In patients with STEMI, grading tools are frequently employed for quantifying the ICT burden, with angiography playing a crucial role in its assessment. Angiographically, ICT is characterized by the identification of a lack of filling accompanied by declined density of contrast or cloudiness. The extensively utilized grading tool is the Thrombolysis in Myocardial Infarction (TIMI) scale, which evaluates the thrombus relative size compared with the affected vessel. This scale ranges from grade 0, indicating the absence of a thrombus, to grade 5, representing a massive thrombus causing complete vessel occlusion.

Grade 0 indicates the absence of thrombus or any angiographic filling defect. Grade 1 denotes the possibility of a thrombus, as indicated by angiographic signs, including irregular lesion contours, smooth convex meniscus, or reduced contrast density at the site of occlusion. Grade 2 indicates a definite thrombus with dimensions ≤50% diameter of vessel. Grade 3 represents a definite thrombus with length exceeding 50% the vessel diameter. Grade 4 indicates a large thrombus with dimensions greater than two vessel diameters. Grade 5 signifies a very large thrombus causing complete vessel occlusion (18).

Sianos et al. suggested that when a grade 5 thrombus is present, a 1.25- or 1.5 mm balloon or a guidewire should be used to recanalize the artery. Residual thrombus is further classified into grade 0, indicating no residual thrombus; grades 1–3, representing small residual thrombi; and grades 4–5, indicating large residual thrombi. Nicoli et al. proposed a simplified classification wherein TIMI grades 1–3 are considered low grade, whereas TIMI grades 4–5 are categorized as high grade. This simplified system provides a practical approach to thrombus evaluation while retaining clinical significance (19, 20).

The presence of ICT during ACS is correlated with suboptimal coronary reperfusion and worse clinical outcomes (1, 22, 23). Quantifying the impact of a thrombus on the microvascular circulation can be assessed using the Myocardial Blush Grade (MBG) or the degree of ST-segment Resolution (STR) (24). MBG, primarily a biomarker for capillary-level perfusion, and STR have both been shown to serve as independent mortality markers (25).

Grading tools provide a standardized approach for assessing thrombus burden and its correlation with clinical outcomes. Moreover, they guide management decisions both before and during PCI. Persistent chest pain, distal vessel occlusion, and electrocardiogram changes can result from ICT presence and distal embolization into the microcirculation. Even when normal epicardial flow is restored, Microvascular Obstruction (MVO) and distal embolization are associated with adverse outcomes, including reduced ventricular function and larger infarct size.

Considering the severe clinical consequences of inadequately resolving thrombus, interventional cardiologists should adopt effective management strategies aimed at ICT management and prevention during STEMI. Lesion characteristics, disease state, and patient-related factors represent the factors contributing to the thrombus burden during ACS, as outlined in Table 2 (26).

GPIs, including abciximab, tirofiban, and eptifibatide, inhibit platelet aggregation by competing with fibrinogen and vWF in binding to the GPIIb/IIIa receptor. These agents are more potent than P2Y12 inhibitors as they halt the final common pathway to platelet aggregation and lower the response of platelets to all agonists, causing rapid and comprehensive inhibition (31). Studies on patients with STEMI have reported that GPIs provide various advantages, including survival benefits and improvements in TIMI flow and thrombus resolution (9, 32). However, these favorable clinical outcomes were predominantly noted in the period preceding significant advancements, such as thrombectomy, contemporary stents, potent P2Y12 inhibitors, and routine DAPT (33). Despite their efficacy in enhancing TIMI flow and reducing thrombus burden, the high bleeding risk associated with GPIs represents a significant limitation.

A meta-analysis of 10,123 patients undergoing PPCI reported that GPIs reduced the incidence of nonfatal MI from 8.3% to 5.1% at the 30-day follow-up; however, this reduction was accompanied by an increased risk of thrombocytopenia and minor bleeding (34).

GPIs routine clinical use of GPIs in STEM1 undergoing PCI is not recommended. Instead, recent guidelines have suggest that GPIs should be reserved for bailout therapy or high-risk patients transferred for PPCI (30).

