The ISCHEMIA Trial: Implication for Cardiac Imaging in 2020 and Beyond

Abstract

Establishing a diagnosis of coronary artery disease (CAD) is more difficult than it would seem. Diagnosis of CAD can be approached in two ways: detection of ischemia (often with stress myocardial perfusion at SPECT, PET, and cardiac MRI) and visualization of the coronary artery anatomy to demonstrate stenosis (noninvasively with cardiac CT). In addition to providing further supportive evidence for the use of coronary CT angiography as the first-line test for the evaluation of CAD, the ISCHEMIA trial also resulted in some interesting findings with regard to imaging; these findings resulted in the open-ended question of “What does this mean for imagers?”

© RSNA, 2020

Summary

Predicting the future is perilous business, but the ISCHEMIA trial only helps build the case for a central role of coronary CT angiography for the evaluation of symptomatic patients suspected of having coronary artery disease.

Key Points

• ■ The ISCHEMIA trial provides further supportive evidence for the use of coronary CT angiography as the first-line test for the evaluation of coronary artery disease.

• ■ Without adherence to best-practice CT acquisition protocols and proper interpretation knowledge, the potential of coronary CT to inform clinical decision making and improve clinical outcomes will not be realized.

Introduction

The treatment of coronary artery disease (CAD) has two goals; on one hand, to improve symptoms so that normal activity and exercise become possible without restriction. On the other hand, to prevent acute coronary syndromes—myocardial infarction with its sequelae heart failure and death, as well as unstable angina leading to urgent hospitalization. Treatment options include medication and revascularization. Medication can be used to treat symptoms (eg, nitrates and β-blockers), and medication substantially lowers the risk of acute coronary syndromes (eg, statins and aspirin). The combination of these two components is often referred to as optimal medical therapy. Revascularization through bypass surgery or percutaneous intervention relieves symptoms, but the benefit of revascularization for prognosis is not that clear; only for some patient subsets, such as individuals with severe left main coronary artery stenosis or three-vessel disease with impaired left ventricular function, has a prognostic advantage of revascularization over medical therapy clearly been demonstrated. It is surprisingly difficult to establish the diagnosis of “coronary artery disease,” and there are two possible approaches. One approach relies on the detection of ischemia, for example, through stress myocardial perfusion at SPECT, PET, and cardiac MRI. The assumption is that the presence of demonstrable ischemia justifies invasive angiography because likely there will be one or more stenoses that require revascularization for symptomatic and prognostic benefit. The absence of demonstrable ischemia, on the other hand, is assumed to make severe coronary atherosclerosis so unlikely that statins and aspirin are not necessary. The other approach is to directly visualize coronary artery anatomy and demonstrate stenoses. Noninvasively, this can be done with cardiac CT. This approach has the downside that not every stenosis causes ischemia; but, on the other hand, it has the advantage that coronary atherosclerosis can be demonstrated even in the absence of ischemia-causing narrowings. Results of the recent SCOT-HEART (Scottish CT of the Heart) trial suggest that the initiation of statin therapy in such patients may reduce the rate of future myocardial infarction (1). In fact, the last several years have seen substantial evidence, including strong clinical utility and cost-effectiveness data, that supports the use of cardiac CT as a first-line diagnostic tool in suspected stable CAD (2), and coronary CT angiography is prominently included in the most recent recommendations. In September 2019, the European Society of Cardiology (ESC) provided the first international class 1 indication for coronary CT angiography with the American guidelines pending (3). The ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial had been planned and initiated many years previously to address the difficulties in the diagnosis and management of CAD, particularly the question of whether patients benefit from revascularization. Cardiac CT was an important nonrandomized component of this trial and by coincidence, the results of ISCHEMIA were presented just a few months after publication of the ESC recommendations at the Scientific Sessions of the American Heart Association (4). The size and importance of the ISCHEMIA trial has left many wondering how the field of diagnostic CAD testing will be affected by its results—and by the fact that owing to the vision of those who planned the trial, coronary CT angiography was part of the study protocol.

