ISCHEMIA: PCI, Surgery Strike Out vs Meds

Patrice Wendling

November 16, 2019

PHILADELPHIA — Viewed by many as the last chance to determine the true value of revascularization in stable ischemic heart disease, the ISCHEMIA trial failed to show fewer major cardiovascular events with an early invasive strategy than optimal medical therapy (OMT).

Over a median of 3.3 years follow-up, Kaplan-Meier curves for the primary endpoint — a composite of cardiovascular (CV) death, myocardial infarction (MI), hospitalization for unstable angina, hospitalization for heart failure, or resuscitated cardiac arrest — were similar between the invasive and conservative strategies (adjusted hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.80 - 1.08; = .34).

The curves crossed at 2 years follow-up, with absolute rates favoring OMT at 6 months by 1.9% and favoring early angiography followed by percutaneous coronary intervention (PCI) or bypass surgery at 4 years by 2.2% (13.3% vs 15.5%).

The same pattern was seen for the major secondary endpoint of CV death or MI (11.7% vs 13.9%; adjusted HR, 0.90; 95% CI, 0.77 - 1.06; P = .21).

Dr Judith Hochman

Rates of all-cause death were also low and similar between the invasive and conservative groups (6.5% vs 6.4%; adjusted HR, 1.05; 95% CI, 0.83 - 1.1). The probability of at least a 10% benefit of revascularization on all-cause mortality was less than 10%, based on a prespecified Bayesian analysis, according to study chair Judith Hochman, MD, New York University School of Medicine, New York City.

In its favor, revascularization provided greater angina relief than OMT, with half of patients angina-free at 1 year vs just 20% of those managed with OMT alone, John Spertus, MD, Saint Luke's Mid America Heart institute, Kansas City, Missouri, reported in the same highly charged, late-breaking trial session here at the American Heart Association (AHA) Scientific Sessions 2019.

"There's been a lot on social media about the $100 million spent; we calculate that if asymptomatic patients didn't get PCI we would save over $500 million dollars every year," Hochman said. "This was not a pragmatic, simple trial; everything was read by a core lab…that costs money. I believe that was money well invested," she said to rousing applause.

The open-label trial assessed a long-standing question vexing the cardiology community, after the COURAGE and BARI 2D trials showed no benefit of PCI over OMT alone in reducing the rate of MI or death. Although observational data suggested benefit with revascularization in patients with greater anatomically severe disease, ORBITA raised doubts by reporting relief of angina and exercise capacity were no better after PCI than OMT and sham PCI.

Concerns were raised that ISCHEMIA would not provide a clear answer after the primary endpoint was changed — late in the trial but as allowed per protocol — from CV death and MI to include the more subjective outcomes. Further, eligibility criteria were expanded beyond at least 10% ischemia on stress imaging tests to patients with only 5% ischemia at low levels of exertion (≤ 7 METS) and those with ECG changes during exercise testing without imaging.

Kim Eagle, MD, University of Michigan, Ann Arbor, who was among those to raise concerns about changes to the trial design, said he was not surprised by the results and highlighted the very low mortality rates in patients with significant coronary disease. In addition, only 23% of patients in the OMT group went on to revascularization, despite nearly one third (28%) having indications for cardiac catheterization.

"It certainly tells us that [the] current medical treatment that we have is really quite effective and it's going to be hard in patients that are not unstable on best medical therapy to show benefit of revascularization when we're able to control the risk factors as well," he told | Medscape Cardiology.

"One of the good news things here is that it's a clear negative trial," Eagle said. "There's not a lot of impressive trends that we're seeing that [say] it's just due to some of the trial's changes that had to be made. That's helpful."

Invited discussant Alice K. Jacobs, MD, Boston University Medical Center, Massachusetts, said ISCHEMIA was sufficiently powered and the results were not altered by the change in the primary endpoint.

"What we know from the trial to date is that in patients with stable ischemia heart disease with angina symptoms controlled or tolerated, I don't think we feel obligated to take them right to the cath lab," she said.

Discussant Glenn Levine, MD, Baylor College of Medicine, Houston, Texas, said the ISCHEMIA and ancillary ISCHEMIA-CKD trials "help to fill important knowledge gaps."

"I would think, without any inside knowledge, [that] ISCHEMIA and ISCHEMIA-CKD will be key studies that are incorporated into the guidelines," he said.

