ISCHEMIA Trials Land in NEJM While ACC.20 Airs Further Insights

April 01, 2020

This week marked the first major, pan-cardiology scientific conference, albeit one conducted entirely in cyberspace, since the ISCHEMIA trial's potentially seismic outcomes were unveiled in November at the American Heart Association (AHA) Scientific Sessions 2019.

Right after, it wasn't unusual to hear some variant of, "When is it supposed to be published?" in the vast hallways of the Philadelphia Convention Center, at a time when medical conferences had vast hallways.

Now, the New England Journal of Medicine has answered the question by dropping the full, peer-reviewed ISCHEMIA publication on the last day of the American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC) virtual meeting. The annual sessions were conducted entirely online this year following the traditional live conference's cancelation because of the COVID-19 pandemic.

Famously in ISCHEMIA, an initial strategy of invasive management in patients with moderate-to-severe ischemic heart disease didn't produce better clinical outcomes than conservative, medication-based care over a median of about 3 years.

Alongside the new ISCHEMIA report, rife with never-before-seen details and at least one telling alternative analysis, NEJM also released a trove of related publications with findings that were at least partially reported live in November.

They include the parallel ISCHEMIA-CKD trial in patients with severe renal dysfunction (who were excluded from the main trial), angina-related-health-status analyses, hefty data supplements for both studies, and an editorial signed by the cardiology equivalent of household names.

Collectively based on the reports, the editorial states: "[P]rovided there is strict adherence to guideline-based medical therapy, patients with stable ischemic heart disease who fit the profile of those in ISCHEMIA and do not have unacceptable levels of angina can be treated with an initial conservative strategy."

"However, an invasive strategy, which more effectively relieves symptoms of angina (especially in patients with frequent episodes), is a reasonable approach at any point in time for symptom relief," write editorialists Elliott M. Antman, MD, and Eugene Braunwald, MD, both of Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.

Patients with stable ischemic heart disease and advanced chronic kidney disease (CKD) have a clinical event risk more than triple the risk for those without CKD, "but an initial invasive strategy does not appear to reduce event rates or relieve angina symptoms for these patients," they continue. "Therefore, patients with stable ischemic heart disease and chronic kidney disease can usually be treated with a conservative strategy."

New at ACC.20/WCC

That assessment was supported by one of several new ISCHEMIA-related follow-up studies presented at ACC.20/WCC: a pooled analysis of ISCHEMIA and ISCHEMIA-CKD patients according to stage of baseline renal function, from normal to kidney failure.

Neither the initial invasive strategy nor the conservative-care approach was meaningfully more effective in any renal-function subgroup, and their relative primary and secondary outcomes mirrored those in both studies on their own.

However, the likelihood that patients would stay angina-free was higher with the invasive approach. "This was heavily dependent on baseline angina frequency since the benefit was greatest in those with daily or weekly angina and negligible in those with no angina," ISCHEMIA-CKD principal Investigator Sripal Bangalore, MD, MHA, New York University Langone Health, New York City, said when presenting the pooled analysis.

"In addition, the probability of being angina free with invasive strategy reduced with lower kidney function."

Patients with renal dysfunction are under-studied in cardiology, even though coronary disease is the leading cause of death in patients with CKD, and they have an increased risk of CAD and MI, observed the invited discussant for Bangalore's presentation, Alice K. Jacobs, MD, Boston University School of Medicine, Massachusetts, who was not involved in the ISCHEMIA reports.

Such patients are "also notoriously difficult to manage. With the invasive strategy, you're always concerned with precipitating acute kidney injury in those who are not on dialysis. And their bleeding risk and guideline-directed medical therapy is not always optimal." That's in part because they aren't candidates for renin-angiotensin-system inhibitors "and sometimes dual antiplatelet therapy," Jacobs said.

"So now we finally have some randomized trial data to help inform our clinical thinking."

Overall, the basic findings were similar over a median of about 2 years in ISCHEMIA-CKD, which mirrored the main trial — and was conducted in parallel even at many of the same centers — in 777 otherwise qualified people excluded from it, with their estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73m2 or on dialysis.

Consistency in Outcomes

The comparable overall benefit observed in the main 5179-patient ISCHEMIA trial was for the primary endpoint, a composite of cardiovascular (CV) death, myocardial infarction (MI), or hospitalization for unstable angina, heart failure (HF), or resuscitated cardiac arrest; as well as secondary outcomes CV death or MI as a composite, and angina-related quality of life.

Overall parity between the invasive and conservative approaches for primary and secondary endpoints extended throughout the range of ischemia severity and other baseline features.

Notably, more severe and extensive coronary disease increased the risk for death and MI, but the invasive approach did not significantly lower that risk at 4 years, even for the subgroup with severe 3-vessel disease or 2-vessel disease with proximal left anterior descending involvement, ISCHEMIA principal investigator David J. Maron, MD, Stanford University School of Medicine, California, said during an ACC.20/WCC virtual presentation focused on anatomic and ischemia severity in the trial.