In the IRA, intracoronary abciximab administration theoretically provides an advantage over the IV route by delivering a higher local concentration of the drug, subsequently resulting in greater receptor occupancy, thereby promoting more effective thrombus resolution (35). Small-scale studies have demonstrated the clinical benefits of intracoronary abciximab bolus administration; however, large-scale clinical trials have not corroborated these findings (36).

At the follow-up of 90 days, no significant difference was observed in the composite primary endpoints of abciximab in patients presenting with STEMI, as shown in the AIDA-STEMI trial, which compared the clinical efficacy of intracoronary vs. IV bolus administration. This lack of significant clinical benefit suggests that although intracoronary administration holds theoretical promise, its role remains uncertain (37, 38).

Considering the current evidence, large-scale randomized trials should be conducted to demonstrate the potential benefits of intracoronary GPIs and determine their precise role in STEMI management (30).

Intracoronary thrombolytic agent administration facilitates the delivery of high drug concentrations directly to the thrombus site, potentially achieving effective thrombolysis. Early anecdotal reports and small series investigating the use of intracoronary thrombolytics led to various randomized controlled trials. These studies assessed endpoints, including microvascular perfusion, left ventricular (LV) function, Major Adverse Cardiovascular Events (MACE), infarct size, and epicardial flow (39–43).

A meta-analysis of these trials suggested that intracoronary thrombolysis was associated with a reduced incidence of in-hospital MACE, no significant bleeding risk, and improved STR (44). Despite these promising results, the available data on intracoronary fibrinolytic use remain inadequate. The precise clinical benefit of thrombolytic agents administered intracoronary remains unclear owing to the heterogeneity in study designs and limited patient populations. Additionally, in several of these studies, potent P2Y12 inhibitors were not utilized, which could have influenced the outcomes.

Currently, two ongoing Phase III trials aim to further clarify the role of intracoronary thrombolytics. Among patients undergoing primary PCI for STEMI and large thrombus burden, intracoronary administration of alteplase was not superior to placebo in reducing the composite primary outcome of MACE at 30 days, MBG 0/1, distal embolization or failure to achieve ≥50% ST-segment resolution. These data do not support the routine administration of this therapy in patients with STEMI undergoing primary PCI (45). RESTORE-MI trial (the Restoring Microcirculatory Perfusion in STEMI trial) is focused on Tenecteplase. This trial is anticipated to provide more definitive evidence regarding the efficacy and safety of intracoronary thrombolytic therapy in STEMI management.

Maintaining adequate anticoagulation is essential to effectively inhibit the coagulation cascade and prevent thrombus development. In PPCI, Unfractionated Heparin (UFH), bivalirudin, and enoxaparin are the most frequently administered anticoagulants. However, no placebo-controlled randomized trials that directly evaluate the role of UFH in PPCI have been conducted.

The ATOLL trial compared enoxaparin (0.4 mg/kg IV bolus) with UFH in the context of PPCI and reported that enoxaparin significantly reduced secondary endpoints, including recurrent MI, ACS, and urgent revascularization, without a marked rise in bleeding events. However, no significant difference was observed in the primary endpoint of 30-day MACE or significant bleeding. In contrast, the superior clinical efficacy of the enoxaparin over UFH has been demonstrated by finding of meta-analysis of 23 PCI trials in which 30,966 patients (33% undergoing PPCI), were enrolled. In patients undergoing PPCI, enoxaparin was associated with a marked decline in bleeding complications and a lower incidence of mortality (46).

Based on this evidence, the routine administration of IV enoxaparin during PPCI has been assigned a Class II recommendation in the recent European Society of Cardiology (ESC) guidelines. This classification highlights its role as a preferred anticoagulant option for improving outcomes in patients with STEMI undergoing PPCI.

During PPCI, vasodilators, including nitroglycerin, nitroprusside, and adenosine, are frequently administered in patients with a HTB to reduce the risk of the no-reflow phenomenon and distal embolization. A guiding catheter, infusion balloon, or infusion catheter are used for the administration of these agents.

Vasodilators used in this context can be classified into the following three categories: (a)

Vasodilators with primary activity on epicardial coronary arteries: these agents, including nitroglycerin, cause significant dilation of the large coronary arteries with minimal or no effect on microcirculation (29).

