International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA)

Coronary Artery Disease Clinical Trial

— ISCHEMIA  

Official title:

International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01471522
• Other study ID #: 11-00498
• Secondary ID: 1U01HL105907
• Status: Completed
• Phase: N/A
• Start date: July 2012
• Est. completion date: May 30, 2023

Study information

• Verified date: May 2023
• Source: NYU Langone Health
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the ISCHEMIA trial is to determine the best management strategy for higher-risk patients with stable ischemic heart disease (SIHD). This is a multicenter randomized controlled trial with 5179 randomized participants with moderate or severe ischemia on stress testing. A blinded coronary computed tomography angiogram (CCTA) was performed in most participants with eGFR ≥60 mL/min/1.73m2 to identify and exclude participants with either significant unprotected left main disease (≥50% stenosis) or those without obstructive CAD (<50% stenosis in all major coronary arteries). Of 8518 participants enrolled, those that had insufficient ischemia, ineligible anatomy demonstrated on CCTA or another exclusion criterion, did not go on to randomization. Eligible participants were then assigned at random to a routine invasive strategy (INV) with cardiac catheterization followed by revascularization, if feasible, plus optimal medical therapy (OMT) or to a conservative strategy (CON) of OMT, with cardiac catheterization and revascularization reserved for those who fail OMT.

SPECIFIC AIMS

A. Primary Aim The primary aim of the ISCHEMIA trial is to determine whether an initial invasive strategy of cardiac catheterization followed by optimal revascularization, if feasible, in addition to OMT, will reduce the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure in participants with SIHD and moderate or severe ischemia over an average follow-up of approximately 3.5 years compared with an initial conservative strategy of OMT alone with catheterization reserved for failure of OMT.

B. Secondary Aims Secondary aims are to determine whether an initial invasive strategy compared to a conservative strategy will improve: 1) the composite of CV death or MI; 2) angina symptoms and quality of life, as assessed by the Seattle Angina Questionnaire; 3) all-cause mortality; 4) net clinical benefit assessed by including stroke in the primary and secondary composite endpoints; and 5) individual components of the composite endpoints.

Condition: Coronary Disease Procedure: Coronary CT Angiogram Procedure: Cardiac catheterization Phase: Phase III per NIH

Condition: Cardiovascular Diseases Procedure: Angioplasty, Transluminal, Percutaneous Coronary, other catheter-based interventions Phase: Phase III per NIH

Condition: Heart Diseases Procedure: Coronary Artery Bypass Surgery Phase: Phase III per NIH

Description:

BACKGROUND:

Evidence supporting a routine invasive practice paradigm for patients with SIHD is outdated. In strategy trials conducted in the 1970s, coronary artery bypass grafting (CABG) improved survival as compared with no CABG in SIHD patients with high-risk anatomic features. The relevance of these studies today is speculative because contemporary secondary prevention-aspirin, beta-blockers, statins, ACE inhibitors, and lifestyle interventions-were used minimally if at all. Subsequent trials have compared percutaneous coronary intervention (PCI) with medical therapy, as PCI has replaced CABG as the dominant method of revascularization for SIHD. To date, PCI has not been shown to reduce death or myocardial infarction (MI) compared with medical therapy in SIHD patients.

COURAGE and BARI 2D, the two largest trials comparing coronary revascularization vs. medical therapy in SIHD patients, found that among patients selected on the basis of coronary anatomy after cardiac catheterization, an initial management strategy of coronary revascularization (PCI, PCI or CABG, respectively) did not reduce the primary endpoints of death or MI (COURAGE), or death (BARI 2D) compared with OMT alone. These data suggest, but do not prove, that routine cardiac catheterization--which often leads to ad hoc PCI through the diagnostic-therapeutic cascade--may not be required in SIHD patients. However, most patients enrolled in COURAGE and BARI 2D who had ischemia severity documented at baseline had only mild or moderate ischemia, leaving open the question of the appropriate role of cardiac catheterization and revascularization among higher-risk patients with more severe ischemia. Observational data suggest that revascularization of patients with moderate-to-severe ischemia is associated with a lower mortality than medical therapy alone, but such data cannot establish a cause and effect relationship. In clinical practice only about half such patients are referred for cardiac catheterization, indicating equipoise. Furthermore, analysis of outcomes for 468 COURAGE patients with moderate-to-severe ischemia at baseline did not reveal a benefit from PCI. This issue cannot be resolved using available data because all prior SIHD strategy trials enrolled patients after cardiac catheterization, introducing undefined selection biases (e.g., highest risk patients not enrolled) and making translation of study results problematic for clinicians managing patients who have not yet had cardiac catheterization.

A clinical trial in SIHD patients uniformly at higher risk (which could not have been performed before COURAGE and BARI 2D results were available) is needed to inform optimal management for such patients.

DESIGN NARRATIVE, INCLUDING MODIFICATIONS DURING THE TRIAL

Primary Endpoint

A composite of CV death, MI, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure was proposed as the primary endpoint in the application that was funded by NLHBI, with a secondary endpoint of CV death or MI. Study protocol version 1.0 was finalized on January 18, 2012 after review and approval by the protocol review committee (DSMB) with the primary endpoint specified as the composite of CV death or MI. Regarding the final status of the primary endpoint, the protocol stated:

"To ensure that the primary analysis is well-powered and useful, a prospective plan to allow extending follow-up and/or changing the primary endpoint based on aggregate event rate data will be established prior to the first review of unblinded trial data. At a designated time during the trial, an analysis will be conducted to estimate the overall aggregate primary endpoint event rate and project the final number of observed events. If the estimated unconditional power (i.e. based on aggregate event rate data; not by treatment group) is less than the originally targeted 90%, then one or more of the following options will be considered:

1. Extend follow-up to allow more events to accrue.

2. Change the primary endpoint to one that occurs more frequently. The current primary endpoint would become a secondary endpoint. The proposed new primary endpoint would be the composite of CV death, MI, resuscitated cardiac arrest, or hospitalization for unstable angina or heart failure.

