% CI, 1.79-3.59).
To evaluate for association of increasing vegetation sizes,
we sought to compare embolic events with vegetation size cut-
offs of 5 mm and 15 mm. We found that with a cutoff of 5 mm,
odds were similar to those with a cutoff of 10 mm (OR, 2.52;
95% CI, 1.78-3.55) but were greater with a cutoff of 15 mm (OR,
4.25; 95% CI, 1.65-10.93) (eFigure 7 in the Supplement).
Association of Vegetation Size Greater Than 10 mm
With All-Cause Mortality
We found that a vegetation size greater than 10 mm was asso-
ciated with increased odds of all-cause mortality (OR, 1.63; 95%
CI, 1.13-2.35; P = .009) (Figure 3). The risk difference was 0.08
(95% CI, 0.02-0.13; P = .006). Cumulative meta-analysis
showed that with serial addition of studies by publication year,
overall effect (as measured by OR) was statistically signifi-
cant only after the publication year 2013 (Hajihossainlou
et al26). On sensitivity analysis by the 1-study-removal method,

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 Association of Vegetation Size With Embolic Risk in Infective Endocarditis Original Investigation Research

Figure 3. Forest Plot for Comparative Odds of All-Cause Mortality

No. of Deaths/No. of Patients

Favors Favors
Vegetation Vegetation Relative Vegetation Vegetation
Source OR (95% CI) Size >10 mm Size <10 mm Weight Size >10 mm Size <10 mm
Wong et al,12 1983 0.38 (0.05-2.78) 2/16 3/11 3.28
Lutas et al,14 1986 0.58 (0.07-4.61) 2/26 2/16 3.05
Buda et al,7 1986 3.43 (0.30-39.64) 4/11 1/7 2.20
Erbel et al,15 1988 1.47 (0.47-4.61) 8/47 6/49 9.24
Vilacosta et al,21 2002 1.31 (0.61-2.80) 40/124 12/45 18.50
Deprèle et al,22 2004 3.58 (0.65-19.71) 5/35 2/45 4.41
Gotsman et al,23 2007 3.46 (0.37-32.18) 5/31 1/19 2.63
Pepin et al,24 2009 0.85 (0.36-2.01) 15/65 13/50 15.27 Data are stratified by vegetation size
less than and greater than 10 mm.
Leitman et al,25 2012 1.81 (0.71-4.63) 13/46 10/56 13.09
Squares represent odds ratios (ORs),
Hajihossainlou et al,26 2013 2.69 (1.52-4.75) 33/96 31/190 28.33
with their size proportional to the
Overall 1.63 (1.13-2.35)
weight of the study using the Mantel
Test for heterogeneity: I 2 = 11%; Q = 10.12, P = .34 0.01 0.10 1 10 100 Haenszel test; horizontal lines, 95%
Test for overall effect: Z = 2.60, P = .009 OR (95% CI) CIs; diamond, overall OR and 95% CI;
and Q, Cochrane Q statistic.

we found that removal of the study by Hajihossainlou et al26
made the overall effect not significant (P = .17) (eFigures 8 and
9 in the Supplement).
Publication Bias
Visual inspection of funnel plots and quantitative assess-
ment using the Egger test revealed no publication bias in the
primary or secondary outcome. Results of assessment for pub-
lication bias are found in eFigure 10 in the Supplement.
Discussion
In our large meta-analysis of 21 studies with more than 6500
cases of infective endocarditis and more than 5000 mea-
sured vegetations, we revealed that patients with a vegeta-
tion size greater than 10 mm had significantly increased odds
of embolic events and mortality. This increased association was
not found to depend on age, sex, or type of valve involve-
ment. We also reported that the strength of association of a
vegetation size greater than 10 mm with embolic outcomes
increased over time.