In the ISCHEMIA trial, investigators aimed to determine whether patients with at least moderate ischemia on a stress test would benefit from an “invasive approach”—that is, the addition of routine coronary angiography to optimal medical therapy. Expectedly, in the “invasive” group, the rate of revascularization was high: 78% of patients underwent percutaneous intervention or bypass surgery. In the “conservative” group, coronary angiography was not routinely performed in everyone, but 23% of patients eventually did undergo revascularization during the follow-up period. The trial was negative with regard to the primary end point, in that the “invasive approach” was not associated with a reduction in the primary outcome of cardiovascular death, myocardial infarction, hospitalization for unstable angina, hospitalization for heart failure, or resuscitated cardiac arrest over a median follow-up of 3.3 years. Keep in mind that the conservative arm was not completely conservative—23% of patients underwent revascularization. Similar results were also observed for the prespecified secondary end point of cardiovascular death or myocardial infarction and across multiple prespecified subgroup analyses. Those in the invasive arm did experience a significant reduction in spontaneous myocardial infarction, and the invasive strategy, with more frequent revascularization, was associated with an improvement in quality of life and a reduction in angina with the greatest benefit found among those with the most significant symptom burden.

From an imaging perspective, there were also some particularly interesting findings. While CT was not used to guide management, the majority of participants underwent CT to rule out left main coronary disease and to also exclude individuals without an anatomic stenosis less than 50% at CT. Interestingly, almost 20% of participants were not found to not have any stenosis greater than 50% at coronary CT angiography, despite moderate-to-severe perfusion abnormality, not only according to site interpretation but confirmed with stress testing at core laboratories. In addition, approximately 6% were found to have significant left main disease and were thereby excluded from the trial.

What does this mean for imagers?

The findings of the ISCHEMIA trial confirm prior real-world studies that have suggested that stress testing cannot confidently identify anatomic CAD. Importantly, these prior publications were commonly criticized as being observational and limited by nonexpert site imaging interpretations. The ISCHEMIA trial serves to refute these comments as all stress tests underwent expert core laboratory adjudication prior to patient enrollment. This disconnect between traditional stress testing and epicardial CAD does not relate to the level of expertise of the interpretation, but rather it reflects that stress testing is not designed to directly interrogate the epicardial coronary arteries. In addition, the burden of left main disease, an anatomic finding that can also prove to be difficult to diagnose with nuclear stress testing (SPECT) (5), identified at CT helps emphasize the need to characterize the extent and severity of CAD prior to making decisions around downstream management. Importantly, 80% of those randomized to an invasive strategy underwent revascularization, highlighting the ability of coronary CT angiography to help enrich referral to the catheterization laboratory in this population at very least.

With the negative predictive value of coronary CT angiography and the potential to help inform medical therapy on the basis of nonstenotic atherosclerosis uniquely identified at CT already established, the results of the ISCHEMIA trial provide further supportive evidence for the use of coronary CT angiography as the first-line test for the evaluation of CAD. Whether the prospective use of coronary CT angiography in the ISCHEMIA trial would have allowed for robust planning of invasive coronary angiography (ICA) and improved complete revascularization is not known. The potential to use coronary CT angiography coupled with CT-derived fractional flow reserve (FFR_CT) has recently been investigated and showed both good correlation between a noninvasive functional SYNTAX (Synergy between PCI with TAXUS and Cardiac Surgery) (coronary CT angiography and FFR_CT) and invasive functional SYNTAX (ICA and FFR), as well as good agreement regarding complex revascularization recommendations between heart teams (6,7). This clearly needs further investigation, but for the first time a noninvasive CAD test has the potential to not only determine the need for ICA, but as an anatomic test, can provide elements that may inform the ICA in a fashion analogous to the planning of structural heart disease interventions. Incomplete revascularization remains common, and its impact on downstream clinical outcomes is increasingly clear. Imagers need to work with interventional cardiologists to learn how to extract as much value out of coronary CT as possible to not only help with the diagnosis of CAD but also to decide on the optimal treatment strategy.

Predicting the future is perilous business, but the ISCHEMIA trial only helps build the case for a central role of coronary CT angiography for the evaluation of symptomatic patients suspected of having CAD. Assuming guideline support will follow, it will be essential that the needed infrastructure and training be provided to serve our collective patients. To meet the clinical needs of the field, the needed education, training, and infrastructure will need to be developed. We need to learn from the experiences in the United Kingdom following the release of the updated National Institute for Health and Care Excellence guidelines in 2016 (8) and grow the needed training resources to meet the educational needs to help grow the capacity to provide high-quality CT care. Without adherence to best-practice CT acquisition protocols and proper interpretation knowledge, the potential of coronary CT to inform clinical decision making and improve clinical outcomes will not be realized.