Failed ISCHEMIA Trial or Failed Ischemia Testing?

Abstract: The results of the ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approach) trial were presented at the American Heart Association Scientific Sessions in November, 2019 in Philadelphia, Pennsylvania, and recently published on March 30, 2020 in the New England Journal of Medicine. After an average follow-up of 3.5 years, invasive therapy did not reduce the major adverse cardiac event (MACE) rate compared with optimal medical therapy (OMT) in patients with stable ischemic heart disease. However, the ISCHEMIA trial results might stem from the revascularization of inappropriate vessels and from the lack of a lesion-specific ischemia detection algorithm to guide revascularization instead of conventional stress testing. The utilization of an initial computed tomography (CT) angiogram with or without fractional flow reserve CT could have produced better revascularization results.

J INVASIVE CARDIOL 2020;32(4):E83-E85. Epub 2020 March 31.

Key words: arteriosclerosis, coronary artery disease, myocardial ischemia, percutaneous coronary intervention

After an almost decade-long endeavor and $100 million in funding, the eagerly awaited results of the ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) trial were presented at the American Heart Association annual meeting in Philadelphia, Pennsylvania in November, 2019 and recently published on March 30, 2020 in the New England Journal of Medicine.^1,2 The ISCHEMIA trial failed to show that routine invasive therapy reduces the major adverse cardiac event (MACE) rate compared with optimal medical therapy (OMT) among patients with stable ischemic heart disease and moderate-to-severe ischemia on non-invasive stress testing. While these practice-changing results compelled cardiologists to think whether “to cath” or “not to cath,” we believe the fundamental problem was in the algorithm used to detect ischemia with initial non-invasive stress testing. 

Percutaneous coronary intervention (PCI) has mortality benefits and reduces recurrent myocardial infarction in patients with acute coronary syndromes, but patients with stable coronary artery disease (CAD) have not benefited as much.^3-7 In patients with stable CAD, Hambrecht et al⁸ found that regular physical exercise resulted in superior event-free survival and exercise capacity at lower costs compared with PCI. In the MASS (Medicine, Angioplasty, or Surgery) II study,⁵ medical therapy for multivessel CAD was associated with a lower incidence of short-term events and a reduced need for additional revascularization compared with PCI. The COURAGE trial by Boden et al⁹ was a landmark study in which 2287 patients with myocardial ischemia and significant CAD were randomized to OMT alone versus PCI plus OMT; the PCI plus OMT arm did not show a reduction in the risk of death, myocardial infarction, or other MACE when compared with OMT alone. Similar results were found in the randomized BARI-2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial, which enrolled patients with type 2 diabetes and stable ischemic heart disease.¹⁰ All of the above studies favored OMT, but used a common approach to detect myocardial ischemia with conventional stress testing and did not consider lesion-specific ischemia. 

Lesion-specific ischemia detection and subsequent revascularization have shown promising results in favor of PCI. The FAME (Fractional Flow Reserve versus Angiography for Guiding Percutaneous Coronary Intervention) study showed that in patients with multivessel CAD, routine measurement of fractional flow reserve (FFR) during PCI, as compared with the standard strategy of PCI guided by angiography, significantly reduced the rate of the primary composite endpoint of death, myocardial infarction, and repeat revascularization.¹¹ A 15-year follow-up of the DEFER (Deferral versus Performance of PCI of Functionally Non-significant Coronary Stenosis) trial showed that deferral of PCI of a functionally non-significant stenosis is associated with a favorable very long-term follow-up.¹² Results from the FAME-2 (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) trial showed that FFR-guided PCI plus OMT decreased the need for urgent revascularization compared with OMT alone in patients with stable CAD.¹³ Furthermore, the 5-year follow-up of the FAME-2 trial showed a significantly lower rate of death, myocardial infarction, or urgent revascularization.¹⁴ 

While FFR has shown promising effects, there are some limitations. FFR is measured during maximal hyperemia (simulating exercise) and requires the administration of a vasodilator, such as adenosine. There is increased procedural time and cost associated with FFR, as well as side effects such as chest pain and dyspnea from bradycardia and heart block. An alternative approach is to measure the instantaneous wave-free ratio (iFR), which is a newer technique that utilizes hyperemia-free physiologic index for measuring pressure in the coronary stenosis and does not require the administration of adenosine. The DEFINE-FLAIR (Use of the Instantaneous Wave-Free Ratio or Fractional Flow Reserve in PCI) trial¹⁵ and the iFR-SWEDEHEART (Instantaneous Wave-Free Ratio versus Fractional Flow Reserve to Guide PCI) trial¹⁶ randomly assigned patients with stable CAD and who had stenosis of intermediate severity to either FFR or iFR. In both trials, iFR was non-inferior to FFR with respect to the 1-year risk of death and non-fatal myocardial infarction. The major advantage of iFR over FFR is its ability to evaluate serial lesions and multivessel disease, whereas FFR can be challenging due to technical issues, length of the procedure, and the need for repeat administration of adenosine.¹⁷

