Angina or ischemia with no obstructed coronary arteries: a specific diagnostic and therapeutic protocol

INTRODUCTION

Ischemic heart disease is the leading cause of disability and mortality worldwide and is commonly characterized by the presence of obstructive coronary artery disease (CAD) (defined as any coronary artery stenosis ≥ 50% in diameter).1 However, up to 60% to 70% of patients with angina and/or documented myocardial ischemia do not have angiographic evidence of CAD.2 This condition is defined as angina with no obstructed coronary arteries (ANOCA) or ischemia with no obstructed coronary arteries (INOCA) when associated with evidence of myocardial ischemia.3 Of note, despite the absence of CAD, these patients are at an increased risk of future cardiovascular events such as acute coronary syndrome, heart failure hospitalization, stroke, and repeat cardiovascular procedures compared with healthy individuals.4,5 Therefore, appropriate management in terms of diagnosis and treatment is of the utmost importance to improve patients’ prognosis and outcomes.6 The Coronary Microvascular Angina (CorMicA) trial demonstrated that a strategy of adjunctive invasive testing for disorders of coronary function together with stratified medical therapy can improve outcomes (ie, reduction in angina severity and enhanced quality of life).7,8 However, there are still concerns about the implementation in real-world practice of a systematic diagnostic and therapeutic approach in INOCA and ANOCA patients, potentially impacting outcomes and quality of life.

We report our single-center experience of the implementation in clinical practice of a specific diagnostic and therapeutic protocol (no obstructed coronary arteries [NOCA] program) in INOCA and ANOCA patients.

METHODS

Eligibility criteria for the NOCA program

All consecutive patients diagnosed either at our hospital or at our referral centers with angina or ischemia with nonobstructive CAD on coronary angiography were referred to a specific outpatient clinic (the NOCA clinic at Hospital Clínic, Barcelona, Spain) for a screening visit. Nonobstructive CAD was defined as angiographic evidence of normal coronary arteries or diffuse atherosclerosis with stenosis < 50% and/or fractional flow reserve (FFR) > 0.80 if there was stenosis between 50% and 70%. During the screening visit, a team of expert cardiologists confirmed patients’ eligibility for the NOCA program based on the following criteria: a) diagnosis of ANOCA, defined as stable, chronic typical angina symptoms (eg, chest pain precipitated by physical exertion or emotional stress and relieved by rest or nitroglycerine); b) diagnosis of INOCA, defined as the demonstration of myocardial ischemia identified by a noninvasive test with pharmacologic or exercise stress tests such as cardiac single photon emission computed tomography, cardiac magnetic resonance, stress electrocardiography, or echocardiography.3 The exclusion criteria were: a) atypical angina symptoms, and b) clearly identifiable noncoronary causes of chest pain (figure 1). The study protocol adhered to the Declaration of Helsinki and the study was approved by our institutional review committee. All patients provided written informed consent to be included in this program and study. The clinical ethics committee gave their approval for a retrospective analysis of the collected data.

Figure 1. Central illustration. Flowchart for the inclusion of patients in the NOCA program. Cath lab, catheterization laboratory; INOCA: ischemia with no obstructed coronary arteries; NOCA, no obstructed coronary arteries; NOCAD, nonobstructive coronary artery disease.

NOCA program: diagnostic approach

After patient inclusion in the NOCA program, specialized counseling was provided by expert cardiologists and nurses. All patients were thoroughly informed about their disease, the importance of reaching a specific diagnosis, and the importance implementing tailored therapy. During the counseling sessions, the predicted benefits and low associated risks of an invasive procedure to specifically study coronary microcirculation and vasospasm were explained in detail. All patients provided written informed consent to undergo coronary angiography and intracoronary provocation testing with acetylcholine (ACh).

Subsequently, all patients underwent a scheduled coronary angiogram with a comprehensive diagnostic work-up consisting of the following: a) coronary function testing to assess coronary flow reserve (CFR) and the index of microvascular resistance (IMR); b) intracoronary ACh provocation testing to assess the presence of coronary vasomotion disorders (eg, epicardial or microvascular spasm).

