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Secondary analyses of the landmark ISCHEMIA trial turned up little to no correlation between the degree of ischemia on dobutamine echocardiography and nuclear imaging and outcomes at around 3 years of follow-up.

No relationship was seen between ischemic severity and all-cause mortality and only a weak trend emerged for a relationship with 4-year cumulative rates of myocardial infarction. No subgroup -- severe, moderate, or mild ischemia -- showed a greater primary endpoint advantage from the early invasive strategy over that of optimal medical therapy alone.

However, there was a strong relationship between anatomy and both all-cause mortality and MI, David Maron, MD, of Stanford University in California, reported at the virtual (ACC) meeting.

While patients with greater anatomic burden had higher event rates, again, none of the groups -- including the Duke score 6 group with three-vessel disease or two-vessel disease involving the proximal left anterior descending artery -- showed a greater benefit of one treatment strategy over the other.

MI and all-cause mortality showed the same patterns.

"Our overall main trial results comparing the invasive and conservative strategies apply to the range of ischemia and anatomic subgroups," Maron said at the late-breaking clinical trial session.

ISCHEMIA's main results, now , failed to show an outcome benefit from adding early stenting or bypass surgery to optimal medication in patients with stable, moderate-to-severe ischemic heart disease. The primary composite outcome of cardiovascular death, MI, hospitalization for unstable angina, hospitalization for heart failure, or resuscitated out-of-hospital cardiac arrest had an adjusted HR of 0.93 (95% CI 0.80-1.08).

The trial included 5,179 patients stable with moderate or severe ischemia who were randomized if the coronary CT angiogram (CTA) ruled out left main disease and affirmed ≥50% stenosis in a major epicardial vessel, or at least 70% blockage in a proximal or mid-vessel.

CTA was performed in 73% of randomized participants. It was not required for patients with an estimated glomerular filtration rate (eGFR) of 30 to <60 mL/min/1.73 m² or coronary anatomy previously defined. Coronary anatomy was assessed by modified Duke prognostic index from coronary CTA with core lab interpretation.

Limitations included the limited, median 3.2 years of follow-up, as well as the use of coronary CT angiography rather than invasive angiography. Also, very severe ischemia patients likely weren't enrolled by sites and those with an unacceptable degree of angina, left main disease, recent acute coronary syndrome, or ejection fraction under 35% were excluded.

"We put a lot of stock in ischemia as being a portent for bad things," commented Ashish Pershad, MD, an interventional cardiologist at Banner – University Medicine Heart Institute in Phoenix. "Previous evidence in the nuclear medicine literature and even in the echocardiography literature made us all very skittish in terms of managing patients with large zones of ischemia medically."

"I think [the ISCHEMIA findings are] going to make us rethink the value of functional testing with either nuclear imaging and/or imaging with MRI/PET scans," he added in an interview with 麻豆传媒. "At least we now know that hanging our hats on just physiology is not enough, and a lot of times the information obtained both anatomically and physiologically we will have to take into consideration as we decide the optimum strategy of how we manage these patients."

ACC session discussant E. Magnus Ohman, MBBS, of Duke University in Durham, North Carolina, called the findings important and a little surprising.

"The anatomy findings are very compelling with the highest event rate among those with three-vessel and two-vessel disease [with proximal left anterior descending coronary artery], as has been shown before," he said. However, he cautioned that longer-term follow-up is needed and that there is not yet data on the combination of how ischemia and anatomy predicted outcomes.

"Three-year follow-up of patients with stable heart disease is not enough," Pershad agreed. "We don't know if that same premise would be valid at years 6, 7, and 8. That is a big question that needs to be answered."

Chronic Kidney Disease

In an analysis of the parallel, a similarly designed of 777 patients with eGFR <30 mL/min/1.73 m², Sripal Bangalore, MD, MHA, of the NYU School of Medicine in New York City, reported at the same late-breaking session:

• An early invasive strategy wasn't better than conservative therapy for any eGFR group

• A nominally higher risk with the invasive strategy for death in those with stage 4 chronic kidney disease and for stroke in those with stage 4 or 5 disease

• Less angina-related quality of life boost from the invasive strategy among those with fewer symptoms and those with eGFR below 30 to 45 mL/min/1.73 m²

Notably, only 85% of this population underwent coronary angiography to begin with; most often skipped due to intercurrent illness or death. Among those, only half got revascularization, with the most common reason not to revascularize being lack of obstructive disease.

"It again highlights that our current modalities, particularly stress testing, which has a low sensitivity and specificity in this group of patients, is definitely problematic," Bangalore said. "Even though these patients are cited as having moderate to severe ischemia, they didn't have coronary artery disease."

Ischemia Without Obstructive CAD

Among patients with ischemia and no obstructive coronary artery disease (INOCA), angina frequency at 1 year correlated strongly with baseline symptoms but no degree of ischemia on the stress test, Harmony Reynolds, MD, of the NYU Grossman School of Medicine in New York City, reported at the conference from the CIAO-ISCHEMIA study.

The study enrolled screen failures from the main ISCHEMIA trial -- the 21% of coronary CTA patients who didn't have evidence of obstructive CAD. Of more than 5,000 screened, a total of 208 symptomatic patients were then enrolled after a stress echo, read at the core lab blinded to CAD or INOCA status and as to timing.

Also notable among the findings was the fact that the stress echo was normal at 1 year for half of the INOCA patients, while angina improved by a clinically meaningful degree in 39% despite little change in angina medications.

ACC session study discussant C. Noel Bairey Merz, MD, of Cedars-Sinai Medical Center in Los Angeles, cautioned that the angina scores were fairly low, so "even if we thought this was a good primary hypothesis, it was probably underpowered."

Symptom management may not be an issue for them, but an abnormal stress echo in the presence of open arteries does have an impact on prognosis, she noted, so a strategy similar to secondary prevention may be warranted, perhaps with a calcium channel blocker and high intensity statin.