Fragmentation of vegetation specimens or cardiac tissue
in patients with infective endocarditis leads to systemic em-
bolic events. This devastating complication can occur in as
many as 80% of cases of infective endocarditis.13 The brain and
spleen are the most frequent sites of embolism in left-sided
infective endocarditis, whereas pulmonary embolism is fre-
quent in right-sided infective endocarditis of a native valve.32
Large vegetation sizes have been linked in multiple studies with
an increased risk of embolic events. These vegetations are
often dichotomized at a seemingly arbitrary cutoff greater than
10 mm. To prevent occurrence of embolic events, the Ameri-
can Heart Association guidelines suggest consideration of
surgical options when the vegetation size is greater than 10 mm,
particularly when involving the anterior leaflet of the mitral
valve and when associated with other relative indications for
surgery (class IIb, level of evidence C).6 Echoing this senti-
ment, the European Society of Cardiology guidelines suggest
consideration of surgical options in aortic or mitral vegeta-
tions greater than 10 mm with 1 or more embolic event
despite antibiotic therapy (class I, level of evidence B).32
However, the evidence behind these recommendations
comes from relatively small observational studies with vary-
ing degrees of bias. Our study therefore adds to the existing
literature by systematically analyzing individual studies and
their risk of bias and by providing pooled odds of embolic
events. Clinicians often need to balance the risk of embolic
events with the risk of surgery, and our analysis will benefit
those discussions by providing quality evidence behind the
odds of embolic events in patients with vegetation size greater
than 10 mm.
A previous meta-analysis by Tischler and Vaitkus 11
revealed that patients with a vegetation size greater than
10 mm had significantly increased odds of embolic events and
all-cause mortality that did not reach statistical significance.
Their analysis of 10 studies had several limitations, including
variable definitions of large vegetation and lack of assessment
of publication bias, study quality, or degree of heterogeneity
using the I2 statistic. We aimed in our analysis to systemati-
cally address these shortcomings and other additional limita-
tions of a meta-analysis based purely on observational data.
First, we included only studies in which using a cutoff of
10 mm to calculate odds of embolic events was possible. We
assessed study quality using the standardized Newcastle-
Ottawa Scale and found that a sensitivity analysis using only
high-quality studies did not change the overall effect for the
primary outcome significantly. In addition, our evaluation
using funnel plots and the Egger test did not reveal any evi-
dence of publication bias.
We used the Higgins I2 statistic to assess the degree of
heterogeneity and found that heterogeneity for the primary
outcome was moderately large (I2 = 58%). We further ex-
plored the cause of this heterogeneity by performing sub-
group analyses by period of publication and study methods.
Our analysis by publication year revealed that studies be-
fore 2000 were more homogenous (I2 = 27%), and the pooled
odds of embolic events in this subgroup, although increased
for those with a vegetation size greater than 10 mm, did not
attain statistical significance. In contrast, when studies after

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 Research Original Investigation
the year 2000 were considered, a vegetation size greater than
10 mm was associated with significantly increased odds of em-
bolic events. Our cumulative meta-analysis (with serial addi-
tion of studies by publication year) showed concordant
findings and revealed that the pooled effect only attained
statistical significance after 2001. This finding appears to be
in contrast to those of Tischler and Vaitkus,11 who owing to their
publication date in 1997, only included studies before 2001
and found a vegetation size greater than 10 mm to be signifi-
cantly associated with embolic events. This finding can likely
be explained by their inclusion of patients with no vegetation
to the cohort with a vegetation size less than 10 mm. The
presence of vegetation specimens has been shown to have
negative prognostic implications, and therefore inclusion of
no vegetation with a vegetation size less than 10 mm likely
overestimates the odds of embolic events with a vegetation size
greater than 10 mm.33 Several possible reasons explain this in-
creased association of vegetation size greater than 10 mm with
embolic events over time. Among the studies in our analysis,
Hajihossainlou et al26 noted that the prevalence of S aureus
infection and intravenous drug use increased over time from
1995 to 2010. In addition, Vilacosta et al21 noted that the in-
creased risk of embolic events in patients with a vegetation size
greater than 10 mm was only significant for those with staphy-
lococcal infections. Therefore, a change in microbiology may
be responsible for the increased effect of a vegetation size
greater than 10 mm seen in our meta-analysis after 2001.
However, given the overlapping years of study, it is difficult
to analyze this increase in our meta-analysis. Our systematic
review of the percentage of S aureus infections among in-
cluded studies (Table) did not show any clear increasing or de-
creasing temporal trend. Another possible explanation is that
the use of Duke and modified Duke criteria helped to better
categorize patients with infective endocarditis after 1994
(publication of Duke criteria). In our review of inclusion cri-
teria in the Table, we found that all studies after De Castro
et al19 (published in 1997) used Duke or modified Duke criteria.
In subgroup analysis by inclusion criteria, we noted that the
summary effect (odds of embolic events with a vegetation size
>10 mm) was significant only in studies that used the Duke or
modified Duke criteria. This finding may partially explain the
temporal trend of increasing effect with publication year.
