The goal of this prospective interventionist cohort study is to assess the prevalence of
infective endocarditis in patients with Staphylococcus aureus bacteremia at low risk of
this complication.

The main questions it aims to answer are:

  -  Determine whether the risk of infective endocarditis in patients with Staphylococcus
     aureus bacteriemia identified as low-risk, using the VIRSTA score, is low enough to
     safely omit transthoracic or transesophageal echocardiography.

  -  Determine whether the risk of infective endocarditis in patients with Staphylococcus
     aureus bacteriemia in patients with no identifiable risk factor is low enough to
     safely omit transthoracic or transesophageal echocardiography.

  -  Calculate a cost-benefit estimate of omitting echocardiographic testing in patients
     identified as low-risk by means of the above methods.

Participants will undergo mandatory transthoracic and transesophageal echocardiography
during the first 2 weeks from Staphylococcus aureus bacteremia onset.

Evaluation of the Usefulness of Echocardiography in Patients With Staphylococcus Aureus Bacteremia (ET-AUREUS Study).

Staphylococcus Aureus Bacteremia

Infective Endocarditis

2- Hypothesis: Prospective evaluation of a cohort of patients with OAB, who undergo TEE,
TTE, will provide insight into the actual risk of IE in those patients at low risk.

3- Objectives:

  -  Main objective:

  -  To estimate the prevalence of IE, defined by the modified Duke criteria, in patients
     with low risk according to the VIRSTA scale.

  -  To determine whether the risk of IE in patients with OAB identified as low risk
     using the VIRSTA scale is low enough to safely omit transthoracic or transesophageal
     echocardiography using this scale.

  -  Secondary objectives

  -  To determine whether the risk of IE in patients with SAAB identified as low risk
     using the PREDICT or POSITIVE scales is low enough to safely omit transthoracic or
     transesophageal echocardiography.

  -  To identify risk factors for IE in patients with SAAB.

  -  Determine whether the risk of IE in patients with no risk factors is low enough to
     safely omit transthoracic or transesophageal echocardiography.

  -  Estimate the number of echocardiographies that could be avoided by these approaches.

  -  Estimate the cost-benefit of omitting echocardiographic testing in patients
     identified as low risk by the above methods.

     3- Material and methods:

     *Design: Multicenter prospective cohort study.

     *Project execution sites: Hospitals with the capacity to detect AFB, contact the
     patient within 72-96h and the possibility of performing transthoracic
     echocardiography (TTE) and transesophageal echocardiography (TEE) in the center
     itself. Currently 13 collaborating centers plus the sponsoring center (Hospital
     Puerta de Hierro).

     * Sample size calculation: Sample size calculation was performed in order to
     estimate the prevalence of IE in patients with OAB identified as low risk using the
     VIRSTA scale. For a confidence level of 95%, with a loss rate of 10%, precision of
     2% and an expected proportion of 2% of IE in low-risk patients, a sample size of 210
     VIRSTA-negative patients was calculated. Given that at inclusion it will be unknown
     whether the patient is VIRSTA negative and that, among the objectives of the study
     is the identification of other subgroups of low-risk patients, taking into account
     that approximately 45% of patients with AFB are VIRSTA negative, a total sample size
     of 470 patients with AFB is estimated.

       -  Intervention:

Systematic performance of TTE and TEE in all included patients. TTE will be performed and
reported first, followed by TEE (same or different days). Both tests should be performed
within 10 days of the patient's inclusion in the study.

The studies will be performed in each of the centers participating in the project with
the latest generation echocardiographic equipment commonly used in each center. All
echocardiograms will be anonymized and assigned a correlative patient number.

The acquisition of the images of the vegetation or infectious complication will be zoomed
and 3 consecutive cardiac cycles will be recorded and sent in DICOM format (both cine and
image) to the centralized imaging laboratory, where interpretation will be performed by
at least two cardiologists with expertise in echocardiography.

The cardiologists interpreting the echocardiograms centrally will be blinded to any
clinical, microbiological and other complementary test data of the patient, as well as to
the local interpretation of the images. The cardiologist interpreting the TTE will be
blind to the TEE and vice versa.

  -  Definitions of positive echocardiographic findings for IE:

Echocardiograms with at least one of the following findings will be considered positive
or suggestive of IE:

  -  Vegetation: echogenic mass, usually mobile attached to an endocardial surface or
     intracardiac device. Most frequently attached to a valve and with independent
     movement. They are usually located on the ventricular side of ventriculo-arterial
     valves and on the atrial side of atrioventricular valves.

  -  Perivalvular abscesses/infection: areas of inhomogeneous perivalvular thickening,
     may be echodense or echolucent, usually located in the valve annuli.

  -  Fistula: communication between two adjacent cavities, the Doppler-color passes from
     one cavity to another depending on the pressure in both.

  -  Pseudoaneurysm: pulsatile perivalvular cavity, without echoes inside, into which
     flow enters, detected by doppler-color.