Distal embolization during PPCI in thrombotic lesions can cause adverse events, including obstruction of the distal epicardial arteries or microvasculature. Direct stenting has been proposed as a strategy for reducing the distal embolization incidence by minimizing thrombus manipulation and executing thrombus entrapment behind the stent. DS is a technique in which thrombus and loose plaque material are compressed by the stent to reduce the risk of distal embolization. In comparison to conventional stenting, DS is associated with various positive outcomes like marked improvement in ST-resolution and a decline in no-reflow phenomenon and in-hospital mortality. This treatment modality is widely clinically practiced; however, no formal guideline recommendations for it exist.

In a major proportion of patients presenting with high-grade thrombus and acute STEMI, DS or direct-like stenting can be utilized specifically in cases where the distal landing zone is visualized after guidewire crossing or when the stent can cross (51, 52). However, inadequate stent expansion, late stent malapposition, underestimating the actual vessel size, and difficulties in crossing calcified and tortuous stenosis constitute the limitations of direct stenting, which can increase the risks of stent thrombosis or restenosis.

A meta-analysis of five RCTs revealed that direct stenting was associated with a reduced incidence of in-hospital cardiovascular death and significant improvements in STR (53) However, considering the absence of definitive clinical benefits in broader contexts, the decision to use direct stenting should be based on lesion anatomy. In carefully selected patients with Acute Myocardial Infarction (AMI) and low-grade thrombus burden, direct stenting, with or without prior Thrombus Aspiration (TA), may be a safe and effective alternative. DS success rates can be increased by using a deflated balloon, as suggested by recent literature. Large thrombus burden angioplasty done by direct stenting is shown in Figure 2.

• Extremely large thrombus burden with compromised distal flow (TIMI 0–1).

• Calcified lesions requiring vessel preparation if the distal landing zone is not visible.

In select cases of large thrombus burden, direct stenting represents a viable first-line approach, particularly when the thrombus composition and lesion morphology are favorable. Combining this strategy with guideline-recommended pharmacotherapy and adjunctive mechanical interventions ensures safe and effective thrombus management. Other strategies, including aspiration thrombectomy or pharmacomechanical interventions, can serve as alternatives in cases when direct stenting is inappropriate.

Bare metal stents with a fine mesh covering are used for developing covered stents, enabling thrombus capture and mitigating the risk of distal embolization. Randomized trials have evaluated two types of coronary covered stents, including InspireMD (MGuard) and STENTYS SA.

The MGuard stent can be extended by balloon. It has closed-cell design and is a bare metal stent that is covered with polyethylene terephthalate. Although it has demonstrated benefits, including a reduced mortality rate at 1-year follow-up and complete STR in the MASTER I trial (50), it was associated with significant limitations, such as bulky double-layer design, high stent dislodgment rate, and increased risk of side-branch occlusion. Due to these drawbacks, the MASTER II trial, in which 1114 patients were planned to enrolled, was prematurely discontinued (54).

The STENTYS stent is a self-expanding, self-apposing nitinol platform coated with a drug-containing durable polymer designed to retain the thrombus against the vessel wall. Although its design offers theoretical advantages, including thrombus containment, evidence supporting the routine clinical use of covered stents is currently insufficient (55). To clarify their role in managing thrombotic lesions during PCI, further research is warranted.

Deferred stenting is a treatment approach designed to mitigate the risk of no-reflow phenomena and distal embolization by allowing time for partial thrombus resolution and improvement in microvascular dysfunction before stent placement. DEFER-STEMI trial (The Deferred Stenting Versus Immediate Stenting to Prevent No or Slow-Reflow in Acute ST-Segment Elevation Myocardial Infarction trial) enrolled 410 patients with STEMI to compare the outcomes of deferred vs. immediate stenting. The study reported a lower incidence of higher TIMI flow grades and no-flow phenomena at the procedure end in the high-risk population (56). However, in comparison to conventional PCI, at the follow-up of 42-months, no significant reduction was seen in the primary composite endpoint of heart failure, MI, repeat re-vascularization, or all-cause mortality in long-term findings from the DEFER-STEMI trial (57).

Based on the current evidence, the routine clinical use of deferred stenting is not recommended and is categorized as Class III/A. The advantages and disadvantages of deferred stenting compared with direct stenting are detailed in Table 3, providing insights into its potential role in selected clinical scenarios (58).

