Clinical Relevance of Ischemia with Nonobstructive Coronary Arteries According to Coronary Microvascular Dysfunction

Nonstandard Abbreviations and Acronyms

CFR: coronary flow reserve
CMD: coronary microvascular disease
FFR: fractional flow reserve
INOCA: ischemia with nonobstructive coronary arteries
MACE: major adverse cardiovascular event

Clinical Perspective

What Is New?

• In the absence of obstructive coronary stenoses, abnormality of noninvasive stress tests in patients with chronic coronary syndromes may indicate myocardial ischemia of nonobstructive coronary arteries (INOCA).
• Coronary microvascular disease (CMD) with or without vasospastic angina is one of the major endotypes of INOCA.
• Only limited data have been available on the prognostic implications of CMD defined by the universal definition among patients with INOCA.

What Are the Clinical Implications?

• Among the patients with anginal symptoms and functionally nonobstructive coronary artery disease, 28.2% showed positive noninvasive stress test results and 45.3% had CMD; the presence of CMD was significantly associated with an increased risk of major adverse cardiovascular events, and the prognostic impact of CMD was higher than that of the presence of INOCA.
• Among the 4 groups classified by INOCA and CMD, only patients with CMD showed a significantly increased risk of major adverse cardiovascular events at 5 years, regardless of the presence of INOCA.
• Intracoronary physiologic assessment is necessary and incorporating it into noninvasive stress test information enables the identification of high‐risk subgroups with CMD for cardiovascular events.

Patients with symptoms and signs of ischemic heart disease (IHD) but found to have nonobstructive coronary arteries (INOCA) are increasingly recognized. Previous studies indicated that the prevalence of INOCA among patients referred to invasive coronary angiography was 20% to 65%. Even among patients with positive noninvasive stress test (NIT) results, only 41.0% had obstructive coronary artery disease (CAD) defined by coronary stenoses ≥50%. These findings indicate that a substantial proportion of stable IHD cases can be diagnosed as INOCA which is caused by functional abnormalities such as vasospastic angina or coronary microvascular disease (CMD) rather than obstructive CAD. Although previous studies have shown that INOCA is associated with a higher risk of adverse clinical outcome than the general population, it has been under‐recognized because of limited understanding of disease entity and diagnostic challenges with heterogeneous criteria.

CMD is a consequence of reduced blood flow through the coronary microcirculation, and CMD with or without vasospastic angina is one of the major endotypes of INOCA. Recent Expert Consensus Documents on INOCA and the European Society of Cardiology guideline of Chronic Coronary Syndrome underlined an importance of evaluating CMD in patients with suspected INOCA and proposed a universal definition of CMD based on (1) functionally nonobstructive CAD defined by a fractional flow reserve (FFR)>0.80 and (2) impaired coronary microvascular function determined by abnormal coronary flow reserve (CFR) and/or microvascular resistance.

Nevertheless, only limited data have been available on the prognostic implications of CMD defined by the universal definition among patients with INOCA. Therefore, we sought to evaluate the long‐term prognostic impact of CMD and INOCA among the patients with typical angina but no obstructive coronary stenosis, using the international multicenter vessel‐level pooled registry of intracoronary pressure and flow assessment.

