Invasive and Non-invasive Assessment of Non-culprit Coronary Lesions in Patients with ST-segment Elevation Myocardial Infarction

The angiographic evidence of coronary multivessel disease (MVD) increases significantly the risk of recurrent ischemic events in patients with ST-segment elevation myocardial infarction (STEMI). Recent evidence suggests that a complete revascularization strategy should be considered the standard of care in these patients and performed for significant non-culprit lesions (NCLs) after careful assessment of the individual risk-benefit ratio. However, the optimal timing and the modality for the assessment of NCLs is not fully standardized. This brief review aims to summarise the management of MVD in patients with STEMI and to provide an overview of the principal techniques used to guide revascularisation in this high-risk clinical setting.


Introduction
A bout half of patients with ST-segment eleva- tion myocardial infarction (STEMI) exhibits coronary multivessel disease (MVD), defined as the presence of two or more epicardial coronary arteries with obstructive luminal narrowing [1].The angiographic evidence of MVD has achieved increasing clinical interest in the last decades due to the robust evidence of its association with recurrent ischemic events and mortality [2e5].
Current guidelines recommend routine revascularization of non-culprit lesions (NCLs), defined as any coronary lesion not responsible for the acute coronary syndrome (ACS), during the index percutaneous coronary intervention (PCI) procedure or within 45 days in haemodynamically stable patients [6].
The decision to perform coronary revascularisation needs to be carefully evaluated against the risks of the procedure and the patient's comorbidities, especially in the case of complex coronary lesions [7e11].
Therefore, the identification of really significant NCLs is central to the decision-making process.No one technique fits all patients, but the integration of invasive and non-invasive techniques is currently considered the most rational approach by the interventional cardiology community [12,13].
This short review aims to summarise the management of MVD in patients with STEMI and to provide an overview of the techniques used to guide revascularisation decisions.

Treatment of non-culprit lesions
Robust evidence of NCLs treatment in patients with ACS and MVD demonstrated the safety and effectiveness of complete revascularization and its value in reducing the risk of long-term adverse events (Table 1) [14e18].The Preventive Angioplasty in Myocardial Infarction (PRAMI) trial included 465 patients with STEMI and MVD, who were randomized to immediate angiography-guided multivessel complete revascularization versus culprit-only lesion primary PCI [7].The study demonstrated the benefit of immediate multivessel PCI with a significant reduction of the composite endpoint including cardiovascular death, non-fatal myocardial infarction or refractory angina at three years follow-up, as compared to culprit-only lesion PCI [14].
Consistently with this study, the Complete versus Lesion-only Primary PCI (CvLPRIT) trial showed a significantly lower risk for the composite of allcause mortality, recurrent myocardial infarction, heart failure, and ischemia-driven revascularization at one-year follow-up in patients with STEMI and MVD undergoing early angiography-guided complete revascularization compared to culprit-only lesion PCI [15].Also, the The mechanisms underlying the association between NCLs and adverse cardiac events are complex and multifactorial.In the acute phase of STEMI, the release of inflammatory substances promotes instability of NCLs and microcirculatory endothelial damage potentially leading to thrombosis, plaque rupture and myocardial ischemia [19e23].After the acute phase, NCLs may undergo disease progression, especially in patients with multiple and not optimally controlled cardiovascular risk factors such as diabetes, high cholesterol levels, hypertension, smoking, and chronic kidney disease [24e29].
The optimal timing to complete myocardial revascularization is controversial, since some trials treated NCLs during index PCI [14,15] and others planned revascularization in staged procedure [16,18].The Direct Complete Versus Staged Complete Revascularization in Patients Presenting With Acute Coronary Syndromes and Multivessel Disease (BIO-VASC) trial enrolled 764 patients with ACS, who were randomized to immediate vs staged complete multivessel PCI.The study showed that complete revascularisation at index PCI was not inferior to staged PCI in terms of the composite of all-cause mortality, myocardial infarction, any unplanned ischemiadriven revascularization, or cerebrovascular events.Moreover, immediate complete PCI of NCLs was associated with a reduction in myocardial infarction and unplanned ischaemic-driven revascularisation [30].
Consistently with this study, MULTivessel Immediate versus STAged RevaScularization in Acute Myocardial Infarction (MULTISTARS AMI) trial compared the safety and efficacy of immediate vs staged complete revascularisation in haemodynamically stable patients with STEMI and MVD.The results showed that achieving complete revascularisation during index PCI was not inferior to staged PCI in terms of mortality and ischaemic events [31].

