INTERNATIONAL JOURNAL OF CARDIOLOGY AND CARDIOVASCULAR MEDICINE (ISSN:2517-570X)

Background and Objectives: Percutaneous coronary intervention (PCI) procedures resulting in direct instrumentation of the coronary arterial vasculature predispose patients to undesirable cardiac events. The purpose of this prospective randomized study was to test the hypothesis that the slow/gradual balloon deflation (SGBD) technique is associated with a higher procedural success rate, fewer in-hospital complications, periprocedural myocardial infarction (PMI) and a lower incidence of procedures-related coronary dissection, compared with the standard/sudden balloon deflation (SSBD) technique in stable patients undergoing elective native single-vessel PCI (NSV-PCI).

Methods: To compare the effect of SGBD versus SSBD on the incidence of procedurerelated coronary dissection and PMI during PCI, 396 stable patients undergoing elective NSV-PCI were randomized to SGBD versus the SSBD technique. Angiographic outcomes, laboratory parameters and in-hospital clinical events were recorded.

Results: The SGBD group had a significantly lower rate of procedure-related coronary dissection and PMI than the SSBD group (6.6% vs 16.2% and 11.6% vs 20.7%; p=0.002 and p=0.01, respectively). The patients with ≥ 3.0mm stent-diameter had a higher rate of coronary dissection than those with <3.0mm diameter (7.4% vs 15%; p=0.01).

Conclusion: We conclude that the SGBD technique is safer and more effective than SSBD technique in reducing procedure-related coronary dissection and PMI; particularly in patients who have ≥ 3.0mm stent-diameter. The use of this novel technique may improve early and late outcomes in patients undergoing elective NSV-PCI.

Elective Percutaneous Coronary Intervention; Native Single Vessel; Periprocedural myocardial infarction; Procedure-Related Coronary Dissection; Slow/Gradual Balloon Deflation; Standard/Sudden Balloon Deflation

Percutaneous coronary intervention (PCI) resulting in direct instrumentation of the coronary arterial vasculature predisposes patients to adverse cardiac events that can lead to procedure-related coronary dissection and subsequent myocardial necrosis. A number of factors have been associated with coronary dissection and myocardial necrosis during PCI, which can broadly be categorized as (a) patient-related, (b) lesion-related; and (c) procedurerelated. Procedure-related variables such as device selection, in particular, atherectomy [1], aggressive stent expansion resulting in plaque extrusion [2], side branch stenting [3], and angiographic complications including distal embolization [4] and coronary dissection [5,6] are all associated with adverse cardiac events. The mechanical trauma caused by the PCI procedure is a major contributor to subsequent cardiac events [7-11]. The mechanisms underlying early and late complications after angioplasty are complex; however, multiple studies in both animal models and humans have demonstrated a high likelihood of extensive vessel wall injury [7-13]. These complications are obviously undesirable and associated with negative follow-up outcomes but an even more frequent and important contributor to the morbidity and mortality associated with PCI is periprocedural myocardial infarction (PMI; type 4a) [14]. An increase of cardiac biomarkers has been shown to occur in 5–30% of patients after otherwise successful PCI [15,16]. Multiple data sets have now definitively demonstrated that PMI is associated with short-, intermediate-, and long-term adverse outcomes, most notably mortality [17,18].

Technological improvements aimed at reducing vessel wall trauma during angioplasty and/or stenting should reduce the incidence of adverse cardiac events. Several previous studies have investigated the utility of slow and gradual balloon inflation in PCI. Ohman et al. [19] demonstrated that a strategy of gradual, prolonged inflation of a perfusion balloon resulted in less residual stenosis and fewer acute dissections compared with standard inflation. Another trial using manual gradual inflation showed a lower acute dissection rate in the gradual inflation group [20]. Otherwise, the impact of the slow/gradual balloon deflation (SGBD) technique during elective coronary angioplasty and/or stenting has not previously been evaluated in a prospective, controlled clinical trial. In the belief that the standard/sudden balloon deflation (SSBD) technique has a powerful undesirable vacuum effect on stent struts and vascular wall endothelium during sudden deflation, we hypothesized that the SGBD technique may reduce the incidence of procedure-related coronary dissection and subsequent myocardial necrosis in patients undergoing elective native singlevessel PCI (NSV-PCI). This randomized clinical trial was performed to test the hypothesis that the SGBD technique was associated with a higher procedural success rate, and fewer in-hospital complications than SSBD.

Patient population

From January 2015 to January 2018, we considered for our study 396 consecutive stable patients with de novo lesion referred to our catheterization laboratory for elective PCI of a single-vessel lesion in a major (diameter≥2.25mm) native coronary artery suitable for angioplasty. Enrolled patients had normal creatine kinase (CK) and creatine kinase–MB isoenzyme (CK-MB) values before the procedure. Patients’ clinical history was obtained to ensure clinical stability before enrolment. Stable patients were defined as having had no worsening of pain in the previous two months or any experience of rest angina in the previous 48 hours and angiographically documented coronary artery stenosis 70-99%. Further criteria for inclusion were that the PCI procedure was successful and an optimal final result was obtained, i.e. a thrombolysis in myocardial infarction (TIMI) flow grade 3 in the treated vessel with a residual stenosis <20%. At the end of PCI, anterograde coronary flow in the target vessel was assessed according to TIMI classification [21]. Patients were consecutively assigned to undergo SGBD and SSBD techniques one by one. The analysis was conducted by a statistician who had no patient contact. The primary endpoint of the study is development of periprocedural MI. The secondary endpoint of the study is development of coronary dissection. All participants provided written informed consent before the angioplasty procedure. The protocol was approved by the local Ethics Committee of Marmara University Hospital.

