Stress Echo 2020 - The International Stress Echo Study
Stress Echo 2020 - The International Stress Echo Study
Background: Stress echocardiography (SE) has an established role in evidence-based
 guidelines, but recently the breadth and variety of applications has extended well beyond
 coronary artery disease (CAD). Purpose: To establish a prospective research study of SE
 applications, in and beyond CAD, also considering a variety of signs in addition to regional
 wall motion abnormalities. Methods: In a prospective, multicenter, international,
 observational study design, > 100 certified high-volume SE labs will be networked with an
 organized system of clinical, laboratory and imaging data collection at the time of physical
 or pharmacological SE, with structured follow-up information. The study is endorsed by the
 Italian Society of Echocardiography and organized in 10 subprojects focusing on: contractile
 reserve for prediction of cardiac resynchronization or medical therapy response; stress
 B-lines in heart failure; hypertrophic cardiomyopathy; heart failure with preserved ejection
 fraction; mitral regurgitation after either transcatheter or surgical aortic valve
 replacement; outdoor SE in extreme physiology; right ventricular contractile reserve in
 repaired tetralogy of Fallot; suspected or initial pulmonary arterial hypertension; coronary
 flow velocity, left ventricular elastance reserve and B-lines in known or suspected CAD;
 identification of subclinical familial disease in phenotype-negative healthy relatives of
 inherited disease (such as hypertrophic cardiomyopathy). Expected Results:To collect about
 10,000 patients over a 5-year period (2016-2020), with sample sizes ranging from 5,000 for
 known or suspected CAD to around 250 for hypertrophic cardiomyopathy or repaired Fallot. This
 data base will allow to investigate technical questions such as feasibility and
 reproducibility of various SE parameters and to assess their prognostic value in different
 clinical scenarios. Conclusions: The study will create the cultural, informatic and
 scientific infrastructure connecting high-volume, accredited SE labs, to obtain original
 safety, feasibility, and outcome data in evidence-poor diagnostic fields, also outside the
 established core application of SE in CAD based on regional wall motion abnormalities. The
 study will standardize procedures, validate emerging signs, and integrate the new information
 with established knowledge, helping to build a next-generation SE lab without inner walls.
In a prospective, multicenter, international, observational study design, > 100 SE labs will
 be networked with systematic clinical, laboratory and imaging data collection at the time of
 SE and with structured follow-up information at least at 6 months and 1 year, up to 3 years
 for specific protocols. For all the groups the primary aim is to evaluate the feasibility of
 several indices of SE in the evaluation of patients with known or suspected specific disease
 (1,2,3). The secondary aim is to assess the value of each of these parameters in predicting
 the functional impairment. The tertiary aim is to assess the prognostic value of SE indices
 for prognostic stratification of the disease in the medium-long-term.

 The study theater is the international network of cardiology SE laboratories, and the study
 is endorsed and promoted by the Italian Society of Echocardiography. The starting point of
 the recruitment phase was a recent electronic survey by the Italian Society of
 Echocardiography, in 2015 censoring 134 laboratories with moderate- (>100/year) to high-
 (>400/year) volume SE activities, which were precisely interrogated for interest in
 participation to SE2020. The recruitment plan forecasts 500 patients by the end of 2016, with
 doubling of the rate of enrollment in subsequent years, in parallel with the increasing
 number of recruiting labs fulfilling quality control criteria, reaching the target number of
 100 at the end of the 5-year schedule (4).

 Data collection Stress protocols are harmonized according to recent European and
 North-American scientific societies' guidelines, with semi-supine exercise recommended and
 pharmacological stress dosages up to 40 mcg/kg/min for dobutamine, up to 0.84 mg/kg in 6 min
 for dipyridamole, and up to a 4-min step of 200 microg/kg/min for adenosine. With dobutamine,
 atropine (up to 1 mg) can be administered in patients with suspected CAD (protocol 9), and it
 is associated with a higher rate of complications in those with a history of neuropsychiatric
 symptoms, reduced left ventricular function, or small body habitus. The maximal allowed
 dobutamine dose is 20 mcg/kg/min in patients with aortic stenosis, in whom higher doses are
 less safe and probably unnecessary (3). All laboratories will share a standardized case
 report form coded in a database format to facilitate retrieval and communication. For
 applications outside CAD and for CAD testing with vasodilator stress, no atropine is given on
 top of pharmacological stress. Although data collection with a dedicated project-specific
 case report form is allowed, we encourage implementing a dedicated, free ad-hoc system for
 data storage and reporting developed at the National Research Council, Institute of Clinical
 Physiology. The software provides a suitable informatics infrastructure for the SE 2020
 Italian multicenter study, with an intuitive graphic interface, eye-catching graphic format
 and convenient reporting option. It could represent the trade-off between the comprehensive
 information required by scientific standards and the smooth workflow priority of busy,
 high-volume, clinically-driven activities. The software was developed and tested in Italian
 and the translation of the last release in other languages (English, Portuguese and Serbian)
 is currently in progress.

