Predilation Ballooning in High Thrombus Laden STEMIs: An Independent Predictor of Slow Flow/No-Reflow in Patients Undergoing Emergent Percutaneous Coronary Revascularization

Background Distal embolization due to microthrombus fragments formed during predilation ballooning is considered one of the possible mechanisms of slow flow/no-reflow (SF/NR). Therefore, this study aimed to compare the incidence of intraprocedure SF/NR during the primary percutaneous coronary intervention (PCI) in patients with high thrombus burden (≥4 grade) with and without predilation ballooning for culprit lesion preparation. Methodology. This prospective descriptive cross-sectional study included patients with a high thrombus burden (≥4 grades) who underwent primary PCI. Propensity-matched cohorts of patients with and without predilation ballooning in a 1 : 1 ratio were compared for the incidence of intraprocedure SF/NR. Results A total of 765 patients with high thrombus burden undergoing primary PCI were included in this study. The mean age was 55.75 ± 11.54 years, and 78.6% (601) were males. Predilation ballooning was conducted in 346 (45.2%) patients. The incidence of intraprocedure SF/NR was significantly higher (41.3% vs. 27.4%; p < 0.001) in patients with predilation ballooning than in those without preballooning, respectively. The incidence of intraprocedure SF/NR also remained significantly higher for the predilation ballooning cohort with an incidence rate of 41.3% as against 30.1% (p=0.002) for the propensity-matched cohort of patients without predilation ballooning with a relative risk of 1.64 (95% CI: 1.20 to 2.24). Moreover, the in-hospital mortality rate remained higher but insignificant, among patients with and without predilation ballooning (8.1% vs. 4.9%; p=0.090). Conclusion In conclusion, predilation ballooning can be associated with an increased risk of incidence of intraprocedure SF/NR during primary PCI in patients with high thrombus burden.


Introduction
ST-segment elevation myocardial infarction (STEMI) is the most common clinical manifestation of acute myocardial infarction (AMI). Primary percutaneous coronary intervention (pPCI) within a 12 hour window period is the recommended management strategy for patients with acute STEMI. Early restoration of antegrade blood fow is the primary target of pPCI in infarct-related arteries [1]. However, the occurrence of the slow-fow or no-refow phenomenon jeopardized the benefts of pPCI. Even with such an efective management strategy, the optimal reperfusion and achievement of target Trombolysis in Myocardial Infarction (TIMI) fow grade III is not possible in all STEMI patients. Te coexistence of a patent epicardial coronary artery and the state of myocardial tissue hypoperfusion is termed "slowfow/no-refow (SF/NR)" [2]. Te etiology and exact mechanism behind this dual state phenomenon are not very clear, and various proposed etiologic aspects include distal coronary embolization, infammatory response, vasospasm, capillary obstruction, endothelial swelling, myocardial edema, and ischemia-reperfusion injury [3,4].
According to recent studies, in the contemporary era, the occurrence of SF/NR ranges from 4% to 30% after pPCI [2,[5][6][7][8][9][10][11]. Various predisposing factors have been identifed, and several explanative mechanisms have been proposed for SF/NR phenomenon along with approaches to overcome SF/NR in clinical practice. Among various clinical factors, thrombosis burden (≥4 grade) has been also reported to be an important factor strongly associated with the development of SF/NR during pPCI [6,[10][11][12][13]. Trombosuction or predilection has been reported to be associated with an increased risk of SF/NR in a few studies [13]. We postulate distal embolization due to microthrombus fragments formed during predilation ballooning as a possible mechanism of SF/NR among patients with a high thrombus burden. Hence, this study aimed to assess the efect of predilation ballooning on the incidence of intraprocedure SF/NR during primary PCI in patients with a high thrombus burden (≥4 grade).