Methods

Study Design of ILIAS Registry

The ILIAS (Inclusive Invasive Physiological Assessment in Angina Syndromes) registry is an international multicenter vessel‐level pooled registry of intracoronary pressure and flow assessment. The registry is composed of 20 institutes from Korea, The Netherlands, Japan, Spain, Denmark, Italy, and the United States. All data were prospectively recorded according to each center’s protocols. Patients who underwent clinically indicated coronary angiography and comprehensive intracoronary physiologic assessment of at least 1 native coronary artery were enrolled. Patients’ symptoms and signs suggesting angina were collected by attending physicians based on the patients’ description. Typical angina was defined as constricting discomfort in the front of the chest or in the neck, jaw, shoulder, or arm, which was precipitated by physical exertion and relieved by rest or nitrates. Patients with hemodynamic instability, significant valvular heart disease, prior coronary artery bypass graft surgery, or culprit vessels of acute coronary syndromes were excluded. Individual patient data were collected using standardized and anonymized spreadsheets by a fully compliant cloud‐based clinical data platform (Castor EDC, Amsterdam, The Netherlands). Standardized definitions were used for all variables including patient‐ and vessel‐level clinical outcomes. The study protocol was approved by the Institutional Review Board or Ethics Committee at each participating center and written informed consent was obtained from all participants. The study protocol was in accordance with the Declaration of Helsinki. The ILIAS Registry is registered at Clinicaltrials.gov (NCT04485234).

Study Population

A total of 2322 patients (3046 vessels) were enrolled in the ILIAS registry. Among them, 570 patients with anginal symptoms who were evaluated by NITs were selected in the current analysis (Figure 1). We excluded patients who underwent revascularization (n=207) or had functionally obstructive CAD with FFR≤0.80 (n=76). Finally, the current study included a total of 287 symptomatic patients with available NIT results in whom revascularization was deferred for functionally nonobstructive CAD (FFR>0.80).

Figure 1. Study flow.
CAD indicates coronary artery disease; CFR, coronary flow reserve; CMD, coronary microvascular disease; FFR, fractional flow reserve; ILIAS, Inclusive Invasive Physiological Assessment in Angina Syndromes; INOCA, ischemia with nonobstructive coronary arteries; and PCI, percutaneous coronary intervention.

Noninvasive Stress Tests

All NITs were performed according to each participating center’s protocol and included exercise treadmill test, exercise or dobutamine stress echocardiography, single‐photon emission computed tomography, positron emission tomography, or cardiac magnetic resonance imaging. The selection of NITs was left to the discretion of the attending physicians based on patient characteristics, local expertise, and availability. The NITs were interpreted according to multicenter study protocols and in line with current guidelines. The final results of NITs were interpreted locally and reported as a binary variable (positive or negative). The positive result was defined as moderate to severe reversible defect on nuclear perfusion imaging (≥10% ischemic myocardium) or high‐risk findings on exercise treadmill test without imaging (≤−11 Duke Treadmill Score). Patients with anginal symptoms who had positive NITs but functionally nonobstructive CAD were diagnosed with INOCA. Patients with anginal symptoms who had negative NITs and functionally nonobstructive CAD were classified into ‘no INOCA’ group (Figure 1).

Coronary Angiography and Intracoronary Physiologic Assessment

Coronary angiography was performed using standard techniques. Angiographic views were obtained following the administration of intracoronary nitrates (100 or 200 µg). After diagnostic coronary angiography, intracoronary physiologic assessment was performed by standard techniques using Doppler velocity‐equipped coronary guidewires (FloWire, Philips‐Volcano, San Diego, CA, USA) or dual pressure and Doppler velocity equipped guidewire (ComboWire, Philips‐Volcano, San Diego, CA, USA). For the patient using FloWire, another pressure wire (PressureWire, AbbottVascular, St. Paul, MN, USA) was used to measure FFR. Intracoronary nitrates (100 or 200 µg) was administered before physiologic measurements. Hyperemia was induced by intravenous infusion of adenosine (140 µg/kg per min) or adenosine triphosphate (150 µg/kg per min) through a peripheral or central vein, intracoronary bolus injection of adenosine (40–200 mcg), or intracoronary bolus injection of nicorandil (2 mg), according to local standards. Doppler or pressure sensor was recommended to be positioned at the very distal part of the coronary artery. Interrogated vessels were primarily the vessels with “nonsignificant” stenotic lesions defined by FFR>0.80. However, when there were no stenotic lesions (near‐normal), the left anterior descending artery was recommended to be used for FFR and CFR measurement. FFR was calculated as the ratio between the mean proximal aortic and mean distal coronary pressures during maximal hyperemia. After measurements were completed, the guidewire was pulled back to the guiding catheter, and the pressure drift was checked. In cases with a drift larger than >0.03 FFR unit, re‐equalizations and repeated measurements were recommended. Using the Doppler velocity technique, resting and hyperemic average peak flow velocities were measured, and CFR was calculated as the ratio of hyperemic to resting average peak flow velocities. Baseline microvascular resistance (BMR) was calculated by dividing the mean distal coronary pressure by average peak flow velocities during resting condition. Hyperemic microvascular resistance was calculated by dividing the mean distal coronary pressure by average peak flow velocities during hyperemia. In the current study, CMD was defined as CFR≤2.5 based on prior studies.