Coronary physiology
Although previous studies have demonstrated the potential benefit of invasive functional assessment for PCI guidance in patients with stable ischemic heart disease [32,33], this evidence cannot be extended to patients with ACS.
FFR is the most used technique to evaluate the functional severity of coronary lesions during adenosine-induced hyperemia.Non-hyperaemic pressure ratios (NHPRs) provide an alternative method for evaluating the ratio between distal coronary pressure and aortic pressure across coronary lesions during the wave-free period of the resting cardiac cycle without the need for hyperaemic stimuli [34].
In the acute or subacute phase of ACS, the release of inflammatory mediators, distal embolization, vasoconstriction of microcirculation and increased left ventricular tele-diastolic pressure may promote a transient change in coronary physiology and thus affect measurements of both hyperaemic-and nonhyperaemic-based indexes [35e39].
Two randomized clinical trials investigated the role of complete revascularization guided by invasive functional vs angiography strategy in patients with ACS and MVD (Table 2) [38,40].
The FLOW Evaluation to Guide Revascularization in Multi-vessel ST-elevation Myocardial Infarction (FLOWER-MI) trial enrolled 1171 patients with STEMI and MVD, who were randomized to receive complete revascularization guided by FFR or angiography alone.At one-year, complete revascularization guided by FFR did not show significant benefit compared to revascularization guided by angiography alone [38].However, the unexpected very low rate of adverse events during follow-up makes the results of this study not conclusive [38].More recently, the Fractional flow reserve versus angiography-guided strategy in acute myocardial infarction with multivessel disease (FRAME-AMI) trial demonstrated a lower risk of the composite of death, myocardial infarction, or repeat revascularization in patients with ACS and MVD undergoing complete revascularization guided by FFR compared to PCI guided by angiography strategy [40].
Therefore, the implementation of physiology to guide PCI decisions of NCLs remains controversial.

Intravascular imaging
The assessment of NCLs using intravascular imaging techniques can help to identify plaque characteristics associated with a higher risk of rupture including a high percentage of lipids, necrotic core, and thin fibrous cap (tin-cap fibroatheroma, TCFA), in patients with STEMI and MVD (Table 2 Currently, the main catheter-based imaging techniques are: intravascular ultrasound (IVUS), near-infrared spectroscopy (NIRS) and optical coherence tomography (OCT).
IVUS is an intravascular coronary imaging technique based on the use of ultrasounds with high penetration depth, which allows the assessment of the plaque burden and of the minimal lumen area (MLA) [42].The Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study enrolled 697 patients with ACS, who underwent three-vessel IVUS for the assessment of NCLs.The authors showed that the presence of plaque burden 70%, the presence of TCFA and an MLA 4 mm [2] were independent predictors of adverse events [19].
The assessment of lipid-rich plaques may be facilitated through NIRS, which is an intravascular coronary imaging technique used to estimate the lipid pool extension in coronary lesions [43,44].In Near-infrared spectroscopy predicts cardiovascular outcome in patients with coronary artery disease (ATHEROREMO-NIRS) study, lipid-rich plaques were associated with cardiovascular adverse events during follow-up [44].More recently, NIRS has been implemented in IVUS catheters to evaluate simultaneously the plaque burden and its lipid percentage [43].Indeed, the high percentage of lipid in coronary lesion and the high plaque burden has been associated with a significantly higher risk of adverse cardiac events [43].
Optical coherence tomography (OCT) is characterized by higher spatial resolution and allows a more accurate estimation of the thickness of TCFA and the detection of plaque components [45].In the Relationship between coronary plaque morphology of the left anterior descending artery and 12 months clinical outcome (CLIMA) study, the authors investigated the predictive value of specific plaque features identified by OCT.Among 1776 coronary lesions, the presence of MLA<3.5 mm 2 , fibrous cap thickness <75 mm, lipid arc circumferential exten-sion>180, and macrophage infiltration were associated with a higher risk of cardiovascular events [46].Also, in the Thin-cap fibroatheroma predicts clinical events in diabetic patients with normal fractional flow reserve (COMBINE OCT-FFR) trial, the presence of TCFA was associated with poor outcome in diabetic patients with negative FFR [47].Therefore, intravascular imaging may help to identify characteristics of plaque vulnerability in NCLs and may improve the prognostic stratification in patients with STEMI and MVD.However, the optimal revascularization strategy for patients with vulnerable NCLs remains to be determined.

