Protocol Summary

Background.

Due to the ageing of the population, cardiovascular disease is still the major cause of death across Europe and a major cause of morbidity and loss of quality of life. In particular, with the diffusion of new risk factors (physical inactivity, diabetes mellitus and obesity), the prevalence of ischemic heart disease (IHD), the most frequent among cardiovascular diseases, is actually increasing. Accordingly, better prevention and management of IHD is needed to further reduce early cardiovascular mortality and morbidity and to improve life expectancy and quality of life. Further achievements in the fight against cardiovascular diseases could be obtained by developing and testing new strategies for the early detection and better characterization of IHD. These strategies should be based on non-invasive methods, should be cost-effective and ready for large scale clinical utilization in the next few years and should allow to identify new reliable end-points for prevention and treatment. Relevant to this approach is the distinction between classical coronary artery disaease (CAD) and IHD. CAD is diagnosed in the presence of anatomic lesions of the large coronary vessels while IHD implies the recognition of reduced coronary blood flow to the myocardial tissue eventually producing myocardial ischemia and its clinical manifestations. IHD may be caused by hemodynamically significant CAD but also by structural or functional abnormalities of the macro and micro coronary vessels with or without significant obstructive coronary lesions. Diagnosis of CAD alone may not be enough to decide treatment. By contrast, recognition of IHD and of its determinants (including significant CAD)  in the single patient would be more relevant for prognostic stratification and appropriate treatment.

Objectives.

The main purpose of the study is to evaluate the impact of combined non invasive, “anatomo-functional” cardiac imaging strategies on the detection and management of IHD. Together with the major objective, four specific goals will be pursued.

1. To test the relative accuracy of  different “anatomo-functional” non-invasive cardiac imaging strategies in the diagnosis of IHD. To this purpose the “anatomic” information provided by CT Angiography on the presence or absence of CAD will be combined in every patient with the “functional” information provided by radionuclide, magnetic resonance or echocardiographic cardiac imaging to assess the relevance of coronary disease by its effects on myocardial perfusion and contraction. Non-invasive results will be tested against invasive reference standards for the detection of significant coronary lesions, coronary atherosclerosis and reduced coronary flow reserve due to either macro or micro coronary disease (Clinical Case Slide Show).
2. To evaluate the association of individual risk profiles assessed from clinical data and biomarkers with the “anatomo-functional” evidence of IHD and patient outcome. To reach this goal the clinical characterization of patients (collected before non-invasive imaging) and the laboratory characterization (that will include novel biomarkers of cardiovascular risk) will be compared with patient characterization derived from “anatomo-functional” imaging and with patient outcome during the follow-up.
3. To develop an advanced clinical and imaging reporting and integrated decision
   making tool in cardiology. An informatics platform will be developed to synthetically and clearly present the integrated clinical and imaging diagnostic profile of individual patients. Specialized clinical decision making tools will be part of the platforms based on “image fusion” of different imaging modalities  and their integrated analysis with other clinical data. The tools will target both researchers and physicians and would speed-up the deployment of the novel results obtained within EVINCI-study, and similar future studies, to clinicians at the point of care.
4. To define the most cost-effective work-up for the diagnosis and characterization of
   IHD. To this purpose the costs and the procedural risks (including radiation exposure) of non-invasive and invasive diagnostic procedures will be prospectively collected. Cost-benefit and cost-effectiveness analyses will be conducted alongside the EVINCI clinical trial.

Expected results.

The major end point of the EVINCI study will be to assess the ability of non-invasive multimodality imaging to  recognize in the single patient not only if coronary disease is present but if it mainly involves the major coronary arteries or the microvessels and most importantly if it causes ischemia and hence should be aggressively treated. Other relevant outputs  would be the standardization of non-invasive imaging procedures throughout Europe and the development of new informatic tools for advanced reporting of multimodal cardiac imaging.

Potential impact.

The expected benefits from the EVINCI results include early diagnosis and accurate characterization of IHD by multimodality imaging in anginal patients avoiding unuseful invasive procedures. If this approach will demonstrate to be accurate, we could expect in the future that heart catheterization could be mainly reserved to interventions, i.e. to revascularize coronary stenosis known to cause myocardial ischemia. Multimodality imaging approach could be apparently more costly in the beginning but could prove to be cheaper at the end.  In the cost/risk-benefit workpackage of the study, this hypothesis will be evaluated. Moreover, it should also be possible to define the most cost-effective diagnostic work-up for the recognition of “significant” coronary disease among the different imaging modalities or combination of modalities. Interestingly, it could also be possible to recognize  patients who don’t have full blown CAD (a stenosis to be revascularized)  but are at high risk of future events due to early and/or functional abnormalities of the coronary system. We know that these patients, if unrecognized and left untreated, are at increased risk of developing myocardial infarction or heart failure. Again, resources used to recognize this population will save lifes and will spare future sanitary costs. Finally, results coming from the EVINCI Study could help in the future to tailor specific imaging modalities or combination of techniques to specific patients. Chosing the most cost-effective approach for the specific clinical question will avoid redundancy in using technology in medicine. A particular advantage of the experimental design of the EVINCI Study consists in the presence of independent core-labs for each different imaging modality. This approach could ensure a fair comparison of different modalities even if this is not the major goal of the study.

