Infect Dis Clin N Am 16 (2002) 255272

Progress toward a global understanding

of infective endocarditis
Early lessons from the International
Collaboration on Endocarditis investigation
Christopher H. Cabell, MDa,*, Elias Abrutyn, MDb
a

Department of Medicine, Box 31020, Duke University School of Medicine,

Duke Clinical Research Institute, Durham, NC 27713, USA
b
Department of Medicine, MCP Hahnemann University, Mail Stop 441, 245 N. 15th Street,
Philadelphia, PA 191021192, USA

It is of use from time to time to take stock, so to speak, of our knowledge of

a particular disease, to see exactly where we stand in regard to it, to inquire
to what conclusions the accumulated facts seem to point, and to ascertain
in what direction we may look for fruitful investigations in the future [1].

With these words William Osler began the rst of three seminal lectures
on endocarditis to the Royal College of Physicians of London in 1885. As
modern medicine moves into the twenty-rst century after decades of rapid
scientic advancement it is once again appropriate to take stock.
Over the past 30 years there have been substantial advances in our knowledge of infective endocarditis (IE). Examples include studies of the incidence
of IE [26], data on the magnitude of the association between certain risk
factors and IE [7,8], clinical criteria related to the diagnosis of IE [9,10], and
the introduction of echocardiography for both diagnosis [1113] and prognosis [1416].
Despite these and other advances, uncertainties remain about many
aspects of IE. For instance, recent evidence regarding the relationship

This study was supported by the following: Four Schools Physician Scientist Program
sponsored by the Lucille P. Markee Charitable Trust (CHC) and Joseph C. Greeneld Jr.
Scholars (CHC), and an investigator-initiated grant from Roche Laboratories Inc., Nutley, NJ.
Some data contained herein was partially presented at the 40th Interscience Conference on
Antimicrobial Agents and Chemotherapy on 18 September 2000.
* Corresponding author.
E-mail address: chris.cabell@duke.edu (C.H. Cabell).
0891-5520/02/$ - see front matter
2002, Elsevier Science (USA). All rights reserved.
PII: S 0 8 9 1 - 5 5 2 0 ( 0 1 ) 0 0 0 0 7 - 1

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between dental and other risk factors and the subsequent development of IE
[7,8] may provoke a need to reexamine the policy of routine antibiotic prophylaxis for the prevention of IE [17]. In addition, although any of several
antibiotics may be used to treat the common causative agents of IE, few randomized trials have been conducted to dene optimal therapy [1820]. This
is also true when surgery is considered because the optimal role and timing
of surgery has not been denitively established. Finally, it is troubling that
mortality remains high, approaching 40% at one year [6,21,22], despite rapid
medical progress over the last 20 years.
In this article the authors take stock by summarizing current understanding of endocarditis in the areas of epidemiology and regional variation,
host factors, microorganisms, diagnosis, and therapy. In addition, the
authors discuss potential future directions for investigations by a newly
constituted multinational consortium, the International Collaboration on
Endocarditis (ICE). This collaboration aims to provide a mechanism to
advance the understanding of endocarditis in areas that are dicult to study
by traditional case reports and case series emanating from single centers.
The multinational nature of the collaboration should also provide a global
view of IE and opportunities for studies such as randomized trials of therapeutic treatment strategies.
Current standing
Epidemiology and regional variation
Recent studies have provided new insights into the epidemiology of IE
and have suggested variation in the rate of IE, the exploration of which may
be worthy of further study. For example, in 1991 Delahaye and colleagues
[3] reported that the crude incidence of IE in France in the early 1990s was
2.4 per 100,000 population, a value similar to that found in Denmark in the
1980s [6]. These incidence rates are lower than that found in the Philadelphia
area (11.6/100,000 population) [2] and Sweden (5.9/100,000 population) [5]
during similar time periods.
Dierences in the incidence of IE may be found when comparing series
reported from urban populations and rural populations. For instance, the
incidence of IE appears higher in an urban population and consistently lower in more rural groups [2,5], which may reect the impact of intravenous
drug users (IVDUs) and other socioeconomic factors on the rate of IE.
Other data suggest that the incidence of IE in the elderly is 4 to 6 times
greater than that of the general population [3,6]. These data suggest factors
that may be important in explaining the variation in incidence and identify
groups that may be at an increased risk for IE.
Variation is also suggested in the relative importance of dierent organisms in dierent series from dierent geographic areas. For instance, in
France, Streptococcus bovis IE appears to be more common (14%) [3] than
in Sweden (1%) [5]. Similarly, dierences can be found in populations

