Controversy in cardiology: clopidogrel or acetylsalicylic acid in the treatment of chronic coronary syndromes?

Secondary prevention of patients with chronic coronary syndrome is based on the long-term use of a single anti-aggregating drug which is traditionally represented by acetylsalicylic acid (ASA) in light of the results of studies and meta-analyses which have demonstrated a clear anti-ischaemic efficacy against of an acceptable increase in the risk of bleeding, especially intracranial and gastrointestinal bleeding. The availability of drugs such as clopidogrel, which inhibits platelet activity through the P2Y12 receptor pathway, has called into question this paradigm, also in consideration of the fact that the scientific evidence that supports the use of ASA in secondary prevention is based on dated studies with some limitations. Over the last few years, randomized trials have demonstrated how clopidogrel has an efficacy profile comparable to that of ASA and a safety profile that is sometimes even better. In light of the new evidence, it is therefore legitimate to ask whether in this clinical scenario, ASA should still be considered the drug of choice or whether clopidogrel could represent the preferable alternative.

Intracoronary imaging to guide percutaneous coronary intervention: from evidence to guidelines.

Despite notable advances in devices and techniques, percutaneous coronary intervention (PCI) is still affected by a substantial number of complications and failure rates. Over the years, the use of intracoronary imaging (ICI) has dramatically improved the understanding of mechanical and technical factors related to successful and failed PCI, becoming a mainstay in complex trans-catheter interventions. However, ICI modalities are invasive, time-consuming, and costly, and a net clinical benefit needs to be shown in order to recommend their routine use in clinical practice. In the past, the lack of evidence from randomized trials has been reflected in the scepticism shown by international guidelines. The recent publication of large randomized clinical trials conducted worldwide has provided new evidence regarding the clinical usefulness of ICI guidance in PCI. The consistent reduction of adverse events achieved in these trials, also demonstrated in an updated meta-analysis, suggested that the use of ICI in PCI is compelling to achieve optimal technical results and better outcomes, especially in complex high-risk interventions. Also considering the burden of information provided by ICI on coronary artery disease, looking from the inside seems today an opportunity that modern cardiology cannot ignore anymore.

Eliminate LDL cholesterol after heart attack but only for a while.

There is a clear demonstration of the inverse linear correlation between LDL cholesterol levels and clinical benefit. However, the timing of the action of lipid-lowering drugs is not clear. According to animal studies with recombinant lipoprotein A-1, the composition of atherosclerosis changes within 40 h (with variations in lipid and inflammatory contents). Progression-regression studies of atherosclerosis in humans confirm the data, highlighting a rapid change in the plaque over 5 weeks. The data are also in line with what emerges from the survival curves of the old study comparing atorvastatin 80 mg vs. placebo (Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering). The spacing of the curves occurs after only 4 weeks, indicating the precociousness of the favourable effects of powerful statins. Finally, a recent Odyssey post hoc analysis compared the risk of cardiac death and coronary revascularization between a group in which alirocumab lowered LDL cholesterol to below 15 mg (Group 1 and in which the drug was therefore stopped) against the subjects in the placebo group (Group 2), applying a propensity score matching. The primary endpoint occurred in a lower percentage of patients in Group 1 (6.4 vs. 8.4%). Furthermore, patients in Group 1 had a significantly lower hazard ratio (HR) for major adverse cardiovascular events [0.72; 95% confidence interval (CI) 0.51-0.997; P = 0.047] compared with the entire alirocumab group vs. placebo (HR 0.85; 95% CI 0.78-0.93; P < 0.001). According to these preliminary observations, aggressive and early treatment of hypercholesterolaemia in subjects with acute coronary syndrome translates into improved clinical results compared with a strategy that provides for more gradual control. These data will need to be confirmed through further prospective clinical studies and ideally with early conducted atherosclerosis regression studies.

The temptation of anticoagulant therapy after transcatheter aortic valve implantation.