Another possibility is that with early echocardiography tech-
niques, smaller vegetations were missed, thereby overesti-
mating the risk of embolism in vegetation size less than 10 mm.
In addition, technological advancement (and increasing
use of TEE) has led not only to detection of smaller vegeta-
tions but also to more accurate determination of vegetation
size. In a cohort that included more than 300 episodes of in-
fective endocarditis, Luaces et al34 reported that their mean
vegetation size of 14 mm was markedly higher than that found
in classic series, and they attributed this greater size to tech-
nological advancements in the field of echocardiography.
Although the European Society of Cardiology and the Ameri-
can Heart Association guidelines suggest that aortic or mitral
valve involvement may enhance the risk of embolic events in
patients with a vegetation size greater than 10 mm, our meta-
regression analysis failed to show any significant effect of type
E8 JAMA Internal Medicine Published online February 19, 2018 (Reprinted)
© 2018 American Medical Association. All rights reserved.
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Association of Vegetation Size With Embolic Risk in Infective Endocarditis
of valve involvement on association of a vegetation size greater
than 10 mm and embolic events.6,32 Although we could per-
form this analysis with only study-level data and the analysis
does not reflect individual risk, it provides evidence that fur-
ther prospective research is needed to validate the effect of
localization of vegetation on strength of association of large
vegetation size with embolic events.
Limitations
Our study has several limitations. First, this meta-analysis
was performed on study-level data encompassing varying
degrees of selection bias that is difficult to ascertain. Second,
the effect of antibiotic use and microbiology could not be in-
corporated into the analysis owing to lack of sufficient data.
Although 3 studies3,21,27 provided detailed information on the
trend of embolic events after initiation of targeted antimicro-
bial therapy and unanimously noted a markedly decreased
risk of embolic events in the second week after initiation of
antimicrobial therapy, only Thuny et al10 provided informa-
tion on the comparative risk of embolic events (with a vegeta-
tion size >10 mm) before and after initiation of antibiotics.
However, even in that study, no statistical testing was per-
formed to determine whether the risk of embolic events with
a vegetation size greater than 10 mm changes after initiation
of antibiotic therapy.
Another limitation is that the association of vegetation size
of exactly 10 mm with embolic events remains ambiguous. This
ambiguity occurs because some studies included these pa-
tients among the group with a vegetation size less than 10 mm,
whereas others included them in the group with a vegetation
size greater than 10 mm (Table). In addition, although most
studies included patients with varied sites of systemic embo-
lism, different sites of embolization may have different prog-
nostic implications. Last, although we aimed to study only na-
tive valves and extracted data only on native valves wherever
feasible, 14 of the 21 included studies had prosthetic valve
involvement ranging from 2% to 30%. However, our meta-
regression analysis showed that the presence of these cases did
not affect the overall results in a significant manner. Our search
was designed to capture studies evaluating embolic events in
infective endocarditis, and it was not designed to evaluate the
secondary outcome of mortality. Despite these limitations,
we believe that the large size of our dataset, standardized
protocol-based analysis, use of multiple subgroup and sensi-
tivity analysis, and use of cumulative meta-analysis make our
results robust and provide strength to our analysis.
Conclusions
In our meta-analysis of 21 studies, we showed that patients
with a vegetation size greater than 10 mm had significantly
increased odds of embolic events and mortality. We also
showed that the strength of association of a vegetation size
greater than 10 mm with embolic events was greater in sub-
groups of publications from 2000 to 2016 (compared with
those from 1980-1999) and was unaffected by age, sex, and
type of valve involved.
jamainternalmedicine.com
 Association of Vegetation Size With Embolic Risk in Infective Endocarditis
ARTICLE INFORMATION
Accepted for Publication: December 22, 2017.
Published Online: February 19, 2018.
doi:10.1001/jamainternmed.2017.8653
Author Contributions: Drs Mohananey and Desai
had full access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Mohananey, Pettersson,
Navia, Rodriguez, Griffin, Desai.
Acquisition, analysis, or interpretation of data:
Mohananey, Mohadjer, Gordon, Shrestha, Grimm,
Desai.
Drafting of the manuscript: Mohananey, Mohadjer,
Desai.
Critical revision of the manuscript for important
intellectual content: All authors.
Obtained funding: Desai.
Administrative, technical, or material support:
Mohadjer, Grimm, Griffin, Desai.