 Data analysis Data will be expressed as mean ± standard deviation (normally distributed data,
 such as wall motion score index), median and inter-quartile (25th, 75th) range (non-normally
 distributed data, such as B-lines) or per cent frequency (categorical data, such as presence
 or absence of severe mitral regurgitation), with absolute numbers. One-sample comparisons
 will be performed using Wilcoxon test, and the chi-squared test without Fisher's correction
 for categorical data. Event rates will be estimated with Kaplan-Meier curves and compared by
 the log-rank test. Univariable analyses by Cox proportional hazards models will be performed
 to assess the association between each candidate variable and outcome. All variables with P
 <0.20 by univariable analysis will be considered as candidate variables for the multivariable
 analyses. Goodness of fit of the models will be based on C-statistics and its variants,
 adjusting for optimism using bootstrap replications (at least 1000). A receiver operating
 characteristic analysis will be used to obtain the best prognostic predictor for the
 individual SE variables. We will also analyze the data according to a clinically guided
 stepwise procedure, where the variables were included in the model in the same order in which
 they are actually considered by the cardiologist. Statistical significance will be set at
 p<0.05.

 Quality control

 It is well-known that the diagnostic performance of SE is closely related to the level of
 expertise of the cardiologist-echocardiographer performing the test, since the evaluation of
 regional wall motion is subjective and qualitative, with considerable variability even among
 experienced centers of undisputed reputation (1). The reproducibility and accuracy of wall
 motion reading can be substantially increased with limited training (2) and through
 development of conservative, pre-specified reading criteria (4). Therefore, quality control
 of the diagnostic performance in the various laboratories is a must in order to enter
 meaningful information in the data bank. The burden of quality control is on the hub center
 of the principal investigator of each subproject, where various spoke centers may converge.
 For the general project, the hub center for regional wall motion analysis is Pisa-CNR, in
 coordination with the principal investigator. There are five different levels of quality
 control, with increasing levels of complexity:

 1. Level 1, pre-requisite: a volume activity of the lab of at least 100 SE tests per year,
 which is the requirement for credentialing of SE activity by scientific societies

 2. Level 2, spoke centers read hub SE images, consisting in 20 selected studies for
 regional wall motion analysis. The concordance requires identification of test
 negativity/positivity and, in positive tests, the correct localization of the ischemic
 zone. For each test, a multiple choice 6-answer test is given. The criterion of ≥ 90%
 concordance (at least 18 out of 20 studies) is required, as previously described for
 first-generation SE multicenter studies (4).

 3. Level 3, hub centers read spoke centers studies, consisting in 20 any-quality
 consecutive studies recorded by the spoke center. The criterion of ≥ 80% concordance (at
 least 16 out of 20 studies) is required, as previously described for first-generation SE
 multicenter studies (4).

 4. Level 4, core lab reading. All centers should grant full access to images of SE studies
 entered in the data bank for audit or reading by core lab laboratory, which is the
 standard for specific subprojects such as number 10 for genetic SE, when every effort
 needs to be made to minimize variability and a single reader will analyze all studies
 acquired by different centers, as required by recommendations for small-to-medium sample
 studies, when resources allow (4).

