Analysis Hints at Survival Benefit With Revascularization in Stable Patients With Myocardial Ischemia

A new, single-center analysis ahead of the long-awaited ISCHEMIA trial suggests that patients with stable CAD and myocardial ischemia identified on PET myocardial perfusion imaging (MPI) have better survival when treated with early revascularization as compared with medical therapy.

The benefit of early revascularization was evident in patients with lower levels of myocardial ischemia than previously identified, with an exploratory analysis showing that the benefit of revascularization over optimal medical therapy (OMT) alone was seen in patients with an ischemic myocardium threshold ranging from 5% to 10%.

Although the researchers state that measures of ischemia on PET MPI can guide post-test management with either PCI or OMT to improve clinical outcomes of patients with stable heart disease, they caution that the ultimate answer awaits the large ISCHEMIA trial.

“Our entire field of cardiology has debated this for more than two decades now,” lead investigator Krishna Patel, MD (Saint Luke’s Mid America Heart Institute, Kansas City, MO), told TCTMD. “Based on COURAGE data, we believed that stable ischemic heart disease patients who undergo PCI in addition to OMT have symptomatic benefit, but not survival benefit compared to OMT, a notion which was challenged by the ORBITA study. There is some evidence that physiology-based revascularization may lead to improved long-term cardiac outcomes in these patients as seen by the FAME series of trials testing [fractional flow reserve]-based revascularization strategies. Even though clinically, patients with significant ischemia on their MPI studies are referred for revascularization hoping that it would reduce their risk, we really only have observational data to support this practice until we get ISCHEMIA trial results.”

The optimal management of patients with stable CAD is one of the most debated topics in cardiovascular medicine, with trials such as COURAGE and BARI 2D previously showing that revascularization did not reduce the risk of major adverse cardiac events or improve survival when compared with OMT. Since those trials were published, research has shifted to test if measures of physiologically important CAD can help identify patients who would benefit from revascularization.

The data thus far are mixed, with several substudies to date, including those from COURAGE, BARI 2D, and MASS II, showing that baseline ischemic burden wasn’t associated with worse clinical outcomes. On the other hand, there are observational studies suggesting a survival benefit with revascularization over medical therapy in patients with higher thresholds of ischemic myocardium.

The National Institutes of Health (NIH)-funded ISCHEMIA trial, which is scheduled for presentation in November at the American Heart Association 2019 Scientific Sessions, is evaluating coronary revascularization on top of OMT versus OMT alone in patients with stable coronary heart disease with moderate-to-severe ischemia on stress testing. The primary endpoint is a composite of cardiovascular death and MI, resuscitated cardiac arrest, hospitalization for unstable angina, and hospitalization for heart failure at 5 years.

Large Observational Study

In the current single-center study, which was published September 23, 2019, in the Journal of the American College of Cardiology, 16,029 patients underwent rest/stress PET MPI between 2010 and 2016 and were followed for 3.7 years. Of these individuals, 32.6% had known CAD at baseline (prior MI, PCI, or CABG surgery) and chest pain was the predominant symptom in approximately 60% of all patients. Individuals with impaired left ventricular ejection fraction were excluded from the analysis.

More than one-third of patients had ischemia at baseline, and the mean percent ischemic myocardium on PET for the entire cohort was 3.4%. In total, 1,277 patients underwent early revascularization, primarily with PCI. For those who were revascularized within 90 days of the PET perfusion imaging, 0.9% had ischemia affecting less than 5.0% of the myocardium, 11.6% had ischemia affecting 5-10% of the myocardium, and 45% had ischemia affecting more than 10% of the myocardium.

In a risk-adjusted model, investigators observed a significant interaction between percent ischemia and early revascularization, “such that patients with higher amounts of ischemic myocardium had a lower hazard of death with early revascularization.” The relationship between the extent of ischemia and early revascularization with mortality was not different in patients with and without a prior history of CAD, and did not differ based on the extent of infarcted myocardium present on MPI.

When the investigators plotted the hazards of death with early revascularization versus medical therapy across the spectrum of percent ischemic myocardium, the point estimate for mortality crossed unity at roughly 5% (10% was the upper limit of the confidence interval). This threshold is lower than what had been previously reported for SPECT MPI, said Patel.

