Angina with non-obstructive coronary arteries: a success story

This editorial refers to ‘Coronary function testing vs angiography alone to guide treatment of angina with non-obstructive coronary arteries: the ILIAS ANOCA trial’, by C.K.M. Boerhout et al., https://doi.org/10.1093/eurheartj/ehaf580. The fascinating story of angina with non-obstructive coronary arteries (ANOCA) started in 1959 when Prinzmetal described ‘variant’ angina. He coined the term ‘variant angina’ because in contrast to ‘classical angina’ it occurs at rest rather than during exercise and is associated with ST segment elevation rather than depression. He proposed that the cause was coronary spasm rather than the presence of a coronary stenosis.1 This hypothesis, challenging the dogma that ischaemia could only be caused by coronary stenoses, remained untested for several years due to the scientific community’s scepticism. At the end of the 1970s, Maseri et al. demonstrated beyond any reasonable doubt that spasm was indeed the cause of ‘variant’ angina and proposed that ‘variant’ angina was only one aspect of a continuous spectrum of ‘vasospastic’ myocardial ischaemia.2 In 1973, Arbogast and Bourassa3 identified a group of patients with effort angina in the absence of obstructive coronary stenoses. They described 10 patients with angina and ST segment depression during atrial pacing, findings similar to those observed in 11 patients with epicardial stenoses. They labelled the first group of patients as ‘group X’ to underline the notion that the cause of angina and ST segment depression did not have a satisfactory explanation. In 1988, Cannon and Epstein coined the term ‘microvascular angina’ (MVA), proposing that coronary microvascular dysfunction (CMD) was the cause of ‘syndrome X’.4 Notably, in 1993, a study by Galassi et al. demonstrated for the first time the presence of CMD in patients with ‘syndrome X’.5 Then, in the year 2000, Buffon et al. convincingly demonstrated for the first time that CMD in patients with ‘syndrome X’ was severe enough to cause myocardial ischaemia.6 These clinical observations progressively led to the acceptance of the term ‘microvascular angina’ proposed by Cannon and Epstein. The medical community then began to recognize that angina without obstructive epicardial stenoses is not a benign condition. Indeed, in 2004, the landmark WISE (Women’s Ischemia Syndrome Evaluation) study, funded by the National Institutes of Health, revealed for the first time that women with angina without epicardial stenoses had a higher risk of adverse cardiovascular outcomes.7 The term ANOCA originated from a COVADIS Summit and included both vasospastic and microvascular angina, while the term ‘ischaemia with non-obstructive coronary arteries’ was introduced in 2017 by a National Heart, Lung, and Blood Institute workshop.8 In 2017, the COVADIS group proposed an international standardization of diagnostic criteria for vasospastic angina,9 and in 2018 an international standardization of diagnostic criteria for microvascular angina.10 In 2018, the CorMicA (Coronary Microvascular Angina) trial represented a pivotal milestone in this evolving field. This randomized controlled trial demonstrated for the first time that patients who underwent invasive coronary functional testing (CFT) followed by therapy guided by the mechanism of ANOCA experienced improved angina control and quality of life compared with those who received standard care.11 In 2019, these findings led the European Society of Cardiology (ESC) Guidelines for the management of Chronic Coronary Syndromes to recommend for the first time the implementation of CFT with coronary flow reserve and index of microcirculatory resistance assessment in ANOCA with persistent symptoms (Class IIa, Level of Evidence B), while acetylcholine provocation testing for detecting coronary spasm received only a class IIb recommendation, probably due to a perceived risk of this procedure. However, in the following years, several studies demonstrated both the safety and the prognostic value of acetylcholine provocation testing in these patients. Accordingly, the latest ESC Guidelines, published in 2024, made a relevant advance by recommending invasive CFT for patients who remain symptomatic despite medical therapy and who do not exhibit obstructive coronary stenoses (Class I, Level of Evidence B).12 The rationale for this approach aims to identify potentially treatable ANOCA endotypes and improve both symptoms and quality of life as achieved in the CorMicA trial discussed above.11 An additional advantage is that a negative response to the functional tests excludes an ischaemic origin of chest pain orienting towards alternative non-coronary diagnoses. In 2020, Kunadian et al. published the European Association of Percutaneous Cardiovascular Interventions (EAPCI) expert consensus on INOCA, defining four INOCA endotypes based on CFT results: (i) microvascular angina; (ii) vasospastic angina; (iii) both microvascular and vasospastic angina; and (iv) non-cardiac chest pain.12 More recently, we demonstrated that the implementation of the 2024 ESC Guidelines in ANOCA patients not only improves clinical outcomes, but also reduces healthcare