CIAO Finds Symptoms, Ischemia Don't Match in Puzzle That Is INOCA

April 07, 2020

Myocardial ischemia at stress testing may be just as severe without as with obstructive coronary artery disease (CAD) at angiography. But patients with ischemia and no obstructive CAD (INOCA) may have greater angina frequency.

Patients with INOCA also have symptoms and positive stress-test results that both vary over time, but within individuals, the symptoms and ischemia don't necessarily correlate with each other.

So concluded a study called CIAO, which entered 208 patients who had been considered for the larger ISCHEMIA trial, based on symptoms and stress-echocardiography results, but were excluded before randomization for not having obstructive CAD at CT coronary angiography (CCTA).

The ancillary study's INOCA patients were significantly more likely to be female than the larger trial's 865 patients with both positive stress-test results and obstructive CAD by CCTA, defined as a narrowing of greater than 50%.

Harmony Reynolds

Stress-test results normalized over the course of a year in about half of the INOCA patients, whose tests were read blindly by the same core laboratory used in the main ISCHEMIA trial. Also, 39% showed "clinically meaningful" improvement in angina frequency. Yet their medications were mostly consistent throughout the year, reported Harmony R. Reynolds, MD, NYU School of Medicine, New York City, March 30 as part of the virtual presentation of the American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC).

In other CIAO findings, patients on calcium-channel blockers (CCB) while performing their screening stress test were significantly more likely than others to show normalization of ischemia on stress testing, and to have significantly improved scores on the Seattle Angina Questionnaire for symptom frequency (SAQ-AF), both at 1 year, compared with the screening evaluation for study entry.

Stress echocardiography can risk-stratify patients with INOCA for clinical outcomes, but the extent to which their documented ischemia and self-reported symptoms are related is unknown, Reynolds noted. Both, in INOCA, are thought to be related to reduced coronary flow reserve from microvascular dysfunction, epicardial coronary or microvascular vasospasm, or some combination of the two mechanisms.

"Or, in theory, people could have neither. There's always a small group that in fact has no abnormality on invasive testing. It's invasive testing that will define these endotypes" by underlying mechanism, Reynolds told | Medscape Cardiology.

Indeed, both mechanisms were likely on display in CIAO, observed C. Noel Bairey Merz, MD, Cedars-Sinai Medical Center, Los Angeles, as an invited discussant following Reynolds' presentation. She pointed out that many of its patients had a low angina frequency and resolution of ischemia as tracked by stress echocardiography, and that CCB therapy predicted symptom improvement. "These strongly endorse an endotype of functional coronary vasoconstriction," she said.

"The other half that did not resolve symptoms and did not resolve the stress echoes; these are the patients that probably have coronary microvascular dysfunction, which is a persistent and chronic problem," Merz said. "It erodes quality of life, SAQ scores are more often in the 50s and 60s [indicating a poor symptom status], and has an adverse prognosis, particularly death, dictated by coronary flow reserve abnormalities."

That reported angina and ischemia weren't correlated over the year of the study was predictable, she said. Chest pain, probably in both obstructive CAD and INOCA, is "impacted by a lot of things in addition to ischemia." According to most literature on the subject, angina-like chest pain is "a construct impacted by sensory, emotional, autonomic, motor, and cognitive components," Merz observed.

CIAO Supports Clinical Experience

That most CIAO participants turned out to be women, and that symptoms tended to vary independent of ischemia, is also consistent with clinical experience and relevant studies, said Eileen M. Handberg, PhD, ARNP, University of Florida Health, Gainesville.

In the vintage WISE and ongoing WISE-Coronary Vascular Dysfunction studies, both conducted exclusively in women, it has been "very difficult to find any type of correlation" between chest pain and stress-test results, observed Handberg, who was an invited discussant at a media briefing on CIAO during the virtual ACC.20/WCC sessions.