Co-ordinator and Partners

• (P1-IFC-CNR) CNR Institute of Clinical Physiology Pisa, Via G. Moruzzi 1, 56126 Pisa, Italy, CONSIGLIO NAZIONALE DELLE RICERCHE, established in Piazzale Aldo Moro 7, ROMA, 00185, Italy
  P.I. and Coordinator of the EVINCI Study :Dr. Danilo Neglia
  CNR Institute of Clinical Physiology
  Fondazione Toscana G. Monasterio
  Via G. Moruzzi 1, 56126 Pisa – ITALY
  Tel/Fax +390503152019/+390503152166 
  E-mail  dneglia@ifc.cnr.it
  Web Site http://www.ifc.cnr.it/,   http://www.ftgm.it/
• (P2-U.Turku)TURUN YLIOPISTO, established in YLIOPISTONMAKI, TURKU, 20014, Finland
  P.I. Prof. Juhani Knuuti
• (P3-UZH) UNIVERSITAET ZUERICH, established in Raemistrasse 71, ZURICH, 8006, Switzerland
  P.I. Prof. Philipp Antonio Kaufmann
• (P4-LUMD) ACADEMISCH ZIEKENHUIS LEIDEN - LEIDS UNIVERSITAIR MEDISCH CENTRUM, established in Albinusdreef 2, LEIDEN, 2333 ZA, Netherlands
  P.I. Prof. Jeroen Bax
• (P5-TUM) TECHNISCHE UNIVERSITAET MUENCHEN, established in Arcisstrasse 21, MUENCHEN, 80333, Germany
  P.I. Dr. Stephan Nekolla
• (P6-IR-HSCSP) INSTITUT DE RECERCA DE L'HOSPITAL DE LA SANTA CREU I SANT PAU , established in CALLE SANT ANTONI M CLARET 167, BARCELONA, 08025, Spain
  P.I. Prof. Albert Flotats
• (P7-NIC) INSTYTUT KARDIOLOGII IM. PRYMASA TYSIACLECIA STEFANA KARDYNALA WYSZYNSKIEGO, established in ul. Alpejska 42, WARSZAWA, 04628, Poland
  P.I. Dr. Anna Teresinska
• (P8-RBHT) ROYAL BROMPTON AND HAREFIELD NATIONAL HEALTH SERVICE TRUST, established in SYDNEY STREET, LONDON, SW3 6NP, United Kingdom
  P.I. Dr. Constantinos Anagnostopoulos
• (P9-APHP) ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS, established in 3 Avenue Victoria, PARIS, 75004, France
  P.I. Dr. Dominique Le Guludec
• (P10-UniGE) UNIVERSITA DEGLI STUDI DI GENOVA, established in Via Balbi 5, GENOVA, 16126, Italy
  P.I. Prof. Gianmario Sambuceti
• (P11-SERMAS) SERVICIO MADRILEÑO DE SALUD, established in PLAZA CARLOS TRIAS BERTRAN 7, MADRID, 28020, Spain
  P.I. Prof. Jose Luis Zamorano
• (P12-UniNA) UNIVERSITA DEGLI STUDI DI NAPOLI FEDERICO II., established in Corso Umberto I, NAPOLI, 80138, Italy
  P.I. Prof. Pasquale Perrone-Filardi
• (P13-HUVHEBRON) INSTITUT CATALA DE LA SALUT, established in GRAN VIA DE LES CORTS CATALANES 587, BARCELONA, 08007, Spain
  P.I. Dr. Santiago Aguade
• (P14-ESC) SOCIETE EUROPEENNE DE CARDIOLOGIE , established in ROUTE DES COLLES 2035, BIOT SOPHIA ANTIPOLIS, 06903, France
  P.I. Mrs. Celine Serio and Mrs. Francoise Heraud (for ESC Working Groups)
• (P15-INF) INFORSENSE LIMITED, established in HAMMERSMITH ROAD COLET COURT 100, London, W6 7JP, United Kingdom
  P.I. Dr. Moustafa Ghanem
• (P16-CFc) CF CONSULTING FINANZIAMENTI UNIONE EUROPEA SRL, established in Via Giuseppe Mussi 1, MILANO, 20154, Italy
  P.I. Dr. Carla Finocchiaro
• (P17-FGM) FONDAZIONE TOSCANA GABRIELE MONASTERIO  per la ricerca medica e di sanità pubblica, established in via Trieste 41, Pisa, 56126, Italy
  P.I. Dr. Alessia Gimelli