The major drawback of either FFR or iFR is that they are done only in the cath lab. Also, a significant proportion of patients who go to the cath lab based on stress testing have non-obstructive coronaries or non-hemodynamically significant stenosis. There is the utmost need for non-invasive tests that can increase the pre-cath probability of identifying those patients with hemodynamically significant stenosis and determine who will actually benefit from revascularization. Fractional flow reserve computed tomography (FFR_CT) is a relatively new and promising modality that uses data from CT angiography (CTA) and creates models based on computational fluid dynamics that can detect functional ischemia arising from a particular lesion. In many clinical trials, the diagnostic accuracy of FFR_CT has been shown to be similar to invasive FFR.^18,19 In addition, the combination of FFR_CT with CTA among stable patients with known CAD further improved the diagnostic accuracy to detect hemodynamically significant ischemia.²⁰ The PLATFORM (Prospective Longitudinal Trial of FFR_CT Outcome and Resource Impacts) study showed that CTA plus FFR_CT can triage patients for invasive procedures more cost-effectively than usual care strategies.²¹ Another study, by Hlatky et al,²² showed that the use of FFR_CT to select patients for invasive coronary angiography (ICA) and PCI would result in 30% lower costs and 12% fewer events at 1 year compared with the most commonly used ICA/visual strategy. A substudy of the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial looked at the cohort of patients with stable chest pain referred to ICA from CTA, and suggested that FFR_CT of ≤0.8 was a better predictor of revascularization or MACE than severe stenosis on CTA.²³ The ADVANCED (Assessing Diagnostic Value of Non-Invasive FFR_CT in Coronary Care) registry enrolled 5083 patients with clinically suspected CAD who underwent CTA and FFR_CT. The 1-year outcome showed less revascularization and lower cardiovascular death or myocardial infarction rates in patients with FFR_CT of >0.8 versus patients with FFR_CT ≤0.8.²⁴ 

While the lesion-based ischemia testing and subsequent revascularization has shown benefits, there is contradictory evidence regarding the benefits from revascularization in patients with moderate-to-severe ischemia detected by stress testing. In 2003, Hachamovitch et al²⁵ published a large observational study which showed that as the amount of inducible ischemia increases, there is more survival benefit in patients with revascularization compared with OMT. On the contrary, a post hoc substudy from the COURAGE trial showed the extent of ischemia did not predict adverse events.²⁶ Another substudy from the COURAGE trial suggested that the anatomic burden (gradation of single-, double-, and triple-vessel disease based on invasive angiography) was a consistent predictor of death, myocardial infarction, and non-ST elevation myocardial infarction, whereas the severity of ischemia was not.²⁷ Into this clinical equipoise of ischemia-testing comes the ISCHEMIA trial, utilizing the same faulty algorithm of initial non-invasive stress testing to classify ischemia and guide revascularization. 

In the ISCHEMIA trial,²⁸ patients with moderate-to-severe ischemia (based on stress testing) first underwent coronary CTA, and then only those with obstructive CAD were randomized to the invasive group or the OMT group. Moderate-to-severe ischemia was defined as nuclear stress testing demonstrating >10% left ventricular ischemia, echocardiography demonstrating ≥3 segments with stress-induced hypokinesis or akinesis, cardiac magnetic resonance imaging demonstrating >12% myocardium perfusion defect, or >3/16 segments with stress-induced severe hypokinesis or akinesis. Exercise tolerance testing (ETT) with angina was also used for the diagnosis of ischemia. In the invasive arm, if the stress test was positive and invasive angiography showed >50% stenosis, then PCI was performed and FFR was not done. If the stenosis was <50%, then FFR was done and vessels were revascularized if FFR was ≤0.8. For ETT-positive patients, PCI was performed if the stenosis on invasive angiography was >80% without doing FFR. Thus, FFR was not routinely done on all suspicious lesions. This protocol is in contrast to the FAME-2 trial, where FFR was done on all lesions, and if FFR was ≤0.8 then patients were randomized to PCI plus OMT versus OMT (where the PCI arm had fewer events). Thus, the success of the FAME-2 trial and the failure of the ISCHEMIA trial could be due to the fact that the wrong vessels may have been revascularized in ISCHEMIA, because the decision to revascularize was made primarily based on the positive stress testing and at least moderate stenosis on cath, whereas only those vessels with positive ischemia based on FFR were revascularized in FAME-2. 

The ISCHEMIA trial has given us an opportunity to opt for OMT in patients with non-severe angina (after ruling out left main disease). However, at the same time, we also feel there was a missed opportunity in the ISCHEMIA trial to show the benefit of PCI over OMT due to the adoption of a faulty algorithm to guide revascularization based on stress testing. Perhaps an algorithm of CTA first — with the selective use of FFR or FFR_CT to target lesion-specific ischemia — would fare better against OMT alone. If the ISCHEMIA trial had been designed with initial CTA ± FFR_CT to screen patients, it would have detected obstructive disease as well as functional ischemia of the lesion, and at the same time ruled out left main disease. Once patients got to the cath lab, revascularization should have been done based on the FFR numbers, as done in the FAME-2 trial; this methodology could have produced very different results in the ISCHEMIA trial. Future clinical trials should focus on this aspect.  

References 

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From the Department of Cardiology, Lundquist Institute at Harbor-UCLA Medical Center, Torrance, California.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Budoff reports support from General Electric and the National Institutes of Health, outside the submitted work. Dr Dahal reports no conflicts of interest regarding the content herein. 

Manuscript submitted February 4, 2020 and accepted February 5, 2020.

Address for correspondence: Matthew J. Budoff, MD, FACC, Professor of Medicine, UCLA School of Medicine, Program Director, Division of Cardiology, Director, Cardiac CT Laboratory, Lundquist Institute at Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA 90502. Email: mbudoff@lundquist.org