 5. Level 5, specific protocols quality control. Although the SE quality control has proved
 to work well for regional wall motion analysis, novel SE applications involve different
 parameters, methodology of acquisition and reading criteria. Therefore, for each
 subproject, a web-based training session and quality control is organized by the
 specific hub center and principal investigator to assure consistency of data (4). The
 principal investigator of each subproject will prepare a set of 20 studies with
 rest-stress images. For each test, a multiple choice 6-answers test is given (only 1
 correct). The criterion of ≥90% concordance (at least 18 out of 20 studies) is required.
 The specific signs tested for certification are: end-diastolic and end-systolic volume
 changes (protocol 1); B-lines (protocol 2, 4, 6 and 9); left ventricular outflow tract
 gradient (protocol 3 and 10); E/e' (protocol 4); mitral regurgitation quantitative
 assessment (protocol 5); aortic stenosis quantitative assessment (protocol 5); right
 ventricular function (protocol 7); systolic pulmonary artery pressure measurements
 during stress (protocol 8); coronary flow velocity reserve (protocol 9); left
 ventricular elastance (protocol 9); global longitudinal strain (protocol 4 and 10).

 This study is also intended as a special level of voluntary accreditation and expertise in
 the specific field of interest, well above the volume activity criteria requested by
 guidelines. The accreditation process is run and certified by the Italian scientific society
 of echocardiography strictly following criteria and procedures of the European association of
 cardiovascular imaging to ensure standardization and independence of the process. When not
 otherwise specified, resting and SE measurements are performed according to the latest joint
 recommendations of European and North-American societies (4).

 Overall study design We will collect the experience of Italian, Brazilian, Hungarian and
 Serbian SE labs over the 5-year period from 2016 to 2020. In this broader framework, 10
 sub-projects will address specific patients' subsets. The target population ranges from
 250-patient samples for protocols focused on specific diseases (such as protocol 7 in
 repaired tetralogy of Fallot) to 2,500 for protocols on heart failure (number 2) to 5,000 to
 all-comers with known or suspected CAD tested with novel indices (number 9).

 Different study projects will cover the entire spectrum of disease, age and clinical status
 of current patients. The recruited participants are "the wellest of the well" (super-fit
 athletes entering project 6), the "worried well" (young first-degree relatives of patients
 with hypertrophic cardiomyopathy or familiar forms of dilated cardiomyopathy or pulmonary
 arterial hypertension, in project 10), the "suspected sick" (for instance patients with
 suspected diastolic heart failure or CAD as in projects 4 and 9), up to the sickest of the
 sick (for instance, patients with advanced heart failure or valvular heart disease entering
 projects 1, 2 and 5). Some degree of overlap is unavoidably present for some projects, for
 instance with subjects eligible for project 2 who are also recruitable for project 1 (if they
 undergo cardiac resynchronization therapy) or for project 5 (if they have heart failure with
 preserved ejection fraction). Over time, patients may move from one project to another: for
 instance, first-degree relatives of hypertrophic cardiomyopathy patients with negative
 phenotype enrolled in project 10 may subsequently develop overt forms of disease and be
 enrolled in project 3. All these potential gray-zone situations will be readily identified in
 individual SE reports.

 Although the setting will be mainly the Italian cardiological community, all essential
 documents will be written in English and we plan to extend the project to other communities
 with long-standing history of cooperation and experience in multicenter trials. Brazilian,
 Hungarian and Serbian centers are already recruiting and additional laboratories from other
 countries are now entering the process of accreditation. The project is curiosity-driven,
 independent from sponsors, and clinically oriented. However, after the planning and start-up
 phase, support from public or private funding agencies or industries is possible - provided
 that it is unrestricted and does not interfere in any way with data collection and analysis.

 There is no bonus payment for subject recruitment and subject referral. Enrolled patients are
 referred to the SE lab for clinically-driven indications. Each patient signs an informed
 consent form allowing scientific utilization of data, respectful of privacy rights, at the
 time of testing. The study project was submitted by the coordinating center of the principal
 investigator on January 31, 2016 and approved in its revised form by the Rome-1 ethical
 committee on July 20, 2016 (protocol number 1487/Lazio1). Ethics committee approval will be
 sought by each participating center, as needed.
Inclusion criteria shared by all projects are:

 -  age < 85 years and > 18 years (except for project 7 regarding repaired tetralogy of
 Fallot and project 10 regarding healthy relatives of patients with familial disease,
 in which children > 10 years can enter the study after parental consent);

 -  technically acceptable acoustic window at rest (with at least 14 segments well
 visualized in at least one projection).

 Exclusion criteria shared by all projects are:

 -  presence of prognosis-limiting comorbidities, such as advanced cancer, reducing life
 expectancy to < 1 year;

 -  pregnancy/lactation;

 -  unwillingness to give informed consent and to enter a regular follow-up program.