Given the pathogenesis of STEMI, the occurrence and development of STEMI are always accompanied by thrombosis in the coronary artery. Intracoronary artery thrombosis can obstruct the coronary artery lumen, which leads to the phenomena of slow flow/no reflow, and acute ischemic injury and necrosis in the myocardium, resulting, clinically, in STEMI. The composition of these thrombi significantly influences the prognosis and selection of therapeutic strategies for STEMI patients. The TIMI flow grade in the IRA is evaluated before and after performing percutaneous transluminal coronary angioplasty (PTCA), and/or thrombus aspiration and stenting. The TIMI flow grade classification standard in the IRA [2, 36] is defined as follows: grade 0 refers to the absence of forward blood flow; grade 1 refers to the imaging of micro blood flow, but the contrast agent cannot reach the distal vessels of coronary arteries; grade 2 is defined as the imaging of partial blood flow perfusion, but the contrast agent cannot reach the distal vessels within three cardiac cycles; grade 3 is normal forward blood flow perfusion and the contrast agent can reach the distal vessels within three cardiac cycles [33]. Meanwhile, ST-segment elevation can be seen on the electrocardiogram when slow blood flow (TIMI flow grade 2) or no blood flow (TIMI flow grade 0–1) occurs in the IRA. The phenomenon of slow blood flow or no reflow refers to the situation where PTCA opens the IRA; however, the antegrade blood flow in the IRA cannot reach TIMI grade 3, remaining at TIMI grade 0–2, and the ischemic myocardial tissue cannot return to normal perfusion, that is, there is no antegrade blood flow in the IRA. The causes of this phenomenon include distal coronary embolism, ischemic myocardial injury, endothelial cell injury or dysfunction, reperfusion injury, microvascular dysfunction, etc. Intracoronary high thrombus burden lesions are the primary factors contributing to slow flow or no reflow in the IRA PCI [36, 37]. For STEMI patients with high thrombus burden, pre-dilation with ballooning may result in thrombus embolization, which increases the incidence of slow flow/no reflow events [38]. The slow flow/no reflow events may aggravate myocardial damage, significantly reduce the benefits from emergency PCI for STEMI, and lead to poor outcomes for some patients [39].

In clinical practice, it has also been found that some patients exhibit coronary slow blood flow and angina symptoms; those patients have no coronary artery lesions and coronary thrombosis confirmed by coronary angiography. The pathogenesis of this slow flow is entirely different from that of slow flow in STEMI patients. Generally, this slow flow is believed to be associated with microcirculatory dysfunction, increased microvascular resistance, reduced coronary perfusion pressure, anatomical factors of the coronary arteries (such as coronary artery dilation, larger diameter, and tortuous vessels), high blood viscosity, hyperlipidemia, hyperglycemia, etc. Inflammatory factors may play an important role in the pathogenesis of the coronary slow flow phenomenon (CSFP) in patients without coronary vessel stenotic lesions and thrombus. A newly developed inflammatory marker, pan-immune–inflammation value (PIV), is an independent predictor factor for CSFP, and has a higher predictive value for the CSFP than other inflammatory markers, such as the neutrophil–lymphocyte ratio, platelet–lymphocyte ratio, and systemic immune–inflammation index [40]. However, the value of these inflammatory factors in predicting slow blood flow during PCI requires further research.