3. Follow the recommendation of an independent advisory panel. An independent advisory panel, separate from the DSMB, will be convened for the purpose of reviewing unconditional power estimates and making a recommendation to the NHLBI Director. Members of this panel will not have access to unblinded data by treatment group or other data that may bias their recommendation." All 5 event types were adjudicated throughout the trial. Study protocol v2.0 (January 2014) allowed ischemia eligibility by non-imaging exercise stress test if more stringent (≥70% stenosis) CCTA criteria were met. The 2016 protocol addendum describes the NHLBI-approved reduction in sample size and extension of recruitment and follow-up due to slower than projected recruitment.

The pre-specified first analysis for monitoring and projecting the final aggregate number of primary endpoint events was conducted in 2015. In 2016, the projected need to increase the power by extending follow-up and elevating the 5-component secondary endpoint to become primary was discussed at Steering Committee and Investigator meetings and communicated by email.

An Independent Advisory Panel convened by NHLBI met in May 2017, and in June 2017 NHLBI approved the Independent Advisory Panel's recommendation to elevate the 5-component secondary endpoint to become primary and retain the 2-component composite as a key secondary endpoint. The panel also recommended extension of follow-up. This was communicated to the Steering Committee and Investigators at August and November 2017 meetings and by email. The last visit date was June 30, 2019.

A statistical plan developed for the Independent Advisory Panel process in 2012 specified that a decision about changing the primary endpoint would be targeted to occur before 75% of the final number of primary endpoint events had accrued. Although the final number of primary endpoint events was unknown during the course of the trial, estimates performed at the time of the Advisory Panel meeting suggested that the ratio of accrued endpoint events to final endpoint events was below 50%. See Maron DJ et al. Am Heart J. 2018 201:124-135. PMC6005768 for additional details about modifications to the trial while it was being conducted.

Analysis of Patients' Health Status as a Key Secondary Endpoint

A key secondary objective of the ISCHEMIA trial is to compare the quality of life outcomes-patients' symptoms, functioning and well-being-between those assigned to an invasive strategy as compared with a conservative strategy. In the protocol, angina frequency and disease-specific quality of life measured by the Seattle Angina Questionnaire (SAQ) Angina Frequency and Quality of Life scales, respectively, are described as the tools that will be used to make this comparative assessment. Recent work has indicated that it is possible to combine the information from the individual domain scores in the SAQ into a new Summary Score that captures the information from the SAQ Angina Frequency, Physical Limitation and Quality of Life scales into a single overall score. The advantages of using a summary score as the primary measure of QOL effects of a therapy are a single primary endpoint comparison rather than two or three (eliminating concerns some may have about multiple comparisons) and a more intuitive holistic (patient-centric) interpretation of the effectiveness results. With these advantages in mind, the ISCHEMIA leadership has agreed that the SAQ Summary Score will be designated as the primary way this outcome for this key secondary endpoint of the ISCHEMIA trial will be analyzed and interpreted, with the individual SAQ scores being used in a secondary, explanatory and descriptive role.

PARTICIPATING COUNTRIES:

North America:

Canada; Mexico; USA

South America:

Argentina; Brazil; Peru

Asia:

China; India; Japan; Malaysia; Singapore; Taiwan; Thailand; Russian Federation

Pacifica:

Australia; New Zealand

Europe:

Austria; Belgium; France; Germany; Hungary; Italy; Lithuania; Macedonia; Netherlands; Poland; Portugal; Romania; Serbia; Spain; Sweden; Switzerland; UK

Middle East:

Egypt; Israel; Saudi Arabia

Africa:

South Africa

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5179
• Est. completion date: May 30, 2023
• Est. primary completion date: June 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years and older

Eligibility

Inclusion Criteria:

• At least moderate ischemia on a qualifying stress test

• Participant is willing to comply with all aspects of the protocol, including adherence to the assigned strategy, medical therapy and follow-up visits

• Participant is willing to give written informed consent

• Age = 21 years

Exclusion Criteria:

• LVEF < 35%

• History of unprotected left main stenosis >50% on prior coronary computed tomography angiography (CCTA) or prior cardiac catheterization (if available)

• Finding of "no obstructive CAD" (<50% stenosis in all major epicardial vessels) on prior CCTA or prior catheterization, performed within 12 months

• Coronary anatomy unsuitable for either PCI or CABG

• Unacceptable level of angina despite maximal medical therapy

• Very dissatisfied with medical management of angina

• History of noncompliance with medical therapy

• Acute coronary syndrome within the previous 2 months

• PCI within the previous 12 months

• Stroke within the previous 6 months or spontaneous intracranial hemorrhage at any time

• History of ventricular tachycardia requiring therapy for termination, or symptomatic sustained ventricular tachycardia not due to a transient reversible cause

• NYHA class III-IV heart failure at entry or hospitalization for exacerbation of chronic heart failure within the previous 6 months

