NCT03049995

Brief Summary

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.

Trial Health

43
At Risk

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Trial has exceeded expected completion date
Enrollment
300

participants targeted

Target at P75+ for all trials

Timeline
Completed

Started Nov 2016

Longer than P75 for all trials

Geographic Reach
1 country

1 active site

Status
unknown

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

November 1, 2016

Completed
3 months until next milestone

First Submitted

Initial submission to the registry

February 2, 2017

Completed
8 days until next milestone

First Posted

Study publicly available on registry

February 10, 2017

Completed
3.8 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

December 1, 2020

Completed
1 year until next milestone

Study Completion

Last participant's last visit for all outcomes

December 1, 2021

Completed
Last Updated

October 11, 2021

Status Verified

October 1, 2021

Enrollment Period

4.1 years

First QC Date

February 2, 2017

Last Update Submit

October 4, 2021

Conditions

Keywords

effectiveness; imaging; prognosis; stress echocardiography

Outcome Measures

Primary Outcomes (3)

  • all cause death

    Death from any cause occurring between 5 years after the time of SE enrollment

    5 years

  • cardiac death

    Death from cardiac cause occurring between 5 years after the time of SE enrollment

    5 years

  • transplantation

    Cardiac transplantation occurring between 5 years after the time of SE enrollment

    5 years

Secondary Outcomes (1)

  • clinical (NYHA class IV) or functional (EF 30>10%)

    5 years

Study Arms (10)

CHEF:Cardiac Resynchronization therapy Forecast

Patients evaluated prior to cardiac resynchronization therapy (CRT), with class I, IIa or IIb for CRT according to ESC 2016 guidelines, and with ejection fraction ≤ 35% and QRS duration ≥ 130 ms. Contractile reserve will be assessed through variations in Wall Motion Score Index and with more advanced parameters such as left ventricular elastance reserve, as the peak stress/baseline ratio of end - systolic pressure/ end-systolic volume (Left ventricular contractile reserve SE). All patients will be followed-up with resting echocardiographic examination to assess left ventricular remodelling and recovery of function. A sample size of 277 patients is required and about the same number is required to predict the response to medical therapy in patients eventually not undergoing CRT (4).

Procedure: Left ventricular contractile reserve SE

BHEF: B-lines in HEart Failure

B- lines are a semiquantitative sign of extravascular lung water present in 1 out of 3 HF patients at rest and in 1 out of 2 during stress, and potentially useful for refining prognostic stratification and titrating diuretic therapy in these patients. We will enroll patients referred to SE with known or suspected HF, with either reduced or preserved ejection fraction. B-lines will be detected using the B-lines SE intervention. A sample size of about 2500 patients is required if the effect on mortality is evaluated.

Procedure: B-lines SE

SEHCA: SE in Hypertrophic Cardiomyopathy

Current guidelines recommend SE in hypertrophic cardiomyopathy (HC) solely for evaluation of left ventricular outflow tract obstruction. Large-scale registry data show that SE positivity for ischemic criteria rather than provocable gradients predict adverse outcome in HC. Low-to-intermediate risk symptomatic or asymptomatic HC patients will undergo exercise SE with assessment at each stage and during recovery of wall motion, mitral insufficiency, left ventricular outflow tract gradient (in orthostatic position)(following specific SE protocol), E/e', B-lines and, if feasible, coronary flow velocity reserve. A sample size of about 250 patients is required.

Procedure: B-lines SEProcedure: Left ventricular outflow tract gradient SE

SEDIA: SE in Diastolic Heart failure

Patients with suspected diastolic heart failure according to guidelines (3) will be selected (1).The diastolic assessment should be included into all exercise SE tests by measuring standard Doppler-derived mitral inflow velocity, pulsed Tissue Doppler of mitral annulus, and retrograde tricuspid gradient of tricuspid regurgitation as well as diastolic left ventricular volume index and B-lines (to provide a direct imaging of extra-vascular lung water accumulation as a direct cause of dyspnea). The test is considered positive for diastolic dysfunction when all of the following three conditions are met during exercise: average E/e' \> 14 or septal E/e' ratio \> 15, peak tricuspid regurgitant jet velocity \>2.8 m/sec and septal e' velocity \< 7 cm/s. A sample size of about 250 patients is required.