Study supervision: Pettersson, Navia, Desai.
Conflict of Interest Disclosures: Dr Desai reports
being supported by the Haslam Family Endowed
Chair in Cardiovascular Medicine and consulting for
Myocardia, Inc. No other disclosures were reported.
REFERENCES
1. Hoen B, Alla F, Selton-Suty C, et al; Association
pour l’Etude et la Prévention de l’Endocardite
Infectieuse (AEPEI) Study Group. Changing profile
of infective endocarditis: results of a 1-year survey
in France. JAMA. 2002;288(1):75-81.
2. Cabell CH, Jollis JG, Peterson GE, et al. Changing
patient characteristics and the effect on mortality in
endocarditis. Arch Intern Med. 2002;162(1):90-94.
3. Rizzi M, Ravasio V, Carobbio A, et al;
Investigators of the Italian Study on Endocarditis.
Predicting the occurrence of embolic events: an
analysis of 1456 episodes of infective endocarditis
from the Italian Study on Endocarditis (SEI). BMC
Infect Dis. 2014;14:230.
4. Sonneville R, Mourvillier B, Bouadma L, Wolff M.
Management of neurological complications of
infective endocarditis in ICU patients. Ann Intensive
Care. 2011;1(1):10.
5. Kang DH, Kim YJ, Kim SH, et al. Early surgery
versus conventional treatment for infective
endocarditis. N Engl J Med. 2012;366(26):2466-2473.
6. Baddour LM, Wilson WR, Bayer AS, et al;
American Heart Association Committee on
Rheumatic Fever, Endocarditis, and Kawasaki
Disease of the Council on Cardiovascular Disease in
the Young; Council on Clinical Cardiology; Council
on Cardiovascular Surgery and Anesthesia; Stroke
Council. Infective endocarditis in adults: diagnosis,
antimicrobial therapy, and management of
complications: a scientific statement for healthcare
professionals from the American Heart Association.
Circulation. 2015;132(15):1435-1486.
7. Buda AJ, Zotz RJ, LeMire MS, Bach DS.
Prognostic significance of vegetations detected by
two-dimensional echocardiography in infective
endocarditis. Am Heart J. 1986;112(6):1291-1296.
jamainternalmedicine.com
© 2018 American Medical Association. All rights reserved.
Downloaded From: by a Stephen F Austin State University User on 02/19/2018
8. Hwang JJ, Shyu KG, Chen JJ, Tseng YZ, Kuan P,
Lien WP. Usefulness of transesophageal
echocardiography in the treatment of critically ill
patients. Chest. 1993;104(3):861-866.
9. Misfeld M, Girrbach F, Etz CD, et al. Surgery for
infective endocarditis complicated by cerebral
embolism: a consecutive series of 375 patients.
J Thorac Cardiovasc Surg. 2014;147(6):1837-1844.
10. Thuny F, Di Salvo G, Belliard O, et al. Risk of
embolism and death in infective endocarditis:
prognostic value of echocardiography:
a prospective multicenter study. Circulation. 2005;
112(1):69-75.
11. Tischler MD, Vaitkus PT. The ability of
vegetation size on echocardiography to predict
clinical complications: a meta-analysis. J Am Soc
Echocardiogr. 1997;10(5):562-568.
12. Wong D, Chandraratna AN, Wishnow RM,
Dusitnanond V, Nimalasuriya A. Clinical implications
of large vegetations in infectious endocarditis. Arch
Intern Med. 1983;143(10):1874-1877.
13. Robbins MJ, Frater RW, Soeiro R, Frishman WH,
Strom JA. Influence of vegetation size on clinical
outcome of right-sided infective endocarditis. Am J
Med. 1986;80(2):165-171.
14. Lutas EM, Roberts RB, Devereux RB, Prieto LM.
Relation between the presence of
echocardiographic vegetations and the
complication rate in infective endocarditis. Am
Heart J. 1986;112(1):107-113.
15. Erbel R, Rohmann S, Drexler M, et al. Improved
diagnostic value of echocardiography in patients
with infective endocarditis by transoesophageal
approach: a prospective study. Eur Heart J. 1988;9
(1):43-53.
16. Mügge A, Daniel WG, Frank G, Lichtlen PR.
Echocardiography in infective endocarditis:
reassessment of prognostic implications of
vegetation size determined by the transthoracic
and the transesophageal approach. J Am Coll Cardiol.
