ISCHEMIA Trial Population Reflects Small Slice of US Practice

Patrice Wendling

May 12, 2021

Although the ISCHEMIA trial is a touchstone in the management of patients with stable ischemic heart disease (SIHD), its population does not reflect most patients seen in US practice today, new research suggests.

The 2019 landmark trial challenged the prevailing belief that offering an initial invasive strategy may confer a benefit in stable patients with moderate or severe ischemia on stress testing. Revascularization, however, produced no significant advantage over optimal medical therapy alone for the hard endpoints of death and myocardial infarction (MI) over 3 years, albeit with better symptom relief and quality of life for those with angina at baseline.

What isn't well recognized is that the trial excluded a significant proportion of patients routinely considered for revascularization, such as those with acute coronary syndromes (ACS), cardiac arrest, cardiogenic shock, ejection fraction less than 35%, left main disease, or end-stage renal disease; and recruited only 16.5% of its participants from the US, observed Saurav Chatterjee, MD, author of the new analysis.

To determine the proportion of stable SIHD patients in the US who meet ISCHEMIA inclusion criteria, Chatterjee and colleagues performed cross-sectional analyses of 927,011 patients undergoing percutaneous coronary intervention (PCI) in the US from October 2017 to June 2019 in the National Cardiovascular Data Registry (NCDR) CathPCI Registry.

After excluding those with ACS, cardiac arrest, or cardiogenic shock, 388,212 patients (41.9%) underwent PCI for stable SIHD at 1662 hospitals.

Of these, 125,302, or 32.3%, met the criteria for enrollment in ISCHEMIA, according to these results presented at the recent Society for Cardiovascular Angiography and Interventions 2021 virtual meeting.

Among those not meeting the trial's inclusion criteria, 18.5% of SIHD patients had high-risk features, such as left main disease (35.2%), ejection fraction below 35% (43.7%), and end-stage renal disease (16.8%).

Another 17.3% of patients had negative or low-risk findings on functional testing and the remaining 31.9% were unclassifiable, reported Chatterjee, from Long Island Jewish and North Shore University Hospitals, New Hyde Park, New York.

Many of the unclassifiable patients lacked stress testing or didn't have ischemic burden reported but also "represented possibly a higher-risk profile population with significant percentages of patients with previous myocardial infarction or cardiomyopathy," Chatterjee said during a press conference highlighting the results.

"We are still doing analyses on better classifying this unclassifiable population, but our impression is that this most likely represents an opportunity to document and select patients more optimally and put that on paper," he said.

Press conference moderator and former SCAI president David A. Cox, MD, said, "I think part of the challenge is how do you classify a patient that comes to the hospital who had chest pain, troponin negative, ECG normal? I think we'd all call that unstable angina, class 3, class 4. That's easy. What do you do when you see somebody in the office with the same symptoms, telling you they're taking two or three nitros at home, and then comes in electively the next day for a diagnostic cath? How do you classify that?

"That's really the conundrum and the fact that we all want to be honest and forthright about what are we saying is stable and what's unstable," said Cox, Cardiovascular Associates, Brookwood Baptist Hospital, Birmingham, Alabama.  

The results also showed significant variation across the country in the proportion of ISCHEMIA-like patients undergoing PCI. Even at the median hospital, only 32.1% of the patients resembled the ISCHEMIA trial population and, at 99% of the hospitals, less than 68% of patients did so, he said.

In terms of in-hospital outcomes, ISCHEMIA-like patients had the lowest rate of in-hospital mortality (0.11%) and bleeding (0.6%) of all the groups, including those at low risk, and the same rate of acute kidney injury requiring hemodialysis as low-risk patients (0.04%), although this comes with the "huge caveat" of this being observational registry data, Chatterjee said.

"While ISCHEMIA guides a certain component of our clinical decision-making, it does not represent all patients who undergo PCI in the US," Chatterjee concluded. "There is a large proportion of patients who do not meet this criteria and future research needs to identify the appropriate patient cohorts who will derive the most benefit."

Besides the inherent limitations of observational studies, he noted that all patients in the NCDR registry underwent revascularization, whereas only 79% of patients did so in the invasively managed arm of ISCHEMIA. Also, the rigor of data auditing in the registry likely cannot approach that of a randomized trial.

Chatterjee and co-authors reported having no relevant conflicts of interest.

Society for Cardiovascular Angiography and Interventions (SCAI) 2021 virtual meeting: Abstract FCR-07. Presented April 29, 2021.

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