The choice of the best antithrombotic strategy after transcatheter aortic valve implantation (TAVI) must be based on the careful balance between the ischaemic risk and the bleeding risk and on the evaluation of some concomitant conditions, such as atrial fibrillation or coronary artery disease which may lead to the choice of anticoagulant treatment or antiplatelet therapy. Another element to consider is the possibility, albeit remote in post-TAVI patients, of thrombosis of the valve leaflets, an event whose clinical impact has yet to be fully clarified and which however appears to present a lower incidence in patients treated with anticoagulants. Recent evidence has shown that in patients who do not require anticoagulant therapy, single therapy with aspirin represents the best treatment compared to dual antiplatelet or to the addition of anticoagulant which in post-TAVI patients should be reserved only for those with a clear indication such as atrial fibrillation. It is still much debated whether in this case the choice should fall on vitamin K antagonists or on the new direct-acting anticoagulants, as the comparison studies have produced inconclusive results.

Does sacubitril/valsartan work in acute myocardial infarction? The PARADISE-AMI study.

Patients with acute myocardial infarction (AMI) complicated by left ventricular dysfunction have an increased risk of death and heart failure. Numerous clinical studies have demonstrated the ability of ACE inhibitors in optimizing the outcome in this particular clinical setting. In recent years, the sacubitril/valsartan association has drastically improved the prognosis of patients with heart failure with reduced ejection fraction with a significant decrease in mortality from cardiovascular causes and hospitalizations due to acute heart failure. However, it has not yet been fully clarified whether this pharmacological association may play a role in patients with AMI. Pre-clinical studies have suggested the possibility that sacubitril/valsartan can reduce the size of the infarct scar and prevent the onset of ventricular arrhythmias in laboratory animals in which myocardial infarction was induced. On the other hand, small clinical experiences with patients after myocardial infarction have provided conflicting data. The results of the PARADISE-MI study were recently presented, which enrolled 5661 patients with AMI complicated by pulmonary congestion and left ventricular dysfunction randomized to therapy with ramipril or sacubitril/valsartan and followed up for ∼2 years. Although combination therapy was associated with an ∼10% reduction in the risk of death from cardiovascular causes or an episode of heart failure, this was not enough to achieve statistical significance. However, treatment with sacubitril/valsartan was shown to be more effective than ramipril in preventing recurrence of heart failure after the first one.

Relationship between coronary plaque morphology of the left anterior descending artery and 12 months clinical outcome: the CLIMA study.

AIMS: The CLIMA study, on the relationship between coronary plaque morphology of the left anterior descending artery and twelve months clinical outcome, was designed to explore the predictive value of multiple high-risk plaque features in the same coronary lesion [minimum lumen area (MLA), fibrous cap thickness (FCT), lipid arc circumferential extension, and presence of optical coherence tomography (OCT)-defined macrophages] as detected by OCT. Composite of cardiac death and target segment myocardial infarction was the primary clinical endpoint. METHODS AND RESULTS: From January 2013 to December 2016, 1003 patients undergoing OCT evaluation of the untreated proximal left anterior descending coronary artery in the context of clinically indicated coronary angiogram were prospectively enrolled at 11 independent centres (clinicaltrial.gov identifier NCT02883088). At 1-year, the primary clinical endpoint was observed in 37 patients (3.7%). In a total of 1776 lipid plaques, presence of MLA <3.5 mm2 [hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.1-4.0], FCT <75 µm (HR 4.7, 95% CI 2.4-9.0), lipid arc circumferential extension >180° (HR 2.4, 95% CI 1.2-4.8), and OCT-defined macrophages (HR 2.7, 95% CI 1.2-6.1) were all associated with increased risk of the primary endpoint. The pre-specified combination of plaque features (simultaneous presence of the four OCT criteria in the same plaque) was observed in 18.9% of patients experiencing the primary endpoint and was an independent predictor of events (HR 7.54, 95% CI 3.1-18.6). CONCLUSION: The simultaneous presence of four high-risk OCT plaque features was found to be associated with a higher risk of major coronary events.

How should the ticagrelor be used? The point after the TWILIGHT and THEMIS-PCI studies.

