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