In clinical practice, antithrombotic drugs and coronary vasodilators are administered via a guide catheter to prevent and treat conditions characterized by slow flow or no reflow. The medications used to inject into the coronary artery include platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor inhibitors (such as tirofiban, which inhibits platelet aggregation and blocks thrombosis, significantly improving the prognosis of patients with thrombosis), verapamil (which can hinder how the calcium ions are transferred into the vascular smooth muscle cells, dilate the coronary artery, relieve and prevent micro-coronary vessel spasms), adenosine (which dilates coronary vessels, reduces the number of neutrophils in the ischemic area, inhibits the production of free radicals from neutrophils, and maintains the integrity of the endothelium in the ischemic area), and sodium nitroprusside (which directly forms nitric oxide and rapidly becomes bradykinin to dilate the coronary artery). Based on our practical experience, when the drugs mentioned above are ineffective, injecting a small amount of epinephrine (20 µg–50 µg/time) into the coronary artery can effectively improve the slow blood flow/no reflow. Epinephrine has a significant effect on blood pressure and heart rate. According to our clinical experience, after the epinephrine is injected into the coronary artery, the heart rate rapidly increases, the myocardial contractility is enhanced, the blood pressure rises sharply, the coronary perfusion pressure increases, and the coronary blood flow accelerates, which rapidly improves the perfusion of the myocardium. The effect of accelerating the heart rate and elevating the blood pressure lasts for 2–3 min, and then the blood pressure and heart rate return to a stable level. Six articles have previously reported [41] that intracoronary epinephrine successfully restored coronary flow in over 90% of patients in managing the no reflow phenomenon following PCI. No malignant ventricular arrhythmias were observed in the patients treated with intracoronary epinephrine. Intracoronary injection of nicardipine (a calcium channel blocker) can relax coronary vascular smooth muscle, increase coronary artery blood flow velocity, and does not affect blood pressure and heart rate. Nicardipine can also increase microcirculatory perfusion and improve the slow flow/no reflow conditions. Tokdil et al. [42] reported that tirofiban (GP IIb/IIIa inhibitor) was infused into the distal infarct-related coronary artery in patients with STEMI and high thrombus burden or slow flow/no reflow, which showed microvascular obstruction and infarct size (that was assessed by cardiac magnetic resonance) in the distal intracoronary infusion group were significantly lower than in the systemic intravenous infusion group (p 0.05). The results of a meta-analysis reported by Shah et al. [43] demonstrated that prasugrel is equally effective compared to ticagrelor in preventing myocardial infarction. The incidence of stent thrombosis, stroke, or major bleeding and all-cause mortality in the prasugrel group (n = 32,759) was not significantly different compared with the ticagrelor group (n = 61,831). Thrombolytic agents, including urokinase, recombinant human urokinase, recombinant tissue plasminogen activator, and pro-urokinase, effectively dissolve distal microthrombi, which improves the slow flow of IRA. The rate of TIMI grade 3 and major adverse cardiovascular events (MACEs) in the intracoronary pro-urokinase combined with the low-pressure balloon pre-dilatation group (n = 90) was significantly higher (p 0.05) than in the intracoronary pro-urokinase without low-pressure balloon pre-dilatation group (n = 89). This result demonstrates that the used thrombolytic agents, followed by the opening of the infarction-related arteries, are associated with better outcomes [44]. Intracoronary tirofiban is related to a role in decreasing the infarct size. Basuoni et al. [45] reported the findings of a study on 100 patients with large anterior STEMI and high thrombus burden, demonstrating that decreased infarction size at 30 days was associated with intracoronary tirofiban, as assessed by cardiac MRI. In summary, intracoronary-administered thrombolytic and antiplatelet agents significantly improved myocardial perfusion and MACEs in patients with STEMI and large intracoronary thrombosis burden [46, 47].

A specially designed aspiration catheter is inserted into the thrombosis site of the IRA, and negative pressure suction is performed to remove the thrombus from the body (Fig. 3). The thrombus aspiration includes a manual and mechanical approach; however, the effects of the two approaches are similar [48, 49, 50]. A recent meta-analysis of small, randomized trials and observational studies indicated that thrombus aspiration helps reduce distal embolization and has a preventive effect on slow flow/no reflow. The findings from large randomized clinical trials (such as TASTE and (ThrOmbecTomy with PCI vs. PCI ALone in patients with STEMI) TOTAL studies) failed to show a mortality benefit and have raised concerns about their efficacy and safety, leading to updated guidelines that do not recommend routine use during primary PCI [51]. Moreover, no significant differences in clinical outcomes have been reported between the thrombus aspiration group (manual or mechanical thrombus aspiration devices) and the non-thrombus aspiration group.

Fig. 3.

The result of thrombus aspiration in the right coronary artery (RCA). (A,C,D) CAG images before and after thrombus aspiration. A 53-year-old male patient was admitted to our hospital due to chest pain for 8 hours. The ECG showed an ST-segment elevation of 0.4–0.6 mV in the inferior leads. CAG revealed complete occlusion in the proximal RCA with a large thrombus burden, as indicated by the arrow in (A). Following the administration of thrombolytic drugs, thrombus aspiration was performed seven times to remove the clot (See (B)). After the thrombus aspiration, CAG showed a residual stenosis of 90% in the RCA (as shown by the arrow in (C)), with a TIMI flow grade of 3. The condition of the patient improved significantly after the procedure. A stent was implanted at the location of the stenosis (as shown by the arrow in (D)). Repeated CAG showed that the RCA was patent, and the blood flow was TIMI grade 3 (See (D)).