Coronary function testing was performed using a pressure-temperature sensor guidewire (PressureWire X Guidewire and Coroventis CoroFlow Cardiovascular System, Abbott Vascular, United States) placed in the left anterior descending artery (LAD) as the prespecified target vessel, reflecting its subtended myocardial mass and coronary dominance. Steady-state hyperemia was induced using intravenous adenosine (140 µg/kg/min). If there was severe tortuosity of the LAD or evidence of myocardial ischemia in a region other than the territory of the LAD, the wire was placed in the right coronary artery or the left circumflex, as per the operator’s decision. CFR was calculated using thermodilution, defined as resting mean transit time divided by hyperemic mean transit time (abnormal CFR was defined as ≤ 2.5). IMR was calculated as the product of distal coronary pressure at maximal hyperemia multiplied by the hyperemic mean transit time (normal value < 25).6,9

Intracoronary ACh provocation testing was performed with a standardized protocol involving serial ACh infusions for 20 seconds at increasing concentrations (2-20-100 µg in the left coronary artery with an interval of 2-3 minutes between each injection) with concomitant assessment of the patient’s symptoms, electrocardiogram documentation, and angiographic scans. Patients taking vasoactive drugs (eg, calcium channel blockers and nitrates) underwent a wash-out period of at least 48 hours before the provocative test.10,11,12 Epicardial coronary spasm was defined as the reproduction of chest pain and ischemic electrocardiogram changes in association with a reduction in coronary diameter ≥ 90% from baseline in any epicardial coronary artery segment.13 Microvascular spasm was diagnosed when typical ischemic ST-segment changes (deviation ≥ 1 mm) and angina developed in the absence of epicardial coronary constriction (< 90% diameter reduction).14

Subsequently, patients were stratified into 4 endotypes: a) microvascular angina (MVA) (evidence of coronary microvascular dysfunction [CMD] defined as any abnormal CFR [< 2.5], IMR [≥ 25], or microvascular spasm); b) vasospastic angina (VSA) (CFR ≥ 2.5, IMR < 25 and epicardial spasm); c) both MVA and VSA (evidence of CMD and epicardial spasm); and d) noncoronary chest pain (CFR ≥ 2.5 and IMR < 25, with neither microvascular nor epicardial spasm).6

Any complications occurring during the invasive diagnostic work-up were documented, including bradyarrhythmias, atrial fibrillation, ventricular tachycardia or fibrillation, coronary perforations, death from any cause, and any other complications.

NOCA program: pharmacological and psychological therapeutic approach

Once the endotype was identified, medical treatment for each patient was optimized accordingly (table 1). In patients with MVA, treatment with beta-blockers and calcium channel blockers (CCBs) was started or up-titrated. Ranolazine was added if angina symptoms were not fully controlled by beta-blockers and CCBs. In patients with VSA, treatment with nondihydropyridine CCBs and long-acting nitrates was started or up-titrated. In patients with both MVA and VSA, treatment with nondihydropyridine CCBs or beta-blockers was started or up-titrated. In patients with noncoronary chest pain, vasoactive drugs were discontinued unless clinically indicated for other reasons. Additionally, treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and statins was started or up-titrated in all patients. If a patient showed intolerance or had contraindications to a specific medication (eg, asthma for beta-blockers, perimalleolar edema for CCBs, severe bradycardia for both beta-blockers and CCBs), the treatment was tailored and modified accordingly.

Because stress is an important trigger factor for angina symptoms, all patients were also referred to a team of expert psychologists for psychological support.15

NOCA program: clinical outcome and quality of life evaluation

All patients were followed up at 1, 3, 6, and 12-months for treatment titration and assessment of clinical outcomes. At the time of coronary angiography (ie, baseline) and at the 3-month follow-up, all patients were administered the Seattle Angina Questionnaire (SAQ) and quality of life questionnaire (EuroQol-5D [EQ-5D]). The SAQ is a validated 19-item self-administered questionnaire that measures 5 dimensions of CAD: physical limitation, angina stability, angina frequency, treatment satisfaction, and disease perception.16 The EQ-5D is a standardized, nondisease-specific questionnaire used to describe and evaluate patients’ health status and was intended to complement other quality-of life measures.17 Figure 2 provides a visual representation of all the steps involved for patients included in the NOCA program.

