LVEF Analysis Digs Anew Into Revascularization Benefits in Ischemic CAD

(UPDATED) There may be a benefit to early revascularization over medical therapy in patients with severe inducible ischemia on SPECT testing, regardless of their baseline left ventricular ejection fraction, a new observational analysis suggests.

Among stable CAD patients who underwent stress/rest SPECT myocardial perfusion imaging, those with severe ischemia (≥ 15%) and normal LVEF had a lower risk of mortality over long-term follow-up if they underwent coronary revascularization early as compared to medical therapy alone (HR 0.70; 95% CI 0.52-0.95). For patients with impaired LVEF, early revascularization also was associated with a lower risk of mortality in those with moderate-to-severe ischemia (≥ 10%), but not in those with no or mild ischemia.

Those findings, published today in the Journal of the American College of Cardiology, contrast with results from prospective randomized trials, most notably ISCHEMIA. In that landmark trial, which included stable patients with moderate or severe ischemia, revascularization did not reduce the risk of ischemic cardiovascular events or death from any cause over a median follow-up of 3.2 years.

One of the main exclusion criteria for ISCHEMIA, however, was a low LVEF (< 35%). In a subanalysis from ISCHEMIA presented in 2020, investigators showed that patients with a history of heart failure or left ventricular dysfunction had better outcomes when compared with those treated conservatively. As reported by TCTMD, though, the subanalysis included just a small number of patients with LVEF ranging from 35% to 44%. Somewhat confirmatory, the older STICH trial, focused on patients with ischemic cardiomyopathy (LVEF ≤ 35%), clearly demonstrated the late benefits of revascularization, although that trial was a comparison of surgery, not PCI, versus medical therapy.

Alan Rozanski, MD (Mount Sinai Morningside, New York), who led the new analysis, said the observational data showed that the lower the LVEF, the greater likelihood the patients will have ischemia. Patients with low LVEF also have more CAD, more risk factors—all of which contribute to greater ischemia—and appear likely to benefit from early revascularization.

All of these factors, he said, prompted this latest study investigating the relationship between ischemic burden, revascularization, and mortality across a range of patients with varying cardiac function.

“A lot of the money will be on patients with low LVEF,” he told TCTMD.

Followed for More Than 11 Years

Rozanski et al’s study included 43,443 patients who underwent stress/rest SPECT testing at Cedars-Sinai Medical Center in Los Angeles, CA, between 1998 and 2017. Of these, 2,300 underwent early revascularization within 90 days of stress testing. Those who underwent revascularization were older, more likely to be male, and more apt to have known CAD, angina, hypertension, hypercholesterolemia, and diabetes.

Overall, the frequency of inducible ischemia varied according to resting LVEF. For example, ischemia was present in 22.9% of the 5,445 patients with a midrange LVEF (45-54%) and 42.2% of the 3,650 patients with low LVEF (< 45%).

During a median follow-up of 11.4 years, 28.8% of patients died. Among the medically treated patients, there was a stepwise increase in mortality with increasing myocardial ischemia. This ranged from 2.6% per year in those without ischemia to 7.3% per year among those with severe ischemia. In contrast, there was no difference in mortality with increasing ischemia among patients who underwent coronary revascularization.

When patients were stratified by their baseline heart function, early revascularization was associated with a lower risk of mortality among those with LVEF ≥ 45% and severe myocardial ischemia. In those with LVEF < 45%, revascularization was linked with lower all-cause mortality in patients with moderate-to-severe ischemia, with the risk of death 33% lower in patients with moderate ischemia and 45% lower in those with severe ischemia.

“The bottom line is that stress testing is still robust and useful,” said Rozanski. “The test identifies a very large number of patients who have normal nuclear stress tests or mild abnormalities—that was a very large block of patients—and in those patients there was no benefit to revascularization. That’s been repeatedly shown and is an important point. The patient is coming in, and the doctor wants the confidence to know they don’t have to do revascularization.”

For those with moderate-to-severe ischemia, on the other hand, “the data shows that it’s still a very big driver of risk,” said Rozanski. “In observational data, in the types of patients doctors see in practice, patients do better with revascularization.”

Rozanski acknowledged the conflicting findings, noting that data from several prospective trials, among them ISCHEMIA, as well as COURAGE and BARI-2D substudies, have shown no benefit to revascularization in stable CAD patients with ischemia. On the other hand, observational studies, including theirs and others, have suggested revascularization is associated with reduced mortality in stable patients with increasing degrees of ischemia. For this reason, he believes both randomized trials and observational data can inform clinical practice.