• Non-ischemic dilated or hypertrophic cardiomyopathy

• End stage renal disease on dialysis or estimated glomerular filtration rate (eGFR) <30mL/min (not an exclusion criterion for CKD ancillary trial, see CKD ancillary trial, Section 18)

• Severe valvular disease or valvular disease likely to require surgery or percutaneous valve replacement during the trial

• Allergy to radiographic contrast that cannot be adequately pre-medicated, or any prior anaphylaxis to radiographic contrast

• Planned major surgery necessitating interruption of dual antiplatelet therapy (note that patients may be eligible after planned surgery)

• Life expectancy less than the duration of the trial due to non-cardiovascular comorbidity

• Pregnancy (known to be pregnant; to be confirmed before CCTA and/or randomization, if applicable)

• Patient who, in the judgment of the patient's physician, is likely to have significant unprotected left main stenosis (Those who are able to undergo CCTA will have visual assessment of the left main coronary artery by the CCTA core lab)

• Enrolled in a competing trial that involves a non-approved cardiac drug or device

• Inability to comply with the protocol

• Exceeds the weight or size limit for CCTA or cardiac catheterization at the site

• Canadian Cardiovascular Society Class III angina of recent onset, OR angina of any class with a rapidly progressive or accelerating pattern

• Canadian Cardiovascular Society Class IV angina, including unprovoked rest angina

• High risk of bleeding which would contraindicate the use of dual antiplatelet therapy

• Cardiac transplant recipient

• Prior CABG, unless CABG was performed more than 12 months ago, and coronary anatomy has been demonstrated to be suitable for PCI or repeat CABG to accomplish complete revascularization of ischemic areas (CCC approval required)

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Coronary Artery Disease
• Coronary Disease
• Heart Diseases
• Ischemia
• Myocardial Ischemia

Intervention

Procedure:
• cardiac catheterization
Narrowed blood vessels can be opened without surgery using stents or can be bypassed with surgery. To determine which is the best approach for you the doctor needs to look at your blood vessels to see where the narrowings are and how much narrowing there is. This is done by a procedure known as a cardiac catheterization.
• coronary artery bypass graft surgery
Artery narrowing is bypassed during surgery with a healthy artery or vein from another part of the body. This is known as coronary artery bypass grafting, or CABG (said, "cabbage"). The surgery creates new routes around narrowed and blocked heart arteries. This allows more blood flow to the heart.
• percutaneous coronary intervention
Percutaneous coronary intervention may be done as part of the cardiac catheterization procedure. With this procedure a small, hollow, mesh tube (stent) is inserted into the narrowed part of the artery. The stent pushes the plaque against the artery wall, and opens the vessel to allow better blood flow.

Behavioral:
• Lifestyle
diet, physical activity, smoking cessation

Drug:
• Medication
antiplatelet, statin, other lipid lowering, antihypertensive, and anti-ischemic medical therapies

