Symptoms, stress test findings of patients with ischemia, nonobstructive CAD can change over time
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In the CIAO ancillary study of patients who were screened for the ISCHEMIA trials but were excluded because they had ischemia but no obstructive CAD, stress echocardiography results and angina frequency changed over time, researchers reported at the virtual American College of Cardiology Scientific Session.
In addition, there was no correlation between change in ischemia and change in angina at 1 year in patients with ischemia but no obstructive CAD (INOCA) on coronary CT angiography, Harmony R. Reynolds, MD, associate professor of medicine and associate director of the Cardiovascular Clinical Research Center at NYU Langone Health, said during a presentation.
The researchers compared 208 patients with INOCA with 865 patients with obstructive CAD who were enrolled in ISCHEMIA. They also conducted longitudinal assessments of the patients with INOCA enrolled in CIAO between baseline and 1 year. The primary outcome was the correlation between change in ischemia and change in angina; 187 patients from the CIAO cohort were available for that analysis.
Changes over 1 year
“Persistent symptoms are a marker of risk among INOCA patients. A positive stress test, such as a stress echocardiogram, is also a marker of risk,” Reynolds said during the presentation. “However, whether myocardial ischemia is solely responsible for angina in INOCA patients is uncertain. Expert recommendations focus on symptom management, and our aim was to investigate changes in symptoms and stress testing in INOCA patients over 1 year, leveraging the enrollment process of the international, NHLBI-funded ISCHEMIA trial.”
The INOCA cohort had a much greater proportion of women than the obstructive CAD cohort (66% vs. 26%; P < .001), Reynolds said. In addition, compared with the obstructive CAD cohort, the INOCA cohort was younger (63 years vs. 66 years; P = .004), less likely to have diabetes (19% vs. 33%; P < .001), less likely to have prior MI (2% vs. 15%; P < .001), less likely to be a current or former smoker (41% vs. 56%; P = .001) and more likely to have depression (19% vs. 9%; P < .001).
Among the INOCA cohort, 71% were indicated for stress testing because of typical angina and/or atypical chess pain, and 49% were indicated because of shortness of breath, she said.
Both groups had a median of four ischemic segments on stress echocardiography, but the difference was significant (P = .03) because more patients from the obstructive CAD cohort had very severe ischemia, Reynolds said. In addition, the INOCA cohort was less likely to have anterior ischemia (44% vs. 58%; P < .001).
At enrollment, the Seattle Angina Questionnaire-7 score was higher in the INOCA cohort than the obstructive CAD cohort (83 vs. 78; P = .036) and the SAQ Angina Frequency score was lower in the INOCA cohort (90 vs. 100; P < .001), according to the researchers.
There was no correlation at enrollment between angina frequency and ischemia severity in the INOCA cohort (P = .462) and the obstructive CAD cohort (P = .353), Reynolds said.
In blinded core laboratory readings of change in ischemia segments in the INOCA cohort, “50% of studies normalized at 1 year and 45% of the studies were unchanged or worse,” she said.
At 1 year, the INOCA cohort improved in SAQ-7 score and SAQ Angina Frequency score (P < .001 for both), with 39% improving at least 10 points in angina frequency score and 52% improving at least 5 points in SAQ-7 score, she said, noting that the median number of anti-anginal medications was 1 at both enrollment and 1 year.
There was no correlation between 1-year change in ischemia severity and 1-year change in either angina score, which held true in all subgroup analyses, Reynolds said.
There was a correlation between symptoms at enrollment and symptoms at 1 year (r based on angina frequency score = 0.49; r based on SAQ-7 score = 0.58; P < .001 for both), she said.
Secondary event prevention
During a discussion of the trial, Cardiology Today Editorial Board Member C. Noel Bairey Merz, MD, FACC, FAHA, FESC, professor of medicine and director of the Barbra Streisand Women's Heart Center, the Preventive and Rehabilitative Cardiac Center, the Cedars-Sinai Clinical Scholars Program and the Linda Joy Pollin Women's Heart Health Program at in the Cedars-Sinai Smidt Heart Institute, said “as many as half of patients did not have frequent angina and had a preserved quality of life, and therefore symptom management would not be an issue for them. We know from other work that an abnormal stress test in the face of open arteries does have an adverse prognosis. We also know from the that CorMicA demonstrated you can improve symptoms in the more symptomatic patients with treatment directed by endotyping, and the SCOT-HEART trial of CT angiography portended an adverse prognosis if there was coronary atherosclerosis and secondary prevention was not deployed.