Recent studies have shown that thrombus aspiration, whether manual or mechanical, can improve coronary blood flow and reduce the distal vessel embolic events of coronary arteries compared to non-thrombus aspiration strategies [48, 52]. The meta-analysis results indicate that using aspiration thrombectomy devices during PCI could reduce the phenomenon of distal embolization and improve myocardial perfusion; however, no improvement was noted in the survival rate and prognosis of patients with STEMI [53]. The results of the TOTAL study [54] differ from the above outcomes. In the TOTAL study, 10,064 cases were randomly divided into the aspiration thrombectomy group (n = 5035) and the PCI-alone group (n = 5029). The results showed that the incidence of endpoint events at 1 year (cardiovascular deaths, recurrent non-fatal myocardial infarction, cardiogenic shock, and heart failure with New York Heart Association (NYHA) class IV) was not significantly different (8.1% vs. 8.3%; p $>$ 0.05) between the two groups. The incidence of stroke at 1 year was significantly higher in the thrombectomy group than in the PCI-alone group (1.2% vs. 0.7%; p 0.05). Recent studies have confirmed aspiration thrombectomy benefits patients with high thrombus burden STEMI. The results of a comprehensive network meta-analysis on a total of 43 randomized trials (n = 26,682) demonstrated the risk of MACEs (odds ratio, OR 0.86), mortality (OR 0.85), myocardial infarction (OR 0.6) and target vessel revascularization (OR 0.86) in the aspiration thrombectomy group were lower than in the PCI-alone group [55]. Zajdel et al. [56] demonstrated that the coronary microvascular obstruction, myocardial infarct size, and left ventricular remodeling in the thrombus aspiration + PCI group were lower than those in the PCI-alone group at 6 months (p 0.05), which was confirmed by MRI. Moreover, Mathews et al. [57] demonstrated that sustained mechanical aspiration before PCI in ACS patients with high thrombus burden was associated with high rates of thrombus removal, flow restoration, and normal myocardial perfusion confirmed by CAG. Jeon et al. [58] also demonstrated a higher rate of myocardial blush grade 3, higher ST-segment resolution, and a lower incidence of microvascular obstruction in the successful thrombus aspiration group (n = 533) compared with the failed thrombus aspiration group (n = 279). Alkhalil et al. [59] proved that thrombus aspiration strategies benefit STEMI patients with a large thrombus burden.

Based on the studies mentioned above, although different outcomes were observed, most results suggest that selective thrombus aspiration is associated with better clinical outcomes. The various outcomes of clinical randomized trials are due to the fact that the intracoronary thrombosis burden in STEMI patients was not considered a grouping factor. The results of the existing studies have proven that thrombus aspiration can benefit patients with high thrombus burden (Fig. 2) and improve the success rate of PCI [60], but cannot benefit those with low thrombus burden.

Updated guidelines suggest that routine thrombus aspiration during PPCI for STEMI patients is not generally beneficial and has been downgraded to a class III recommendation. The description in the ESC guidelines is “Routine thrombus aspiration is not recommended, but in cases of large residual thrombus burden after opening the vessel with a guide wire or a balloon, thrombus aspiration may be considered” [61, 62]. In view of the above, the following principled recommendations are in favor of selective thrombus aspiration for STEMI patients: (1) Routine thrombus aspiration is not recommended during primary PCI; (2) the patients with a high thrombus burden in IRA and TIMI flow of 0 to 1 grade, and with a larger vessel diameter in IRA, may benefit from thrombus aspiration (IIb recommendation); (3) when the manual aspiration for patients with high thrombosis burden is ineffective the mechanical thrombus aspiration may be used. These recommendations have practical guiding significance and have been widely recognized. Selective thrombus aspiration benefits patients with high thrombus burden [2].

