Abstract
Ischemia and no obstructive coronary arteries (INOCA) is a common clinical presentation, with a variety of causes that are often not fully investigated in routine clinical practice. The goal of our study was to characterize a real-world population of patients with INOCA, with a deeper focus on symptoms and stress test findings. The study population consisted of 435 patients who underwent diagnostic coronary angiography for anginal symptoms and/or evidence of myocardial ischemia at non-invasive imaging. In all patients angiography demonstrated nonobstructive coronary artery disease (CAD, less than 30% luminal diameter stenosis or fractional flow reserve > 0.8 and/or instantaneous wave-free ratio > 0.89). Fifty-four percent of the patients were women. Atypical clinical presentation was more common in women (59.5 vs. 49.5%, p = 0.037). Women were more likely to have normal coronary arteries than men (41.8 vs. 16.2%, p < 0.001), and less likely than men to have hemodynamically non-significant CAD (32.1 vs. 55.1%, p < 0.001). No significant correlation between typicality of symptoms and evidence of ischemia was found in those patients (244/435, 56.1%) who had either dobutamine stress echocardiography or electrocardiogram stress test. INOCA is a common clinical condition, prevalent in women often presenting with atypical symptoms.
Keywords: Ischemic heart disease, chronic coronary syndrome, INOCA, nonobstructive coronary artery disease, stress tests, atypical symptoms, heart disease in women
Invasive coronary angiography is the gold standard diagnostic test for the identification of obstructive coronary artery disease (CAD) in patients with chronic stable angina. In Europe, almost 250 thousand coronary angiograms are performed annually. 1
A large US multicenter study recently showed that only 30% of patients undergoing elective angiography have evidence of obstructive CAD. 2 Ischemia and no obstructive CAD (INOCA) was observed to have a worse long-term prognosis than the absence of heart disease. INOCA was more common in women and was associated with higher risk of major cardiovascular adverse events in this group. 3 However, in clinical practice, patients with nonobstructive CAD are often inadequately treated or falsely reassured and told their heart is normal.
In this study, we report observational data from a cohort of consecutive patients with INOCA. We explore the gender-related differences in presenting symptoms, ischemic tests, and angiographic findings.
Materials and Methods
Inclusion and Exclusion Criteria
Consecutive patients undergoing diagnostic coronary angiography at Imperial College Healthcare NHS Trust, UK, from 01/01/2016 to 31/07/2017 were retrospectively studied.
Inclusion criteria were:
a) Clinical presentation of chronic stable angina or anginal equivalent symptoms and/or evidence of ischemia on noninvasive preprocedural tests (dobutamine stress echocardiogram (DSE); exercise treadmill test (ETT); single-photon emission computed tomography; stress cardiac magnetic resonance);
b) Absence of anatomically severe CAD (defined as stenosis ≥70%) and hemodynamically significant (fractional flow reserve (FFR) ≤0.8 and/or instantaneous wave-free ratio (iFR) ≤0.89) lesions.
Exclusion criteria were acute coronary syndrome, severe left ventricular systolic dysfunction (defined as ejection fraction < 40%), valvular disease or other structural abnormalities of the heart, atrial fibrillation or other arrhythmia, inflammatory diseases of pericardium, myocardium and/or endocardium, angiograms performed as pre-operative assessment for other surgical intervention.
Clinical and Angiographic Characteristics
Noninvasive tests performed prior to the index angiogram were categorized into positive for ischemia, negative for ischemia or equivocal. In our symptom-based analysis, patients were stratified into typical and atypical symptoms. Typical symptoms included typical cardiac-sounding chest pain only. Atypical symptoms were a composite of shortness of breath on exertion not associated with chest pain (SOBOE), atypical chest pain, and absence of symptoms.
Patients were classified into three groups based on angiographic findings: no lesions, minor atheroma only (stenosis <30%), and mild-to-moderate disease (stenosis 30–70%).