Figure 2. Visual representation of the NOCA program. EQ-5D, EuroQol-5D; NOCA, no obstructed coronary arteries; SAQ, Seattle Angina Questionnaire. * See text for more details.

Statistical analysis

Data distribution was assessed according to the Kolgormonov-Smirnov test. Continuous variables were compared using the unpaired Student t-test or the Mann–Whitney U test, as appropriate. The data are expressed as mean ± standard deviation (SD) or as median and interquartile range [IQR]. Categorical data are expressed as numbers and percentages and were evaluated using the chi-square test or Fisher exact test, as appropriate. A 2-sided P value < .05 was considered significant. All analyses were performed using SPSS version 21 (SPSS, United States).

RESULTS

Baseline characteristics of the study population

From January 2021 to December 2021, a total of 77 patients were screened at the NOCA clinic for inclusion in the NOCA program. Following the screening visit, 23 (29.9%) patients were excluded from the NOCA program: 12 due to atypical angina symptoms and 11 due to a clearly identifiable noncoronary cause. Consequently, 54 patients were included in the NOCA program (mean age 64.4 ± 9.4 years, 39 [63.9%] women). A total of 29 (53.7%) patients had INOCA and 25 (46.3%) had ANOCA. All clinical and angiographic characteristics of the study population are shown in table 1.

Table 1. Medical therapy according to the specific endotype of ANOCA/INOCA

NOCA program: diagnosis of the specific endotype and complications

The results of the invasive functional assessment are presented in table 2. The mean IMR and CFR values were 21.2 ± 10.6 and 2.3 ± 1.4, respectively. MVA was diagnosed in 19 (35.2%) patients, VSA in 12 (22.2%), and both MVA and VSA in 18 (33.3%). Finally, 5 (9.3%) patients were diagnosed with noncoronary chest pain.

Table 2. Clinical and angiographic characteristics of patients included in the NOCA program

Among INOCA patients, MVA was diagnosed in 11 (37.9%) patients, VSA in 7 (24.1%), both MVA and VSA in 8 (27.6%), and noncoronary chest pain in 3 (10.3%). Among ANOCA patients, MVA was diagnosed in 8 (32.0%) patients, VSA in 5 (20.0%), both MVA and VSA in 10 (40.0%), and noncoronary chest pain in 2 (8.0%). There were no statistically significant differences in the prevalence of any endotype between INOCA and ANOCA patients (all P > .05, figure 3).

Figure 3. Prevalence of the different endotypes among INOCA and ANOCA patients. ANOCA, angina with no obstructed coronary arteries; INOCA, ischemia with no obstructed coronary arteries; MVA, microvascular angina; NCCP, noncoronary chest pain; VSA, vasospastic angina.

Complications occurred in 3 (5.5%) patients during intracoronary ACh provocation testing: 2 (3.7%) patients had transient bradyarrhythmias and 1 (1.8%) patient had paroxysmal atrial fibrillation that spontaneously reverted to sinus rhythm.

NOCA program: treatment optimization according to the specific endotype

Inclusion in the NOCA program led to statistically significant changes in medications after diagnosis of the specific endotype. There was a significant increase in the use of beta-blockers (33.3% before vs 57.4% after, P = .008), nondihydropyridine CCBs (9.3% before vs 37.0% after, P < .001), and long-acting nitrates (46.3% before vs 63.0% after, P = .012). There were no statistically significant differences in any other medications before and after the invasive assessment (all P > .05, figure 4). All changes in medications according to the specific endotype of ANOCA/INOCA are shown in figure 5.

Figure 4. Differences in medical treatment before and after patient inclusion in the NOCA program. ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; DP-CCBs, dihydropyridine calcium channel blockers; LA, long-acting; ND-CCBs, nondihydropyridine calcium channel blockers.

