International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial: Rationale and design

Abstract

Background: Prior trials comparing a strategy of optimal medical therapy with or without revascularization have not shown that revascularization reduces cardiovascular events in patients with stable ischemic heart disease (SIHD). However, those trials only included participants in whom coronary anatomy was known prior to randomization and did not include sufficient numbers of participants with significant ischemia. It remains unknown whether a routine invasive approach offers incremental value over a conservative approach with catheterization reserved for failure of medical therapy in patients with moderate or severe ischemia.

Methods: The ISCHEMIA trial is a National Heart, Lung, and Blood Institute supported trial, designed to compare an initial invasive or conservative treatment strategy for managing SIHD patients with moderate or severe ischemia on stress testing. Five thousand one-hundred seventy-nine participants have been randomized. Key exclusion criteria included estimated glomerular filtration rate (eGFR) <30 mL/min, recent myocardial infarction (MI), left ventricular ejection fraction <35%, left main stenosis >50%, or unacceptable angina at baseline. Most enrolled participants with normal renal function first underwent blinded coronary computed tomography angiography (CCTA) to exclude those with left main coronary artery disease (CAD) and without obstructive CAD. All randomized participants receive secondary prevention that includes lifestyle advice and pharmacologic interventions referred to as optimal medical therapy (OMT). Participants randomized to the invasive strategy underwent routine cardiac catheterization followed by revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery, when feasible, as selected by the local Heart Team to achieve optimal revascularization. Participants randomized to the conservative strategy undergo cardiac catheterization only for failure of OMT. The primary endpoint is a composite of cardiovascular (CV) death, nonfatal myocardial infarction (MI), hospitalization for unstable angina, hospitalization for heart failure, or resuscitated cardiac arrest. Assuming the primary endpoint will occur in 16% of the conservative group within 4 years, estimated power exceeds 80% to detect an 18.5% reduction in the primary endpoint. Major secondary endpoints include the composite of CV death and nonfatal MI, net clinical benefit (primary and secondary endpoints combined with stroke), angina-related symptoms and disease-specific quality of life, as well as a cost-effectiveness assessment in North American participants. Ancillary studies of patients with advanced chronic kidney disease and those with documented ischemia and non-obstructive coronary artery disease are being conducted concurrently.

Conclusions: ISCHEMIA will provide new scientific evidence regarding whether an invasive management strategy improves clinical outcomes when added to optimal medical therapy in patients with SIHD and moderate or severe ischemia.

Figure 1. Study Design

Patients who underwent stress testing for clinical indications at enrolling sites were screened for eligibility if the site determined that moderate or severe ischemia was present on a stress imaging test, or severe ischemia was present on a non-imaging exercise tolerance test. Consenting participants were enrolled and most underwent blinded CCTA. (CCTA was usually performed in participants with normal renal function and not performed in participants with eGFR <60 mL/min). Participants with left main stenosis ≥50% or no obstructive disease were excluded. If prior CCTA or cardiac catheterization demonstrated the absence of significant left main stenosis and the presence of significant obstructive disease in other coronary arteries, a study CCTA was not required. Eligible participants were randomized to invasive or conservative management strategies (see text for details). The primary endpoint is a composite of cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, hospitalization for unstable angina, and hospitalization for heart failure. The composite of cardiovascular death or nonfatal myocardial infarction is a key secondary endpoint. Patients with advanced chronic kidney disease and moderate or severe ischemia on stress testing were considered for the ISCHEMIA-CKD ancillary trial. Participants with no obstructive disease who qualified for enrollment with stress echocardiography were considered for the CIAO-ISCHEMIA ancillary study. Lab, laboratory; CCTA, coronary computed tomography angiography; cath, cardiac catheterization; CV, cardiovascular; MI, myocardial infarction; QOL, quality of life.

Figure 2. Timeline of Active Sites, Enrollments, and Randomizations

The figure shows the cumulative number of randomizing sites, participant enrollments, and participant randomizations between July 2012 and January 2018. Although 320 sites randomized at least one participant, some of those sites closed and transferred participants to another site, with a final number of 299 active sites at the end of the recruitment phase.

Figure 3. Invasive Procedures and Protocol Adherence

In addition to receiving optimal medical therapy, participants randomized to the invasive strategy were to undergo cardiac catheterization followed by complete revascularization of all ischemic territories when feasible. For complex anatomy, the local Heart Team recommended the optimal method of revascularization. FFR was recommended for stenosis <50% if PCI was considered and stress imaging showed ischemia in the corresponding territory. FFR was also recommended for stenosis <80% if PCI was considered and stress imaging did not show ischemia in the corresponding territory (see Figure S2a). Use of instantaneous wave-free ratio instead of FFR (where available) was permitted, using a cutoff of ≤0.89 for physiologic significance. Among participants randomized to the conservative strategy, urgent revascularization for diagnosed or suspected acute coronary syndrome or elective revascularization for unacceptable symptoms despite maximal medical therapy is adherent to the protocol. Cardiac catheterization with or without revascularization in the absence of these clinical indications is non-adherent to the protocol for the conservative strategy. CAD, coronary artery disease; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft surgery; FFR, fractional flow reserve; iFR^®, instantaneous wave-free ratio.