“So, we can learn from the CIAO study that CT angiography maybe helpful to risk-stratify INOCA patients, and possibly do a better job for prevention of secondary events, not necessarily symptom management,” she said.
If identified correctly, these patients could be treated with traditional anti-anginal therapies such as calcium channel blockers and beta-blockers, but “we are also testing if medications from secondary prevention guidelines such as high-intensity statins, ACE inhibitors or angiotensin receptor blockers and aspirin should be deployed in these patients, in the WARRIOR trial,” she said.
Of note, she added, patients with INOCA whose symptoms did not resolve “probably have coronary microvascular dysfunction, which is a persistent and chronic problem which erodes quality of life and raises risk of adverse cardiac events. Adverse prognosis dictated by coronary flow reserve abnormalities is important and should be attended to. These trials endorse further probe trials of pharmacological therapies for flow reserve, as well as large MACE trials because of this adverse prognosis.” – by Erik Swain
Reference:
Reynolds HR, et al. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 28-30, 2020 (virtual meeting).
Disclosures: Reynolds reports she has received donated products for research from Abbott and BioTel. Bairey Merz reports no relevant financial disclosures.
Perspective
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Viviany R. Taqueti, MD, MPH, FACC
Ischemia with no obstructive CAD is a real clinical phenomenon. It has been underrecognized and understudied for years, but high-quality data from the ISCHEMIA trial suggest that it is common. In ISCHEMIA, more than 20% of patients who were enrolled, and ostensibly required to demonstrate moderate-to-severe ischemia on objective, core-lab-verified diagnostic testing, actually did not demonstrate obstructive CAD on very sensitive evaluation using coronary CTA. This is a remarkable finding, and a surprise to many in the field, though perhaps less so to those of us who have been seeing these patients and studying this phenomenon.
ISCHEMIA-CIAO smartly leveraged a subset of these patients identified as having INOCA — who were all essentially “screen failures” from the main ISCHEMIA trial — into a clinical registry to follow natural history of these patients longitudinally. But there were notable limitations. Only a small subset of patients with INOCA, approximately 17%, were included — that is, those who underwent stress echocardiography as their initial diagnostic test for ischemia prior to entry into the main trial. This is likely a highly selected group. These patients underwent a repeat stress echocardiogram in 1 year and repeat symptom questionnaires at 6 months and 1 year, to compare with baseline results. There was no noninvasive or invasive testing for coronary microvascular dysfunction, which is thought to drive adverse CV outcomes in patients with INOCA. Medical management strategies were not specified by the study protocol.
Investigators found no significant correlation between reported angina and ischemic findings on stress echocardiography. This was true in the ISCHEMIA-CIAO and ISCHEMIA main cohorts. On longitudinal assessment, change in reported angina was also not correlated with change in ischemia in CIAO, despite overall improvements in both endpoints.
Of note, CIAO participants were much more likely than those in ISCHEMIA main trial to be women despite similar ischemia severity between groups; both groups had a median of four ischemic segments. This finding is consistent with prior data, but nonetheless important, and emphasizes that both women and men may present with INOCA, although it is more prevalent in women.
Most patients with INOCA were symptomatic of angina and/or dyspnea despite high prevalence of medical therapies, and had high prevalence of CV risk factors/comorbidities.
This study, which was tied to the rigorously-designed ISCHEMIA trial and conducted by expert investigators, raises awareness of the importance of the INOCA phenotype and highlights the need for more precise diagnosis of coronary microvascular dysfunction, which can now be done noninvasively through clinically available and reimbursed positron emission tomography or other noninvasive and invasive imaging approaches. It also leaves many important questions unanswered. Only by better defining who has coronary microvascular dysfunction can we begin to target effective treatment strategies in a personalized and evidence-based way for our patients.
Also notable, the vast majority of patients with INOCA still demonstrated some CAD even if atherosclerotic plaques were nonobstructive. Beyond regional wall motion abnormalities on stress echo, it will be of great interest for future studies to investigate the role of more sensitive biomarkers of disease, including atherosclerotic plaque burden characteristics, coronary flow reserve, myocardial strain, and serum biomarkers of injury and inflammation on adverse CV outcomes in patients with INOCA.
The bottom line is that INOCA is quite prevalent, in as many as 20% of patients with documented moderate-severe ischemia, and occurs in both women and men, but with a clear predominance in women, despite high use of existing medical therapies. More research and investment need to be done to improve outcomes in this emerging patient population.
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