Lessons learnt after 1-Year Follow-up of Invasive Coronary Function Testing for the Management of Angina with Non-Obstructed Coronary Arteries

Summary of the original article

Background

Up to one-half of all patients with angina pectoris have symptoms and/or signs of myocardial ischaemia with no obstructive coronary artery disease (INOCA) [1]. Vasospasm and coronary microvascular dysfunction (probably) are the two leading underlying pathophysiological mechanisms [2]. The standardised interventional diagnostic procedure (IDP) can identify coronary vasomotion abnormalities, enabling a tailored medical therapy [3]. The efficacy of this “stratified-medicine” approach has been tested in the blinded randomized controlled CorMicA (Coronary Microvascular Angina) trial, with positive 6-month effects on angina symptoms and the quality of life [4].

Methods

Ford T. et al. extended the follow-up of the CorMicA trial analysing the 1-year effects of the IDP-guided INOCA treatment on patient-reported angina severity (Seattle Angina Questionnaire; SAQ) as the primary efficacy endpoint and the quality of life (by the EQ-5D index), the health status and major adverse cardiac events (MACE) as the secondary efficacy endpoints [5]. From the initial 391 patients referred for elective invasive coronary angiography, 46% had INOCA and were randomized and tested by the IDP. Four INOCA endotypes were distinguished: microvascular angina (MVA; in 52% of the randomized patients), vasospastic angina (VS; 17%), a combination of both (20%) or the absence of vasomotion abnormality (11%). Randomization was 1:1 to the intervention group (IDP testing with the disclosure of the results and tailored medical therapy), or to the control group (IDP testing done, but with the blinding of the results, followed by the standard medical therapy). The baseline therapy (aspirin, statin, ACE inhibitor and PRN sublingual GTN) was considered both for the MVA and VS patients. A specific antianginal included beta blocker for MVA and non-dihydropyridine calcium channel blockers for VS as the first-line therapy. Long acting nitrates were not advocated for MVA. For the patients with the normal functional testing, the cessation of the antianginal therapy was advocated.

Results

At 1 year, the interventional group sustained an improvement in overall angina (the SAQ summary score increased by 27%, p < 0.001) and the quality of life (the EQ-5D index improved by 18%, p < 0.010), relative to the control group. The values were similar to those at 6 months. At 1 year, the intervention group also demonstrated lower blood pressures and higher attendance at cardiac rehabilitation. However, after the median follow-up duration of 19 months, MACE was similar in the interventional vs control group (12% vs 11%, p = 0.803).

Conclusion

The study demonstrated that stratified medical therapy in the INOCA patients produced a marked angina improvement and a better quality of life, which sustained at 1 year following invasive coronary angiography. 

Comments on the article

INOCA patients represent a large and still underserved portion of patients with angina, despite substantial morbidity, a reduced quality of life, and a consistent need for medical assistance. The CorMicA trial is a wisely designed, and meticulously and carefully conducted pilot study, valuable for several reasons. Firstly, it underlines that a normal coronary angiogram (anatomy) does not imply a normal coronary vasculature (function). The reported prevalence of coronary vasomotor dysfunction (almost 89%) is in keeping with the other studies of epicardial and/or microvascular coronary dysfunction in unobstructed coronary arteries (64-77%) [6, 7]. Secondly, it shows that personalized antianginal therapy focused on the dominant pathophysiological INOCA mechanism has the potential to improve outcomes in a clinically meaningful and sustainable manner. For example, a 14-unit higher SAQ summary score in the IDP group at 1 year – compared to baseline – corresponds with 1 grade in the Canadian Cardiovascular Society classification, which is greater than the minimum clinically important difference. Thirdly, the CorMicA trial pragmatically demonstrates that IDP is feasible and applicable in a daily routine as an adjunct to elective invasive coronary angiography. IDP was completed in 96% of the patients with the median procedure duration of 60 min, including IDP performed over 20 min.

Indisputably, the treatment effects on the self-reported end-points are clear in the CorMicA trial. However, the exact mechanisms behind these effects still need be clarified. Several mechanistic differences between the intervention and control groups offer potential explanations: (1) more appropriate stratification of the therapy according to the initial recommendation based on IDP testing in the intervention group; (2) lower systolic and diastolic blood pressures relative to control; (3) greater participation in cardiac rehabilitation, with trends toward improved functional capacity and physical activity levels in the IDP group. Importantly, patients with higher rates of psychological distress at the beginning of the study benefited more from the tailored therapy, suggesting the necessity to address the psychological factors during angina management. A lack of translation of the potentially beneficial effects of the treatment on MACE might be explained by the relatively modest sample size (which also precludes valuable comparisons within patient endotypes) and a relatively short follow-up time. Identifying endotypes is definitely helpful in personalizing treatment. It has previously been observed that MVA patients frequently have a poor response to nitrates or developed tolerance to these drugs, in contrast to patients with VS, in whom nitrates were the foundation of the therapy, whereas beta-blockers were relatively contraindicated [8].

In order to move to advance the field, a better understanding of the underlying pathophysiology of INOCA is fundamental. This includes a better understanding of the potential importance of non-obstructive plaque characteristics, vascular/perivascular inflammation, specific risk factors, the perception of chest pain, with the concordant development of even more specific, well-standardised and validated (non)invasive functional tests embracing the whole coronary tree – i.e. not testing only one artery – as well as the identification of specific biomarkers (e.g. the endothelin pathway) with the potential to guide therapy.

In conclusion, the CorMicA trial has introduced a new concept of pathophysiology-guided INOCA treatment, with the potential to be more effective. It represents the foundation for larger, randomized, prospective, patient-centred studies, which are needed to further improve the efficacy of INOCA patient management.