The ticagrelor represents a cornerstone of antiplatelet therapy and its use has been supported, over the years, by several clinical trials that have enrolled thousands of patients; while the PLATO study initially demonstrated its effectiveness in the immediate treatment of acute coronary syndromes, the PEGASUS study documented the benefit of prolonging this treatment beyond 12 months from the heart attack. Over the past few months, two new randomized clinical trials have been published that have seen the use of ticagrelor in different clinical settings. The TWILIGHT study showed that in high-risk patients who completed 3 months of double antiplatelet drugs after coronary angioplasty, ticagrelor monotherapy is associated with a 44% reduction in the risk of clinically relevant bleeding in the absence of an increase in the ischaemic risk. The THEMIS study instead concluded that in the population of diabetics with stable coronary artery disease, but without a history of heart attack or stroke, a strategy that involves the addition of ticagrelor to the acetylsalicylic acid is not advisable as in the face of a benefit in the prevention of events ischaemic an increased risk of bleeding has been observed. Only in the subgroup of diabetic patients with a history of previous angioplasty would a more powerful antithrombotic therapy seem to be advantageous.

Subclinical atherosclerosis: how and when to treat it?

Atherosclerosis is a condition characterized by a long, initial, asymptomatic phase. Progression of disease could lead to acute coronary events, such as acute myocardial infarction, unstable angina, or sudden cardiac death. However, there are imaging techniques, namely vascular echography and assessment of coronary calcium, capable to make the diagnosis of atherosclerosis at an early stage. There are several studies demonstrating the ability of statins to delay, and in some situation even revert the progression of this condition. Subclinical atherosclerosis is highly prevalent in people with optimal control of the risk factors, and the imaging techniques have been shown to provide an added value over the traditional risk factors: by identifying directly the condition, these techniques allow the reclassification of low-risk to intermediate- or high-risk subjects, thus directing the primary prevention therapeutic strategies, based on high efficacy statins, aimed at delaying or reversing the progression of the disease.

The CLIMA study: assessing the risk of myocardial infarction with a new anatomical score.

Atherosclerosis is a chronic degenerative disease, with a significant inflammatory component, characterized by phases of rapid activation leading to important clinical events, such as myocardial infarction. One of the major challenges of modern cardiology is limiting the progression of atherosclerotic disease and anticipating the phases of instability as to limit its consequences. In this contest modern techniques of intra-coronary imaging, such as optical coherence tomography, could have a pivotal role in identifying patients at higher risk of acute events in the short term. The purpose of the CLIMA study is to identify and map the vulnerability criteria of atherosclerotic coronary plaques in the individual patient, and provide a personalized risk score for coronary events.

Role of residual acute stent malapposition in percutaneous coronary interventions.

OBJECTIVES: Assess clinical consequences of acute stent malapposition (ASM) in the context of the multicenter Centro per la Lotta Contro l'Infarto-Optimization of Percutaneous Coronary Intervention (CLI-OPCI) registry. BACKGROUND: ASM as important determinant of stent thrombosis (ST) risk remains controversial. METHODS: From 2009 to 2013, we retrospectively analyzed postprocedural optical coherence tomography (OCT) findings in 864 patients undergoing percutaneous coronary intervention, assessing prevalence and magnitude of ASM and exploring correlation with outcome, especially ST. RESULTS: Postprocedural OCT revealed a variable grade of ASM in 72.3% of stents without correlation between maximal strut-vessel distance and longitudinal extension (R = 0.164, P < 0.01). At a median follow up of 302 (IQ 127-567) days, ASM did not affect risk of following major cardiac adverse events (MACE); residual ASM was comparable in terms of thickness (median [quartiles] 0.21[IQ 0.1-0.4] vs. 0.20[IQ 0.0-0.3], P = 0.397) and length (2.0[IQ 0.5-4.1] vs. 2.2[IQ 0.0-5.2], P = 0.640) in patients with versus without MACE. The predictive accuracy for outcome was low (C-statistic 0.52, CI 95% 0.47-0.58, P = 0.394) as well for target lesion revascularization (HR 0.80, CI 95% 0.5-1.4) and ST (HR 0.71, CI 95% 0.3-1.5). Likewise, timing to MACE was not influenced by presence of such an ASM with similar rate of acute-subacute (HR 1.09, CI 95% 0.6-1.9), late (HR 0.91, CI 95% 0.5-1.8), and very late (HR 1.23, CI 95% 0.5-2.9) events. CONCLUSIONS: Limited ASM was a common finding after stent implantation, but was not associated to increased risk of stent failure or ST during mid-term follow-up. © 2017 Wiley Periodicals, Inc.

Suboptimal stent deployment is associated with subacute stent thrombosis: optical coherence tomography insights from a multicenter matched study. From the CLI Foundation investigators: the CLI-THRO study.