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257

depending on the place of acquisition. For example, IE acquired in hospitals

is associated predominantly with staphylococci [23], which is similar to community IVDU patients [18,24]. In contrast, in community patients without
IVDU streptococcal species are more common [7].
Not only is variation present in the population and microbiologic spectrum of IE, there are also dierences in the therapies that patients receive.
In Switzerland, for example, the reported surgical rate has been as high as
36% (45/125) [25], which contrasts with the United States (27%) [14], France
(24%) [3], and Sweden (15%) [5].
Due to the inherent diculties in studying a disease of low incidence,
published studies of IE tend to be case reports or single center observational
studies. These types of investigations often, of necessity, lack adequate control groups for comparison, and dierences between reports are sometimes
dicult to interpret.
A further limitation of current data is that referral bias may have an
impact on the reported spectrum of disease. Steckelberg and colleagues
[26] have shown that IE patients identied in the community dier from
patients transferred to tertiary care centers. In their community cohort, age
was an important risk factor for acquiring endocarditis, while episodes in
elderly patients were underrepresented in the referral practice. The proportion of cases due to Staphylococcus aureus was greater in the community,
while a trend toward overrepresentation of enterococcal endocarditis was
seen in the referral population. Interestingly, these dierences had no apparent aect on mortality.

Host factors associated with endocarditis

debilitated and dissipated (with) habits of intemperance, and exposure to
vicissitudes of heat and cold secondary to other causes, primarily scarlet
fever and diptheria, but also primary rheumatic fever, ague, and pneumonia external septic lesions, surgical, traumatic, or puerperal. [27]

These observations by Osler regarding those at risk for IE in the late

nineteenth century remain strikingly accurate today, although recent studies
have improved the understanding of the risk of IE associated with certain
predisposing factors.
Cardiac risk factors
Based upon available data and expert opinion [28,29], the American
Heart Association (AHA) has provided a classication of certain pre-existing cardiac conditions that predispose patients to developing IE [30]. Admittedly, there are few studies available that quantify the risk of developing IE
for patients with specic cardiac conditions. It is more clear which conditions, when associated with active IE, are more likely to be associated with

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complications and death. Therefore, the AHA guidelines stratify patients

primarily on the basis of risk for adverse outcomes if IE should occur.
High-risk conditions include prosthetic cardiac valves, previous bacterial
endocarditis, complex cyanotic congenital heart disease, and surgically constructed systemicpulmonary shunts or conduits. Moderate-risk conditions
include most other congenital cardiac malformations, acquired valvular dysfunction, hypertrophic cardiomyopathy, and mitral valve prolapse with
valvular regurgitation or thickened leaets.
Although the scope of risk for IE is not fully known for patients with preexisting cardiac conditions, these conditions are common in patients with
IE. Studies have shown that approximately three quarters of patients with
endocarditis have pre-existing cardiac disease [28,29,31]. Although the magnitude of risk for the development of IE associated with most structural
heart diseases is not well dened, the risk associated with some specic conditions has been studied more fully [29,3234]. For example, patients with
mitral valve prolapse and regurgitation may have a 3- to 8-fold increase
in IE risk compared to the general population [32,33]. This risk is lower than
the estimated risk for patients with either a history of previous IE or prosthetic cardiac valves (60185-fold increased risk) [29].
Recently, data has emerged related to pre-disposing cardiac conditions
and the subsequent development of IE. Strom and colleagues [7] utilized a
population-based casecontrol study to quantify associations between certain predisposing risk factors and IE. Strong associations were found in
patients with previous valvular surgery, previous IE, rheumatic fever involving the heart, and mitral valve prolapse, consistent with previous ndings
[35]. This evidence supports the AHA classication scheme and provides
further evidence of the magnitude of risk for IE associated with specic
pre-existing cardiac conditions.
Dental risk factors
Dental risk factors and antibiotic prophylaxis for IE prevention is likely
the most debated, controversial, and litigated aspect of endocarditis prevention and management. Despite clear recognition that certain cardiac diseases
may increase the risk for developing IE, the utility of attempted prevention
by means of antibiotic prophylaxis given at the time of dental and other procedures remains controversial [17,35,36].
Conventional practice dened by the AHA guidelines [30] dictates administration of antibiotic prophylaxis for specic patient groups and procedures, yet clinical data supporting its eectiveness are lacking [11]. Recent
data from human studies examining a link between dental procedures and
IE have not shown a signicant relationship [7,37,38]. For instance, Strom
and colleagues [7] did not nd any association between dental procedures
(with the possible exception of tooth extraction) and subsequent endocarditis in a population-based casecontrol study.