The study's results were "helpful, in that the stress echoes demonstrated the presence of ischemia. That's almost always a question that gets asked about this patient population; there's this sense that these women and men do not have associated ischemia, because the symptoms are often not totally typical," Handberg said.

"They do have events and use of resources that approximate those with obstructive coronary disease, and it is a persistent issue that still has a lot of bias in terms of how these patients are taken care of by their normal providers as well as being seen in emergency rooms and evaluated for persistent chest pain."

Also at the media briefing, Reynolds agreed that "sometimes these patients with INOCA get a little bit of a brush off, and get told, 'your arteries are open, so there's not much wrong with you.' And we're showing that their stress tests are just as bad as people who have severe and extensive coronary disease. In fact, their symptom burden was very similar, even a little bit worse."

Angina Similar in Severity

At the screening stress test in CIAO, the degree of ischemia in the INOCA patients was similar to that of the comparator patients from ISCHEMIA. Both showed a median of four myocardial segments with wall motion abnormalities, although the segments were less often anterior in the INOCA patients than in the patients with CAD (44% vs 58%; P < .001).

At 1 year, stress-test results were normal in about half of the INOCA group, but they were the same or worse in 45%, Reynolds reported.

Angina had been more frequent among the INOCA group, 16.5% of whom experienced it at least weekly, compared with only 4.2% of the CAD patients from ISCHEMIA.

After 1 year, symptoms had improved in 42% and worsened in 14% of the INOCA patients, although the number of anti-ischemic medications they were on was consistent throughout, at a median of one.

Significant predictors of normal stress echocardiograms at 1 year included use of CCBs at the initial stress test and clinical depression; predictors of improved symptoms at 1 year included CCBs and, separately, short-acting nitrates at initial stress testing.

Angina Severity and Frequency at Baseline and INOCA Change to 1 Year in CIAO

Angina End Points CAD, baseline (n = 865) P Value INOCA, baseline (n = 203) P Value INOCA, 1 year (n = 197)
SAQ-AF score, median* 100 <.001 90 <.001 100
None in previous month (%) 62 <.001 41 <.001 59
At least weekly in previous month (%) 4.2 <.001 16.5 <.001 8.1

*Lower SAQ scores = worse angina

Optimal medical therapy for patients with INOCA isn't well established, Reynolds observed. Patients who show coronary spasm at a provocation test performed during invasive angiography would likely receive nitrates or a CCB, she said, pointing to the latter drug's association with symptom improvement in CIAO.

Treatment is less clear for patients with the microvascular-dysfunction endotype, she said. Renin-angiotensin-system inhibitors, nitrates, and CCBs are used variously without a lot of guidance from trials.

"There's a certain amount of trial and error in the medical therapy of these patients," she said. It usually takes invasive spasm-provocation testing to know which endotype predominates, "and the field may ultimately move toward more invasive testing."

Reynolds said she'd start with CCBs, and "when WARRIOR comes out, it may be that we'll be starting with ACE inhibitors and statins." That study, the Women's Ischemia Trial to Reduce Events in Non-Obstructive CAD (WARRIOR), now in early stages, with an projected enrolment exceeding 4400 women with INOCA, is comparing usual care with "intensive medical treatment" with high-dose statins, an ACE inhibitor or angiotensin-receptor blocker, and aspirin for at least 3 years.

CIAO was funded by the National Heart, Lung and Blood Institute. Reynolds discloses research involving or receiving research grants from Abbott Vascular and BioTelemetry. Merz discloses research involving or receiving research grants from the California Institute for Precision Medicine, DoD Warrior, and Sanofi-Aventis; serving on the speaker's bureau of Abbott Diagnostics; and having unidentified relationship with iRhythm. Handberg discloses receiving consultant fees or honoraria from Amgen, unrestricted educational grants from Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, and Sanofi; and research involving or receiving research grants from Gilead, inVENTIVE Health, Medtronic, and Merck.

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC): Abstract 411-16. Presented March 30, 2020.

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