  -  Perforation: Destruction of the valvular surface that causes acute valvular
     insufficiency; the valvular defect is usually seen by 2D and the insufficiency that
     passes through it, which is usually eccentric. Multiple perforations may coexist in
     the same valve.

  -  Endocarditis on prosthetic valve: in addition to all of the above, images compatible
     with paravalvular leak of new appearance, detected with color Doppler, or valve
     dehiscence will be considered.

       -  Predefined cutoff points to reasonably rule out IE:

IE will be considered reasonably ruled out when the estimated risk of IE is low enough
that the costs and risks of the tests needed for diagnosis (TTE or TEE) outweigh the
benefits.

In defining cutoff points for this low risk of IE, we consider several recent
publications that estimate the risk of IE above which a patient benefits from such
evaluations (8,24), as well as the usefulness of the negative likelihood ratio (LR(-) or
likelihood ratio (-)) in predicting this risk, as has been reported by other authors
(25). In line with these studies, the following cut-off points are predefined:

  1. If the risk of IE was less than 0.5% and the CP(-) of the scale less than 0.05, IE
     would be considered reasonably ruled out without the need for any echocardiographic
     assessment;

  2. If the risk of IE was between 0.5-2% or the CP(-) of the scale between 0.05-0.10, IE
     would be considered reasonably ruled out without the need for TEE when a negative
     TTE with good visualization of the heart valves is available.

  3. If the risk of IE was between 2-5% or the CP(-) of the scale between 0.10-0.20, IE
     could be considered reasonably ruled out with a negative TTE (without the need for
     TEE) only if the prevalence of IE after TTE was less than 1%. Otherwise, the use of
     TEE would be considered necessary.

  4. If the risk of IE was greater than 5% or the CP(-) of the scale was greater than
     0.20, TEE would be considered necessary to safely rule out IE.

       -  Variables to be studied:

Demographic data, comorbidities, mode of acquisition and primary focus of bacteremia,
clinical, microbiological, echocardiographic and evolution data from patients' medical
records, as well as echocardiographic findings will be collected. Data will be collected
from the electronic history of each center and included in an anonymized form in an
online medical database platform (eCDR).

*Statistical analysis: Quantitative variables will be presented as median and 25th and
75th percentiles; and qualitative variables by absolute and relative frequencies.

An interval estimation (95%) of the prevalence of IE in patients identified as low risk
will be performed using the VIRSTA, PREDICT and POSITIVE scales. The prevalence of IE in
patients without any of the identified factors will also be estimated using secondary
analyses (see below). The diagnostic validity indices sensitivity, specificity, negative
(PC-) and positive (PC+) likelihood ratios, and negative (NPV) and positive predictive
values (PPV) vs. the gold standard (modified Duke criteria) will be estimated. With these
data, we will estimate the risk of IE in an identified low-risk patient from a population
with a prevalence similar to ours. Echocardiography (TTE and/or TEE) will be considered
dispensable in patients with SAAB when the estimated risk of IE in patients identified as
low risk and the CP(-) of the scale is below the aforementioned predefined cut-off
points.

For the study of IE risk factors, univariate inferential analysis will be performed using
the Mann-Whitney U test for quantitative variables and with the χ2 test or Fisher's exact
test when necessary for qualitative variables. Those variables that are clinically and
statistically significant will be included in a multivariate logistic regression model.

Finally, the number of echocardiographic tests, both TTE and TEE that could have been
safely omitted using the different approaches will be estimated. For the cost-benefit
study, the following risks will be taken into account: increased mortality due to
nondiagnosis of IE: 15% (2), increased mortality due to TEE: 0.1% (3), increased
mortality due to TTE: 0%. The costs of performing tests are estimated following the
catalog of public prices of the Community of Madrid (Order 727/2017): cost TEE: €80.

Bilateral p-values of less than 0.05 will be considered statistically significant. All
statistical analyses will be performed using the SPSS version 25 software package.

Echocardiography evaluation

Evaluation of the Usefulness of Echocardiography in Patients With Staphylococcus Aureus Bacteremia at Low Risk of Infective Endocarditis (ET-AUREUS Study).

If the prevalence of infective endocarditis is lower than 0.5% it would be considered
that no echocardiography is needed to exclude infective endocarditis. If the prevalence
is greater than 5%, a transesophageal echocardiography will be considered needed. If the
prevalence is between 0.5-5%, transesophageal echocardiography will be consireded needed
unless the prevalence of those patients with negative transthoracic echocardiography is
below 1%.

Patients will undergo mandatory transthoracic echocardiography during assessment of
Staphylococcus aureus bacteremia.

Later, they will also undergo mandatory transesophageal echocardiography.

Both test will be performed during the first 14 days from bacteremia onset.

Evaluation of the Usefulness of Echocardiography in Patients With Staphylococcus Aureus Bacteremia (ET-AUREUS Study).

About this trial

Study ID

Status

Type

Phase

Placebo

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Not accepting

Trial Timing

What is this trial about?

What are the participation requirements?

Locations

Location

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