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259

These studies may renew debate concerning the potential harm from
widespread antibiotic use for endocarditis prophylaxis, which may actually
be more dangerous on a population level than the possibleyet unprovenbenet. Collectively, these studies begin to create a critical mass of evidence that justies the re-examination of current practice.
Intensive medical care and other non-dental exposures
The changing face of endocarditis has been a common title for IE studies over the decades. As epidemiologic shifts occur in the overall population,
such as longevity of life and decreased prevalence of rheumatic heart disease, there have been parallel shifts in patients with IE. These shifts did not
go unnoticed by those involved in endocarditis care and research.
In 1978 Watanakunakorn [39] noted that the typical IE patient
described in textbooks was no longer representative of the majority of the
IE cases seen in medical centers. He hypothesized that medical progressnamely invasive medical proceduresplayed an important role in the
evolution of the spectrum of endocarditis. Specically, procedures such as
cardiopulmonary bypass, open heart surgery, hemodialysis, long-term intravenous cannulation, and intracardiac devices all contributedand would
continue to contributeto the changing spectrum of IE. Similar observations have been made by others [40,41]. Recent studies have conrmed relationships between particular procedures and pathogens associated with IE.
For example, hemodialysis appears to be a predictor of S. aureus IE [22].
Additionally, other studies have found an association between certain hospital-based procedures [35,42] and the subsequent development of IE.
Based on the aging of the population, the increasing reliance on intensive
and invasive medical care, and the decreasing prevalence of certain cardiac
risk factors, it seems reasonable to assume that an increasing proportion of
IE care in the future will be related to sequellae of previous medical exposures. This provides both a challenge and an opportunity for the medical
community. The challenge results from the recognition that medicallyrelated exposures may increase the risk of IE in certain vulnerable populations. The opportunity then exists to further characterize these relationships
such that medical care is impacted and devastating complications, such as
endocarditis, are targeted and prevented.
Microorganisms
we are only at the threshold of inquiries relating to the culture of these
organisms, to the macroscopic characteristics of their growth [27]

At the time of Oslers Gulstonian lectures the study of microorganisms

was in its infancy. Over the past century tremendous advances in microbiology and the introduction of antibiotics have moved IE from near 100% mortality to a disease in which the majority of patients survive the initial infection.

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Although virtually any organism can cause IE, infective endocarditis was,
historically, a disease of patients with pre-existing valvular abnormalities
and community-associated bacteremia. Streptococcal species accounted for
60% to 80% of all cases, and most patients had rheumatic heart disease
[43,44].
For a variety of reasons, there has been a shift in the spectrum of microbiologic etiologies of IE [40]. Some of these reasons have been highlighted in
the previous discussion and include regional variation, changing prevalence
of predisposing cardiac conditions, the aging of the population, changes in
IVDU demographics, and increased exposures to intensive and invasive
medical care.
When studies are compared in aggregate over time, certain shifts in the
microbiologic spectrum are apparent (Table 1). For instance, viridans group
streptococci have decreased by approximately 35% over time while S. aureus
has increased by 50%. Additionally, streptococci other than viridans group
have increased. Finally, the no growth rate has dropped approximately
72% across these study periods with the development of better microbiologic
techniques and procedures.