BACKGROUND: Acute or subacute stent thrombosis (ST) is a well-described complication usually causing acute coronary syndromes and, in the worst case scenario, sudden cardiac death. In this study, we aimed at exploring the potential role of optical coherence tomography (OCT) in the understanding of the mechanism of ST. METHODS: Twenty-one consecutive patients, after acute coronary syndromes due to a definite subacute ST, were assessed with OCT and matched 1:2 with 42 patients undergoing OCT for scheduled follow-up. Optical coherence tomography assessment was focused on features indicative of nonoptimal stent deployment: underexpansion, malapposition, edge dissection, and reference lumen narrowing. RESULTS: Optical coherence tomography revealed a minimum stent area sensibly smaller in the ST group (5.6 ± 2.6 vs 6.8 ± 1.7 mm(2); P = .03) with a higher incidence of stent underexpansion when compared with the control group (42.8% vs 16.7%; P = .05). Dissection at stent edges was more commonly detected in ST group (52.4% vs 9.5%; P < .01). No significant differences between the 2 groups were observed for malapposition (52.4% vs 38.1%; P = .651) and reference lumen narrowing (19.0% vs 4.8%; P = .172). At least 1 OCT finding indicative of suboptimal stent deployment was detectable in 95.2% of patients experiencing ST versus 42.9% of the control group (P < .01). CONCLUSIONS: Optical coherence tomography assessment in patients experiencing subacute ST revealed nonoptimal stent deployment in almost all cases with higher incidence of stent underexpansion and edge dissection, potentially explaining the cause of this adverse event. The adoption of an OCT-guided percutaneous coronary intervention protocol could have a potential for the prevention of ST in complex cases.

Randomized evaluation of intralesion versus intracoronary abciximab and aspiration thrombectomy in patients with ST-elevation myocardial infarction: The COCTAIL II trial.

BACKGROUND: Thrombus burden and distal embolization are predictive of no-reflow during primary percutaneous coronary intervention (PCI) in patients with acute ST-elevation myocardial infarction (STEMI). We sought to compare the efficacy of pharmacological and catheter-based strategies for thrombus in patients with STEMI and high atherothrombotic burden. METHODS: Between January 2012 and December 2013, 128 STEMI patients undergoing primary PCI at 5 centers were randomly assigned in a 2 × 2 factorial design to intracoronary (IC) abciximab bolus (via the guide catheter) versus intralesion (IL) abciximab bolus, each with versus without aspiration thrombectomy (AT). Study end points were residual intrastent atherothrombotic burden, defined as the number of cross-sections with residual tissue area >10% as assessed by optical coherence tomography, and indices of angiographic and myocardial reperfusion. RESULTS: Residual intrastent atherothrombotic burden did not significantly differ with IL versus IC abciximab (median [interquartile range] 6.0 [1-15] vs 6.0 [2-11], P = .806) and with AT versus no aspiration (6.0 [1-13] vs 6.0 [2-12], P = .775). Intralesion abciximab administration was associated with improved angiographic myocardial reperfusion in terms of thrombolysis in myocardial infarction (TIMI) flow (3 [3-3] vs 3 [2-3], P = .040), corrected TIMI frame count (12 ± 5 vs 17 ± 16, P = .021), and myocardial blush grade (3 [2-3] vs 3 [2-3], P = .035). In particular, IL abciximab was associated with higher occurrence of final TIMI 3 flow (90% vs 73.8%, P = .032) and myocardial blush grade 3 (71.6% vs 52.4%, P = .039). Conversely, AT had no significant effect on indices of angiographic or myocardial reperfusion. CONCLUSIONS: In patients with STEMI and high thrombotic burden, neither IL versus IC abciximab nor AT versus no aspiration reduced postprocedure intrastent atherothrombotic burden in patients with STEMI undergoing primary PCI. However, IL abciximab improved indices of angiographic and myocardial reperfusion compared to IC abciximab, benefits not apparent with AT.

Thresholds for platelet reactivity to predict clinical events after coronary intervention are different in patients with and without diabetes mellitus.