Adjunctive tests for evaluation of coronary microvascular dysfunction (CMD) and epicardial or microvascular vasospastic angina (VSA) were not performed in these patients.
Statistical Analysis
The distribution of continuous variables was verified using the Kolmogorov–Smirnov test. Normally distributed variables were reported using mean and standard deviation. Frequencies of categorical variables were calculated.
For gender-based and symptom-based comparisons, the independent sample t -test was used for normally distributed metric variables and the chi-squared test was used for categorical variables. A p -value <0.05 was considered to be statistically significant. Statistical analyses were conducted using SPSS version 24.0 (SPSS Inc., Chicago, IL).
Results
A total of 1,675 angiograms were reviewed. One-thousand fifty-six patients were found to have either obstructive or nonobstructive CAD. Four-hundred thirty-five patients (41.1%) met the inclusion criteria and were subsequently included in the registry.
Gender Associations
Table 1 shows the comparison between male ( n = 198) and female patients ( n = 237). Mean age at index procedure was higher in females (64.1 vs. 61.5, p < 0.001).
Table 1. Baseline characteristics in males and females.
| Males ( n = 198) | Females ( n = 237) | All patients ( n = 435) | p -Value | |
|---|---|---|---|---|
| Baseline characteristics | ||||
| Age (years, mean [SD]) | 61.5 (10.3) | 64.1 (9.9) | 63.6 (10.2) | <0.001 a |
| BMI (kg/m 2 , mean [SD]) | 28.6 (4.9) | 28.2 (5.7) | 28.4 (5.4) | 0.418 |
| Family history of CAD (%) | 60 (30.3) | 54 (22.8) | 114 (26.2) | 0.076 |
| Hypertension (%) | 125 (63.1) | 154 (65) | 279 (64.1) | 0.689 |
| Smoking (%) | 81 (40.9) | 57 (24.1) | 138 (31.7) | <0.001 a |
| Dyslipidemia (%) | 136 (68.7) | 146 (61.6) | 282 (64.8) | 0.123 |
| Diabetes (%) | 59 (29.8) | 77 (32.5) | 136 (31.2) | 0.569 |
| Autoimmune disease (%) | 17 (8.6) | 30 (12.7) | 47 (10.8) | 0.173 |
| PVD or CVD (%) | 8 (4.1) | 9 (3.8) | 17 (3.9) | 0.902 |
| COPD (%) | 20 (10.2) | 20 (8.5) | 40 (9.3) | 0.558 |
| CKD (%) | 4 (2) | 10 (4.3) | 14 (3) | 0.360 |
| Prior coronary angiogram (%) | 72 (36.5) | 38 (16.2) | 110 (25.3) | <0.001 a |
| Prior PCI (%) | 55 (27.9) | 21 (9) | 76 (17.4) | <0.001 a |
| Prior no CAD (%) | 30 (15.2) | 19 (8.2) | 49 (11.4) | 0.021 a |
| Clinical presentation | ||||
| Typical angina (%) | 100 (50.5) | 96 (40.5) | 196 (45.1) | 0.037 a |
| Atypical angina (%) | 72 (36.4) | 105 (44.3) | 177 (40.1) | 0.093 |
| Dyspnea only (%) | 13 (6.6) | 29 (12.2) | 42 (9.7) | 0.046 a |
| Asymptomatic (%) | 13 (6.5) | 7 (3) | 20 (4.6) | 0.152 |
| Discharge therapy | n = 153 | n = 189 | n = 342 | |
| Beta-blockers (%) | 72 (47.1) | 67 (35.4) | 139 (40.6) | 0.030 a |
| ACEi and ARBs (%) | 89 (58.6) | 87 (46) | 176 (51.6) | 0.021 a |
| CCBs (%) | 45 (29.6) | 51 (27) | 96 (28.2) | 0.593 |
| Antiplatelet agents (%) | 115 (75.1) | 98 (51.6) | 181 (50.7) | < 0.001 a |
| Statin (%) | 138 (90.2) | 141 (74.6) | 279 (81.6) | <0.001 a |
| Nitrates (%) | 31 (20.5) | 29 (15.3) | 60 (17.6) | 0.213 |
| Other antianginals (%) | 9 (5.9) | 6 (3.2) | 15 (4.4) | 0.219 |
| OACs (%) | 0 | 2 (1.1) | 2 (0.6) | 0.203 |
p -value < 0.05.