Procedure: Diastolic function SE

SETA: SE in Transcatheter Aortic Valve implantation

Transcatheter Aortic Valve Implantation is an extraordinarily effective novel technology, and its short and long term morbidity and mortality remains significant. Patients with previous (from 6 months to 10 years) surgical or Transcatheter Aortic Valve Implantation capable of exercising will be enrolled and studied with semisupine SE. The full quantitative evaluation of mitral regurgitation and aortic stenosis will be performed. A sample size of about 100 patients is required to detect a significant stress-induced increase in mitral regurgitation severity. For the prognostic analysis 250 patients with 3 years follow-up are required.

Procedure: Mitral regurgitation SE

SEO: SE in Outdoor in Extreme conditions

SE can also be performed outdoors, with pocket size or portable instruments, in a setting of ecological stress entirely different from standard indoor testing. The diagnostic target is the early subclinical identification of pulmonary edema. Subjects involved in extreme sporting events (competitive triathlon, marathon, apnea diving etc) or ordinary exercise in extreme environments (trekking at high altitude) will undergo lung ultrasound scan for B-lines before, soon after (within 10 minutes) and (when positive) soon after, later after (6 to 24 h) the acute extreme exercise. A sample size of 80 patients is required to detect a significant stress-induced increase in B-lines in each of the three major study subgroups: high altitude trekkers (n=100); marathon runners (n=80) and apnea divers (n=70).

Procedure: B-lines SE

SETOF: SE in operated Tetralogy of Fallot

Patients with repaired Tetralogy of Fallot or Fallot-like pathology (double-outlet right ventricle Fallot type, tetralogy of Fallot with pulmonary atresia), evaluated at least 1 year after the last surgical or percutaneous procedure, will be recruited by regional reference centers for congenital heart disease. Additional inclusion criteria are age \> 10 years, height \> 140 cm, New York Heart Association class I or II. Right ventricular function will be assessed at baseline and peak stress with variations (rest and peak stress) of tricuspid annular plane systolic excursion. A sample size of about 250 patients is required to detect a significant stress-induced increase in tricuspid annular plane systolic excursion.

Procedure: Pulmonary hemodynamics SE

DOSPAH: Doppler SE in Pulmonary Arterial Hypertension

Patients at risk, borderline, or early established pulmonary hypertension capable of exercising will be recruited by regional reference centers, a physical stress will be performed and the hemodynamic assessment will include the assessment of pulmonary hemodynamics. The primary positivity criteria are the increase in systolic pulmonary artery pressure (\> 40 mmHg) and the flow-adjusted variation in pulmonary vascular resistances. A sample size of about 250 patients is required to detect a significant stress-induced hemodynamic changes with a 3 -year follow-up.

Procedure: Pulmonary hemodynamics SE

DITSE: Diagnosis of CAD by imaging SE

A clear step-up in diagnostic sensitivity (with a modest loss in specificity) and risk stratification capability is obtained with assessment of coronary flow velocity reserve in the left anterior descending coronary artery,left ventricular contractile reserve through changes in left ventricular elastance, and B-lines. "Allcomers" referred to the SE lab with suspected CAD will be evaluated with standard regional wall motion analysis and also - whenever feasible - with left ventricular coronary flow reserve and left ventricular elastance reserve and - when possible- B-lines ("quadruple imaging").A sample size of about 5,000 patients will be required.

Procedure: Left ventricular contractile reserve SEProcedure: B-lines SEProcedure: Coronary flow reserve SE

GENES: Genetic Stress echocardiography

The identification of phenotype-negative and genotype positive carriers of pathologic mutations is an important, still elusive, target. We will initially select 75 patients (25 for each disease) with documented disease and mutant gene. We will enroll 250 first-degree relatives of the initially considered probands, with normal findings at rest and age range preferentially between 10 and 21 years. SE testing will be tailored on the specific question: hypertrophic cardiomyopathy as in protocol 3 (left ventricular outflow tract gradient); pulmonary hypertension as in protocol 8 (pulmonary vascular resistances);dilated cardiomyopathy as in protocol 1 (left ventricular elastance). A sample size of about 80 patients for each disease will be required.

Procedure: Left ventricular contractile reserve SEProcedure: Left ventricular outflow tract gradient SEProcedure: Pulmonary hemodynamics SE

Interventions

Stress protocols (either physical or pharmacological) will be performed according to recent guidelines recommendations (1,2,3). with special focus on Wall Motion Score Index.

CHEF:Cardiac Resynchronization therapy ForecastDITSE: Diagnosis of CAD by imaging SEGENES: Genetic Stress echocardiography
B-lines SEPROCEDURE

SE will be performed with special focus on lung sonography and B-lines score (3,4).B-lines will be scored with the 28-regions antero-lateral chest assessment as previously described at baseline and immediately after stopping exercise. A simplified 8-region scan is also allowed in order to save time without loss of critical information.