Locations

Country	Name	City	State
Argentina	Hospital Italiano Regional del Sur Bahia Blanca	Bahia Blanca	Buenos Aires
Argentina	Fundacion Favaloro	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	Clinica Del Prado	Cordoba
Argentina	Clínica Privada Vélez Sarsfield	Cordoba
Argentina	Clinica Romagosa and Clinica De La Familia	Cordoba
Argentina	Instituto Medico DAMIC	Cordoba	CBA
Australia	Flinders Medical Centre	Adelaide	South Australia
Australia	John Hunter Hospital	New Lambton Heights	New South Wales
Australia	Royal Perth Hospital	Perth	Western Australia
Australia	The Queen Elizabeth Hospital	Woodville South	South Australia
Austria	LKH Graz West Austria	Graz	Stmk
Austria	Medical University of Vienna, Department of Cardiology	Vienna	Wien
Austria	Wilhelminen Hospital Vienna	Vienna	Wien
Belgium	University Hospital Leuven	Leuven	Brabant
Brazil	Hospital Lifecenter	Belo Horizonte	Minas Gerais
Brazil	Hospital Pró-Cardíaco	Botafogo	Rio De Janeiro
Brazil	Hospital Cardiologico Costantini	Curitiba	Parana
Brazil	Quanta Diagnostico & Terapia	Curitiba	Parana
Brazil	Hospital Sao Vicente de Paulo	Fundo	RS
Brazil	Instituto Dante Pazzanese de Cardiologia	Ibirapuera	Sao Paulo
Brazil	Hospital Maternidade e Pronto Socorro Santa Lucia	Pocos de Caldas	Minas Gerais
Brazil	Hospital de Clinicas de Porto Alegre	Porto Alegre	RS
Brazil	Hospital Sao Lucas da Pontificia Universidade Catolica do Rio Grande do Sol	Porto Alegre	Rio Grande Do Sul
Brazil	Instituto de Cardiologia de Porto Alegre	Porto Alegre	Rio Grande Do Sul
Brazil	Hospital das Clinicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo	Ribeirao Preto	Sao Paulo
Brazil	Fundacao Bahiana de Cardilogia	Salvador	Bahia
Brazil	Hospital da Bahia	Salvador
Brazil	Heart Institute (InCor) University of São Paulo	Sao Paulo
Brazil	Hospital Celso Pierro	Sao Paulo
Brazil	Hospital TotalCor	Sao Paulo	SP
Brazil	Unifesp - Hospital Sao Paulo	Sao Paulo
Canada	University of Calgary	Calgary	Alberta
Canada	University of Alberta	Edmonton	Alberta
Canada	West Lincoln Memorial Hospital	Grimsby	Ontario
Canada	Hamilton General Hospital	Hamilton	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	Dixie Medical Group	Mississauga	Ontario
Canada	Montreal Heart Institute	Montreal	Quebec
Canada	Centre Intégré Universitaire de Santé et de Services Sociaux du Montréal	Montréal	Quebec
Canada	Dr. James Cha	Oshawa	Ontario
Canada	University of Ottawa Heart Institute	Ottawa
Canada	Scarborough Cardiology Research	Scarborough	Ontario
Canada	Saint Catharines General Hospital	St. Catharines	Ontario
Canada	CISSSL - Hopital Pierre-Le Gardeur	Terrebonne	Quebec
Canada	St. Michael's Hospital	Toronto	Ontario
Canada	University Health Network	Toronto	Ontario
Canada	Women's College Hospital	Toronto	Ontario
Canada	Centre Hospitalier de Regional Trois-Rivieres	Trois-Rivieres	Quebec
Canada	Vancouver General Hospital	Vancouver	British Columbia
Canada	Northwest GTA Cardiovascular and Heart Rhythm Program	Vaughan	Ontario
China	Beijing Anzhen Hospital	Beijing	Chaoyang
China	Beijing Chao-yang Hospital, Capital Medical University	Beijing	Beijing
China	Chinese Academy of Medical Sciences, Fuwai Hospital	Beijing	Beijing
China	Liangxiang Hospital, Beijing Fangshan District	Beijing	Fangshan
China	Peking Union Medical College Hospital	Beijing	Beijing
China	Affiliated Zhongshan Hospital of Dalian University	Dalian	Liaoning
China	Guangdong General Hospital	Guangzhou	Guangdong
China	The Second Affiliated Hospital Zhejiang University School of Medicine	Hangzhou	Zhejiang
China	Affiliated Hospital of Jining Medical University	Jining	Shandong
China	Qingdao Fuwai Hospital	Qingdao	Shandong
China	Shanxi Cardiovascular Hospital	Taiyuan	Shanxi
China	Tangshan Gongren Hospital	Tangshan	Hebei
China	TEDA International Cardiovascular Hospital	Tianjing	Tianjing
China	First Affiliated Hospital of Xinjiang Medical University	Urumqi	Xinjiang
China	Tongji Medical College	Wuhan	Hubei
China	Wuhan Asia Heart Hospital	Wuhan	Hubei
China	Wuhan Union Hospital, Tongji Medical College, Huazhong Science and Tech University	Wuhan	Hubei
China	Shanxi Provincial People's Hospital	Xian	Shanxi
China	The First Affiliated Hospital of Zhengzhou University	Zhengzhou	Henan
China	The Second Affiliated Hospital of Zhengzhou University	Zhengzhou	Henan
Egypt	Cairo University	Cairo
France	Centre Hospitalier Universitaire d'Angers	Angers Cedex 9	Pays De La Loire
France	Ambroise Pare Hospital	Boulogne	Ile De France
France	C.H. Louis Pasteur	Chatres	Centre
France	Antoine-Beclere Hospital	Clamart Cedex	Ile-de-France
France	Centre Hospitalier Sud Francilien	Corbeil-Essonnes cedex	Ile De France
France	Grenoble University Hospital	Grenoble	Isere
France	Bichat Hospital	Paris	Ile-de-France
Germany	Universitatsklinikum Bonn	Bonn	NRW
Germany	Praxisklinik Herz Und Gefaesse	Dresden	Saxony
Germany	University Hospital Jena	Jena	Thuringia
Germany	Robert-Bosch-Krankenhaus	Stuttgart	BW
Hungary	Eszszk- Szent Istvan Hospital	Budapest
Hungary	George Gottsegen National Institute of Cardiology	Budapest
Hungary	Heart and Vascular Center, Semmelweis University	Budapest
Hungary	Military Hospital, Budapest	Budapest