Abbreviations: ACEi, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; BMI, body mass index; CAD, coronary artery disease; CCBs, calcium-channel blockers; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; OACs, oral anticoagulants; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease; SD, standard deviation.
Smoking prevalence was higher in males (40.9 vs. 24.1%, p < 0.001). Males were also more likely to have had a previous coronary angiogram (36.5 vs. 16.2%, p < 0.001).
About 47.1% of males and 35.4% of females were discharged with beta-blockers ( p = 0.03). In 58.6% of males and 46% of females, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were prescribed ( p = 0.021).
Fig. 1A shows that atypical symptoms were more common in females (59.5 vs. 49.5%, p = 0.037).
Fig. 1.
Presenting symptoms and angiographic findings in males and females. SOBOE, shortness of breath on exertion.
Fig. 1B shows the percentage of males and females in each angiographic group. About 16.2% of males and 41.8% of females had normal coronary arteries ( p < 0.001), while 55% of males and 32% of females had mild-to-moderate lesions ( p < 0.001).
Previous Diagnostic Tests
Of the complete group ( n = 435), 110 had had at least one previous coronary angiogram (25.3%), 76 had had previous percutaneous coronary intervention (PCI) (17.4%), and 49 had previously reported nonobstructive CAD (11.4%).
Two-hundred and sixty-three of the 435 patients (60.5%) had had a noninvasive preprocedural test and, among these, 171 (39.3%) had evidence of ischemia. There was no statistically significant difference in DSE and ETT findings based on presenting symptoms ( Fig. 2 ). One hundred and fifteen patients had performed a DSE, of whom 45 with typical symptoms and 70 with atypical symptoms; rates of positive DSE were 57.8% ( n = 26/45) and 67.1% ( n = 47/70) in the two groups, respectively. Among those who had an ETT prior to coronary angiogram ( n = 129), 68.3% of patients with typical symptoms ( n = 41/60) and 68.1% of patients with atypical symptoms ( n = 47/69) had a clear evidence of ischemia according to the clinicians. All rates did not differ between patients with typical and atypical symptoms (all p > 0.05).
Fig. 2.
Positive (i) dobutamine stress echocardiograms (DSE) and (ii) exercise treadmill tests (ETT) in patients with (A) typical and (B) atypical symptoms.
Discussion
This is an observational study of patients undergoing coronary angiography and diagnosed with nonobstructive CAD. The major findings are discussed as follows.
Gender Distribution
Women were more likely to be affected by CAD without coronary artery obstruction than men, as previously described. 4 If compared with previous studies, 5 our registry displayed a mild discrepancy in the proportion of women (54%) versus men (46%) with INOCA and this could be due to the broader inclusion criteria adopted. We defined the absence of obstructive CAD both by anatomical (stenosis <30%) and physiological criteria (negative FFR and/or iFR), according to recent expert recommendations. 6 While patients with normal coronary arteries were significantly more likely to be women, nonflow-limiting mild-to-moderate atherosclerotic lesions were more common in men. The integration of coronary physiology to classify INOCA patients could therefore attenuate gender differences related to this condition.
Women were also older at the time of their index procedure. However, this may be due to referral bias as the diagnosis of ischemic heart disease is often more likely to be considered in postmenopausal women rather than in younger women. 7
Normal Coronary Arteries and Atypical Symptoms in Women
Two possible causes of INOCA described in previous studies could explain the gender-related differences in clinical presentation and angiographic findings.