Diagnosis
Few diseases present greater diculties in the way of diagnosis than malignant endocarditis, diculties which in many cases are practically insurmountable. It is no disparagement to the many skilled physicians who
have put their cases upon record to say that, in fully one-half the diagnosis
was made post mortem. [45]

The ability to diagnose IE has advanced rapidly over the last century.
Two important advancements were the creation of standardized clinical criteria for the diagnosis of IE and the development of imaging technology
such as echocardiography.
The diagnosis of IE has always hinged upon clinical suspicion derived
from association with appropriate signs and symptoms and, most importantly, the demonstration of continuous bacteremia. A major diagnostic
advance came in 1981 when von Reyn and colleagues [10] published an anal-

Table 1
Microorganisms in endocarditis by decades

Prior to 1970 [4,60]

1970s [4,61]
1980s [6,25,61,62]
1990s [3,24,63]

Viridans
group

Other
strept

S. aureus

CNS

Gram-negative

Other

No
growth

43%
42.5%
29%
28%

12.5%
16%
19%
23%

14%
13%
24%
28%

4%
3%
9%
7%

5.5%
5%
4%
4%

3%
10%
7.5%
5%

18%
10%
7.5%
5%

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261

ysis that provided four diagnostic categories in cases of suspected IE

(rejected, possible, probable, and denite). These criteria gained wide acceptance and provided the rst opportunity for investigators to standardize the
diagnosis of IE, thereby enabling comparisons between studies. In 1994 IE
diagnostic criteria were rened further by Durack and colleagues [9]. The
revised criteria, which have come to be known as the Duke criteria, incorporated echocardiographic evidence of IE for the rst time. These criteria had
improved test performance characteristics when compared to previous criteria [9] and have been validated subsequently by many other studies [45
49]. Recently, proposed modications have been published [5052] but the
test performance characteristics of the modied criteria have yet to be fully
evaluated by other investigators.

Therapy
No treatment that has been tried cures Death is generally the result of
poisoning, the patient weakening progressively. Embolism of the brain or
heart occasionally kills. Recovery is almost unknown. [53]

Thus Sir Thomas Lewis commented on the near 100% mortality rate for
patients with IE in the early part of the twentieth century. Nearly half a century later, the introduction of penicillin, followed by intracardiac surgery,
provided eective treatment and increased survival rates.
Although the use of antibiotics and surgery has led to dramatic improvements in the overall outcomes of patients with endocarditis, there are few
data to help maximize the use of these choices to benet patients. For
instance, the timing of surgery in selected patients to prevent adverse outcomes yet limit surgical complications is poorly dened. In the absence of
denitive studies, particularly randomized trials, physicians must rely on
accepted guiding principles [54]. For antibiotic therapy, management
demands careful attention to antibiotic choice, susceptibility testing, dosing,
and duration of therapy. Whenever possible, the etiologic agent must be isolated in a pure culture with minimum inhibitory and bactericidal concentrations determined for the antibiotics used. Parenteral antibiotics are
recommended over oral agents because of the importance of sustained antibiotic activity. Additionally, long-term therapy is recommended because of
the relapse rate associated with shorter courses of therapy, but two-week
regimens have also shown to be eective.
Surgery has become an important component in the management of IE.
Generally accepted indications for surgical intervention include refractory
heart failure, more than one serious embolic event, uncontrolled infection,
signicant valve dysfunction, ineective antimicrobial therapy, mycotic
aneurysm, most cases of prosthetic valve IE, and invasive complications
(e.g., myocardial abscess) [54,55]; see also Chapter 11.