Materials and Methods
Tis prospective descriptive cross-sectional study was approved by the ethical review committee (ERC) of the National Institute of Cardiovascular Diseases (NICVD), Karachi, Pakistan (ERC-30/2020). Te study sample consisted of consecutive patients diagnosed with STEMI undergoing pPCI during the study duration of August 2020 to July 2021. Inclusion criteria were patients diagnosed with STEMI, fulflling the criteria of pPCI, and angiographic evidence of high thrombus burden (≥4 grade). Patients who underwent manual thrombus aspiration were excluded. Before inclusion, verbal informed consent was obtained from all patients. All primary PCI procedures were performed by clinical practice guidelines for the management of STEMI.
A structured proforma was used to collect the demographic data, clinical characteristics, and PCI procedural details of the study cohort. Te periprocedure occurrence of an episode of SF/NR was defned as SF/NR based on lowanterograde coronary fow (TIMI fow grade of <III) in the infarct-related artery. Te thrombus grade was categorized as grade G0 to G5. High thrombus burden was taken as ≥4 grade which is thrombus in more than half of the vessel diameter with total vessel occlusion. Te decision of stenting was made by the primary operator based on distal edge visualization of the culprit segment after guidewire Dottering or preballooning. Angiographic flms were assessed for SF/NR by independent consultant cardiologists blinded to the predilation ballooning status. As per the guideline recommendations and institutional primary PCI protocol, all patients were premedicated with unfractionated heparin and dual antiplatelet therapy (DAPT) along with a bolus dose of glycoprotein inhibitors (IIb/IIIa). Te use of ticagrelor was limited to patients with diabetes, high-risk anatomy, or stent thrombosis, while clopidogrel and aspirin were the most commonly used DAPT due to cost-efectiveness.
Considering the statistical implications of signifcant diferences in clinical characteristics of cohorts with and without predilation ballooning for the comparison of the incidence rate of SF/NR, propensity matching was performed in a 1 : 1 ratio of predilation ballooning and nonpredilation ballooning cohorts. Propensity matching was performed using R software version 3.6.1 with the help of the "MatchIt" package. Clinical characteristics used for propensity matching were age (years), gender, total ischemic time (minutes), systolic blood pressure (mmHg), heart rate (bpm), random blood sugar (mg/dL), Killip class, intubation status, cardiac arrest, diabetes mellitus, hypertension, smoking, history of prior PCI, history of stroke, left ventricular end-diastolic pressure (mmHg), left ventricular ejection fraction (%), use of intra-aortic balloon pump, number of diseased vessels, infarct-related artery, preprocedure and postprocedure TIMI fow grade, vessel diameter, and length of the lesion. Two groups were compared by applying an independent sample t-test/Mann-Whitney U test or Fisher's exact test/chi-square test with the help of IBM SPSS version 21. Te criteria for statistical signifcance of the diference between men and women were p ≤ 0.05 throughout the analysis.
To minimize the confounding efect of various clinically and statistically signifcant variables on the incidence of intraprocedure SF/NR, the predilation ballooning cohort was compared to a propensity-matched non-predilation ballooning cohort (Table 2).
Te incidence of intraprocedure SF/NR remained signifcantly higher for the predilation ballooning cohort with an incidence rate of 41.3% against 30.1% (p � 0.002) for the non-predilation ballooning cohort with the relative risk of 1.64 [95% CI: 1.20 to 2.24]. Moreover, the in-hospital mortality rate remained higher but insignifcant, among the predilation ballooning cohort (8.1% vs. 4.9%; p � 0.090) compared to the non-predilation ballooning cohort.

