Is Anatomy Destiny? Digging Deeper Into the ISCHEMIA Findings

The findings presented in November were eye-catching: patients with stable coronary disease and ischemia were no less likely to avoid a heart attack, cardiovascular (CV) death, or other event with an invasive procedure than with medication. And, the results held for a subset of patients with chronic kidney disease (CKD), a group often excluded from clinical trials.

Results for ISCHEMIA and ISCHEMIA-CKD, first presented at the American Heart Association (AHA) and due to publish shortly, continued to generate discussion Sunday, when the 2020 American College of Cardiology / World Congress of Cardiology Virtual Experience featured a pair of online presentations with additional insights into these trials, funded by the National Institutes of Health.

Ischemia occurs when there is a disruption of the blood flow from the arteries to an organ or an area of tissue; patients can suffer tissue death if untreated. Physicians can opt for angiography and revascularization followed by medication, compared with medication only; results presented in November showed that patients receiving the invasive procedure were more likely to experience a CV event within the first 2 years, but this relative risk stopped around 3 years, and those having procedures had a slight benefit at 5 years.

David Maron, MD, of the Cleveland Clinic, who made the presentation on behalf of Harmony Reynolds MD,¹ of NYU Langone Health, said the new analysis examined whether there was any difference in outcomes depending on a pair of factors: How severe is the ischemia? And what is the patient’s anatomy—how many blood vessels are involved in the underlying coronary artery disease (CAD), and how much have they narrowed?

ISCHEMIA investigators placed patients in ischemia risk categories—from severe to none—based on a composite that included nuclear tests, echocardiogram, cardiovascular magnetic resonance imagining (CMR), and ST depression exercise treadmill test. Of the 5105 patients evaluated, 4499 had moderate or severe ischemia.

To analyze CAD anatomy, they used the Modified Duke Prognostic Index, which accounts for how many blood vessels are involved and how much narrowing has occurred.

Then, they looked at whether either factor affected outcomes in (1) all-cause death, (2) heart attacks, or (3) the primary trial outcome, which was a composite of CV death, heart attack, hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. Results were adjusted for age, geography, and social and demographic factors, smoking status, level of kidney decline, and angina quality-of-life scores from the initial study.

The analysis showed that the overall findings of ISCHEMIA and ISCHEMIA-CKD reported in November still held: “There was no statistically significant evidence of a benefit from the invasive strategy on 4-year event rates for any level of ischemia,” Maron reported.

As would be expected, those patients with the more severe CAD had higher risk for death and heart attacks, but the invasive approach “did not significantly lower that risk at 4 years.” This included patients with the most severe CAD, based on the Duke scores.

However, Maron said, it’s not to say that ischemia severity and especially physical features of CAD don’t matter at all—they can drive outcomes by themselves, based on the data:

• Among patients with moderate or severe ischemia, who made up the vast majority of patients in the trial, there was no association between ischemia severity and death, based on core laboratory tests performed prior to treatment. There was, however, “a marginal association” between ischemia severity and heart attack risk.
• Investigators found a “strong association” between CAD severity and a patient’s risk of death or heart attack.

During the discussion period, Maron was asked about patients who have a combination of severe ischemia and multivessel CAD; he said this information is not yet available but it is being investigated. Commentators also called for patients to be followed for a longer period to gain more insights.

ISCHEMIA-CKD. Sripal Bangalore, MD, of NYU Langone Health then presented additional insights from ISCHEMIA-CKD, which randomized 777 patients who had an estimated glomerular filtration rate (eGFR) < 30 or were on dialysis. As commenter Alice Jacobs, MD, of Boston University School of Medicine said, these patients “are notoriously difficult to manage,” because they are not good candidates for many medications and they are included in very few studies.

Bangalore’s presentation, Clinical and Quality of Life Outcomes Across the Spectrum of Baseline Kidney Function,² look at results across patients from both the main trial and the CKD subgroup, examining time to death or heart attack as a primary endpoint and a major secondary endpoint of death, heart attack, hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. He also reviewed safety outcomes, including procedural complications and a composite of the start of dialysis or death.

Investigators reported no difference in invasive versus conservative approaches for the primary or secondary outcome, and “no evidence of meaningful heterogeneity of treatment for clinical outcomes across the eGFR spectrum.”

However, the main insights from this new analysis have less to do with the difference between invasive procedures vs medication, but more about the poor fate of patients who reach the later stages of renal decline.

• Investigators found an “exponential increase in cardiovascular events” among patients with lower kidney function.
• The adjusted hazard ratio (HR) for all-cause death over 3 years jumped from 3.64 at Stage 2 CKD to 8.61 at Stage 3 CKD, to 25.37 at Stage 4 and 28.91 at Stage 5 (CI 95%, P < .001).
• The adjusted HR for myocardial infarction over 3 years rose from 7.9 at Stage 2 CKD to 11.98 at Stage 3, 13.4 at Stage 4 and 16.74 at Stage 5 (CI 95%, P < .001).
• Investigators also observed high levels of complications, including bleeding, for patients in later stages of renal decline.

Jacobs pointed out during the discussion that these results are important, as renal decline is on track to increase with rising levels of diabetes and obesity. “Now, we finally have some randomized clinical data to inform our clinical thinking.”

But there’s still much that’s not known, such as reasons why some patients don’t opt for revascularization. As for quality of life benefits, there appeared to be “significant and durable” benefits of having revascularization if patients are having angina symptoms, but the effect declines for those with less severe symptoms and lower eGFR rates.

References

1. Reynolds HR, Shaw L, Min J. Relationships of ischemia severity and coronary artery disease extent with clinical outcomes in the ISCHEMIA trial. Presented at the 2020 American College of Cardiology / World Congress of Cardiology. Abstract 20-LB-19454-ACC.
2. Bangalore S, Hochman J, O’Brien S, et al. Clinical and quality of life outcomes with invasive vs conservative strategy in patients with stable ischemic heart disease across the spectrum of baseline kidney function: insights from the ISCHEMIA and ISCHEMIA-CKD trials. Presented at the 2020 American College of Cardiology / World Congress of Cardiology. Abstract 20-LB-20199-ACC.