Patients with diabetes mellitus (DM) have increased baseline platelet reactivity and impaired response to antiplatelet drugs, compared to non-diabetics. Aim of the present study was to investigate whether thresholds for high platelet reactivity (HPR) that predict clinical outcomes after percutaneous coronary intervention (PCI) are similar in diabetic compared to non-diabetic patients. A total of 640 (32.6% with DM) consecutive patients taking aspirin and clopidogrel undergoing elective PCI were recruited. Platelet reactivity was measured immediately before the procedure with the VerifyNow P2Y12 assay. Primary end point was the 30-day incidence of major adverse cardiac events (MACE) in relation to the presence of DM and to P2Y12 reaction units (PRU) distribution. The optimal cut-off to predict 30-day MACE was a PRU value of >256 in diabetics, and a PRU value of >229 in non-diabetics. Accordingly, we redefined HPR on the basis of these two specific thresholds (HPR-ST), now including 60/209 (29%) diabetic patients with PRU >256, and 130/431 (30%) non-diabetic patients with PRU >229. HPR-ST discriminates significantly (p < 0.001) patients with and without MACE, with a diagnostic accuracy of 73%. The combination of DM and HPR-ST resulted in the highest incidence of MACE (23.3%; p for trend <0.001). At multivariate analysis, HPR-ST was the strongest independent predictor of 30-day MACE (odds ratio 4.80, 95% confidence interval 2.58-8.93; p < 0.001). Redefining HPR based on specific thresholds for patients with and without DM significantly improves prediction of MACE post-PCI. Patients with HPR-ST, especially in the presence of DM, are at increased risk for ischemic events and may benefit from more aggressive antiplatelet strategies.

Subacromial contact after acromioplasty in the rotator cuff deficient shoulder.

Subacromial impingement (SAI) is associated with shoulder pain and dysfunction and is exacerbated by rotator cuff tears; however, the role of acromioplasty in mitigating subacromial contact in the rotator cuff deficient shoulder remains debated. This study aimed to quantify the influence of isolated and combined tears involving the supraspinatus on subacromial contact during abduction; and second, to evaluate the influence of acromioplasty on joint space size and subacromial contact under these pathological conditions. Eight fresh-frozen human cadaveric upper limbs were mounted to a computer-controlled testing apparatus that simulated joint motion by simulated force application. Shoulder abduction was performed while three-dimensional joint kinematics was measured using an optoelectronic system, and subacromial contact evaluated using a digital pressure sensor secured to the inferior acromion. Testing was performed after an isolated tear to the supraspinatus, as well as tears involving the subscapularis and infraspinatus-teres minor, both before and after acromioplasty. Rotator cuff tears significantly increased peak subacromial pressure (p < 0.001), average subacromial pressure (p = 0.001), and contact force (p = 0.034) relative to those in the intact shoulder. Following acromioplasty, significantly lower peak subacromial contact pressure, force and area were observed for all rotator cuff tears involving the supraspinatus at 30° of abduction (p < 0.05). Acromioplasty predominantly reduces acromion thickness anteriorly thereby reducing subacromial contact in the rotator cuff deficient shoulder, particularly in early to mid-abduction where superior glenohumeral joint shear force potential is large. These findings provide a biomechanical basis for acromioplasty as an intervention for SAI syndrome and as an adjunct to rotator cuff repairs.

Muscle and joint function in the rotator cuff deficient shoulder.

Full-thickness rotator cuff tears can lead to poor coaptation of the humeral head to the glenoid, disrupting muscle forces required for glenohumeral joint stability, ultimately leading to joint subluxation. The aim of this study was to evaluate muscle forces and glenohumeral joint translations during elevation in the presence of isolated and combined full-thickness rotator cuff tears. Eight fresh-frozen upper limbs were mounted to a computer-controlled testing apparatus that simulated joint motion by simulated muscle force application. Scapular-plane abduction was performed, and glenohumeral joint translations were measured using an optoelectronic system. Testing was performed in the native shoulder, a following an isolated tear to the supraspinatus, as well as combined tears involving the supraspinatus and subscapularis, as well as supraspinatus, infraspinatus, and teres minor. Rotator cuff tears significantly increased middle deltoid force at 30°, 60°, and 90° of abduction relative to that in the native shoulder (p < 0.05). Significantly greater superior translations were observed relative to the intact shoulder due to combined tears to the supraspinatus and infraspinatus at 30° of abduction (mean increase: 1.6 mm, p = 0.020) and 60° of abduction (mean increase: 4.8 mm, p = 0.040). This study illustrates the infraspinatus-teres minor complex as a major humeral head depressor and contributor to glenohumeral joint stability. An increase in deltoid force during abduction occurs in the presence of rotator cuff tears, which exacerbates superior migration of the humeral head. The findings may help in the development of clinical tests in rotator cuff tear diagnostics, in surgical planning of rotator cuff repair, and in planning of targeted rehabilitation.