During a discussion of the findings, Jacobs asked whether including a 50% threshold in the definition of significant coronary disease in the trial "had any influence or diluted your results in any way?"

"We're going to look at that very specifically," Maron replied. "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."

Additional analyses are also planned looking at patients with the combination of severe ischemia and multivessel disease, crossover rates by anatomic disease and ischemia severity, and attainment of risk factor goals and outcomes, he noted.

The investigators have submitted a grant to the trial sponsor, National Institutes of Health, to extend follow-up out to 10 years.

New Data, Insights in NEJM

The Antman-Braunwald editorial refers to a much-discussed irregularity in the accrual of at least one endpoint in ISCHEMIA, a reversal in the balance of incident MI between the two strategies through its first 4 years.

As the editorial notes, "Kaplan–Meier curves showed a trend for a greater number of myocardial infarctions (predominantly procedural) in the invasive-strategy group than in the conservative-strategy group during the first 6 months of the trial, but as the trial proceeded, the curves crossed, and more myocardial infarctions (predominantly spontaneous) occurred in the conservative-strategy group."

After 4 years, the incidence of the primary endpoint as prospectively defined "was higher in the conservative-strategy group than in the invasive-strategy group (13.9% vs. 11.7%). It is possible that ISCHEMIA ended before a substantial difference in favor of the invasive strategy emerged."

But when MI rates were analyzed according to a secondary definition, "the number and pattern of myocardial infarctions differed, leading to results that favored the conservative strategy throughout follow-up," the editorial notes. That secondary MI analysis had not been previously reported.

"Although there is some uncertainty regarding the interpretation of the ISCHEMIA results — given that the difference in outcomes between the two strategies is driven by results for myocardial infarction, and those results depend on the definition used in the analysis — the invasive strategy does not appear to be associated with clinically meaningful differences in outcomes during 4 years of follow-up," the editorial states. "This finding underscores the benefits of disease-modifying contemporary pharmacotherapy for coronary artery disease."

Insights From the Pooled Cohorts by Renal Function

The broad-spectrum heterogeneity of outcomes in the two trials also applied to the entire range of renal function represented in the ISCHEMIA and ISCHEMIA-CKD pooled analysis, observed Bangalore in his presentation.

It included the 5179 patients in ISCHEMIA with stable angina and moderate to severe ischemia who were required to have an eGFR 30 mL/min/1.73m2 or higher; and the 777 patients in ISCHEMIA-CKD with moderate or severe ischemia and eGFR less than 30 mL/min/1.73m2 or on dialysis.

The pooled cohorts were stratified by renal functional stages 1 through 5, representing five successive eGFR ranges from 90 mL/min/1.73m2 or higher in stage 1 (1889 patients) through eGFR less than 15 mL/min/1.73m2 for patients in stage 5 or on dialysis (467 patients).

Event rates were inversely related to renal function regardless of management strategy.

Relative rates for the main primary and secondary composite endpoints, which mirrored the main ISCHEMIA trial, showed consistent and significant increases with progressive stages of renal function, as did rates for death from any cause and MI on their own (P < .001 for all).

"We observed an exponential increase in cardiovascular events with lower kidney function," and a similar rise in procedure-related complications and bleeding, Bangalore said. "There was no evidence of meaningful heterogeneity of treatment effect for clinical outcomes across the eGFR spectrum." That was true for both primary and secondary endpoints.

There was a "significant and durable benefit of the invasive strategy at improving angina-related quality of life" that fell off precipitously with worsening renal function and fewer symptoms, he said.

"I don't think it's surprising that as you increase the severity of your kidney disease, you have worse cardiovascular outcomes and more complications,"  Jacobs, the Boston University professor and invited discussant, said.

"It's probably also intuitive that quality of life and angina is not significantly changed at the lower eGFR," she added. "I think these patients on dialysis go to dialysis three times a week, their quality of life must be limited, and probably not limited by angina."

Deputy News Editor Patrice Wendling contributed to this report.

Devices used in the trial were donated by Abbott Vascular, Medtronic, St. Jude Medical, Volcano, and Omron Healthcare. Medications were provided by Arbor Pharmaceuticals, AstraZeneca Pharmaceuticals, and Merck Sharp & Dohme. Disclosures for all report authors can be found at nejm.org.

Antman and Braunwald have disclosed no relevant financial relationships. Bangalore discloses receiving c onsultant fees or honoraria from Abbott Vascular, Amgen, Biotronik, Meril, Pfizer, REATA, and SMT, and conducting research or receiving research grants from Abbott Laboratories. Jacobs discloses conducting research or receiving research grants from Abbott Vascular.

N Engl J Med. All published March 30, 2020.
ISCHEMIA main report, ISCHEMIA-CKD report, ISCHEMIA Health-status outcomes report, ISCHEMIA-CKD Health-status outcomes report, Editorial

American College of Cardiology 2020 Scientific Session/World Congress of Cardiology: Featured Clinical Research II, session 409-16. Presented March 29, 2020.

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook.

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