1989;14(3):631-638.
17. Hwang JJ, Shyu KG, Chen JJ, et al. Infective
endocarditis in the transesophageal
echocardiographic era. Cardiology. 1993;83(4):
250-257.
18. Jung HO, Seung KB, Kang DH, et al. A clinical
consideration of systemic embolism complicated to
infective endocarditis in Korea. Korean J Intern Med.
1994;9(2):80-87.
19. De Castro S, Magni G, Beni S, et al. Role of
transthoracic and transesophageal
echocardiography in predicting embolic events in
patients with active infective endocarditis involving
native cardiac valves. Am J Cardiol. 1997;80(8):
1030-1034.
20. Di Salvo G, Habib G, Pergola V, et al.
Echocardiography predicts embolic events in
infective endocarditis. J Am Coll Cardiol. 2001;37
(4):1069-1076.
21. Vilacosta I, Graupner C, San Román JA, et al.
Risk of embolization after institution of antibiotic
therapy for infective endocarditis. J Am Coll Cardiol.
2002;39(9):1489-1495.
(Reprinted) JAMA Internal Medicine Published online February 19, 2018
Original Investigation Research
22. Deprèle C, Berthelot P, Lemetayer F, et al. Risk
factors for systemic emboli in infective
endocarditis. Clin Microbiol Infect. 2004;10(1):
46-53.
23. Gotsman I, Meirovitz A, Meizlish N, Gotsman M,
Lotan C, Gilon D. Clinical and echocardiographic
predictors of morbidity and mortality in infective
endocarditis: the significance of vegetation size. Isr
Med Assoc J. 2007;9(5):365-369.
24. Pepin J, Tremblay V, Bechard D, et al. Chronic
antiplatelet therapy and mortality among patients
with infective endocarditis. Clin Microbiol Infect.
2009;15(2):193-199.
25. Leitman M, Dreznik Y, Tyomkin V, Fuchs T,
Krakover R, Vered Z. Vegetation size in patients
with infective endocarditis. Eur Heart J Cardiovasc
Imaging. 2012;13(4):330-338.
26. Hajihossainlou B, Heidarnia MA, Sharif Kashani
B. Changing pattern of infective endocarditis in
Iran: a 16 years survey. Pak J Med Sci. 2013;29(1):
85-90.
27. García-Cabrera E, Fernández-Hidalgo N,
Almirante B, et al; Group for the Study of
Cardiovascular Infections of the Andalusian Society
of Infectious Diseases; Spanish Network for
Research in Infectious Diseases. Neurological
complications of infective endocarditis: risk factors,
outcome, and impact of cardiac surgery:
a multicenter observational study. Circulation. 2013;
127(23):2272-2284.
28. Aherrera JA, Abola MT, Balabagno MM, et al.
Prediction of symptomatic embolism in Filipinos
with infective endocarditis using the embolic risk
French calculator. Cardiol Res. 2016;7(4):130-139.
29. Moher D, Liberati A, Tetzlaff J, Altman DG;
PRISMA Group. Preferred Reporting Items for
Systematic Reviews and Meta-analyses: the
PRISMA statement. PLoS Med. 2009;6(7):e1000097.
30. Li JS, Sexton DJ, Mick N, et al. Proposed
modifications to the Duke criteria for the diagnosis
of infective endocarditis. Clin Infect Dis. 2000;30
(4):633-638.
31. Durack DT, Lukes AS, Bright DK; Duke
Endocarditis Service. New criteria for diagnosis of
infective endocarditis: utilization of specific
echocardiographic findings. Am J Med. 1994;96(3):
200-209.
32. Habib G, Lancellotti P, Antunes MJ, et al; Task
Force per il Trattamento dell’Endocardite Infettiva
della Società Europea di Cardiologia (ESC). 2015
ESC guidelines for the management of infective
endocarditis [in Italian]. G Ital Cardiol (Rome). 2016;
17(4):277-319.
33. Wann LS, Hallam CC, Dillon JC, Weyman AE,
Feigenbaum H. Comparison of M-mode and
cross-sectional echocardiography in infective
endocarditis. Circulation. 1979;60(4):728-733.
34. Luaces M, Vilacosta I, Fernández C, et al.
Vegetation size at diagnosis in infective
endocarditis: influencing factors and prognostic
implications. Int J Cardiol. 2009;137(1):76-78.
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