Hungary	University of Szeged	Szeged	Szeged Megyei Varos
India	Sri Jayadeva Institute of Cardiovascular Sciences and Research	Bangalore	Karnataka
India	Government Medical College	Calicut	Kerala
India	Apollo Research and Innovation	Chennai	Tamil Nadu
India	Apollo Research & Innovations	Hyderabad	Telangana
India	CARE Hospital	Hyderabad	Andhra Pradesh
India	CARE Nampally	Hyderabad	Telangana
India	Gurunanak CARE Hospital	Hyderabad	AP
India	MOSC Medical College Hospital, Kolenchery	Kolenchery	Kerala
India	King George's Medical University, Department of Cardiology	Lucknow	Uttar Pradesh
India	Hero DMC Heart Institute, Dayanand Medical College and Hospital	Ludhiana	Punjab
India	All India Institute of Medical Sciences	New Delhi
India	Batra Hospital and Medical Research Centre (BHMRC)	New Delhi	Delhi
India	Dr Ram Manohar Lohia Hospital	New Delhi	Delhi
India	Fortis Escort Heart Institute	New Delhi	Delhi
India	Fortis Healthcare Fl.t Lt. Rajan Dhall Hospital	New Delhi	Delhi
India	Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER)	Pondicherry	Tamil Nadu
India	KEM Hospital Pune	Pune	Maharashtra
India	Ruby Hall Clinic,Grant Medical Foundation	Pune	Maharashtra
India	Sree Chitra Tirunal Institute for Medical Sciences and Technology	Trivandrum	Kerala
Israel	Rambam Medical Center	Haifa
Israel	Assuta Medical Centers	Tel-Aviv
Italy	Cardiology and CCU - Ospedali Riuniti Ancona	Ancona	Marche
Italy	Ospedale Regionale Umberto Parini	Aosta
Italy	Azienda Ospedaliera S. Croce e Carle	Cuneo	Piemonte
Italy	Ospedale "G.B. Morgagni - L. Pierantoni" Forli (AUSL della Romagna)	Forli	Emilia-Romagna
Italy	Policlinico di Monza, Monza MB	Monza	MB
Italy	Clinica Mediterranea	Naples
Italy	AORN Dei Colli "V. Monaldi" UOC Cardiologia Università della Campania "L.Vanvitelli"	Napoli	Campania
Italy	University of Padua- Cardiology Clinic	Padua	Veneto
Italy	UO Cardiologia Ospedale SS Cosma e Damiano	Pescia	Tuscany
Italy	Humanitas Research Hospital, Rozzano (MI)	Rozzano	Milano
Italy	IRCCS "Casa Sollievo della Sofferenza"	San Giovanni Rotondo	FG
Italy	Azienda Servizi Sanitaria n.3 Alto Friuli-Collinare-Medio Friuli	Tolmezzo	Udine
Italy	Ospedale di Circolo e Fondazione Macchi	Varese
Japan	Saitama Medical University	Hidaka	Saitama
Japan	Keio University Hospital	Shinjuku-Ku	Tokyo
Japan	National Cerebral and Cardiovascular Center	Suita-shi	Osaka
Lithuania	Vilnius University Hospital Santariskes Clinic	Vilnius
Malaysia	Institut Jantung Negara	Kuala Lumpur	Wilayah Persekutuan
Mexico	Instituto Mexicano del Seguro Social	Benito Juarez	DF
Mexico	Instituto Nacional de Cardiología "Ignacio Chávez"	Mexico City	Distrito Federal
Netherlands	Cardio Research Hartcentrum OLVG	Amsterdam	NH
Netherlands	Radboudumc	Nijmegen
Netherlands	Isala Klinieken	Zwolle
New Zealand	Auckland City Hospital	Auckland
New Zealand	Waikato Hospital	Hamilton	Waikato
North Macedonia	University Clinic of Cardiology	Skopje	Republic Of Macedo
Peru	Instituto Neuro Cardiovascular De Las Americas	Miraflores	Lima
Poland	University Hospital in Bialystok	Bialystok	Podlaskie
Poland	Department of Coronary Disease, John Paul II Hospital, Jagiellonian University Medical College	Krakow	Maopolskie
Poland	Cardiology Clinic, Medical University in Lodz	Lodz	Lodzkie
Poland	Szpital Kliniczny Przemienienia Panskiego	Poznan
Poland	Coronary and Structural Heart Diseases Department, Institute of Cardiology	Warsaw	Mazowieckie
Poland	Department of Interventional Cardiology & Angiology, Institute of Cardiology	Warsaw	Mazowieckie
Poland	Institute of Cardiology, Warsaw	Warsaw	Mazovian
Poland	Medical University of Warsaw	Warsaw	Mazowieckie
Poland	Department of Internal Medicine and Cardiology, Infant Jesus Teaching Hospital, Medical University of Warsaw	Warszawa	Mazowieckie
Poland	Military Hospital / Medical University	Wroclaw
Poland	T.Marciniak Hospital	Wroclaw	Dolny Slask
Poland	Medical University of Silesia, School of Medicine with the Division of Dentistry, Department of Cardiology, Congenital Heart Diseases and Electrotherapy, Silesian Center for Heart Diseases	Zabrze	Wojewodztwo Slaskie
Portugal	Hospital de Santa Marta	Lisboa
Portugal	Santa Maria University Hospital, Cardiology Department, CHLN	Lisbon
Portugal	Centro Hospitalar de Vila Nova de Gaia/Espinho, EPE	Vila Nova de Gaia
Romania	Emergency County Hospital Baia Mare	Baia Mare
Romania	Emergency Institute of Cardiovascular Diseases ''Prof. Dr. C. C. Iliescu''	Bucharest
Russian Federation	National Medical Research Center for Cardiovascuar Surgery	Moscow	Gorod Moskva
Russian Federation	E.Meshalkin National Medical Research Center of the Ministry of Health of the Russian Federation	Novosibirsk	Novosibirskaya Oblast
Russian Federation	North-Western State Medical University	Saint Petersburg
Russian Federation	Federal Almazov North-West Medical Research Centre	Saint-Petersburg
Saudi Arabia	King AbdulAziz Cardiac Center	Riyadh	Central Province
Serbia	Clinical Center of Serbia	Belgrade
Serbia	Faculty of Medicine, University of Belgrade; Cardiology Clinic, Clinical Center of Serbia	Belgrade
Serbia	University Clinical Hospital Zvezdara	Belgrade
Serbia	University Hospital Center Bezanijska Kosa	Belgrade