Figure 5. Changes in medications according to the specific endotype of ANOCA/INOCA. A: patients with MVA. B: patients with VSA. C: Patients with MVA and VSA. D: patients with noncoronary chest pain. DP-CCBs, dihydropyridine calcium channel blockers; LA, long-acting; MVA, microvascular angina; ND-CCBs, nondihydropyridine calcium channel blockers; VSA, vasospastic angina.

NOCA program: clinical outcome evaluation

At 3 months of follow-up, there was no statistically significant difference in the mean EQ-5D score compared with baseline (64.8 ± 18.1 at baseline vs 66.1 ± 17.1 at 3 months of follow-up, P = .302) (figure 6). However, there was a statistically significant improvement in the SAQ score in terms of physical limitations (59.7 ± 19.3 at baseline vs 66.2 ± 16.9 at 3 months of follow-up, P = .037), angina stability (57.1 ± 28.1 at baseline vs 75.8 ± 22.3 at 3 months of follow-up, P = .010), and disease perception (42.5 ± 13.9 at baseline vs 50.8 ± 16.3 at 3 months follow-up, P = .015). No statistically significant difference was found in angina frequency (74.3 ± 20.4 at baseline vs 80.7 ± 19.8 at 3 months of follow-up, P = .193) or treatment satisfaction (68.1 ± 12.6 at baseline vs 70.5 ± 12.5 at 3 months of follow-up, P = .950) (figure 7). No events were recorded at the 1-year follow-up.

Figure 6. Differences in EuroQol-5D (EQ-5D) score at baseline and at 3 months of follow-up.

Figure 7. Differences in SAQ score at baseline and at 3 months of follow-up. AF, angina frequency; AS, angina stability; DP, disease perception; EQ-5D, EuroQol-5D; PL, physical limitations; SAQ, Seattle Angina Questionnaire; TS, treatment satisfaction.

DISCUSSION

The main results of our experience can be summarized as follows: a) the implementation of a specific diagnostic and therapeutic protocol (NOCA program) in patients with diagnosed with nonobstructive CAD is feasible and allowed a parsimonious use of medical resources; b) a comprehensive diagnostic work-up in INOCA and ANOCA patients is safe, with a low rate of mild and transient complications (5.5%); c) the inclusion of patients in the NOCA program led to significant changes in medications and a significant improvement in their angina symptoms at the 3-month follow-up with no adverse events at 1 year.

Although accumulating evidence has demonstrated that an approach consisting of a comprehensive diagnostic assessment and stratified medical therapy in INOCA and ANOCA is crucial to improve patients’ prognosis, such an approach is far from routinely implemented in clinical practice.7,8 There are still concerns mainly related to the cost-benefit ratio, the associated prolonged procedural time, increased costs, and the risk of possible associated complications. Furthermore, in the most recent European Society of Cardiology guidelines, invasive coronary function testing is assigned a class IIa (“should be considered”) recommendation, while ACh provocation testing is supported by a class IIb recommendation (“may be considered”) to assess microvascular spasm and class IIa in patients under consideration for VSA.3 As a result, the management of these patients is commonly left to physicians’ discretion or relies on the experience of each center. Consequently, diagnosis of a specific NOCA endotype is frequently missed, and medical therapy is not optimized. This, in turn, has a significant negative impact on patients’ quality of life and clinical outcomes, as well as on health care costs, due to the need for repeat hospitalization or invasive procedures.18

