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)