In 1995, Auth et al. introduced the first aspiration catheter system. Subsequent catheter design innovations have yielded substantial improvements, including hydrophilic coatings, enhanced flexibility, tapered distal tips, and lower crossing profiles. Among the manual TA devices, the Export AP remains one of the most frequently employed in clinical practice.

The REMEDIA trial, the first randomized clinical trial to evaluate manual aspiration, demonstrated a significant reduction in the no-reflow phenomenon, distal embolization, and improved STR. However, these improvements did not translate into better clinical outcomes (59). Similarly, the TAPAS trial, which enrolled 1,071 patients, demonstrated a marked decline in MACE, when aspiration manually was utilized alongside PPCI (60). In contrast, subsequent large-scale trials, including TASTE trial (Thrombus aspiration in ST-Elevation Myocardial infarction) TOTAL trial (61) and Thrombectomy with PCI vs. PCI Alone) (62), demonstrated no clinical benefits of routine TA.

Considering these findings, the 2017 ESC guidelines do not recommend routine TA before PPCI (Class III, Level of Evidence A). although, particular or rescue TA may be considered (Class IIb, Level of Evidence C-LD) in patients who have a massive residual thrombus following vessel following crossing with guidewire and no distal landing zone visible. Large thrombus burden angioplasty done aided by manual aspiration catheter is shown in Figure 3.

Owing to their ease of use and convenience, manual thrombectomy devices provide advantages over motorized equivalents. These devices primarily comprise monorail catheters with a lumen at centre that communicates with one or more openings. Proximally, the attachment of the catheter with a syringe is carried out for manual thrombotic aspiration.

The Diver CE (Invatec), Hunter (IHT Cordynamic), Quick Cat (Spectranetics), Export (Medtronic), and Pronto (Vascular Solutions) are currently available manual thrombectomy devices. Although the operational mechanism of these devices is fundamentally similar, the difference in various aspects like aspiration lumen size, catheter material and theoretical efficiency in thrombus deliverability and extraction is seen. These design variations may influence their performance in clinical practice, providing physicians a variety of options to tailor thrombectomy strategies on the basis of individual patient and lesion characteristics.

(a) Diver CE

Furthermore, the risks of slow-reflow, distal embolization, and no-reflow phenomenon were mitigated owing to the device. Subgroup analysis revealed that patients with a HTB or occluded arteries exhibited the most pronounced primary clinical benefits, emphasizing the potential value of manual TA in these specific patient populations.

In patients present with anterior STEMI, more effective STR at 90 min and marked better post-procedure MBG was seen with Diver CE catheter in the findings of another small randomized study (64). These findings confirm the role of manual thrombectomy devices as a valuable adjunct in selected patients with a HTB during PPCI.

(b) Pronto

Two versions of the Pronto catheter, V3 and low profile, are utilized in PPCI. The LP version features improved deliverability, facilitating effective navigation and treatment of vessels with diameters as small as 1.5 mm. This advantage makes it a versatile tool for managing challenging thrombotic lesions in small and tortuous vessels during PCI.

(c) Export

Furthermore, the larger TAPAS trial, a single-center randomized study involving 1,071 patients, utilized the Export catheter. At the follow-up of 1-year, a reduced incidence of cardiac death and nonfatal reinfarction was seen with manual thrombectomy as suggested by the study findings (59). However, LV function or infarct size was not evaluated in the TAPAS trial; instead, it focused on myocardial perfusion improvements. These findings highlight the utility of manual thrombectomy in enhancing myocardial perfusion in patients with STEMI, particularly with the export catheter.

(d) Thrombuster

The outcomes of randomized clinical trials comparing standard PCI with PCI plus manual thrombectomy are summarized in Table 4, providing a comprehensive overview of the clinical impact of thrombectomy devices in enhancing the procedural and long-term outcomes.

Depending on the potential to undergo fragmentation of the atherosclerotic thrombus material before aspiration, mechanical l thrombectomy devices exhibit distinct operational mechanism. The AngioJet, X-Sizer, and Rinsipratory system are associated with a significant risk of active thrombus fragmentation.

(a) AngioJet rheolytic thrombectomy

The JETSTENT trial, which enrolled 501 patients with STEMI with visible thrombus, reported no significant differences between direct stenting and mechanical thrombectomy in terms of STR, TIMI blush grade-3, or infarct size. However, follow-up at 1 and 6 months revealed a significant reduction in MACE and improved 1-year event-free survival with the use of MT (71).

