The ISCHEMIA trial’s primary outcome — validation for conservative over invasive management to some, but also contentious from the start — was never going to be the final word. A pair of new subgroup analyses may provide some guidance, researchers say, for giving invasive management an edge over a meds-only approach in these patients with coronary artery disease (CAD) and at least moderate ischemia at stress testing.

The trial of more than 5000 patients famously showed no advantage to invasive management — cardiac catheterization and possibly coronary revascularization as an initial strategy — compared with medical therapy alone on a composite endpoint that included cardiovascular (CV) death and other events. Speculatively, there had been a signal of superiority for invasive management in later follow-up.

But those in the invasive group who went on to complete revascularization (CR) seemed to fare better on the primary endpoint than those assigned to conservative care, the new analyses concludes. The catch: that benefit went only to patients for whom CR was attained with anatomic guidance — that is, by quantitative coronary angiography (QCA) alone, without help from functional testing.

“Among selected patients with chronic coronary disease and at least moderate ischemia, the outcomes of the invasive strategy may be improved if anatomic complete revascularization is achieved,” said Gregg Stone, MD, Icahn School of Medicine at Mount Sinai, New York City, when presenting the findings May 17 during the American College of Cardiology (ACC) 2021 Scientific Sessions.

“The likelihood of safely achieving anatomic complete revascularization should therefore be considered when selecting between an invasive and conservative approach in patients with chronic coronary disease,” concluded Stone, an ISCHEMIA coprincipal investigator.

How much credence one gives the two analyses “depends on your judgment or prejudice how to interpret the secondary endpoints in a trial where primary and key secondary endpoints are not met,” Sanjay Kaul, MD, Cedars-Sinai Medical Center, Los Angeles, told theheart.org | Medscape Cardiology.

The analyses were “designed to make the invasive strategy in ISCHEMIA look in the best light,” said Kaul, who wasn’t associated with the trial. There appears to be a “convoluted attempt” to “rewrite the narrative” by showing a benefit from the invasive strategy.

“There’s sleight of hand here,” said William E. Boden, MD, Boston University School of Medicine and VA New England Healthcare System, also an ISCHEMIA coprincipal investigator and chair of the prequel COURAGE trial.

The two analyses are intended to show that if CR can be achieved, “it somehow will offset the negative results of ISCHEMIA. But when the day is done, it’s a negative trial,” Boden told theheart.org | Medscape Cardiology.

“We have to remember that this is now a secondary analysis with nonrandomized data from a randomized trial,” cautioned Rasha K. Al-Lamee, MBBS, PhD, Imperial College Healthcare NHS Trust and Hammersmith Hospital, London, in an interview.

“The way in which they presented the data is probably fair, but I think we have to be careful with what the message is for us in clinical practice.” For example, the angiographic definition of CR was stricter in the trial than it typically is in practice.

Patients will likely fare much better if CR can be achieved, the current analyses suggest, but “you probably won’t meet the complete revascularization criteria in most of your patients,” said Al-Lamee, an interventional cardiologist and director of the ORBITA trial.

Angina-related Quality of Life

Whereas anatomic CR seemed preferable to functional CR — that is, guidance by angiography with either stress testing or invasive flow-reserve assessment — both forms of CR appeared better than incomplete revascularization (ICR) at controlling symptoms.

By either guidance method, CR seems to improve angina-related quality of life better than ICR, “particularly in patients with baseline weekly or daily angina,” said Kreton Mavromatis, MD, Atlanta VA Healthcare System, Decatur, Georgia.

For patients with chronic CAD and stress angina who are managed invasively, the findings suggest, “safe achievement of complete revascularization will optimize quality of life,” Mavromatis said when presenting the ISCHEMIA analysis of CR and symptoms after Stone’s presentation at the ACC sessions.

It’s been long recognized for such patients that symptoms are reduced by revascularization, which in ISCHEMIA could be percutaneous coronary intervention (PCI) or coronary bypass grafting (CABG). And that’s what happened as a secondary outcome in ISCHEMIA.

But the trial failed to show superiority of the invasive approach over a median 3.2 years for the primary endpoint, a composite of CV death, myocardial infarction (MI), hospitalization for heart failure or unstable angina, and resuscitated cardiac arrest. Cumulative event rates at 4 years were 13.3% and 15.5% for the invasive and conservative groups, respectively.

In the new secondary analysis, the corresponding rate of these events was 11.8% for patients assigned to invasive management who went on to anatomic CR at revascularization.

The 4-year rate of CV death or MI, a secondary endpoint, was 11.7% for the invasive group and 13.9% for the conservatively managed group in ISCHEMIA overall, compared with 10.8% for those with anatomic CR in Stone’s report.