Non-invasive assessment
The timing and the modality for non-invasive evaluation of residual ischemia in patients with NCLs and recent STEMI is still a matter of debate and depends largely on the local availability and expertise [6].
In addition, coronary computed tomography angiography (CCTA) may be implemented to identify specific features of atherosclerotic plaques such as low-attenuation plaque, napkin-ring sign, positive remodeling and spotty plaque calcification, which are associated with a higher risk of further adverse events (Table 2) [48e51].Ferencik and colleagues, in a secondary analysis of the PROMISE trial including 4415 patients, showed that high-risk plaques as defined by CCTA were associated with cardiovascular adverse events during follow-up.However, the study showed a low positive predictive value for CCTA which limits its clinical perspectives [52].
Currently, CCTA has been combined with computational fluid dynamics technologies to evaluate simultaneously both anatomical features and functional information of atherosclerotic plaques [53,54].
Lee et al. evaluated the prognostic significance of non-invasive hemodynamic parameters using CCTA in patients with NCLs and recent ACS.The study suggested that integrating non-invasive haemodynamic information with anatomical plaque characterization may improve the identification of NCLs with the highest risk of adverse events [55].However, the diagnostic accuracy of non-invasive hemodynamic parameters by CCTA for detecting residual ischemia in patients with NCLs and recent ACS was only modest when compared to invasive physiology techniques [56].
Cardiac magnetic resonance (CMR) is another non-invasive imaging modality that allows simultaneous assessment of left ventricular morphology and function, tissue characterization, and stress myocardial perfusion [57,58].
A recent sub-study from the Reducing Micro Vascular Dysfunction in Acute Myocardial Infarction by Ticagrelor (REDUCE-MVI) trial including 77 patients demonstrated the usefulness of stress perfusion CMR with adenosine for detecting residual ischemia in patients with NCLs and recent ACS.However, the diagnostic performance of this noninvasive technique was moderate when compared to invasive FFR assessment at one month (Table 2) [59].
Currently, the main limitation to the implementation of non-invasive diagnostic tools for the assessment of NCLs in patients with recent STEMI is the modest positive predictive value for the identification of lesions associated with a higher risk of future adverse events compared to invasive techniques [56,59].However, these methods are virtually risk-free and have the potential to avoid invasive examinations in patients with non-significant NCLs who do not require further coronary revascularization.
Future studies will determine whether non-invasive methods can be employed to guide the decision-making in STEMI patients with MVD.

Future perspectives
Currently, the optimal strategy for defining the anatomical and hemodynamic significance of NCLs to guide complete revascularisation decisions in patients with STEMI and coexisting NCLs remains to be determined.
Currently, the application of invasive physiology measurements to guide decisions on PCI of NCLs remains controversial.Therefore, the Physiologyguided vs Angiography-guided Non-culprit Lesion Complete Revascularization for Acute MI & Multivessel Disease (COMPLETE-2) study, a phase 3 trial, will investigate the prognostic role of physiologyguided complete revascularization compared to conventional angiography strategy in patients with MVD and recent ACS.
The Preventive PCI or medical therapy alone for vulnerable atherosclerotic coronary plaque (PRE-VENT) study will investigate the prognostic impact of preventive PCI in patients with high-risk plaque features quantified by intravascular imaging and negative value of FFR (FFR >0.80), compared to medical therapy alone.

Conclusions
In patients with STEMI, the prevalence of MVD is high and modern evidence supports the complete revascularization strategy during the index PCI procedure or at least within the first month to improve the patients' short-and long-term outcomes [6].
What is the best invasive or non-invasive modality for assessing the clinical relevance of NCLs remains an open question.In daily practice, the assessment of patients' comorbidities, hemodynamic status and coronary anatomy, together with the experience of the individual center in percutaneous treatment of complex lesions, directs patients toward dedicated pathways of clinical management.
Further evidence from large randomized trials is needed to establish a standardized approach in this complex clinical scenario.

Sources of funding
None.
Treatment of Culprit Lesion Only or Complete Revascularization (DANAMI-3 PRIMULTI), the FFR Guided Revascularization Versus Conventional Strategy in Acute STEMI Patients With MVD (COMPARE-ACUTE) and the Complete vs. Culprit-only Revascularization to Treat Multi-vessel Disease After Early PCI for STEMI (COMPLETE) trials demonstrated the benefit of complete revascularization guided by early fractional flow reserve (FFR) or coronary angiography compared to culprit-only lesion primary PCI [16e18].

Table 1 .
Randomized clinical trials comparing complete revascularization vs. culprit-only lesion revascularization strategies.
and 69% and FFR <0.80 Coprimary outcome 1. Composite of CV death and MI 2. Composite of CV death, MI, and ischemia-driven revascularization at 36 months FU Complete multivessel PCI reduced the risk of both coprimary outcome compared to culprit-only PCI CV, cardiovascular; FFR, fractional flow reserve; FU, follow-up; HF, heart failure; MI, myocardial infarction; MACE, major adverse cardiac events; MVD, multivessel disease; NCLs, non-culprit lesions; PCI, percutaneous coronary intervention.

Table 2 .
Studies providing the invasive and non-invasive assessment of NCLs in patients with multivessel coronary disease.