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Direction for fruitful investigations in the future

Limitations in the current understanding of endocarditis
The dierent modes of onset, and the extraordinary diversity of symptoms
which may arise, render it very dicult to present a satisfactory clinical picture. [56]

With this statement Osler dened the diculty inherent in studying a

relatively rare and diverse disease such as endocarditis. Denitive studies
of IE have been dicult to perform due to the low incidence of the disease,
a limitation that is compounded by the heterogeneous nature of populations
at risk, variable underlying risk factors, and a wide array of infecting organisms. Out of necessity, most studies are derived from case reports or series of
cases collected at a single clinical site. There have been few casecontrol studies or large prospective cohort studies, and even fewer randomized controlled trials. Most of these small studies are not adequately powered to
examine important groups of patients with IE such as those with specic
cardiac risk factors, aected anatomic sites, or particular microorganisms.
These are serious limitations in a heterogeneous disease that aects at least
15,000 patients per year in the United States [57] and has a one-year mortality approaching 40% [6,21,22].
A shift in approach is necessary to further the understanding of endocarditis and to denitively study therapeutic choices. Establishment of a multicenter study group has the potential to overcome some of the limitations
that plague investigations in infective endocarditis.
Toward a more global understanding of endocarditis
As a result of these considerations, a group of investigators formed a collaborative study consortium, the International Collaboration on Endocarditis (ICE). ICE was formed to (1) establish a group of investigators who
would work together and would be dedicated to furthering the understanding of endocarditis, (2) combine existing databases to study regional dierences in IE, (3) begin a large prospective cohort study of endocarditis, and
(4) develop a network of investigators to perform randomized clinical trials.
ICE working group
The ICE investigation was launched at the Fifth International Symposium on Modern Concepts in Endocarditis and Cardiovascular Infections,
Amsterdam, Netherlands, in July 1999. Since its inception, 23 sites in 15
countries have become involved in the project (Table 2). An International
Steering Committee charged with promoting collaboration and discovery
governs the working group. The Steering Committee directs the activities
of the ICE consortium and coordinates research activity by member investigators and institutions.

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263

ICE database merger

The initial project of the ICE investigation involved the merger of existing databases from throughout the world. The purpose of the database merger project was to begin evaluation of regional dierences in endocarditis
and to provide a large sample of IE patients that would permit sub-group
analyses.
ICE investigators were queried to ascertain which sites had existing electronic databases that were available for evaluation and merger. Seven sites
with existing databases (Table 2) were willing to contribute data for analysis. The databases were sent to the Coordinating Center (Duke Clinical
Research Institute, Durham, NC, USA) for characterization and merger.
The process of database merger was as follows. The databases from each
site were provided in an electronic format to the Coordinating Center. Documentation was obtained regarding the characteristics of the individual
databases and denitions of the variables. Core variables, common to individual databases, were identied.
For the core variables, a hierarchical variable structure was used that
incorporated the most specic data available from each site. For example, for
Table 2
ICE participating sites (as of 1 January 2002)
City

Country

Amsterdam
Ann Arbor
Barcelona
Beirut
Besancon
Birmingham
Birmingham
Buenos Aires
Christchurch
Durham
Goteborg
London
Marseille
Nancy
Napoli
Paris
Philadelphia

Netherlands
USA
Spain
Lebanon
France
United Kingdom
USA
Argentina
New Zealand
USA
Sweden
United Kingdom
France
France
Italy
France
USA

Santiago
Sao Paulo
Sydney
TelAviv
Victoria
Zagreb

Chile
Brazil
Australia
Israel
Australia
Croatia

X participating site.

Principal
investigator
Jan van der Meer
Suzanne Bradley
Jose Miro
Souha Kanj
Bruno Hoen
Thomas Elliott
William Dismukes
Liliana Clara
David Murdoch
G. Ralph Corey
Lars Olaison
Susannah Eykyn
Gilbert Habib
Christine Selton-Suty
Utili Riccardo
Catherine Leport
Elias Abrutyn
Brian Strom
Sandra Braun
Auristelo Ramos
Philip Jones
Ethan Rubinstein
Denis Spelman
Bruno Barsic