First, eccentric atherosclerotic plaque progression seems to be frequent in women and may cause an underestimation of angiographically detected atheromas due to lumen preservation. 8 9 This is responsible for frequent reporting of normal coronary arteries at coronary angiogram in women, 10 as observed in our study.
Second, CMD and VSA are known to be more common in women and often not associated with classical presentation of exertional chest pain. 11 12 In our cohort, 40% of all patients and 45% of female patients had atypical angina at clinical presentation. CMD and VSA may contribute to myocardial ischemia in patients with minimal or mild-to-moderate atherosclerotic lesions or represent the cause in patients with normal coronary arteries.
Previous Coronary Angiograms and Angina Recurrence after PCI
All the patients we studied had an invasive diagnostic coronary angiography procedure that did not lead to a targeted therapeutic intervention. Importantly, over one-tenth of patients in this study had already had a previous normal coronary angiogram and had now returned for further study. Performing unnecessary invasive procedures is not optimum for patient care for several reasons. First, these procedures are associated with a risk, albeit low, of major complications. 13 Second, diagnostic uncertainty may affect patients' quality of life and trust in clinicians. Lastly, there is the cost implication for healthcare providers with cost-effectiveness being inversely related to the likelihood of identifying obstructive CAD. 14
About 17.5% of patients were known to have had previous significant CAD with previous PCI, confirming findings of other studies on high rates of symptom recurrence after PCI. 15 The fact they had repeat angiography demonstrating nonobstructive CAD suggests that other causes of symptoms such as VSA, CMD, or noncardiac causes should be considered. 16
The Accuracy of Noninvasive Tests and Symptoms
No relationship between angiographic findings, stress test results, and clinical presentation was found in this population. More than one-third of the patients (39.3%) had evidence of ischemia at noninvasive imaging, but they were found not to have a significant CAD at the invasive angiographic study. The previous findings could suggest we should rely on the presence of ischemia rather than on typicality of symptoms while evaluating a patient with CAD. In fact, functional causes of ischemia such as CMD or VSA could often be associated with atypical angina. 17 18 19
The recent results of the Percutaneous Coronary Intervention in Stable Angina (ORBITA) trial suggested that there may be a discordance between cardiac symptoms and ischemia assessed by DSE and invasive physiology, suggesting that symptomatology is complex, multifactorial, and likely to be influenced by more than just significant epicardial coronary disease and myocardial ischemia. 20 21 This may play an important role in patients with INOCA.
Conclusions
Angina associated with INOCA contributes to significant symptom burden and healthcare resource utilization in clinical practice. It also poses a potential risk from invasive diagnostic coronary angiographies that may not have added clinical value. From this observational registry, INOCA was frequently associated with atypical symptoms and normal coronary arteries in women, and with mild-to-moderate CAD in men. Also, a considerable proportion of patients with INOCA had evidence of ischemia at noninvasive tests. This common clinical condition remains poorly understood and requires further study.
Limitations
This is a large observational registry and therefore is subject to the inherent bias and confounding factors of real-world clinical practice. The main limitation is the lack of long-term follow-up in this descriptive observational registry. We did not study patient outcomes after the index coronary angiogram.
This was a clinical registry in which patient symptoms and angiographic findings were reported by a range of clinicians, whose interpretations may vary. However, this is representative of normal clinical practice.
The analysis of ETT made no distinction between ischemic symptoms and electrocardiogram changes. A positive ETT was one that a clinician had reviewed and deemed worthy of follow-up angiography.
Acknowledgments
The authors thank Matthew Shun-Shin, Henry Seligman, Christopher Rajkumar, James Howard, Prof. Paolo Guido Camici, and Prof. Darrel Francis for their precious contribution to the development of this project.
Footnotes
Conflict of Interest Rasha Al-Lamee receives speaker's honoraria from Phillips Volcano. Alaide Chieffo received a consultant fee from Abbot Vascular. The other authors report no conflicts of interest.
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