“This is not surprising given that PET is more sensitive and has better diagnostic accuracy than dual-isotope SPECT that was studied then, and there have been advances in revascularization strategies including DES and medical therapy of CAD in the last 2 decades,” she said. “However, I would like to note that this was an exploratory analysis done in an observational retrospective setting at a single center and is subject to referral and interpretive biases. This threshold is by no means definitive, but surely raises the point that the ischemic threshold of equipoise above which benefit is noted with revascularization might be different for different modalities, and there is no one size fits all.”

Hopeful ISCHEMIA Is Positive

On the whole, Patel said their results don’t necessarily contradict the COURAGE nuclear substudy findings, noting that that analysis was powered only to determine the relative effectiveness of PCI/OMT versus OMT alone for reducing the proportion of ischemic myocardium. The COURAGE substudy was not powered to determine whether the reduction in ischemia would translate into a lower risk of MI or death. Similarly, BARI 2D also showed that the proportion of residual abnormal myocardium on follow-up MPI after revascularization predicted the risk of death/MI, but it, too, was not designed to compare outcomes with revascularization and OMT based on the extent of ischemia on stress testing.

Ron Blankstein, MD (Brigham and Women’s Hospital, Boston, MA), who was not involved in the new study, said that MPI is widely used in the US to evaluate patients with stable CAD in order to determine the severity of ischemia and to guide treatment decisions about the potential benefit of coronary revascularization. Data from this analysis, as well as others, do suggest that patients with more ischemia derive greater benefit from PCI, although these data are observational and subject to limitations.

“The cardiology community is certainly waiting for data from the ISCHEMIA trial in order to determine how medical therapy and coronary revascularization may compare when treating such patients, particularly in the current era where medical therapies have improved,” he told TCTMD.  

Patel said the ISCHEMIA results are critical since it will be the first randomized comparison of a noninvasive physiology-guided revascularization strategy in patients with stable ischemic heart disease. “I am certainly hopeful that the ISCHEMIA trial results are positive,” she said to TCTMD. “But I am also aware of the controversy and concerns surrounding the change in enrollment criteria and the size of the study population. I guess we will find out soon enough what it shows.”

Improvement in Symptoms and Health Status

In a second study, which was also published in JACC as a research letter, the researchers showed that ischemia on PET MPI identified patients who had improvements in angina symptoms and overall health status following revascularization. Using data from the ASPIRE study, they identified 322 patients with known CAD and new/worsening symptoms who underwent PET perfusion imaging and who were followed for 1 year. Slightly more than 15% of patients underwent revascularization, all but three with PCI.

At 12 months, patients treated with medical therapy and revascularization both had improvements in the Seattle Angina Questionnaire (SAQ) angina frequency and summary scores (P < 0.43 for between-group difference). In the adjusted analysis, however, there was a “significant interaction” between ischemia and revascularization where those with greater ischemia had higher odds of improvement in angina symptoms and overall health status with revascularization.

“This small study not only supports these findings of survival benefit, but extends it to benefit in symptoms, function, and quality of life,” said Patel. “They are also the first data really evaluating health status, angina, and quality of life outcomes for this important question of ischemia-guided revascularization.”

“Strikingly Low Threshold”

In an editorial, Rory Hachamovitch, MD (Cleveland Clinic, OH), and Marcelo Di Carli, MD (Brigham and Women’s Hospital), write that the benefits of early revascularization are more evident in patients with a greater extent of ischemia, noting that equipoise between medical therapy and revascularization is typically observed in patients with ischemia ranging from 10% to 12.5%. With an ischemic burden threshold of just 5%, only two or more of the 17 measured segments with PET MPI would need to be ischemic for physicians to consider revascularization over medical therapy. Such a threshold, they state, is “strikingly low.”

The editorialists also note that quantitative PET measures of myocardial blood flow and flow reserve can be helpful as an adjunct to perfusion imaging as they “provide a more comprehensive evaluation of myocardial ischemia by integrating the hemodynamic effects of focal stenosis, diffuse atherosclerosis, and microvascular dysfunction.” Such metrics, they add, “enhance PET’s diagnostic and prognostic accuracy and may identify patients who benefit from early revascularization.”

Blankstein agreed that the while the study supports the concept that patients with severe ischemia would benefit from coronary revascularization, the actual threshold of ischemic burden is less certain, “especially if one were to integrate the magnitude of ischemia with other measures such as myocardial blood flow reserve or ejection fraction.”

Regarding the improvement in angina frequency and health status, Hachamovitch and Di Carli state that such a patient-reported outcome is often overlooked in patient management. They suggest that future studies may identify different thresholds of ischemia for improving survival and softer outcomes, as well as the optimal treatment approach such as that studied in ISCHEMIA.