Anatomic Burden, Ischemia Severity, and Outcomes in ISCHEMIA

Anatomic severity of disease—but not severity of ischemia—predicted the risk of death or MI over 4 years of follow-up in the ISCHEMIA trial, a new analysis shows. However, an invasive strategy as compared with medical therapy offered no benefit regardless of disease severity based on level of ischemia or extent of coronary disease, according to ISCHEMIA investigators.

Harmony Reynolds, MD (NYU Langone Medical Center, New York, NY), led the analysis, which was presented on her behalf by ISCHEMIA primary investigator David J. Maron, MD (Stanford University School of Medicine, CA), as featured clinical research today at the virtual American College of Cardiology (ACC) 2020 Scientific Session.

“The analysis shows that our overall main trial results comparing an invasive and conservative strategy apply to the range of ischemia and anatomic subgroups,” Maron said. “There was no statistically significant evidence of a benefit from the invasive strategy on 4-year event rates for any level of ischemia and, although more severe and extensive coronary disease increased risk for death and MI, the invasive approach did not significantly lower that risk at 4 years. This was true for the subgroup with severe three-vessel disease or two-vessel disease with proximal LAD.”

Reynolds, speaking with TCTMD, pointed out that current ACC/American Heart Association guidelines give a class I recommendation for CABG in patients with both three-vessel disease or two-vessel disease involving the proximal LAD, with PCI getting a class IIb (“of uncertain benefit”) in these groups. Moreover, the criteria used for these guideline recommendations mirror those used in the current analysis, she noted.

While Reynolds said she wouldn’t “presume” to tell guideline committees what they should write, she added: “I think it’s very helpful that we are able to provide these data from ISCHEMIA that can provide a more contemporary underpinning for any future guidelines of the use of revascularization  [as pertains to reducing] the risk of cardiovascular events and survival.”

Ischemia, Anatomy, and Revascularization Benefits

The notion that revascularization might be of particular benefit in patients with the most-severe ischemia was one of the big questions remaining following the COURAGE trial and a key rationale for doing ISCHEMIA. But as its researchers said when the trial was presented last year, revascularization had no benefit over standard care in reducing the rate of cardiovascular death, MI, or hospitalization for unstable angina, heart failure, or cardiac arrest—the trial’s primary endpoint—across a range of prespecified subgroups including CAD severity and degree of baseline ischemia.

In the new data released at ACC today, investigators delved deeper into the question of ischemia and anatomic severity and its impact on the individual components of the endpoint most likely to be impacted. Ischemia severity was determined by the core lab using prespecified criteria. Anatomic severity was based on the Modified Duke Prognostic Index (MDPI). Reynolds noted that the MDPI has been well-validated and is known to be predictive of events in patients with lesser amounts of coronary disease than those in ISCHEMIA, where 1,261 patients had a score of 6 (three-vessel disease ≥ 70% or two-vessel disease ≥ 70% with proximal LAD) and 1,027 had a score of 5 (two-vessel disease ≥ 70% or three-vessel disease of ≥ 50% or an LAD with ≥ 70% obstruction).

Using patients with none or mild ischemia as the reference group, there was no association between ischemia severity and all-cause mortality, and only a modest association between worsening ischemia and MI (P for trend = 0.04). By contrast, patients with lesser degrees of anatomic disease (with MDPI 6 as the reference) had a lower risk of all-cause mortality and a lower risk of MI (both P for trend < 0.001).

Across all three ischemia categories and all four MDPI scores, revascularization had no benefit in reducing the risk of the primary outcome, MI, or all-cause mortality over a median of 3.2 years.

“Our data would certainly suggest that anatomic extent of disease is what we should be focusing on and so would data from COURAGE that preceded this,” Reynolds told TCTMD. “There seems to be a common thread that coronary anatomy is more predictive and ischemia severity is not, especially after risk adjustment.”

More Analyses Forthcoming

During the discussion following Maron’s presentation, E. Magnus Ohman, MBBS (Duke Clinical Research Institute, Durham, NC), called the anatomy findings “compelling,” corroborating what other analyses have shown before about the link between anatomic disease burden and outcomes. “What is surprising I think to many people is that even among the highest risk—both ischemic and high burden of disease—cohorts, that there is no interaction with the treatment, ie, the invasive approach in these patients,” Ohman said.

Importantly, he added, the original concept linking anatomical disease burden and outcomes used much longer follow-up, underscoring the need for more long-term data. ISCHEMIA investigators have previously said they are asking the National Institutes of Health (NIH), which funded the original trial, to provide additional support to allow them to follow patients out to 10 years. “I hope anybody from NIH listening [will understand that] the extension of follow-up of this trial becomes very, very important, and I encourage you and the investigators to extend follow-up beyond what has been presented here,” Ohman said.

Ohman also asked whether investigators had looked at a combination of ischemia and anatomic burden, or if they had any information on the number of patients with three-vessel disease randomized to medical therapy who crossed over to revascularization during follow-up.

Neither of these analyses have yet been done but are planned, Maron said. “I’m sorry to disappoint you.”

Alice K. Jacobs, MD (Boston Medical Center, MA), also one of the panelists for today’s presentation, pointed to the fact that anatomic severity of disease has been described differently over the decades, sometimes 50% or greater, sometimes 70% or greater. “If you look at FAME, a little over 40% of their group had 50-70% stenoses but only a third of those had a positive [fractional flow reserve],” Jacobs said. “I’m wondering if you thought that including that greater than 50% definition influenced or diluted your results in any way.”

Maron, in response, noted that investigators plan to evaluate the difference in outcomes between patients using the 50% and 70% thresholds. “I think that it’s quite possible that including people with a less than 70% stenosis might have weakened our ability to show a difference, but we don’t know the answer to that yet,” he said.

Responding to a second question of Jacob’s, Maron also promised future analyses looking not only at completeness of revascularization—expected for the TCT 2020 meeting—but also adherence to guideline-directed medical therapy, saying an analysis looking at attainment of risk factor goals and outcomes is “forthcoming.”

Surrogates and Symptoms

Commenting on the current analysis for TCTMD by email, Marc Dweck, MBChB, PhD (University of Edinburgh, Scotland), said, “The study appears to support the increasingly popular hypothesis that plaque causes myocardial infarction and ischemia causes symptoms, demonstrating that anatomic assessments of disease severity are more closely related to subsequent events—death and MI—than ischemia assessments. It is therefore consistent with many recent studies and with the basic pathology of coronary artery disease wherein myocardial infarction is caused by acute plaque rupture or erosion not ischemia.”

As he’s said before, Dweck believes that ischemia severity and anatomic scores are likely surrogates for atherosclerotic plaque burden “and, in particular, the burden of adverse plaque,” he said. “The more adverse plaques you have the more likely one will rupture and cause an event. I look forward to seeing whether such plaque burden assessments, which are now readily available on CT, provide even better risk stratification” in ISCHEMIA.

The caveat to those views, he added, “is that clinical experience informs us that very severe ischemia, such as that from critical left main stem disease, does result in adverse clinical events, but these patients were not captured in this ISCHEMIA trial.”