BHEF: B-lines in HEart FailureDITSE: Diagnosis of CAD by imaging SESEHCA: SE in Hypertrophic CardiomyopathySEO: SE in Outdoor in Extreme conditions

SE will be performed with special focus on left ventricular outflow tract obstruction (3,4).

GENES: Genetic Stress echocardiographySEHCA: SE in Hypertrophic Cardiomyopathy

SE will be performed with special focus on E/e', pulmonary artery systolic pressure, B-lines and left ventricular end-diastolic volume (3,4).

SEDIA: SE in Diastolic Heart failure

SE will be performed with special focus on mitral regurgitation and aortic valve gradients assessment (3,4).

SETA: SE in Transcatheter Aortic Valve implantation

SE will be performed with special focus on pulmonary artery systolic pressure and pulmonary artery hemodynamics.

DOSPAH: Doppler SE in Pulmonary Arterial HypertensionGENES: Genetic Stress echocardiographySETOF: SE in operated Tetralogy of Fallot

SE will be performed with special focus on regional wall motion + coronary artery flow velocity reserve.

DITSE: Diagnosis of CAD by imaging SE

Eligibility Criteria

Age18 Years - 85 Years
Sexall
Healthy VolunteersYes
Age GroupsAdult (18-64), Older Adult (65+)
Sampling MethodNon-Probability Sample
Study Population

1. Heart Failure patients candidates for cardiac resynchronization therapy. 2. Patients with known or suspected HF. 3. Hypertrophic cardiomyopathy. 4. HF with preserved ejection fraction. 5. Patients with aortic valve replacement. 6. Healthy volunteers involved in extreme sporting events (competitive triathlon, marathon, apnea diving etc). 7. Tetralogy of Fallot operated patients. 8. At risk borderline, or early established pulmonary hypertension. 9. Known or suspected CAD. 10. First degree relatives with familial dilated cardiomyopathy, pulmonary hypertension or hypertrophic cardiomyopathy.

You may qualify if:

  • 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).

You may not qualify if:

  • 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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Fatebenefratelli Hospital

Benevento, Italy

RECRUITING

Related Publications (6)

  • Pellikka PA, Nagueh SF, Elhendy AA, Kuehl CA, Sawada SG; American Society of Echocardiography. American Society of Echocardiography recommendations for performance, interpretation, and application of stress echocardiography. J Am Soc Echocardiogr. 2007 Sep;20(9):1021-41. doi: 10.1016/j.echo.2007.07.003. No abstract available.

    PMID: 17765820BACKGROUND
  • Sicari R, Nihoyannopoulos P, Evangelista A, Kasprzak J, Lancellotti P, Poldermans D, Voigt JU, Zamorano JL; European Association of Echocardiography. Stress Echocardiography Expert Consensus Statement--Executive Summary: European Association of Echocardiography (EAE) (a registered branch of the ESC). Eur Heart J. 2009 Feb;30(3):278-89. doi: 10.1093/eurheartj/ehn492. Epub 2008 Nov 11. No abstract available.

    PMID: 19001473BACKGROUND
  • Lancellotti P, Pellikka PA, Budts W, Chaudhry FA, Donal E, Dulgheru R, Edvardsen T, Garbi M, Ha JW, Kane GC, Kreeger J, Mertens L, Pibarot P, Picano E, Ryan T, Tsutsui JM, Varga A. The clinical use of stress echocardiography in non-ischaemic heart disease: recommendations from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. Eur Heart J Cardiovasc Imaging. 2016 Nov;17(11):1191-1229. doi: 10.1093/ehjci/jew190.

    PMID: 27880640BACKGROUND
  • Picano E, Ciampi Q, Citro R, D'Andrea A, Scali MC, Cortigiani L, Olivotto I, Mori F, Galderisi M, Costantino MF, Pratali L, Di Salvo G, Bossone E, Ferrara F, Gargani L, Rigo F, Gaibazzi N, Limongelli G, Pacileo G, Andreassi MG, Pinamonti B, Massa L, Torres MA, Miglioranza MH, Daros CB, de Castro E Silva Pretto JL, Beleslin B, Djordjevic-Dikic A, Varga A, Palinkas A, Agoston G, Gregori D, Trambaiolo P, Severino S, Arystan A, Paterni M, Carpeggiani C, Colonna P. Stress echo 2020: the international stress echo study in ischemic and non-ischemic heart disease. Cardiovasc Ultrasound. 2017 Jan 18;15(1):3. doi: 10.1186/s12947-016-0092-1.

