Ischemia Burden Not Linked to Angina in Nonobstructive CAD: CIAO

For patients with moderate-to-severe ischemia but without obstructive coronary disease, the so-called INOCA patient, there is no correlation between the severity of ischemia on stress echocardiography and chest pain symptoms, according to the results of the CIAO study, an ancillary investigation from the ISCHEMIA trial.

The findings throw cold water on the hypothesis that the extent of myocardial ischemia is responsible for angina in patients without obstructive CAD and suggest that other factors are contributing to patient symptoms.

“There is more to heart symptoms than the degree of artery narrowing or the number of narrow arteries,” said lead investigator Harmony Reynolds, MD (NYU Langone Medical Center, New York, NY), during a press conference at the virtual American College of Cardiology 2020 Scientific Session. “This is true when looking at the INOCA patients in CIAO or our comparator obstructive coronary artery disease population that had a stress echo in the randomized ISCHEMIA trial. CIAO adds to the emerging body of literature showing there are many factors that affect symptom severity. Here we show that the symptoms at 1 year were very significantly related to the symptoms at the start of the study but not related to how much heart muscle had ischemia on the stress test.”

It is estimated that 3 to 4 million people have INOCA—the condition hits women harder than men—and optimal treatment is unknown. INOCA is associated with increased risk of death, MI, heart failure, and stroke compared with healthy individuals, said Reynolds, as well as reduced quality of life and increased healthcare costs owing to ER visits and cardiac testing due to ongoing symptoms. These patients can get a little bit of a brush off, she added, especially when testing reveals no arterial blockages.

“We’ve showed that their stress tests are just as bad as people with severe and extensive coronary disease,” said Reynolds. “That’s very important. In fact, their symptom burden was very similar, and even a little bit worse.”

More Women Affected by INOCA

To TCTMD, Reynolds explained that when stable patients with moderate-to-severe ischemia were screened for randomization in the ISCHEMIA trial, they underwent blinded coronary CT angiography to confirm obstructive CAD. In total, 21% of patients screened for ISCHEMIA had no obstructive CAD on CT angiography and these patients were enrolled in the CIAO study if they had ischemic symptoms. The comparator group included 865 patients with obstructive CAD enrolled in ISCHEMIA with a stress echocardiogram. Angina was assessed with the Seattle Angina Questionnaire (SAQ) at enrollment, 6 months, and 1 year. Stress echocardiography was repeated at 1 year and importantly, the echo readers were blinded to the CT angiography results (ie, whether the patient had obstructive CAD or INOCA).

Of the 208 INOCA patients, 66% were female, compared with the 26% of patients in ISCHEMIA with obstructive CAD (P < 0.001). The INOCA patients were also less likely to have diabetes, to have a prior MI, and to be smokers (or have a history of smoking), and more likely to have depression.   

At enrollment, there was little difference in ischemia severity on stress echocardiography between the INOCA patients and those with obstructive CAD. The median number of segments with moderate or severe wall motion abnormalities on echocardiography was 4, which is considered severe, and that was similar in both groups. With respect to angina symptoms, the median SAQ score was slightly higher in INOCA patients than those with obstructive CAD and they tended to have more frequent angina. There was no correlation between ischemia and angina at enrollment in either the INOCA patients or those with obstructive CAD.

From enrollment to 1 year, half of the INOCA patients had a normalized change in ischemic segments while 45% were unchanged or worse. “Over time, remarkably, even though the stress tests were quite abnormal at baseline—and in an example I put into a slide, you really see the ventricle fall apart, the ejection fraction goes down, and it looks bad—50% of them were normal at 1 year,” said Reynolds. “On the flip side, 45% of them were the same or worse.” With angina, 39% of the INOCA patients had an improvement in the SAQ angina frequency score by 10 points or greater and 52% had an improvement in the overall SAQ score by 5 points or more.

Still, even at 1 year, there was no correlation between the changes in ischemia and changes in angina among patients with INOCA, the study’s primary endpoint.  

“Our hypothesis was that the changes in ischemia would correlate with changes in symptoms, and that was not the case,” said Reynolds. “It wasn’t true at enrollment that the severity of ischemia went along with the severity of anginal symptoms, it wasn’t true at 1 year, and the change wasn’t correlated. So now getting back to the sex differences study, that sort of looks the same and it hangs together as a story: the amount of ischemia is not the only factor in figuring out what the patient will have in the way of anginal symptoms.”

Medication Trial and Error    

Highlighting the substantial changes in symptoms and stress test findings over 1 year, Reynolds said the variability likely reflects changes in the underlying disease processes. “We know there are differences from patient to patient and over time in activity levels, mental and emotional stress, and in the oxygen capacity of blood, and even in the nervous system influences on pain,” she said. “All of these relate to the severity of chest pain.”

C. Noel Bairey Merz, MD (Cedars-Sinai Medical Center, Los Angeles, CA), who discussed the trial following the late-breaking presentation, said CIAO provides new information about INOCA, and potentially about coronary microvascular disease, but the lack of correlation between changes in ischemia and changes in angina symptoms—tested to determine if ischemia was responsible for symptoms in INOCA—might have been predicted. Studies of patients with chest pain have suggested it is “impacted by sensory, emotional, autonomic, motor, and cognitive components,” said Bairey Merz.

The ORBITA trial, she noted, showed that PCI improved wall motion abnormalities in patients with stable, obstructive CAD but did not improve angina symptoms when compared with a sham control. “Chest pain in all of our patients—obstructive or nonobstructive—is probably impacted by a lot of things in addition to ischemia,” said Bairey Merz.  

Eileen Handberg, PhD, ARNP (University of Florida, Gainesville), who spoke to the results following the press conference, said INOCA is a persistent condition with a large degree of bias in terms of how these patients are treated by ER physicians and cardiologists. The CIAO study is helpful in that the stress echocardiography clearly demonstrated the presence of ischemia, something that is frequently questioned when a patient has nonobstructive CAD. CIAO also showed that symptoms can improve, especially when acknowledged and the patient is provided support.

In the absence of randomized data, Reynolds said physicians typically resort to trial and error with medications for INOCA patients. They have some preliminary data suggesting a potential benefit of calcium channel blockers, but those results need further analysis. In her discussion, Bairey Merz noted that as many as half of INOCA patients don’t have symptoms and have decently preserved quality of life. In these patients, symptom management might not be an issue.

“But we know from other work, our and others, that an abnormal stress echo in the face of open arteries does have an adverse prognosis,” said Bairey Merz. Evidence from CIAO, such as the low frequency of angina, the resolution of abnormal wall motion abnormalities, and the preliminary data showing a symptomatic benefit of calcium channel blockers, suggest an underlying problem of functional coronary vasoconstriction, and that physicians can potentially identify this type of microvascular dysfunction for treatment, said Bairey Merz.  

WARRIOR, a study funded by the US Department of Defense, is currently enrolling approximately 4,400 women with symptoms of ischemia and nonobstructive CAD on invasive or coronary CT angiography. The women will be randomized to intensive medical care (high-potency statin and ACE inhibitor plus aspirin) or usual care, with an average follow-up of 3 years. The primary outcome will be first occurrence of death, MI, stroke, or hospitalization for heart failure or angina.