Mechanisms and Diagnostic Evaluation of Persistent or Recurrent Angina Following Percutaneous Coronary Revascularization

Filippo Crea; Cathleen Noel Bairey Merz; John F. Beltrame; Colin Berry; Paolo G. Camici; Juan Carlos Kaski; Peter Ong; Carl J. Pepine; Udo Sechtem; Hiroaki Shimokawa; On behalf of the Coronary Vasomotion Disorders International Study Group (COVADIS)


Eur Heart J. 2019;40(29):2455-2462. 

In This Article

Diagnostic Evaluation of Persistent or Recurrent Angina After Percutaneous Coronary Intervention

Non-invasive Diagnostic Tests

European Society of Cardiology guidelines for stable obstructive CAD recommend a stress test at follow-up in patients with persistent or recurrent angina post-PCI, preferably a stress test that is combined with imaging (Class I, level of evidence C).[1] Thus, non-invasive stress tests represent, in most cases, the first diagnostic assessment for patients presenting with angina post-PCI.

ECG stress testing in the diagnostic and prognostic assessment of patients with stable ischaemic heart disease is well established as it helps guide the initial treatment strategy.[1] The diagnostic performance of computed tomography coronary angiography for the evaluation of in-stent restenosis is generally lower than in a native vessel, and adjunctive estimation of FFR-computed tomography in a vessel with a stent is relatively contra-indicated.[42] The role of ECG stress testing alone after PCI is debated because the positive predictive value for obstructive stenosis/restenosis is only moderately high.[43] A key issue is that an abnormal ECG stress test can be caused by both obstructive CAD and functional mechanisms (CMD, epicardial vasoconstriction, etc.). In both clinical scenarios, evidence of exertional angina and ECG abnormalities consistent with ischaemia provide objective evidence that should be useful for onward management.

Similar considerations apply to stress myocardial perfusion imaging by single-photon emission tomography (SPECT). Positron emission tomography (PET) is a well-validated technique that provides non-invasive, accurate, and reproducible quantification of both global and regional myocardial blood flow (mL/g/min) and CFR. Clinical research using PET has provided substantial new knowledge on CMD in various clinical settings. Indeed, evidence of segmental abnormalities more often reflects an epicardial problem while CMD is associated with a global reduction of CFR.[44,45] Recent studies suggest that cardiac magnetic resonance may discriminate between epicardial and microvascular causes of myocardial ischaemia.[46,47]

Stress echocardiography (with either exercise or pharmacological stressor) may be useful to distinguish between epicardial and microvascular coronary mechanisms. Indeed, a dissociation between angina and ischaemic ST-segment changes on the one hand and lack of regional wall motion abnormalities on the other hand, is a typical feature of microvascular angina due to the patchy distribution of ischaemia.[48–51] In sharp contrast, as established in the ischaemic cascade concept where regional wall motion abnormalities precede electrical abnormalities and both precede symptoms, it is very unlikely for patients with epicardial coronary stenoses to experience angina and ischaemic ST-segment changes in the absence of regional wall motion abnormalities.[48]

Invasive Diagnostic Tests

Current European Society of Cardiology guidelines on stable CAD recommend invasive coronary angiography in clinically stable patients with high-risk ischaemic findings (>10% of myocardium) at stress imaging (Class I, level of evidence C).[1] However, the threshold for coronary angiography might be lower after high-risk PCI (Class IIb, level of evidence C).[1] Considering the limited negative predictive value of a non-invasive test, then an invasive approach may be chosen independent of non-invasive test results, particularly when the history is strongly supporting angina recurrence because it offers the opportunity to test both structural and functional alterations of coronary circulation (Figure 3). Multi-territory ischaemia (both transmural and regional) may not be detected by most non-invasive tests.[3] Moreover, patients with persistent or recurrent angina and incomplete revascularization need to be reassessed if additional revascularization is considered to be technically feasible. Finally, in case of an intermediate stenosis on coronary angiography, FFR or NHPR measurements can be helpful to confirm the presence of a haemodynamically significant epicardial stenosis. However, the caveat is that in the presence of CMD, it may be unclear whether near maximal hyperaemia is achieved, thus limiting the usefulness of FFR measurements without measuring CFR or indices of myocardial resistance.[52]

Figure 3.

A full investigation of the mechanisms of persistence or recurrence of angina after percutaneous coronary intervention in the catheterization laboratory should include the assessment of both structural and functional alterations of epicardial coronary arteries and of coronary microcirculation. A-Ch, acetylcholine; CFR, coronary flow reserve; IVUS, intravascular ultrasound; OCT, optical coherence tomography.