Serbia	Clinical Center Kragujevac	Kragujevac
Serbia	Clinic for Cardiovascular Diseases, Clinical Center Nis	Nis
Serbia	Institute of Cardiovascular Diseases Vojvodina, Sremska Kamenica, Serbia and Faculty of Medicine, University of Novi Sad	Sremska Kamenica	Vojvodina
Singapore	National Heart Centre Singapore	Singapore
Singapore	National University Heart Center Singapore	Singapore
Singapore	Tan Tock Seng Hospital	Singapore
South Africa	Groote Schuur Hospital / University of Cape Town	Cape Town	Western Cape
Spain	Complexo Hospitalario Universitario A Coruña (CHUAC) Sergas, Department of Cardiology. INIBIC A Coruña. CIBER-CV. Universidad de A Coruña, Spain	A Coruna
Spain	Hospital De Bellvitge	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Hospital General Universitario Gregorio Maranon	Madrid
Spain	Hospital La Paz. IdiPaz	Madrid
Spain	HUVA, Hospital Clínico Universitario Virgen De La Arrixaca	Murcia
Spain	Hospital Clinico Universitario de Santiago	Santiago de Compostela	La Coruna
Spain	Hospital Universitario y Politecnico La Fe	Valencia
Spain	Hospital Universitario Miguel Servet	Zaragoza
Sweden	Karolinska Institutet at Danderyd Hospital	Stockholm
Sweden	Uppsala University	Uppsala
Switzerland	Cardiocentro	Lugano	Ticino
Taiwan	Mackay Memorial Hospital	Taipei City
Thailand	Ramathibodi Hospital	Bangkok
Thailand	Maharaj Nakorn Chiang Mai Hospital	Chiang Mai	Meung
United Kingdom	Hampshire Hospitals NHS Foundation Trust	Basingstoke	Hampshire
United Kingdom	Bedford Hospital NHS Trust	Bedford	Bedfordshire
United Kingdom	Belfast Trust	Belfast	Antrim
United Kingdom	South Eastern Health and Social Care	Belfast	Northern Ireland
United Kingdom	Blackpool Teaching Hospitals	Blackpool	Lancashire
United Kingdom	Royal Bournemouth Hospital	Bournemouth	Dorset
United Kingdom	Bradford Royal Infirmary	Bradford	West Yorkshire
United Kingdom	Papworth Hospital	Cambridge	Cambridgeshire
United Kingdom	Broomfield Hospital	Chelmsford	Essex
United Kingdom	University of Glasgow	Clydebank	Strathclyde
United Kingdom	The University of Hull/Castle Hill Hospital	Cottingham	East Yorkshire
United Kingdom	Cardiovascular Research Unit, Craigavon Area Hospital	Craigavon	Northern Ireland
United Kingdom	Dorset County Hospital	Dorchester	Dorset
United Kingdom	Russells Hall Hospital	Dudley	West Midlands
United Kingdom	Royal Infirmary of Edinburgh	Edinburgh	Scotland
United Kingdom	Northwick Park Hospital Harrow/ Royal Brompton Hospital London	Harrow	Middlesex
United Kingdom	Imperial College Healthcare NHS Trust	London
United Kingdom	King's College NHS Foundation Hospital	London
United Kingdom	Royal Free London NHS Foundation Trust	London
United Kingdom	University College London Hospitals NHS Foundation Trust/Barts Health NHS Trust	London
United Kingdom	Luton and Dunstable University Hospital NHS FT	Luton	Berdfordshire
United Kingdom	Central Manchester University Hospital	Manchester
United Kingdom	The James Cook University Hospital, Middlesbrough	Middlesbrough	Cleveland
United Kingdom	Nottingham University Hospitals	Nottingham	Notts
United Kingdom	The Pennine Acute Hospitals NHS Trust	Oldham	Lancashire
United Kingdom	Peterborough City Hospital	Peterborough	Cambs
United Kingdom	Pinderfields Hospital	Wakefield	West Yorkshire
United Kingdom	Southend University Hospital	Westcliff-on-Sea	Essex
United States	Albany Medical Center Hospital	Albany	New York
United States	Capital Cardiology Associates	Albany	New York
United States	Samuel Stratton VA Medical Center of Albany NY	Albany	New York
United States	Asheville Cardiology Associates	Asheville	North Carolina
United States	Emory University	Atlanta	Georgia
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	University of Washington Medical Center	Bellevue	Washington
United States	NIH Heart Center at Suburban Hospital	Bethesda	Maryland
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Saint Luke's Hospital and Health Network	Bethlehem	Pennsylvania
United States	Cedars Sinai Medical Center	Beverly Hills	California
United States	UAB Vascular Biology and Hypertension Program	Birmingham	Alabama
United States	Boston Medical Center	Boston	Massachusetts
United States	Brigham & Women's Hospital, Harvard Medical School	Boston	Massachusetts
United States	Jacobi Medical Center	Bronx	New York
United States	NYU-HHC Lincoln Medical and Mental Health Center	Bronx	New York
United States	Coney Island Hospital	Brooklyn	New York
United States	New York -Presbyterian/Brooklyn Methodist Hospital	Brooklyn	New York
United States	NYU-HHC Kings County Hospital Center	Brooklyn	New York
United States	NYU-HHC Woodhull Hospital	Brooklyn	New York
United States	Holy Spirit Hospital Cardiovascular Institute	Camp Hill	Pennsylvania
United States	Cardiovascular Associates, Ltd.	Chesapeake	Virginia
United States	Cincinnati VA Medical Center	Cincinnati	Ohio
United States	Louis Stokes Cleveland Veterans Affairs Medical Center	Cleveland	Ohio
United States	Ohio Health Grant Medical Center	Columbus	Ohio
United States	NYP Medical Medical Group Hudson Valley Cardiology	Cortlandt Manor	New York
United States	V.A. North Texas Health Care System	Dallas	Texas