Discussion
Predilation in patients with a high thrombus burden increases the risk of intraprocedure SF/NR with a possible mechanism of distal embolization due to microthrombus fragments which can be worsened during predilation ballooning while preparing the thrombus laden culprit lesion during pPCI. Hence, we conducted this study to assess the efect of predilation ballooning on the incidence of intraprocedure SF/NR during primary PCI in patients with a high thrombus burden (≥4 grade). In our study, the patient cohort with predilation ballooning had a signifcantly higher incidence of intraprocedure SF/NR than in the cohort without preballooning. However, the construction of both cohorts was signifcantly diferent in terms of various clinical characteristics such as age distribution, total ischemic time, Killip class III/IV, presence of diabetes, LVEDP, stent diameter, and total length of stent implanted, and three-vessel disease. Hence, we constructed a propensity-matched cohort of non-predilation ballooning patients and compared it with the predilation ballooning cohort for the incidence of intraprocedure SF/NR, and we observed that even after matching for diferences in clinical characteristics, the incidence of intraprocedure SF/NR remained signifcantly higher among the predilation ballooning cohort with the incidence rate of 41.3% as against 30.1% (p � 0.002) for nonpredilation ballooning cohort with a relative risk of 1.64 [95% CI: 1.20 to 2.24]. Following our observations, several studies have shown that a high thrombus burden is a prominent risk factor for SF/NR phenomena [14,15]. In a study of 794 patients with AMI, high thrombus burden emerged as an independent predictor of SF/NR after emergency PCI [16]. Another study indicated that the percentage of individuals having high thrombus burden in the SF/NR cohort was higher compared to the cohort with normal fow [6]. In one way or another, the risk of no refow was signifcantly correlated with preprocedure TIMI fow, grade I, collateral fow, multivessel involvement, and high thrombus burden. Furthermore, TIMI fow and thrombus burden were the two most commonly related covariates to SF/NR compared to other covariates. Patients with large infarct size along with high thrombus burden [17], decreased TIMI fow, and absence of collateral fow [18] are more likely to develop SF/NR [19].
Microembolization following percutaneous coronary intervention has been associated with a high thrombus burden in magnetic resonance imaging (MRI) study within one year of acute myocardial infarction reported by Amabile et al. [20] Data from the recent studies also identifed thrombus burdens of ≥4 before PCI as among some of the independent predictors of SF/NR [10,11,21,22]. In a typical clinical setting, extended ischemic time is generally accompanied by a high thrombus burden, as late reperfusion results in more erythrocytes and more thrombus accumulation. Prolonged ischemia can also cause capillary integrity to deteriorate, as well as polymorphonuclear cell plugging and edema in the myocardial cell and capillary bed [13,21]. Particularly, in the process of balloon dilatation, red thrombi form fragments and cause distal embolization by washing into the distal end of the artery, consequently leading to reduced perfusion of myocardial tissue [13,18,21,[23][24][25][26]. Consequently, microcirculatory dysfunction worsens myocardial reperfusion injury and increases the risk of SF/NR and adverse cardiovascular events. Okamura et al. [27] reinforced these observations for patients who underwent PCI with the fnding of multiple embolic particles in a study using Doppler guidewires. Embolization has been observed to be associated with an irreversible reduction of myocardial blood fow with the blockage of up to 50% of the coronary capillaries [28]. In addition to fragmentation of the thrombus, there can be other multiple possible causes for predilatation induced SF/NR, such as microembolization of older and more mature thrombi, which may become worse with acute plaque rapture and may result into more severe infarct-related artery occlusion and higher coronary wedge pressure [29]. Hence, in this study, we have taken the total ischemic time as one of the main parameters of propensity matching between the two groups.
Tis is the frst study on the impact of balloon dilation on the incidence of SF/NR in patients with high thrombus burden. Te observational nature of the study is one of the major limitations of this study. Secondly, data on myocardial blush grade (MBG) were not available for comparison between the two cohorts. A randomized study of predilation ballooning in high thrombus burden can provide conclusive evidence in the context of SF/NR.

Conclusion
In conclusion, pre-dilation ballooning can be associated with an increased risk of incidence of intraprocedure SF/NR during primary PCI in patients with a high thrombus burden. Considering the prognostic signifcance of SF/NR, it is important to avoid predilation ballooning and limit the hardware used during primary PCI of patients with high thrombus burden to avoid SF/NR.

Data Availability
Te data materials used to support the fndings of this study can be obtained upon reasonable request.

Conflicts of Interest
Te authors declare that they have no conficts of interest.