Percutaneous coronary artery thrombolysis involves injecting thrombolytic agents into the IRA of STEMI patients through CAG catheters or PCI guide catheters, enabling the thrombolytic agents to directly contact and rapidly dissolve the thrombus, thereby reopening the IRA. Thrombolytic therapy is mainly applicable to patients with a TIMI flow grade of 1–2 in the IRA. In patients with a TIMI flow grade of 0, it is difficult for a thrombolytic agent to reach the thrombus or to come into direct contact with thrombi, meaning the effect of thrombolysis remains uncertain. CAG can observe the impact of IRA recanalization and thrombus reduction within 20–30 minutes after the thrombolytic agents are injected. Intracoronary thrombolysis can also dissolve residual thrombi after aspiration thrombectomy, which is beneficial in reducing the occurrence of slow flow/no reflow. The thrombolytic agents include urokinase (200,000 u are injected into the coronary arteries), alteplase (15–30 mg are injected into the coronary arteries), reteplase (10 MU plus 10 MU intravenously in two separate injections, with a 30-minute interval), prourokinase (intracoronary injection of 100 mg, which can be repeated), and so on [62, 63, 64]. For the use of thrombolytic drugs in coronary arteries, please refer to the drug’s instruction manual.

PTCA is an effective method for opening an IRA vessel. Utilizing a PTCA balloon, under adequate anticoagulation therapy (heparinization), dilates the occluded coronary artery to restore forward blood flow, with reported success rates of up to 96.3%. When the blood flow is restored to TIMI flow grade 2–3, the intracoronary thrombus will slowly dissolve spontaneously (automatic thrombolysis). It has been clinically proven that the intracoronary thrombus in patients with STEMI will disappear or be significantly reduced after the antithrombotic (antiplatelet plus anticoagulant) treatment is performed for one week following PTCA. At this stage, the severity of the fixed stenotic lesions in the IRA became clear, and the implantation of stents (known as deferred stenting) can effectively reduce the complications of slow flow/no reflow and distal embolism, and improve myocardial perfusion and the left ventricular ejection fraction [65].

However, it has been debated whether delayed stenting is beneficial to STEMI. Liu et al. [2] reported that in STEMI patients with high intracoronary thrombosis burden, deferred stenting could significantly reduce the incidence of slow flow/no reflow and distal embolization, and improve the rate of target lesion vessel patency compared to immediate stenting. A total of 208 geriatric patients (aged $\ge$80 years) with STEMI and a high thrombus burden (thrombus score $\ge$4) in the IRA were categorized into a deferred stenting group (n = 132, with stenting delayed by 7–8 days) and an immediate stenting group (n = 76). The results of the study demonstrated that in the deferred stenting group and the immediate stenting group, the rate of TIMI flow grade 3 was 98.48% vs. 84.21% (p 0.01), and the rate of distal embolization was 3.03% vs. 36.84% (p 0.01); the rate of myocardial blush grade (MBG) 3 was 98.48% vs. 76.32% (p 0.01), the rate of MACEs 9.32% vs. 20.27% (p 0.05), and left ventricular ejection fraction (LVEF) was 0.60 $\pm$ 0.05 vs. 0.58 $\pm$ 0.05 (p 0.01). These results suggest that the patient outcomes in the deferred stenting are better than those in the immediate stenting, which is consistent with the results reported by Carrick et al. [66].

However, the DANAMI 3-DEFER trial yielded contrasting outcomes [67], whereby 1215 STEMI patients were randomly divided into an immediate stenting group (n = 612) and a delayed stenting group (n = 603; delayed for 48 hours), with an average follow-up of 42 months (33–49 months) in both groups. The results of the study showed that there was no significant difference in the incidence of MACEs (including all-cause mortality, hospitalization for heart failure, recurrent non-fatal myocardial infarction, and target vessel revascularization between the two groups (p = 0.92), which indicated that delayed stenting was not beneficial to STEMI patients. However, the study results showed a significant improvement in LVEF in the delayed stenting group (p 0.05) compared with the immediate stenting group; it cannot be considered that deferred stenting is not beneficial for all STEMI patients. In the study design, because the thrombus burden score in the IRA is not considered a grouping factor, the results and conclusion in the randomized controlled trial study differ from the outcomes of other observed studies. If patients with a high thrombus burden are further divided, potentially diverse outcomes could emerge by assigning the intracoronary thrombus burden in patients with STEMI to the immediate and delayed stenting groups for subgroup analysis. Therefore, it cannot be conclusively stated that deferred stenting is universally beneficial for all STEMI patients. Consequently, it cannot be denied that selective deferred stenting may benefit patients with a high thrombus burden, as suggested by clinical studies. A delay of less than 48 hours may not be sufficient for effective spontaneous thrombolysis in IRA, as indicated by studies [2].

