Nonstandard Abbreviations and Acronyms

• ANOCA
• angina and nonobstructive coronary arteries
• CA
• coronary angiography
• CFT
• coronary function testing
• CMD
• coronary microvascular dysfunction
• SIHD
• stable ischemic heart disease

Clinical Perspective

What Is New?

• In women with suspected ischemic heart disease, coronary function testing adds diagnostic utility to invasive coronary angiography by revealing the underlying vasomotor phenotype in >80% of patients.
• After coronary function testing, there was more frequent intensification of antianginal therapy, which could lead to improvement in symptom burden and quality of life in women with angina and nonobstructive coronary arteries.

What Are the Clinical Implications?

• Coronary function testing should be considered routinely in the evaluation of women with suspected stable ischemic heart disease and angina and nonobstructive coronary arteries.

Stable ischemic heart disease (SIHD) is a leading cause of morbidity and mortality in women. As many as 50% to 70% of women who undergo clinically indicated angiography are found to have nonobstructive coronary arteries compared with 30% to 50% seen in their male counterparts. Because of sex differences in vascular biology, the prevalence of obstructive coronary artery disease (CAD) is lower for women in all age groups compared with men, but women are more likely to present with chest pain and anginal equivalents. Angina and nonobstructive coronary arteries (ANOCA) is an umbrella term used to describe a mismatch in the demand‐supply of coronary artery blood flow in the absence of flow‐limiting stenosis. The 2 primary subtypes of ANOCA include vasospastic angina and coronary microvascular dysfunction (CMD), but other syndromes, such as symptomatic myocardial bridging and elevated resting flow, have been increasingly recognized. Vasospastic angina is defined as symptomatic angina with an associated vasomotor disorder, including endothelial dysfunction, coronary vasospasm, and/or microvascular vasospasm (Data S1). Although noninvasive and invasive testing for diagnosing ANOCA are recommended by the 2021 American College of Cardiology/American Heart Association chest pain guidelines and the 2023 American College of Cardiology/American Heart Association guidelines for management of chronic coronary disease, many patients do not undergo further diagnostic evaluation.

In a patient self‐reported assessment, over a third of women with ANOCA were found to live with symptoms without a diagnosis for >3 years. Underdiagnosis of ANOCA may lead to increased morbidity, adverse cardiovascular events, and higher health care costs. Recently, the British Heart Foundation Coronary Microvascular Angina (CorMicA) trial demonstrated a significant benefit in patient‐reported outcomes (including angina and quality of life) with medical therapy stratified by the underlying endotype for patients with ANOCA. However, in clinical practice, ANOCA is often not diagnosed, which precludes the implementation of targeted medical therapy. To describe the real‐world management of women with ANOCA, we evaluated the diagnostic yield of invasive coronary function testing (CFT) in comparison with coronary angiography (CA) alone, and changes in medical therapy following the procedure in both groups.

Methods

Deidentified data that support the findings of this study are available from the corresponding author on reasonable request pending approval from Yale University Institutional Review Board.

Study Population

Participants were consecutively selected from a local registry of women with known or suspected ischemic heart disease who underwent clinically indicated invasive coronary angiography with coronary function testing at Yale New Haven Hospital between February 2018 and March 2023. We used a purposeful sampling approach to select a comparison group who underwent coronary angiography alone without CFT, referred to as the CA alone cohort. Inclusion criteria were composed of women with cardiac symptoms who presented for clinically indicated cardiac catheterization to evaluate for SIHD. SIHD was defined as patients with suspected cardiac ischemia without unstable symptoms or evidence of an acute coronary syndrome. This included patients with cardiac‐related symptoms, including stable angina, new‐onset angina, dyspnea on exertion, with or without abnormal stress test results, and patients with persistent symptoms after percutaneous coronary intervention despite relief of obstructive coronary artery disease. Exclusion criteria were obstructive coronary artery disease on coronary angiography based on the presence of >50% stenosis or <50% with a fractional flow reserve ≤0.80, or referral for coronary angiography for preoperative testing or evaluation of cardiomyopathy. A waiver of informed consent was obtained from the Yale University Institutional Review Board.

End Point Definition

The primary outcome of interest was the postprocedure diagnosis, as described in the procedure report. For patients undergoing CFT, all invasive physiology findings were recorded and grouped for analysis to compare baseline medications against a final angina‐associated diagnosis (Figure 1; Figure S1). Secondary outcomes included changes of cardiac medications at 24 hours after the procedure and at 30 days. Change to the cardiac medication regimen was defined by either the addition or the subtraction of a medication used to manage cardiac disease. Medications were then stratified by class (preventative, antiplatelet, and antianginal) to compare frequency of use before and after angiography. Preventative therapies included angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, and statin therapy. Antiplatelet agents included aspirin and P2Y12 inhibitors. Antianginal therapy was composed of ranolazine, ivabradine, nitrates, calcium channel blockers, and β‐blockers.

Figure 1. Demonstration of study population and outcomes.
CAD indicates coronary artery disease; and CMD, coronary microvascular dysfunction.

Coronary Function Testing

Invasive CFT was performed using a standardized protocol (Data S1). Invasive coronary angiography was followed by acetylcholine testing to assess for endothelial dysfunction/coronary vasospasm, and guidewire‐based coronary thermodilution testing to assess for CMD by deriving the index of microcirculatory resistance and coronary flow reserve. Results were reported in the cardiac catheterization report in the medical record and made available to the patient’s primary cardiologist immediately after the procedure. CMD was defined as index of microcirculatory resistance ≥25 and/or coronary flow reserve ≤2.5; epicardial vasospasm was defined as ≥90% visual diameter stenosis after intracoronary administration of acetylcholine with either ischemic electrocardiographic changes or reproduction of the presenting chest pain; microvascular spasm was defined as ≤90% epicardial narrowing after acetylcholine administration but with ischemic electrocardiographic changes and chest pain; endothelial dysfunction was classified as epicardial narrowing >0% and <90% after acetylcholine administration; symptomatic myocardial bridging was defined on the basis of pressure wire assessment of the myocardial bridge during dobutamine administration; and elevated resting flow was defined as coronary flow reserve <2.5 with index of microcirculatory resistance <25 and baseline thermodilution mean transit time <0.50.

Clinical Characteristics

We retrospectively collected patient demographics, comorbidities, preprocedure diagnostic testing, procedure details, including postprocedure diagnosis, and postprocedure changes to medications. Data were extracted from the medical record by 2 independent reviewers, (N.C. and N.L.), and discrepancies were resolved by a third adjudicator.

Statistical Analysis

Patient characteristics were summarized using mean and SD for continuous variables and count and percentage for categorical variables. Analysis of differences in characteristics between cohorts was performed using t‐test for continuous variables, and χ test or Fisher exact test, as appropriate, for categorical variables. Rate ratios were used for the difference in incidence of baseline medication use between groups. Logistic models were used to find association of diagnosis with change in medications at 24 hours, association of baseline medications with diagnosis of CMD, association of baseline medications with diagnosis of vasospastic angina, among the coronary function testing cohort only. Medication classification at baseline, 24 hours, and 30 days was compared between cohorts. The risk ratio was calculated by unconditional maximum likelihood estimation (Wald), and χ P values are presented. P < 0.05 is considered statistically significant.

Analysis was preformed using R statistical software (© 2022 The R Foundation for Statistical Computing). Packages used included MASS, Hmisc, rms, gtsummary, and epitools.