ICE retrospective ICE prospective

study
cohort study

X
X

X
X
X
X
X

X
X

X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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C.H. Cabell, E. Abrutyn / Infect Dis Clin N Am 16 (2002) 255272

brain embolic events, the most specic information provided by individual

sites was used to code a dichotomous brain embolic event variable as yes/
no. In addition, the specic data (e.g., ischemic, hemorrhagic, or ischemic
plus hemorrhagic) was retained as a sub-classication under brain embolic
event. In this way, all patients were coded with the core variable, yet important specic information was also incorporated into the merged database.
Variables from each site were then converted to match the core set of
variables and structure. Once the variables from each individual database
were converted, the individual databases were merged to form the ICE
retrospective database (ICERD). All characterizations, including microorganism determination, were based upon the data supplied by the individual
databases. ICERD contains over 2200 well-characterized patients with
denite IE by the Duke criteria [9].
General characteristics from ICERD
The median age of these patients was 58.0 years, 67.5% were men, 14%
were IVDUs, and 77% had native valve IE. Overall, S. aureus was found
in 32%, coagulase-negative staphylococci in 16%, viridans group streptococci in 23%, S. bovis in 5%, Enterococcus faecalis in 4%, gram-negative organisms in 2%, and other in 18% (Fig. 1).
Although the number of patients in ICERD should allow for analyses
that examine subtle dierences that were not previously possible due to sample size constraints, there are limitations. These limitations include disparate
data acquisition techniques in multiple institutions, loss of data precision by
mapping individual data to a core set of variables, referral bias, observational study design, and dierent time periods from which patients were
accrued into the individual databases. Despite these limitations, analyses
from ICERD may provide data regarding regional variation and IE characteristics that can form hypotheses for future studies.
ICE prospective cohort study
The prospective cohort study began on 15 June 2000. This observational
study aims to collect data on IE cases, as they are identied, using a standard case report form and denitions. To date, 23 sites have enrolled
patients in the prospective cohort study (Table 2). Several advantages in this
study can be identied.
The prospective design will minimize ascertainment and sampling bias
from any individual site, but clustering will need to be evaluated. The registry should also provide rapid accrual of patients, which can limit the eect of
changing demographics of disease over time. The large sample size provided
by the registry will provide the power necessary for detailed analyses and the
study of rare IE characteristics. Because valid data can be accrued rapidly,
ICE should also have the capacity to answer questions about IE soon after
the need for specic data is identied. Finally, the multicenter design will

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265

Fig. 1. Distribution of organisms in ICE retrospective database. S. aureus Staphylococcus

aureus, CNS coagulase-negative staphylococci, viridans group viridans group streptococci,
S. bovis Streptococcus bovis, E. faecalis Enterococcus faecalis, gram neg gram stain
negative organisms.

provide the opportunity to analyze natural experiments regarding practice

variation and associated patient outcomes.
The core set of domains found on the case report form include the following: patient demographics, pre-existing conditions, medication history, recent
procedures, focus of infection, previous endocarditis episodes, initial valve
status, clinical presentation, echocardiographic data, microbiologic data, serologic data, complications, and outcomes. Denitions were established for
all variables to ensure standardization of data collection. ICE sites will identify consecutive patients with IE for enrollment in the prospective cohort
study. Completed case report forms are sent to the Coordinating Center for
data entry. Data managers are responsible for the quality and completeness
of the data. A critical set of elds has been identied that must be completed
before a patients le will be incorporated. Data managers contact the site
data coordinators when there is a need to correct missing values or errors.
An additional feature of the ICE prospective cohort study involves the
development and utilization of core laboratories in echocardiography and
microbiology, allowing for additional standardization and central interpretation.
Patients enrolled in the ICE cohort study will undergo echocardiographic examination as clinically indicated by clinicians at each site. The echocardiograms will be performed as previously described [22,58,59]. For
transthoracic echocardiography (TTE), two-dimensional imaging from multiple tomographic planes, along with spectral Doppler and color ow imaging, will be used in all patients. Transesophageal echocardiography (TEE)
will be performed on fasting patients using topical pharyngeal anesthesia,
and conscious sedation per local practice patterns. Images will be recorded
on one-half inch videotape in either SVHS or PAL format, depending on
the country of origin.