Takotsubo Syndrome and Gender Differences: Exploring Pathophysiological Mechanisms and Clinical Differences for a Personalized Approach in Patient Management.

Takotsubo syndrome (TTS), also known as the broken-heart syndrome, is a reversible condition typically observed in female patients presenting for acute coronary syndromes (ACS). Despite its increasing incidence, TTS often remains undiagnosed due to its overlap with ACS. The pathophysiology of TTS is complex and involves factors such as coronary vasospasm, microcirculatory dysfunction, increased catecholamine levels, and overactivity of the sympathetic nervous system. Diagnosing TTS requires a comprehensive approach, starting with clinical suspicion and progressing to both non-invasive and invasive multimodal tests guided by a specific diagnostic algorithm. Management of TTS should be personalized, considering potential complications, the presence or absence of coronary artery disease (CAD), diagnostic test results, and the patient's clinical course. The current data primarily derive from case series, retrospective analyses, prospective registries, and expert opinions. In recent years, there has been growing recognition of gender differences in the pathophysiology, presentation, and outcomes of TTS. This review provides an updated overview of gender disparities, highlighting the importance of tailored diagnostic and management strategies.

Aspirin in Primary Prevention: Looking for Those Who Enjoy It.

Based on a wealth of evidence, aspirin is one of the cornerstones of secondary prevention of cardiovascular disease. However, despite several studies showing efficacy also in primary prevention, an unopposed excess risk of bleeding leading to a very thin safety margin is evident in subjects without a clear acute cardiovascular event. Overall, the variability in recommendations from different scientific societies for aspirin use in primary prevention is a classic example of failure of simple risk stratification models based on competing risks (atherothrombosis vs. bleeding), perceived to be opposed but intertwined at the pathophysiological level. Notably, cardiovascular risk is dynamic in nature and cannot be accurately captured by scores, which do not always consider risk enhancers. Furthermore, the widespread use of other potent medications in primary prevention, such as lipid-lowering and anti-hypertensive drugs, might be reducing the benefit of aspirin in recent trials. Some authors, drawing from specific pathophysiological data, have suggested that specific subgroups might benefit more from aspirin. This includes patients with diabetes and those with obesity; sex-based differences are considered as well. Moreover, molecular analysis of platelet reactivity has been proposed. A beneficial effect of aspirin has also been demonstrated for the prevention of cancer, especially colorectal. This review explores evidence and controversies concerning the use of aspirin in primary prevention, considering new perspectives in order to provide a comprehensive individualized approach.

Effects of Lipid Lowering Therapies on Vulnerable Plaque Features: An Updated Narrative Review of the Literature.

The clinical evidence on the efficacy of lipid lowering therapy in patients with coronary artery disease (CAD) is unequivocally established. However, the effects of these therapies on plaque composition and stability are less clear. The use of intracoronary imaging (ICI) technologies has emerged as a complement to conventional angiography to further characterize plaque morphology and detect high-risk plaque features related to cardiovascular events. Along with clinical outcomes studies, parallel imaging trials employing serial evaluations with intravascular ultrasound (IVUS) have shown that pharmacological treatment has the capacity to either slow disease progression or promote plaque regression, depending on the degree of lipid lowering achieved. Subsequently, the introduction of high-intensity lipid lowering therapy led to much lower levels of low-density lipoprotein cholesterol (LDL-C) levels than achieved in the past, resulting in greater clinical benefit. However, the degree of atheroma regression showed in concomitant imaging trials appeared more modest as compared to the magnitude of clinical benefit accrued from high-intensity statin therapy. Recently, new randomized trials have investigated the additional effects of achieving very low levels of LDL-C on high-risk plaque features-such as fibrous cap thickness and large lipid accumulation-beyond its size. This paper provides an overview of the currently available evidence of the effects of moderate to high-intensity lipid lowering therapy on high-risk plaque features as assessed by different ICI modalities, reviews data supporting the use of these trials, and analyse the future perspectives in this field.