    PMID: 28100277BACKGROUND
  • Merli E, Ciampi Q, Scali MC, Zagatina A, Merlo PM, Arbucci R, Daros CB, de Castro E Silva Pretto JL, Amor M, Salame MF, Mosto H, Morrone D, D'Andrea A, Reisenhofer B, Rodriguez-Zanella H, Wierzbowska-Drabik K, Kasprzak JD, Agoston G, Varga A, Lowenstein J, Dodi C, Cortigiani L, Simova I, Samardjieva M, Citro R, Celutkiene J, Re F, Monte I, Gligorova S, Antonini-Canterin F, Pepi M, Carpeggiani C, Pellikka PA, Picano E; Stress Echo 2020 and 2030 study group of the Italian Society of Echocardiography and Cardiovascular Imaging (SIECVI). Pulmonary Congestion During Exercise Stress Echocardiography in Ischemic and Heart Failure Patients. Circ Cardiovasc Imaging. 2022 May;15(5):e013558. doi: 10.1161/CIRCIMAGING.121.013558. Epub 2022 May 17.

  • Scali MC, Zagatina A, Ciampi Q, Cortigiani L, D'Andrea A, Daros CB, Zhuravskaya N, Kasprzak JD, Wierzbowska-Drabik K, Luis de Castro E Silva Pretto J, Djordjevic-Dikic A, Beleslin B, Petrovic M, Boskovic N, Tesic M, Monte I, Simova I, Vladova M, Boshchenko A, Vrublevsky A, Citro R, Amor M, Vargas Mieles PE, Arbucci R, Merlo PM, Lowenstein Haber DM, Dodi C, Rigo F, Gligorova S, Dekleva M, Severino S, Lattanzi F, Morrone D, Galderisi M, Torres MAR, Salustri A, Rodriguez-Zanella H, Costantino FM, Varga A, Agoston G, Bossone E, Ferrara F, Gaibazzi N, Celutkiene J, Haberka M, Mori F, D'Alfonso MG, Reisenhofer B, Camarozano AC, Miglioranza MH, Szymczyk E, Wejner-Mik P, Wdowiak-Okrojek K, Preradovic-Kovacevic T, Bombardini T, Ostojic M, Nikolic A, Re F, Barbieri A, Di Salvo G, Merli E, Colonna P, Lorenzoni V, De Nes M, Paterni M, Carpeggiani C, Lowenstein J, Picano E; Stress Echo 2020 Study Group of the Italian Society of Echocardiography and Cardiovascular Imaging. Lung Ultrasound and Pulmonary Congestion During Stress Echocardiography. JACC Cardiovasc Imaging. 2020 Oct;13(10):2085-2095. doi: 10.1016/j.jcmg.2020.04.020. Epub 2020 Jul 15.

Biospecimen

Retention: SAMPLES WITH DNA

Blood and saliva will be collected in patients of "GENES"protocol.

MeSH Terms

Conditions

Coronary Artery DiseaseHeart FailureCardiomyopathy, HypertrophicAortic Valve DiseaseTetralogy of FallotPulmonary Arterial Hypertension

Condition Hierarchy (Ancestors)

Coronary DiseaseMyocardial IschemiaHeart DiseasesCardiovascular DiseasesArteriosclerosisArterial Occlusive DiseasesVascular DiseasesCardiomyopathiesAortic Stenosis, SubvalvularAortic Valve StenosisHeart Valve DiseasesHeart Defects, CongenitalCardiovascular AbnormalitiesCongenital AbnormalitiesCongenital, Hereditary, and Neonatal Diseases and AbnormalitiesHypertension, PulmonaryLung DiseasesRespiratory Tract Diseases

Study Officials

  • Quirino Ciampi, MD

    Fatebenefratelli Hospital

    PRINCIPAL INVESTIGATOR

Central Study Contacts

Quirino Ciampi, MD

CONTACT

Study Design

Study Type
observational
Observational Model
CASE ONLY
Time Perspective
PROSPECTIVE
Target Duration
5 Years
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

February 2, 2017

First Posted

February 10, 2017

Study Start

November 1, 2016

Primary Completion

December 1, 2020

Study Completion

December 1, 2021

Last Updated

October 11, 2021

Record last verified: 2021-10

Data Sharing

IPD Sharing
Will not share

Locations