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Echocardiograms of patients with IE will be copied at participating sites

and sent to the core facility. These studies will be interpreted in the central
laboratory using a modication of the scheme published by Sanlippo and
colleagues [16]. All echocardiograms from patients that meet the criteria for
denite endocarditis will be blindly interpreted at the core laboratory facility
using standardized denitions and data collection forms and compared to
site interpretations for quality assurance purposes.
Similarly, the core microbiology laboratory will provide quality assurance measures by banking organisms isolated from patients with IE. The
enrolling sites will sub-culture etiologic isolates onto chocolate agar (or
other appropriate media). These isolates will then be shipped to the core
microbiology facility adhering to international shipping guidelines. Once
received at the core laboratory, isolates will be frozen at )70C.

Controlled clinical trials

Although retrospective data analyses and observational studies provide
important information and insights into disease processes, these study
designs are of limited use in testing treatment strategies. Randomized clinical trials provide the opportunity to test treatment strategies and maximally
control for other factors aecting outcome. Without randomized trials, it is
not possible to fully control for all potential confounding factors and accurately assess the full impact of therapeutic decision making.
In diseases of high morbidity and mortality, such as IE, randomized trials
are necessary to move forward the treatment of patients. ICE investigators
have developed a core network of dedicated scientists and an established
infrastructure from which clinical trials will be possible. The capacity to
meet sample size requirements of controlled clinical trials oers great opportunities. Future randomized clinical trials may include treatment with novel
therapeutic agents, testing of therapeutic decision strategies to minimize
adverse events such as stroke, and timing of valve surgery to maximize the
chance for valve repair and minimize risk for relapse of IE.
Diculties encountered and lessons learned from the inception
of the global database
As might be anticipated, logistic and quality assurance issues arose as
organization and infrastructure was created for this multicenter eort. Work
proceeded with the following thoughts in mind: that multiple study sites,
each with multiple contributing clinicians, would be involved; that study
sites would be located in dierent countries; that dierent languages would
be involved but that English would be used as the common language; that
laboratory tests would not be standardized across all sites; that normal
ranges for laboratory results might dier; and that site variation in units

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267

of measure for diagnostic laboratory values would exist. The authors

recount their experience with these and other issues with the hope of aiding
others mounting a similar eort.
These dierences and the problems created by them were noted most
acutely while working to merge the seven pre-existing databases for the retrospective database merger. The merger required adjusting for variability in
the specic tests that were employed in dierent centers, the units for reporting results, and the breakpoints (or intervals) that were employed when stratication was used to report results. As described earlier (see ICE database
merger), the solution involved creation of a hierarchical system for reporting
results that permitted entering the most precise nding for an individual
patient. For instance, some sites only coded for thromboembolic events in
general, while others provided more specic characterizations such as stroke
or splenic emboli. The authors, therefore, created a hierarchical variable
structure such that all embolic events were coded as a general variable
(e.g., thromboembolic event yes); if a site provided more specic information then that was coded as well (e.g., stroke yes). As described, a core
variable, brain embolic event, was coded yes or no along with a subclassication (ischemic, hemorrhagic, or ishemic/hemorrhagic), if that additional
information was available. This organizational structure allowed us to keep
the most specic information from each database while also creating core
main variables present in all databases. In contrast, results for other variables were so disparate that a composite variable for reporting purposes
could not be created; results for these variables were not entered into the
database. The results for C-reactive protein levels, rheumatoid factor titers,
and sedimentation rates are representative examples.
The process for creating the case report form for the prospective cohort
study was somewhat simpler. The pivotal problem for the retrospective
database merger was determination of the data elements that could be
extracted from each database in the creation of the merged database. In contrast, the pivotal issue for the prospective cohort study was design of a case
report form that embodied all of the data elements needed for future analyses while adjusting for the considerations outlined previously. It is well
known that case reporting forms are most successful when the purpose for
which the data would be used has been dened clearly. Delineation of specic aims should precede discussion of items to be incorporated in the form,
because clarity in the focus of the study helps investigators dene what
information will be needed and in what form. Without specic research
aims, it is dicult to assess the completeness of the protocol and data collection instruments. While these decisions are critical to serving the scientic
purposes of the study, choices about data variables and data structure also
greatly inuence the costs of the study by aecting eort associated with
data entry, storage, queries, and data error resolution. After much deliberation and multiple rounds of review involving investigators at many of the
sites, a case report form was created and implemented. After experience with