United States	Midwest Cardiovascular Research Foundation	Davenport	Iowa
United States	Daytona Heart Group	Daytona Beach	Florida
United States	Atlanta VA Medical Center	Decatur	Georgia
United States	Henry Ford Health System	Detroit	Michigan
United States	Doylestown Health Cardiology	Doylestown	Pennsylvania
United States	Duke University Medical Center	Durham	North Carolina
United States	Englewood Hospital and Medical Center	Englewood	New Jersey
United States	Advanced Heart Care Group	Fairview Heights	Illinois
United States	Sanford Health	Fargo	North Dakota
United States	New York University - Langone Cardiovascular Associates	Flushing	New York
United States	UCSF - Fresno Community Regional Medical Center	Fresno	California
United States	Malcom Randall VAMC	Gainesville	Florida
United States	Spectrum Health	Grand Rapids	Michigan
United States	Baylor College of Medicine	Houston	Texas
United States	Baylor St. Luke's Medical Center	Houston	Texas
United States	Houston Heart & Vascular Associates	Houston	Texas
United States	Indiana University/Krannert Institute of Cardiology	Indianapolis	Indiana
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	Mayo Clinic Florida	Jacksonville	Florida
United States	Conemaugh Valley Memorial Hospital	Johnstown	Pennsylvania
United States	Kansas City VA Medical Center	Kansas City	Missouri
United States	Saint Luke's Hospital	Kansas City	Missouri
United States	Mid Valley Cardiology	Kingston	New York
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	Cardiovascular Specialists of Southwest Louisiana	Lake Charles	Louisiana
United States	Lexington VA Medical Center	Lexington	Kentucky
United States	University of Kentucky	Lexington	Kentucky
United States	South Denver Cardiology Associates, P.C.	Littleton	Colorado
United States	Ronald Reagan UCLA Medical Center	Los Angeles	California
United States	University of Louisville	Louisville	Kentucky
United States	Medical Center of the Rockies	Loveland	Colorado
United States	Stroobants Cardiovascular Center	Lynchburg	Virginia
United States	Northwell Health - Manhasset	Manhasset	New York
United States	Loyola University Medical Center	Maywood	Illinois
United States	NYU Winthrop	Mineola	New York
United States	Minneapolis VAMC	Minneapolis	Minnesota
United States	University of Minnesota	Minneapolis	Minnesota
United States	Saint Thomas Hospital	Nashville	Tennessee
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Beth Israel Medical Center	New York	New York
United States	Columbia University Medical Center	New York	New York
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Mount Sinai Saint Luke's Hospital	New York	New York
United States	NYU Langone Medical Center-Bellevue Hospital	New York	New York
United States	NYU New York Medical Associates	New York	New York
United States	VA New York Harbor Health Care System	New York	New York
United States	University of California Irvine Medical Center	Orange	California
United States	Palo Alto Medical Foundation Research Institute	Palo Alto	California
United States	VA Palo Alto HealthCare System	Palo Alto	California
United States	Baylor Research Institute at Legacy Heart Center	Plano	Texas
United States	The Heart Hospital Baylor	Plano	Texas
United States	AtlantiCare Regional Medical Center	Pomona	New Jersey
United States	Oregon Health & Science University	Portland	Oregon
United States	Providence Heart and Vascular Institute	Portland	Oregon
United States	Miriam Hospital	Providence	Rhode Island
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Hackensack University Medical Center	Saddle Brook	New Jersey
United States	Covenant Medical Center, Inc.	Saginaw	Michigan
United States	HealthEast Saint Joseph's Hospital	Saint Paul	Minnesota
United States	Salt Lake City VA Medical Center	Salt Lake City	Utah
United States	Audie Murphy V.A.	San Antonio	Texas
United States	Kaiser Permanente San Jose	San Jose	California
United States	Coastal Heart Medical Group	Santa Ana	California
United States	Cardiovascular Center of Sarasota	Sarasota	Florida
United States	Sarasota Memorial Hospital	Sarasota	Florida
United States	Cardiology Associates of Schenectady P.C.	Schenectady	New York
United States	Providence - Providence Park Hospital	Southfield	Michigan
United States	Stanford University School of Medicine	Stanford	California
United States	Medicus Alliance Clinical Research Org., Inc.	Sugar Land	Texas
United States	University of South Florida	Tampa	Florida
United States	Torrance Memorial Medical Center	Torrance	California
United States	Oklahoma Heart Institute	Tulsa	Oklahoma
United States	Kent Hospital	Warwick	Rhode Island
United States	VA Connecticut Healthcare System	West Haven	Connecticut
United States	VA Boston Healthcare System	West Roxbury	Massachusetts
United States	VAMC-White River Junction	White River Junction	Vermont
United States	Wichita Falls Heart Clinic	Wichita Falls	Texas
United States	Winchester Cardiology and Vascular Medicine, PC	Winchester	Virginia
United States	Saint Vincent Hospital at Worcester Medical Center	Worcester	Massachusetts
United States	Michigan Heart, PC	Ypsilanti	Michigan
United States	Yuma Regional Medical Center	Yuma	Arizona