Asked for her key takeaway during the discussion of the results, panelist Roxana Mehran, MD, Icahn School of Medicine at Mount Sinai, New York City, said, "One thing that comes to mind, importantly, is are we doing too many stress tests on these patients who have mild or moderate symptoms, one episode of angina a month? That's a big question. Maybe it's more important to rule out left main disease with a [computed tomography angiography] CTA and really understand this."

"This will change practice," she added. "This is practice changing because at the moment most of these patients are landing in the cath lab and we're expected to fix them."

In response, Jacobs said, "I think we'll still need stress to make the diagnosis...but in a patient [in whom] you are certain that they have angina or you know they have coronary disease, the only conundrum in my mind is the left main issue. Because if you do [perform] the stress test and it's markedly positive, you are going to want to exclude that; so then are you going to do a CTA on everybody?"

Mehran interjected, "Why not do a CT up front to make the diagnosis?" To that, Jacobs replied, "If it's available, then that might be a reasonable outcome."

Global Trial

ISCHEMIA investigators at 320 sites in 37 countries randomly assigned 5179 stable patients with moderate or severe ischemia on stress imaging or exercise tolerance testing to early invasive coronary catheterization followed by PCI or coronary bypass surgery, if feasible, plus OMT or to OMT alone.

The trial enrolled 8518 patients, but to avoid the charge of referral bias leveled against prior studies, randomization was done after blinded CTA to identify and exclude those with left main disease (LMD) (≥ 50% stenosis) or without obstructive coronary artery disease (CAD) (< 50% stenosis in all major coronaries). Ultimately, 73% of patients underwent CTA, of whom 434 were excluded for LMD, 1218 for no obstructive CAD, and 1350 for insufficient ischemia.

At baseline, 87% of patients had moderate or severe ischemic disease based on core lab findings, 90% had angina, and 75% had stress imaging as the qualifying test.

There was no heterogeneity of treatment effect on the primary endpoint in prespecified subgroups, Hochman said.

Table. Outcomes for Individual Components


Adjusted HR

95% CI

CV death


0.66 - 1.15



0.76 - 1.11

Hospitalization for Unstable Angina


0.27 - 0.91

Hospitalization for Heart Failure 


1.38 - 3.61

Resuscitated Cardiac Arrest


0.29 - 3.49


Notably, the invasive strategy was associated with an increase in up-front, type 4a or 5 procedural MIs compared with OMT (adjusted HR, 2.98; P < .01) but a lower rate of spontaneous type 1, 2, 4b or 4c (adjusted HR, 0.67; P < .01).

"We're going to dig deep into the spontaneous MI issue," Hochman said. "We know that spontaneous MI has a higher risk of death subsequently; it's just surprising that the all-cause mortality curves were so superimposable. But we want to look in ISCHEMIA Extend for divergence of the curves."

Speaking to | Medscape Cardiology, Ajay Kirtane, MD, NewYork-Presbyterian Hospital and Columbia University Irving Medical Center, New York City, commented, "The early periprocedural harm of the invasive approach was offset by a late reduction in spontaneous MI, which actually led to an absolute reduction in the major secondary endpoint of CV death/MI at 4 years."

Also commenting on the trial, Patrick O'Gara, MD, Brigham and Women's Hospital, Boston, told | Medscape Cardiology that ISCHEMIA is reminiscent of TOPCAT, the interpretation of which changed over the years.

"We as a community need to be careful not to recoil from the reality that there's not a significant treatment difference between these two groups, and we're very quick to do that," he said. "Trials are remembered on the basis of their positivity and there's going to be a lot to learn from this one."

What several observers agreed on was the need for shared decision making between patients and physicians about the risks and benefits of either strategy and the need for greater OMT compliance. Although 96% of patients at the last visit were on statins, only two thirds were on high-dose statins and only 41% achieved a high level of medical therapy optimization, up from 20% at baseline, Hochman observed.

"And that's better than clinical practice," she said. "The major challenge in medicine is to get people to comply with their medicines and change lifestyles to reduce risk factors."

ISCHEMIA is supported by a grant from the National Heart, Lung, and Blood Institute and financial donations from Arbor Pharmaceuticals and AstraZeneca. Devices and medications were provided by Abbott Vascular/St. Jude Medical, Medtronic, Volcano, Arbor Pharmaceuticals, AstraZeneca, Merck Sharp & Dohme, and Omron Healthcare.

American Heart Association (AHA) Scientific Sessions 2019: Presented November 16, 2019.

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