Treatment, Patient Follow‐up, and Clinical Outcomes

For vessels with functionally obstructive CAD with FFR≤0.80, percutaneous coronary intervention was recommended according to clinical practice guidelines at the time of the procedure. However, final decisions about revascularization were left at the discretion of the operator. Optimal medical treatments, including antiplatelet agents, statins, and antianginal medications, were provided based on guidelines.

Follow‐up was performed by outpatient visits or telephone contacts. The median follow‐up duration of the study population was 1194.0 days (interquartile range, 730.0–1826.0 days). Major adverse cardiac event (MACE) was defined as a composite of all‐cause death, target vessel‐related myocardial infarction, and clinically driven revascularization by means of coronary artery bypass graft surgery or percutaneous coronary intervention. Cardiac death was defined as death from any cardiac cause including sudden cardiac death, acute myocardial infarction, heart failure, stroke, arrhythmias, or other cardiovascular cause. Revascularization events were separately assessed as target vessel revascularization (TVR) and non‐TVR. All adverse clinical events were verified by evaluating hospital records or contacting the treating cardiologist or general practitioner.

Classification of Patients According to Presence of INOCA and CMD

Based on the presence of INOCA and CMD, patients were classified into 4 groups: group 1 (no INOCA without CMD, n=116); group 2 (no INOCA with CMD, n=90); group 3 (INOCA without CMD, n=41); and group 4 (INOCA with CMD, n=40) (Figure 1).

Statistical Analysis

Data including clinical outcomes were analyzed on a per‐patient basis. Continuous variables were presented as means and standard deviations according to their distributions, which were checked by the Kolmogorov‐Smirnov test and visual inspection of Q‐Q plots. All categorical variables were presented as numbers and relative frequencies (percentages). Continuous variables were compared based on a one‐way analysis of variance, and dichotomous variables were compared using Chi‐square tests or Fisher exact tests. No post‐hoc adjustments were performed. Correlation coefficients between anatomical and physiologic indexes were analyzed by Pearson or Spearman methods according to the normality.

Restricted cubic spline curves with 3 knots were used to evaluate the continuous effects of CFR on the outcomes at 5 years. Event rates were calculated based on Kaplan–Meier censoring estimates and presented with cumulative incidences at the 5‐year follow‐up; the log‐rank test was used to compare survival curves between the groups. A Cox proportional hazard regression was used to calculate hazard ratio (HR) and 95% CIs. The assumption of proportionality was assessed graphically by the log‐minus‐log plot, and the Cox proportional hazard models for all clinical outcomes satisfied the proportional hazards assumption. Multivariable Cox proportional hazard models were constructed using all variables with a P value <0.1 from the univariable analyses and variables considered clinically relevant. The final model included age, sex, diabetes, hyperlipidemia, and previous percutaneous coronary intervention. All analyses were 2‐tailed, and clinical significance was defined as P<0.05. Statistical analyses were performed using SPSS 25.0 for Windows (SPSS‐PC, Chicago, IL, USA) and R version 3.6.0 (R Foundation for Statistical Computing, Vienna, Austria).