“The problem with the trials, in general, is that the enrollment process tends to be just a sample of patients we see in clinical practice,” he told TCTMD. “On the other hand, trials are very valuable because they can control all the variables, including the medical therapy that was prescribed. The observational data can’t do that, because they don’t have that type of follow-up. Each provides a difference slice of the answer.”

Exploding Ischemia Narrative

William Boden, MD (Boston University School of Medicine/VA New England Healthcare System, MA), who led the COURAGE trial, doesn’t believe the new observational study offers much beyond what been shown in the randomized trials. This latest nonrandomized data set is from a single center and is largely outdated, he said, noting that patients weren’t treated with contemporary optimal medical therapy.  

“It’s all to show that [moderate-to-severe] ischemia and mortality can be improved by revascularization, but the ISCHEMIA trial findings exploded that narrative,” he said.

While it’s possible that revascularization may benefit those with really severe ischemia, these patients represent only a minority of stable CAD cases, said Boden. “I do think that on the extreme end of the range—say 15% or 20% of the left ventricle—I think those may likely benefit from revascularization, but it’s a very small subset,” said Boden.

For Harmony Reynolds, MD (NYU Langone Medical Center, New York, NY), one of the ISCHEMIA investigators, the randomized trial is definitive.

“In general, when observational data and randomized trial data don’t line up, I’m inclined to favor the randomized trial data because that’s the type of research we’re supposed to use to infer causality,” she told TCTMD. “Propensity-score weighting, adjustment, all of these are nice tools, but nothing is the same as a randomized, controlled trial.”  

With respect to LVEF, Boden said there has long been the idea that patients with severe LV dysfunction do benefit from revascularization. In the STICH trial of patients with ischemic cardiomyopathy, CABG surgery was associated with a lower risk of death and hospitalization at 10 years when compared with medical therapy alone. However, medical therapy again has continued to evolve since that trial was conducted, he noted.  

“When you start amplifying medical therapy, it becomes very multidimensional,” he said. Not only are patients treated with statins, ACE inhibitors/ARBs, and beta-blockers, but others like mineralocorticoid receptor antagonists, angiotensin-receptor neprilysin inhibitors, and sodium-glucose cotransporter 2 inhibitors. In the aggregate, these “are having a profound effect on reducing events and improving outcomes,” said Boden.  

The REVIVED-BCIS2 trial, which is scheduled to be presented at the 2022 European Society of Cardiology Congress, will help provide some clarity on the issue of revascularization in patients with low LVEF. Not unlike the STICH trial, only with PCI instead of CABG, investigators are testing whether revascularization provides any benefit beyond medical therapy in patients with ischemic ventricular dysfunction. This will be a pivotal trial to settle issue, said Boden.

Ischemic Testing Part of Cardiology

In an editorial, Mouaz Al-Mallah, MD (Houston Methodist DeBakey Heart and Vascular Center, Houston, TX), and Vasken Dilsizian, MD (University of Maryland School of Medicine, Baltimore), say that the new analysis highlights the differences that exist between registries and randomized trials. Registries, unlike trials, usually represent clinical practice. That has pros and cons, the downside being that patients are unlikely optimized on medical therapy, which may account for some of the differences seen here.

“As acknowledged by the authors, the main limitation of their study is the fact that the intensity and quality of medical therapy after the scan is not available, which weakens the conclusions and the generalizability of the results,” write Al-Mallah and Dilsizian.

Myocardial perfusion imaging, said Boden, remains embedded in the fabric of clinical cardiology, and this may take time to change after the ISCHEMIA trial challenged its merits.

“And I’ll admit, I haven’t completely migrated over to only doing coronary CT angiography,” said Boden. “I know that’s where the field seems to be moving, but as a cardiologist, I think it’s important to know what a patient can do on a treadmill, for example. What’s their exercise capacity? What’s their functional status? I still find that very useful. Somebody who has a markedly positive stress test in the first 3 minutes of a Bruce protocol, and who develops symptoms and ST-segment depression, shows me that this person is having a lot of ischemia and symptoms at a low workload.”

Such testing, he said, can help distinguish high- from low-risk patients, said Boden. Reynolds added that while the field is moving more and more towards CT angiography, nuclear testing is still used, often in people who have known CAD.