A second indication for coronary angiography is the occurrence of angina at rest, despite optimal medical treatment and negative non-invasive testing. This scenario should strongly suggest functional coronary alterations. In this patient subset, invasive coronary angiography might sometimes establish the presence of subcritical unstable coronary plaques, which can be further investigated by intravascular imaging (optical coherence tomography, intravascular ultrasounds, etc.). In the absence of subcritical unstable plaques, the assessment of epicardial and microvascular coronary vasomotion may reveal functional causes of persistent angina. In both scenarios, invasive coronary angiography is necessary to elucidate the causes of angina.

Coronary artery vasomotion is mainly assessed invasively, usually by intracoronary administration of drugs, such as ACh or ergonovine.[1,3] The safety of intracoronary provocative testing has been convincingly proven in previous studies.[53] Some have advocated non-invasive assessments using ergonovine stress echocardiography in patients known to have non-obstructive CAD.[54] Coronary vasomotion in response to ACh reflects the interplay between endothelial and smooth muscle cell responses. Acetylcholine elicits endothelium-dependent vasodilatation when the endothelium is functional, but in pathological conditions, characterized by endothelial dysfunction and/or smooth muscle cell hyper-reactivity, it may result in no dilatation or even trigger vasoconstriction or spasm via stimulation of smooth muscle cell muscarinic receptors. Ergonovine acts primarily via serotoninergic receptors on vascular smooth muscle cells but also on α-adrenergic and dopaminergic receptors, unmasking predisposition to vasoconstriction or spasm. Acetylcholine is preferred because it is relatively short-acting, specific in its selectivity for muscarinic receptors and the intracoronary dosing is devoid of systemic effect; whereas ergonovine effects multiple receptors, is longer acting and even with intracoronary dosing may have some systemic effects (blood pressure increases). Nevertheless, at present, it is unclear whether ACh or ergonovine is superior to detect spasm in patients with persisting angina post-PCI also because they might identify different subsets of patients with vasospastic angina.[55]

Coronary artery spasm is defined as a transient (e.g. reversible) coronary artery occlusion/subocclusion (>90% narrowing) with signs (ST changes) and symptoms of myocardial ischaemia.[56,57] Spasm may involve discrete coronary segments in one or multiple arteries, or can be diffuse and, when it involves distal coronary vessels, can be suspected to also extend into the microvasculature.[56]

Lack of epicardial coronary spasm by angiography in the presence of ischaemic ECG changes and angina suggests microvascular spasm.[58] When epicardial spasm occurs, objective determination of concomitant microvascular spasm is difficult.

Coronary reactivity testing is only performed in a limited number of cardiac catheterization laboratories worldwide. The reasons for the low adoption of coronary reactivity testing are multifactorial and include lack of evidence from randomized controlled trials, and lack of education and training in who to administer the tests. The European Society of Cardiology (ESC) and the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines make spasm provocation testing only Class IIa and Class IIb, respectively.[1,20] However, the Japanese Circulation Society and the Coronary Vasomotion Disorders International Study Group (COVADIS) have recommended routine testing in selected patients.[56–58]

Coronary flow reserve and microvascular resistance can be measured using a pressure- and flow-sensitive Doppler catheter or a thermodilution guidewire. These techniques can be performed during coronary angiography enabling a comprehensive assessment of CMD by assessing microvascular dilatory function,[59,60] which may complement coronary reactivity testing within the same procedure.

The Coronary Microvascular Angina clinical trial (CorMicA) is the first to prove the diagnostic, health and economic value of an interventional diagnostic procedure,which combines a guidewire and coronary vasoreactivity testing, to inform the diagnosis and treatment of patients with angina and no obstructive CAD, where the primary outcome is Seattle Angina Score at 6 months.[61]

Diagnostic Flowchart

We recognize that randomized controlled trials for management of post-PCI angina are lacking. Nonetheless, given the clinical necessity, practice guidelines are needed. Although symptom assessment is important, it is frequently insufficient to establish the cause of persistent or recurrent angina after PCI, the only distinctive feature of vasospastic angina being angina at rest, frequently nocturnal, with preserved effort tolerance[62] and the only distinctive feature of microvascular angina being prolonged chest pain not immediately responsive to nitrates.[63] We propose a diagnostic algorithm that may assist in the evaluation of patients in this setting (Figure 4). The rationale prioritises a person-centred approach with diagnostic tests according to local availability and onward management, including coronary angiography, as appropriate. A non-invasive assessment will be sufficient in some patients, but in many cases, invasive management including to assess coronary vascular function will be needed.

Figure 4.

Diagnostic flowchart in patients with persistent or recurrent angina after percutaneous coronary intervention. Colour coding: symptoms in yellow, diagnostic tools in purple, diagnostic findings in green, and therapeutic recommendations in red. ACh, acetylcholine; CFR, coronary flow reserve; Ergo, ergonovine maleate; FFR, fractional flow reserve; IMR, index of microvascular resistance; NHPR, non-hyperaemic pressure ratio; RWMA, regional wall motion abnormalities.