In the quality-of-life analysis, achieving anatomic CR, compared with ICR, corresponded to a 62% likelihood of improvement in Seattle Angina Questionnaire 7 (SAQ-7) summary scores at 1 year. The likelihood more than doubled for the SAQ-7 angina frequency score.

Mavromatis and Stone described the two analyses as only suggestive but worthy of at least consideration in practice under some circumstances.

If his patient has a lot of angina and he’s in the cath lab “staring at their angiogram,” Mavromatis said, “I’m going to think harder about how I accomplish complete revascularization,” and give more thought to whether PCI or CABG would be more appropriate. “It will make me put that into the equation and think about it more strongly.”

But, Stone said, “we really must be honest with ourselves.” If CR appears feasible, the patient could be “informed a little bit more that their outcomes may be slightly better with an invasive approach. But we also have to appropriately use bypass surgery” if CR is judged to be out of PCI’s reach.

“Not Statistically Robust”

Some have questioned whether the two analyses are solid enough to be the basis for recommendations, especially as they derive from subgroups in a negative study.

“In the ISCHEMIA trial proper, there was a null clinical outcome benefit and a modest quality-of-life benefit. In the ISCHEMIA-CKD ancillary study, there was a null clinical outcome benefit and there was a null health-related benefit,” observed Kaul. The trial therefore provides “insufficient or weak evidence to inform clinical practice.”

The “slicing and dicing” of nonrandomized data in these exploratory analyses make them “susceptible to substantial bias and residual confounding,” he said. The differences between groups “are overall small and not statistically robust.”

Moreover, Kaul added, by comparing CR patients with the broad conservative-care group, the analysis “stacks the deck in favor of the invasive arm by selectively choosing the best-case scenario.” Patients with CR are less likely to have chronic total occlusions, smaller target vessels, or higher SYNTAX lesion complexity scores, he noted. “You cannot control for those all those variables in any model; there’s always going to be residual confounding.”

The secondary analyses “compare the best-case scenario in the invasive strategy to an all-comers scenario in the conservative strategy, which puts this conservative strategy at a disadvantage,” Boden agreed. “It’s not a level playing field.”

“I think it was reasonable that they presented newly adjusted outcome curves based on these new criteria,” but given that the CR and ICR groups “are just very different patients,” Al-Lamee said, “perhaps the results just speak to that.”

The likely sicker group with ICR by the ISCHEMIA core-lab definition probably did no better with the invasive than with the conservative approach “because they need a lot of risk factor modification and treatment of a much wider burden of disease than just the disease that we see,” she said.

Stone addressed these issues during a panel discussion after his presentation. Most differences between the CR and ICR patients in the adjusted analyses “were in the extent of anatomic disease,” he said. “We controlled for clinical variables, as well as anatomic variables and the modality of revascularization, and it did look like completely revascularizing patients, after controlling for all of that, could modestly improve their outcomes.”

Anatomic, Functional CR Definitions

All angiograms in ISCHEMIA were analyzed at a core laboratory using prespecified definitions for both anatomic and functional CR. Anatomic CR primarily meant successful revascularization of all lesions with a stenosis-severity of at least 50% of the luminal diameter and at least 2.0 mm in overall diameter. Functional CR was defined by different levels of QCA stenosis, depending on degree of regional myocardial ischemia at stress testing or alteration in invasively measured coronary flow reserve.

Among patients in the invasive group who went on to revascularization, 43.3% and 58.3% achieved anatomic and functional CR, respectively. The rates were essentially the same at 43.6% and 58.5%, respectively, within the entire invasive-management cohort — that is, by intention to treat.

The CR group’s unadjusted hazard ratio (HR) for the primary endpoint, compared with ICR patients, was reduced 39% (P = .001). But Stone said the effect was attenuated in adjusted analysis.

• Anatomic CR: adjusted HR, 0.79 (95% CI, 0.55 – 1.15; P = .22)

• Functional CR: adjusted HR, 0.96 (95% CI, 0.68 – 1.34; P = .80)

The primary endpoint benefit at 4 years seen in patients with CR, compared with the entire conservatively managed cohort, was more pronounced for anatomic CR than for functional CR.

The outcome was a mean 3.6 percentage points lower after anatomic CR than after conservative care, with corresponding drops in CV death and CV death or MI. Stone characterized those differences, given their confidence intervals, as “technically statistically significant.”

Adjusted 4-Year Outcomes, Anatomic CR Subgroup and Overall Conservative Care Group
Endpoint	ACR (%)	CON (%)	Adjusted Difference in Percentage Points (95% CI)
Primary	11.8	15.4	–3.6 (–6.9 to –0.7)
CV death or MI	10.8	13.8	–3.0 (–6.5 to –0.1)
CV death	2.8	5.0	–2.2 (–4.5 to –0.5)
ACR, anatomic complete revascularization subgroup of overall invasive group; CON, conservative group.