Based on the available evidence, the AngioJet system provides clinical benefits in patients with substantial thrombus burdens but does not offer considerable advantages in those with minimal thrombus burdens. For optimized outcomes, selective use of this system should be considered in cases of HTBs.

(b) X-sizer thrombectomy system

The X-TRACT-AMI study, involving 216 patients, showed no significant improvement in TIMI III flow or MBG after using the X-Sizer device. Despite this, MACEs were avoided in 93% of patients at 30 days and 83% at 360 days. Overall, clinical outcomes remained favorable (72).

Despite these advantages, the X-Sizer catheter has notable limitations. Its rigidity restricts its use in heavily calcified or tortuous vessels. Additionally, its bulky design precludes its use in arteries smaller than 2.5 mm and in very tight lesions. The risk of coronary artery perforation is increased owing to the presence of the cutting blade, housed within the outer lumen, further limiting its routine application in PPCI (73). These drawbacks underscore the need for careful patient selection when considering the X-Sizer catheter for thrombus management.

(c) Rinspirator system

Considering the limitations of existing devices, which frequently fail to remove organized thrombus, adequately revascularize vessels with large clot burdens, or prevent distal embolization, a novel system called the Indigo™ Catheter System (Penumbra®, Alameda, CA, USA) has emerged. Commercially introduced in the United States in 2014, this system has garnered substantial attention for managing thromboembolic disease in peripheral arteries, including the visceral and upper extremities.

The Indigo system utilizes a vacuum pump that generates substantial suction (29 mmHg) to aspirate clots of varying lengths and sizes, thereby promoting effective thrombectomy. The device comprises the following three main components: the separator, pump, and aspiration catheter. Two sizes of aspiration catheters, CAT 5 and CAT 3, are primarily used. The separator facilitates clot mobilization and catheter lumen cleaning, ensuring continuous aspiration and flow restoration. This system offers a major advantage in that it eliminates the requirement for lytics, enabling rapid blood flow reestablishment.

To evaluate its safety and clinical performance in patients with large ICT burdens, a multicenter prospective CHEETAH study was conducted. This single-arm post-market registry included 400 patients from 25 hospitals in the United States enrolled between August 2019 and December 2020. The study demonstrated that sustained mechanical aspiration before PCI using the CAT RX Aspiration Catheter was safe and yielded favorable clinical outcomes, including successful flow restoration, normal myocardial perfusion on final angiography, and high ICT removal rates. Notably, no device-related serious adverse events were reported, further supporting its safety and efficacy in this high-risk patient population (75). Large thrombus burden angioplasty done aided by CAT RX Aspiration Catheter is shown in Figure 4

New suction devices, including the Penumbra, present viable alternatives to manual aspiration, particularly in cases of high-risk STEMI or when a large thrombus burden is present. Their efficiency, safety, and adaptability make them a valuable addition to the PPCI armamentarium. However, broader adoption will depend on further clinical data, cost-effectiveness, and operator experience.

A flexible tube with occlusion balloon, which can be inflated is a major characteristics feature of distal occlusion aspiration devices. In this procedure, several centimetres distal to the lesion, the balloon was passed and inflated using a carbon dioxide-filled syringe to block antegrade blood flow. This strategy prevents distal embolization during PCI. However, it has significant drawbacks, including the inability to fully visualize the lesion owing to complete flow blockage and the risk of thrombogenesis and slow-flow states.

EMERALD trial (The Exploring the Mechanism of Plaque Rupture in ACS Using Aspiration of Liberated Debris in Acute MI with GuardWire Plus System trial) evaluated the safety and efficacy of adjunctive PercoSurge (a distal occlusion device) compared with conventional PCI (68). Device safety is demonstrated by the study, but it did not demonstrate the clinical outcomes in terms of infarct size reduction. These findings indicate that although distal occlusion devices may be safe, their routine use in PCI for STEMI lacks robust clinical impact and remains unsupported for broad adoption (68).

New suction devices, including the Penumbra Indigo System, provide considerable advancements over manual aspiration for PPCI, particularly in cases with large thrombus burdens.