Refractory angina: mechanisms and stratified treatment in obstructive and non-obstructive chronic myocardial ischaemic syndromes

Abstract

The diagnosis of refractory angina has conventionally been limited to patients with angina and ischaemia secondary to obstructive atherosclerotic epicardial coronary disease who experience persistent symptoms despite optimal pharmacological and revascularization therapies. It is now well-established that angina may also be caused by ischaemia resulting from coronary microcirculatory disorders, coronary vasospasm, and bridging in the absence of obstructive epicardial coronary disease or after "successful" revascularization. This increasingly prevalent and symptomatic group of patients, with both angina and demonstrable ischaemia, have been excluded from the conventional definition of refractory angina. In patients with obstructive epicardial coronary disease, disturbed microcirculatory and vasomotor function, amongst other ischaemic mechanisms, may account for continuing symptoms despite revascularization. Under-recognition of these mechanisms results in inadequate treatment and symptom persistence. In this review, a redefinition of refractory angina is proposed to include the full spectrum of patients experiencing persistent angina despite current maximal guideline-directed medical and revascularization therapies. Systematic approaches for comprehensive investigation are suggested to identify underlying mechanisms of ischaemia and stratify treatments accordingly. The complex needs of patients with refractory angina are likely best addressed by an inter-disciplinary Angina Heart Team with the aim of improving patient symptoms, quality of life, and clinical outcomes.

Keywords: ANOCA; Chronic coronary syndromes; INOCA; Non-acute myocardial ischaemic syndromes; Refractory angina pectoris.

Graphical Abstract

A contemporary approach to the stratified management of refractory angina resulting from obstructive and non-obstructive coronary artery disease. Guideline recommended stratified anti-ischaemic therapies are shown in bold. CAD, coronary artery disease; CBT, cognitive behavioural therapy; CFVR, coronary flow velocity reserve; CMD, coronary microvascular dysfunction; CMR, cardiac MRI; CSR, coronary sinus reducer; CT, computed tomography; ECSWT, extracorporeal shockwave therapy; EECP, enhanced external counterpulsation; ETT, exercise tolerance test; LIPUS, low-intensity pulsed ultrasound; PET, positron emission tomography; SCS, spinal cord stimulation; SENS, subcutaneous electrical nerve stimulation; SGB, stellate ganglion block; TENS, transcutaneous electrical nerve stimulation; VSA, vasospastic angina

Figure 1

Summary of known mechanisms that cause ischaemia in patients with obstructive epicardial coronary artery disease with or without previous revascularization and ANOCA/INOCA at the level of both the epicardial coronary arteries and the coronary microcirculation. CABG, coronary artery bypass grafting; CAD, coronary artery disease; CTO, chronic total occlusion; INOCA, ischaemia and non-obstructed coronary arteries; PCI, percutaneous coronary intervention

Figure 2

A compartmentalized approach to the non-invasive and invasive investigation of the coronary circulation to identify myocardial ischaemia. AChFR, acetylcholine flow reserve; CFR, coronary flow reserve; CFVR, coronary flow velocity reserve; CMR, cardiac magnetic resonance imaging; CT, computed tomography; CTCA, computed tomography coronary angiography; FFR, fractional flow reserve; FFR-CT, fractional flow reserve computed tomography; hMR, hyperaemic microvascular resistance; IHDVPS, instantaneous hyperaemic diastolic velocity-pressure slope index; IMR, index of microvascular resistance; LAD, left anterior descending artery; MBF, myocardial blood flow; MCE, myocardial contrast echocardiography; MRR, microvascular resistance reserve; MRR-CT, microvascular resistance reserve computed tomography; MPR, myocardial perfusion reserve; MPRI, myocardial perfusion reserve index; PET, positron emission tomography; Pzf, pressure at zero flow; PPG, pullback pressure gradient; Qperf, quantitative perfusion; RRR, resistance reserve ratio; SPECT, single-photon emission computed tomography; WIA, wave intensity analysis; WMSI, wall motion score index

Figure 3

Non-pharmacological anti-ischaemic therapies for patients with refractory angina

Figure 4

The multi-disciplinary Refractory Angina Heart Team. ANOCA: angina and non-obstructive coronary arteries, INOCA: ischaemia and non-obstructive coronary arteries