Sponsors (16)

Lead Sponsor

Collaborator

NYU Langone Health

Albany Stratton VA Medical Center, Cedars-Sinai Medical Center, Columbia University, Duke University, East Carolina University, Emory University, Harvard University, Massachusetts General Hospital, Montreal Heart Institute, National Heart, Lung, and Blood Institute (NHLBI), New York University, Stanford University, University of British Columbia, University of Missouri, Kansas City, Vanderbilt University

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  China,  Egypt,  France,  Germany,  Hungary,  India,  Israel,  Italy,  Japan,  Lithuania,  Malaysia,  Mexico,  Netherlands,  New Zealand,  North Macedonia,  Peru,  Poland,  Portugal,  Romania,  Russian Federation,  Saudi Arabia,  Serbia,  Singapore,  South Africa,  Spain,  Sweden,  Switzerland,  Taiwan,  Thailand,  United Kingdom, 

References & Publications (4)

Hochman JS, Reynolds HR, Bangalore S, O'Brien SM, Alexander KP, Senior R, Boden WE, Stone GW, Goodman SG, Lopes RD, Lopez-Sendon J, White HD, Maggioni AP, Shaw LJ, Min JK, Picard MH, Berman DS, Chaitman BR, Mark DB, Spertus JA, Cyr DD, Bhargava B, Ruzyllo W, Wander GS, Chernyavskiy AM, Rosenberg YD, Maron DJ; ISCHEMIA Research Group. Baseline Characteristics and Risk Profiles of Participants in the ISCHEMIA Randomized Clinical Trial. JAMA Cardiol. 2019 Mar 1;4(3):273-286. doi: 10.1001/jamacardio.2019.0014. Erratum In: JAMA Cardiol. 2019 May 1;4(5):497. — View Citation

ISCHEMIA Trial Research Group; Maron DJ, Hochman JS, O'Brien SM, Reynolds HR, Boden WE, Stone GW, Bangalore S, Spertus JA, Mark DB, Alexander KP, Shaw L, Berger JS, Ferguson TB Jr, Williams DO, Harrington RA, Rosenberg Y. International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial: Rationale and design. Am Heart J. 2018 Jul;201:124-135. doi: 10.1016/j.ahj.2018.04.011. Epub 2018 Apr 21. — View Citation

Maron DJ, Stone GW, Berman DS, Mancini GB, Scott TA, Byrne DW, Harrell FE Jr, Shaw LJ, Hachamovitch R, Boden WE, Weintraub WS, Spertus JA. Is cardiac catheterization necessary before initial management of patients with stable ischemic heart disease? Results from a Web-based survey of cardiologists. Am Heart J. 2011 Dec;162(6):1034-1043.e13. doi: 10.1016/j.ahj.2011.09.001. — View Citation

Phillips LM, Hachamovitch R, Berman DS, Iskandrian AE, Min JK, Picard MH, Kwong RY, Friedrich MG, Scherrer-Crosbie M, Hayes SW, Sharir T, Gosselin G, Mazzanti M, Senior R, Beanlands R, Smanio P, Goyal A, Al-Mallah M, Reynolds H, Stone GW, Maron DJ, Shaw LJ. Lessons learned from MPI and physiologic testing in randomized trials of stable ischemic heart disease: COURAGE, BARI 2D, FAME, and ISCHEMIA. J Nucl Cardiol. 2013 Dec;20(6):969-75. doi: 10.1007/s12350-013-9773-4. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Primary Composite Outcome: Death From Cardiovascular Causes, Myocardial Infarction, or Hospitalization for Unstable Angina, Heart Failure, or Resuscitated Cardiac Arrest		3.2 year follow-up (median)
Primary	Cumulative Event Rate of Primary Composite Outcome (Death From Cardiovascular Causes, Myocardial Infarction, or Hospitalization for Unstable Angina, Heart Failure, or Resuscitated Cardiac Arrest)	This measure represents the estimated cumulative probability of experiencing the primary endpoint within the indicated timeframe in each treatment group. The interpretation of the measure is similar to Kaplan-Meier event rates. Estimates are expressed as percentages ranging from 0% (endpoint is certain not to occur) to 100% (endpoint is certain to occur).	5 years
Primary	Number of Participants That Experienced Death From Cardiovascular Causes or Myocardial Infarction		5 years
Primary	Cumulative Event Rate of Death From Cardiovascular Causes or Myocardial Infarction	This measure represents the estimated cumulative probability of experiencing Death from cardiovascular causes or myocardial infarction within the indicated timeframe in each treatment group. The interpretation of the measure is similar to Kaplan-Meier event rates. Estimates are expressed as percentages ranging from 0% (endpoint is certain not to occur) to 100% (endpoint is certain to occur).	5 years
Primary	Number of Participants That Experienced Death From Any Cause		5 years
Primary	Cumulative Event Rate of Death From Any Cause		5 years
Primary	Number of Participants That Experienced Myocardial Infarction		5 years
Primary	Cumulative Event Rate of Myocardial Infarction		5 years
Primary	Estimated Difference in Cumulative Event Rate ( %) of Primary Composite Outcome: Invasive Minus Conservative	The primary composite outcome includes death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest.	5 years
Primary	Estimated Difference in Cumulative Event Rate of Death From Cardiovascular Causes: Invasive Minus Conservative or Myocardial Infarction Between Invasive and Conservative Strategies		5 years
Primary	Estimated Difference in Cumulative Event Rate of Death From Any Cause: Invasive Minus Conservative		5 years
Primary	Estimated Difference in Cumulative Event Rate of Myocardial Infarction: Invasive Minus Conservative		5 years

External Links

•   Angioplasty
•   Coronary Artery Bypass Surgery
•   Coronary Artery Disease
•   Heart Diseases
•   ISCHEMIA Trial Update
•   Main Website for ISCHEMIA Trial