The results are only hypothesis-generating, and “whether striving for CR in all cases of PCI and CABG would safely improve outcomes is unknown,” Stone concluded.

“I think it was quite admirable to set out standards for complete revascularization and then try to analyze how often patients in ISCHEMIA met the criteria. My worry is that the standards they set for what was considered by the core lab to be anatomical or functional complete revascularization are actually quite different from clinical practice,” Al-Lamee told theheart.org | Medscape Cardiology.

“I think many will be surprised to see complete revascularization rates that are so low, at 40% to 60% in the invasive arm. But I think that’s partly because the threshold that was set was possibly unachievable in most cases,” she said. For example, “very few of us would consider revascularization in a vessel of 2 mm diameter, even if the disease is severe.”

Patients who are revascularized and have “lesions that are easy to tackle” and no other residual disease “might do better or as well with revascularization as with conservative management,” Al-Lamee said. “But I think that’s maybe not the conclusion many will take. I think a lot of people will just say, ISCHEMIA didn’t completely revascularize over 50% of patients in the invasive arm and I can do better.”

That would be the wrong message, she cautioned, because many patients judged to have CR in practice would not have met the ISCHEMIA standard for CR. “I’d love to see the angiograms and see examples of what they mean by complete revascularization to get a sense of how realistic it is in clinical practice.”

Symptoms a Year Later

Quality-of-life improvements a year after CR were most pronounced in patients who initially reported daily to weekly symptoms, and more so when CR was anatomic rather than functional, Mavromatis reported.

Among patients with that much angina at baseline, the covariate-adjusted odds ratio (OR) for improved health status after anatomic CR vs ICR was 1.62 (95% CI, 1.07 – 2.44; P = .04) for the SAQ-7 summary score and 2.20 (95% CI, 1.28 – 3.77; P = .04) for the SAQ-7 angina frequency score. The ORs for functional CR vs ICR went in the same direction but without reaching significance.

Patients in the invasive group consistently showed numerically greater scores than those in the conservative-care group in all of the assessed SAQ-7 domains. The same applied to the subset in which CR was achieved, whether anatomically or functionally.

Differences in Adjusted Mean Quality-of-Life Scores: Invasive Group CR-guidance Subgroups vs Conservative Group at 1 year in ISCHEMIA
SAQ-7 Domain Score	INV-ACR vs CON (in Substudy)	INV-FCR vs CON (in Substudy)	INV vs CON (in Overall Trial)
Summary	4.3	4.3	3.7
Angina frequency	4.3	4.7	3.7
Quality of life	5.6	5.9	4.6
Physical limitation	3.0	3.3	2.6
ACR, anatomic complete revascularization subgroup; CON, conservative group; FCR, functional complete revascularization subgroup; INV, invasive group.

A SAQ-7 summary score difference of 5 points is considered clinically significant, and “reflects often an angina frequency score improvement of at least 10 points or a quality-of-life [score] improvement at least 10 points,” Mavromatis told panelists after his presentation.

“Some of the mean improvements that we see are less than 5 points, but that still doesn’t exclude the fact that some patients are improving a lot, maybe 10-plus points, and other patients are improving very little,” he said.

The distribution of SAQ-7 scores in ISCHEMIA suggests that “only 21% of the patients had daily or weekly angina, so that’s the group that benefits the most” from revascularization, observed Boden. “If you’re having frequent symptoms or if your symptoms are not responding to medical therapy, you clearly should get considered for revascularization.”

But for a patient with angina only monthly or even twice a month, for example, “I personally find it hard to justify doing a PCI procedure knowing that there’s procedural risk and patients are going to be back with more symptoms.” And, “they’re going to have to be on more drugs for at least the short term,” Boden said. “There are a lot of downsides to PCI.”

Stone discloses serving as a consultant for Valfix, TherOx, Robocath, HeartFlow, Ablative Solutions, Miracor, Neovasc, Abiomed, Ancora, Vectorious, Elucid Bio, Occlutech, CorFlow, Cardiomech, and Gore; and holding equity or options in Ancora, Cagent, Applied Therapeutics, the Biostar family of funds, SpectraWave, Orchestra Biomed, Aria, Cardiac Success, and Valfix. Mavromatis and Kaul had no disclosures. Boden has previously disclosed receiving consultant fees or honoraria from AbbVie, Amgen, AstraZeneca, and Janssen; and research grants from Amarin. Al-Lamee discloses receiving consulting fees or honoraria from Philips Volcano.

American College of Cardiology (ACC) 2021 Scientific Session: Abstracts 412-10 and 412-12. Presented May 17, 2021.

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