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300 cases, the form was revised. In retrospect, revision probably could
have been accomplished earlier, perhaps after the rst 50 cases.
Throughout clinical research, the quality and strength of the evidence and
the generalizability of results are of concern to investigators. The authors
thoughts regarding a few issues relevant to the ICE eort follow. The
authors recognize the potential for referral bias; this study is not population-based and referrals are likely since the contributors at each site are well
known, locally and internationally, for expertise in the diagnosis and management of infective endocarditis. Referral bias is probably unavoidable
under these circumstances, so ndings from these studies must be interpreted
with this constraint in mind. Regarding the composition of the study sample,
the authors note that from the outset the importance of having each site collect consecutive cases has been stressed; however, eorts to validate eectiveness in this regard are dicult and have not been undertaken to date. Data
recording and entry, another potential issue, has been addressed by having
data coordinators at each site ll out case report forms under the supervision
of the principal investigator, and data sent to Duke are entered using double
data entry. Unfortunately, funding is not available for data monitors to verify chart abstraction by site visit because ICE is largely a volunteer eort.
Finally, the potential for clustering to aect results is recognized and will
be considered when data are analyzed. Because a single standardized case
report form is used for data collection of consecutive cases of infective endocarditis in all sites, the strength of the evidence generated from the cohort
study should be stronger than that derived from the merged database.
Logistical issues were also of concern. The authors were concerned about
the use of dierent computer systems and software at various study sites, but
major problems did not arise. The absence of problems may have been
related to our belief that Microsoft programs including Excel and
Access are in wide use, and these as well as other software programs have
the capacity to export information easily. Additionally, SAS, the foundation for the merged and cohort databases, imports data from many sources
with ease. In the end, the dominant mode of communication was by e-mail
using Adobe Acrobat and a PDF format for documents. E-mail was highly
ecient and largely problem free. Interpretation of eld names caused a
minor diculty because languages dier and truncated words for eld
names are sometimes used in databases and spreadsheets; creation of a dictionary of eld names solved the problem. To assure completeness and correctness, data sent to Duke were reviewed carefully before data entry to
identify errors and missing items needing completion. Variability in reading
and interpreting cardiac echocardiograms is well recognized, necessitating
development of a process to assure consistency and accuracy in the readings.
Therefore, in the prospective cohort study, copies of echocardiograms are
sent to a core ECHO laboratory to permit standardized readings using standard criteria as noted above. Lastly, the collection, preservation, and shipping of the etiologic organisms to the central laboratory at Duke could have

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269

presented diculties. However, a mechanism for mailing and storing the

organisms has been established and, although mailing of organisms is not
yet in wide use, there have been no problems with the system to date.

Conclusion
In the century and a quarter since William Osler delivered his famed Gulstonian lectures on endocarditis [27] continual advancements have been
made in understanding and treating this disease. Here the authors have
reviewed some key aspects of current knowledge in the areas of population
epidemiology, host factors, microorganisms, and diagnosis. The advent of
the ICE investigation provides the opportunity to further expand our understanding of IE by developing a very large, global database of IE patients
whose clinical, echocardiographic, and microbiologic ndings have been
characterized with standard methodology. Further, ICE may serve as a rich
source of material for investigators seeking to perform specic studies.
Finally, the ICE infrastructure creates the opportunity for performing randomized trials to test therapeutic strategies. Although many obstacles
remain to be overcome, ICE has created the opportunity for a quantum leap
in our knowledge of IE over the next 25 years.

Acknowledgment
This work could not have been possible without the tremendous eorts
put forth by the individual ICE investigators.

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