costs13 (Graphical Abstract). Continuing this fascinating story, Boerhout et al. present in this issue of the European Heart Journal the results of the ILIAS ANOCA (Inclusive Invasive Physiological Assessment in Angina Syndromes—Angina with No Obstructive Coronary Artery Disease) trial, a multicentre study that randomized 153 patients with suspected ANOCA to treatment guided by CFT during coronary angiography vs usual care.14 Treatment guided by CFT resulted in a significant reduction of angina burden and in an improvement in quality of life. Of note, CFT was shown to be both feasible and safe, with no adverse events reported and an average additional procedure time of just 20 min. Notably, the study’s CFT protocol employed intracoronary bolus injections of both acetylcholine and adenosine, which may have shortened the overall procedure time compared with other protocols used worldwide. These findings externally validate the results of the CorMicA trial11 and provide further support to current guideline recommendations advocating the use of CFT in patients with suspected ANOCA. Importantly, adding CFT to coronary angiography increased the diagnostic yield to 87%, compared with only 40% when relying on angiography alone. Of particular interest, coronary spasm—often under-recognized in clinical practice—emerged as the most common underlying mechanism, identified in 42% of patients as an isolated cause and in 20% in combination with CMD. These findings largely explained the major changes in medical therapy observed in the intervention group compared with the control group, including a higher prescription rate of calcium channel blockers and short-acting nitrates, and again suggesting that a complete CFT, including acetylcholine provocation testing (still underused in clinical practise), is needed to improve outcomes in ANOCA patients. Notably, the magnitude of improvement in Seattle Angina Questionnaire Summary Scores achieved through the intervention in both the ILIAS ANOCA and CorMicA trials was substantially greater than that observed after revascularization in patients with obstructive coronary artery disease in the ISCHEMIA and ORBITA trials. These results underscore the urgent need for widespread implementation of a stratified medicine approach in ANOCA to meaningfully improve patients’ quality of life. This is extremely important also considering that up to 50% of anginal patients exhibit ANOCA.12 An obvious important limitation is that, although the symptomatic improvement observed in patients allocated to CFT is compelling, the potential contribution of the placebo effect must be considered as a possible confounding factor in an unblinded study. This is particularly relevant in ANOCA patients, where symptoms may be subjectively influenced by the clinical context, reassurance, and patient–physician interaction with greater perception of thorough care and increased confidence in the diagnosis and management plan. ANOCA is a diagnostic and therapeutic challenge in the management of patients with non-acute myocardial ischaemic syndromes, as the existence of various ANOCA endotypes necessitates a stratified medicine approach, incorporating an advanced diagnostic algorithm and a tailored therapy. This approach aims to identify potentially treatable ANOCA endotypes and improve both symptoms and quality of life. Both CorMicA and ILIAS ANOCA have addressed these important challenges. Both trials build on a long journey of clinical and scientific progress that began ∼60 years ago. Further research is needed to address several important knowledge gaps. Indeed, the current endotype classification does not fully capture the spectrum or combinations of pathophysiological mechanisms, and more granular endotyping is needed probably using multimodal diagnostic tools (e.g. combined invasive/non-invasive testing and molecular profiling) to better define novel or overlapping endotypes. In addition, prognosis is guarded and is likely to vary across endotypes, while long-term outcomes and predictors of adverse events remain poorly characterized and warrant further investigation. Notably, current antianginal medications do not specifically target the mechanisms of epicardial spasm and of CMD. Finally, while the development of tailored therapies based on specific endotypes has been a major advance in symptom control, effective disease-modifying treatments for ANOCA are still lacking. In conclusion, ANOCA progressed from the initial scepticism of the scientific community regarding its existence to the demonstration of its clinical relevance and the need for a standardized diagnostic algorithm (as recommended in current ESC Guidelines12), which leads to the identification of successful antianginal treatments for patients who frequently present invalidating symptoms. Thus, although unfinished, this is a success story. F.C. reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, and Menarini. A.M.L. is a consultant for Abbott Vascular, Menarini, and Acist/Bracco Imaging, and reports personal fees from Abbott, Medtronic, Menarini, Bruno Farmaceutici, Novo Nordisk, Daiichi Sankyo, Sanofi, and Novartis. R.A.M. declares no disclosure of interest for this contribution.