In reporting our experience, we demonstrate that a specific diagnostic and therapeutic protocol (ie, the NOCA program) in patients with a previous diagnosis of nonobstructive CAD can be easily implemented in clinical practice. A key innovation of our study, compared with prior publications, is the creation and implementation of a specific protocol for the INOCA/ANOCA population. Additionally, our approach involves a screening visit with assessment by a team of expert cardiologists for patients with a suspected diagnosis of INOCA/ANOCA. This approach improves identification of such patients, and, in our experience, led to the exclusion of almost one third of patients (29.9%) due to atypical angina symptoms or no clearly identifiable coronary causes of chest pain. This is another novelty of our study that could be extremely relevant in the management of these patients. Indeed, the selection of patients to be included in the program may allow clinical resources to be directed to patients who are most likely to benefit, while avoiding repeat invasive procedures and related risks in patients with unclear indications. Additionally, the specialized counseling provided by cardiologists and nurses during the screening visit, together with psychological support, are likely to be vital components of the management of INOCA/ANOCA patients. Indeed, recent studies have demonstrated how psychological factors, such as chronic stress, anxiety, depression, and social stressors are involved in the pathogenesis of MVA and VSA.19-23 Mental stress has been demonstrated to determine CMD mainly through endothelium-dependent mechanisms and endothelial dysfunction.24 Similarly, by activating brain areas involved in regulation of neuroendocrine and autonomic nervous systems, mental stress can lead to hyperreactivity of vascular smooth muscle cells, autonomic nervous system dysfunction, oxidative stress, vascular inflammation, and endothelial dysfunction, resulting in an increased propensity to coronary vasospasm.25-27

Furthermore, in line with previous studies,28-30 our experience demonstrates that performing a comprehensive invasive diagnostic assessment for the diagnosis of the specific endotype in INOCA and ANOCA patients is safe and is associated with a low rate of mild and transient complications. For all these reasons, patients and clinicians should be reassured about the lack of serious complications and cardiologists should be strongly encouraged to implement a specific diagnostic and therapeutic program in these patients. Indeed, the availability of such a program for INOCA and ANOCA patients may have significant clinical and therapeutic implications, as, in our experience, it resulted in substantial changes in medications and a marked improvement at the 3-month follow-up of the SAQ questionnaire regarding physical limitations, angina frequency, and disease perception. The lower and nonsignificant improvement in the other parameters (eg, angina frequency and treatment satisfaction) could be attributed to the already high baseline values (74.5 ± 19.9 and 69.6 ± 11.9, respectively). Similarly, the absence of a significant improvement in the EQ-5D questionnaire at 3 months might be due to the short follow-up period or the fact that it is a nondisease-specific questionnaire designed to describe and assess patients’ health status and is intended to complement other quality-of-life measures.31

Study limitations

Some limitations of this study should be acknowledged. First, this is a single-center study with a relatively small sample size and short follow-up. Second, we did not perform a cost-analysis and therefore we cannot speculate on the impact of the NOCA program on health care-related costs. Further studies in larger ANOCA and INOCA populations are warranted. Finally, the absence of a control group precluded a thorough assessment of the improvement in the quality of life among these patients.

CONCLUSIONS

Our experience demonstrates that a specific diagnostic and therapeutic protocol (NOCA program) can be easily and safely implemented in routine clinical practice. Such a protocol could ensure the best care for INOCA and ANOCA patients, as well as improve their quality of life and avoid inappropriate treatments and incomplete investigations. Future evidence from randomized clinical trials or recommendations from international clinical guidelines supporting the implementation of a specific protocol in these patients are strongly warranted.

FUNDING

This study received no funding.

ETHICAL CONSIDERATIONS

The study protocol complied with the Declaration of Helsinki and the study was approved by our Institutional Review Committee. All patients gave written informed consent to be included in this program and study. The clinical ethics committee gave their approval for a retrospective analysis of the data collected. In this work, the possible variables of sex and gender have been taken into account.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence tools were used during the preparation of this work.

AUTHORS’ CONTRIBUTIONS

R. Rinaldi, F. Spione, F.M. Verardi: data extraction and analysis and manuscript drafting; R. Rinaldi, F. Spione, S. Brugaletta: design and manuscript revision; P. Vidal Calés, V. Arévalos, R. Gabani, D. Cánovas, M. Gutiérrez, M. Pardo, R. Domínguez, L. Pintor, X. Torres, X. Freixa, A. Regueiro, O. Abdul-Jawad Altisent, M. Sabaté: manuscript revision. All authors have read and agreed to the published version of the manuscript.

CONFLICTS OF INTEREST

The authors have nothing to disclose.

ACKNOWLEDGMENTS

F. Spione has been supported by a research grant provided by the Cardiopath PhD program.z

REFERENCES