The debate continues on the optimal interval between the initial PTCA that opens an IRA and restores TIMI flow grade 3, and the subsequent PCI with stenting. Liu et al. [2] reported that the ideal deferral time is 7 to 8 days. In 208 geriatric patients with STEMI and a high thrombus burden, the deferred stenting group (delay 7–8 days) was associated with shorter stent implantation in length, larger stent implanted in diameter, a lower incidence of distal embolism in the IRA, higher rates of TIMI flow grade 3 and myocardial blush grade 3, increased LVET and lower MACEs compared to those in the immediate stenting group (p 0.05). Those results are similar to the study outcomes reported by Magdy et al. [68] and Pradhan et al. [69]. The study results reported by Magdy et al. [68] revealed that the deferred stenting (delayed 7 days) was associated with a higher rate of TIMI flow grade 3 and MBG grade 3, and a lower incidence rate of no reflow and MACEs at 6 months, compared with the immediate stenting. Pradhan et al. [69] reported that the deferred PCI stenting (delayed 5–7 days) for STEMI with high thrombus burden can reduce the thrombus burden, improve blood flow and myocardial blush grade, and prevent unnecessary stent implantation. The outcomes of the sub-study from the DANAMI-3-DEFER trial [70] revealed that the deferred stenting (549 STEMI patients with large thrombus burden) was associated with lower incidences of slow flow/no reflow and distal embolization (p 0.05) compared with immediate stenting (n = 656).

These studies found that clinical outcomes were improved in deferred stenting compared to immediate stenting when the delay was around 7 days, as evidenced by various clinical analyses and meta-analyses. The good outcomes may be because the thrombus naturally dissolves, the vasospasm is relieved, TIMI blood flow improves, and the risk of slow flow/no reflow is reduced during the 7–8-day period of antithrombotic therapy. The extent of the lesion and the diameter of the IRA can be demonstrated after the thrombus autolysis or disappearance during a 7–8-day delay, which avoids the implantation of small-diameter stents and long stents, and unnecessary stent implantation, which will theoretically reduce the long-term target vessel revascularization rate [2].

Most STEMI patients should undergo primary stenting after PTCA. Delayed stenting should be used only in patients with the intracoronary high thrombus burden, those at high risk of slow flow/no reflow, or those with hemodynamic and electrocardiographic instability. According to the updated guidelines, PPCI with stenting is the preferred treatment for patients with STEMI, particularly when initiated within 12 hours from symptom onset to balloon inflation [61]. The results from previous studies showed that emergency PPCI for STEMI patients under the support of hypothermia may reduce mortality [71, 72]. Nevertheless, the latest research results from a meta-analysis of randomized controlled trials reported by Mhanna et al. [73] revealed that therapeutic hypothermia did not benefit patients more than the standard PCI in 706 patients with STEMI (in 10 randomized controlled trials). The application of hypothermia in conjunction with PCI has increased the complexity and cost of the procedure, without conferring any additional clinical benefits [72, 73], thereby hindering its widespread adoption.

Drugs that reduce thrombus burden include heparinization and platelet glycoprotein (GP) IIb/IIIa receptor inhibitors, calcium ion antagonists, vasodilators, etc. Those drugs have a good effect on reducing thrombosis and preventing slow flow/no reflow. For STEMI patients with an intracoronary high thrombus burden, statins and antiplatelet new medicines used before PCI help to reduce the thrombus burden. The GP IIb/IIIa receptor inhibitors (such as tirofiban, ticagrelor, and prasugrel) prevent platelet activation and aggregation to block thrombosis and distal embolization. Tirofiban can be injected into the coronary artery to increase the local drug concentration in the IRA, which helps the drug enter the thrombus, relaxes the thrombus, reduces the thrombus burden, and reduces circulation embolism [74]. The dual antiplatelet therapy (DAPT) of aspirin and the P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) in patients with ACS who undergo PCI was recommended by clinical guidelines. Ticagrelor and prasugrel may be more effective and safer than clopidogrel in ACS patients. The effect of ticagrelor on inhibiting platelet aggregation is faster and stronger than that of clopidogrel. Studies have shown that ticagrelor reduces the incidence of cardiovascular death and myocardial infarction compared with the clopidogrel group [75].