Exclusion criteria

The presence of major (≥ 1.5mm) side-branch occlusion, distal embolization of a large thrombus, no-reflow phenomenon, untreated diffuse vasospasm, unsuccessful procedures, target lesion in the left main coronary artery, target lesion in ostial LAD, LCX and RCA, target lesion in saphenous graft, bifurcation lesions, in-stent lesion, patients with total occlusions, the need for repeat catheterization and repeat intervention in-hospital, severe congestive heart failure (ejection fraction <30%), suspected myocarditis or pericarditis during procedure, untreated diabetes mellitus, unstable angina pectoris, ST and non ST-segment elevation myocardial infarction, impaired renal function (creatinine ≥ 1.4mg/dL), unstable endocrine or metabolic diseases, patients with concomitant inflammatory diseases such as infections and autoimmune disorders, acute/chronic hepatic or hepatobiliary disease and malignancy, contraindications to aspirin or clopidogrel, and inability to provide informed consent. Patients with major complications occurring in the catheterization laboratory including emergency coronary artery bypass grafting (CABG) or death were also excluded. Blood sampling and laboratory methods: Blood samples of all individuals were taken from an antecubital vein following overnight fasting just before procedure and routine periinterventional assessment of cardiac biomarkers (CK and CK-MB) were performed to screen for PCI-related myocardial necrosis up to 24 hours (at 6-hours intervals) after PCI or until the highest value of CK and CK-MB were measured. Total CK activity (normal ≤ 195IU/L) and CK-MB activity (normal ≤ 24IU/L) were measured on a Hitachi 917 (Boehringer, Mannheim, Germany) analyzer with the automatic enzyme immunoassay method. PMI was defined as three times the upper limit of normal (ULN) of CK, confirmed by elevation of the MB fraction of CK [22]. The highest CK and CK-MB value within 24-hour post-PCI was used for analysis.

Percutaneous coronary intervention

All PCI procedures were performed according to standard clinical practice and with approved devices by the femoral approach with digitized coronary angiography equipment (Philips Allura Xper FD10 Cardiovascular X-ray System 2012, Netherlands). We used iohexol (Omnipaque, Nycomed, Cork, Ireland) as a contrast agent during intervention in all patients. All patients were treated with aspirin (300mg) and clopidogrel (600mg) on admission unless already started in the days preceding PCI. Intravenous unfractionated heparin (100IU/kg), followed by additional boluses as needed to maintain an activated clotting time >300 seconds and intracoronary nitroglycerin (200 µg) were administered before PCI in all patients. Other cardiac medications were left at the discretion of the treating physician. All intervention procedures were visually assessed by at least two experienced invasive cardiologists who were unaware of the patients’ status, and a consensus was reached. For this study, we defined significant lesion as minimal lumen diameter stenosis ≥ 70% on the angiogram. Procedural complications such as coronary spasm and dissection, thromboembolism, transient vessel closure, abrupt closure, slow flow, side branch closure, and persistent chest pain (>30 minutes postprocedure) were recorded. Dissection of the coronary artery at the end of the procedure was graded using the classification of the National Heart, Lung, and Blood Institute (NHLBI) [23]. Coronary dissection: procedure-related coronary dissections were graded from A to F according to the NHLBI classification, and dissection grades A–B were considered minor and grades C–F were considered major. Coronary spasm: exhibited focal or diffuse narrowing of vessel without any evident coronary dissection. Side branch closure: showed 1.5mm diameter with normal flow preprocedure. The grade of coronary dissection and spasm, distal embolization of a large thrombus, and side branch closure was determined by the consensus of three reviewers, including the primary on-site operator and two experienced invasive cardiologists at the angiographic laboratory. The laboratory reviewers were blinded to the inflation and a deflation protocol was used for each patient; and reviewers could not distinguish balloon inflation and deflation from the angiograms. 

The patients undergoing PCI were eligible and randomized to the SGBD group that underwent manual slow/gradual balloon deflation or the SSBD group that underwent standard/sudden balloon deflation. The patients were blinded to the treatment received. The angioplasty balloons and/or stent size was selected to achieve a 1:1 balloon-to-artery ratio at nominal inflation pressures. Stenting was used in both groups for suboptimal results. In all patients, manual inflation of the angioplasty balloons and/or stent was performed by the operator within 30 seconds. The angioplasty balloon and/or stent are inflated during a preset inflation protocol of 10 seconds to a maximal pressure. The pressure is kept constant at that maximal pressure for another 10 seconds in both groups and by a sudden deflation in the SSBD group and slow/gradual deflation in the SGBD group within 10 seconds. Balloon and stent expansion was carefully observed under fluoroscopy to determine the pressure at which the lesion indentation on the balloon was fully resolved. Images of the balloon inflated at maximum pressure were recorded. In cases where a second balloon and/or stent were used, the inflation and deflation protocol was repeated with the new balloon and/or stent. A final arteriogram was taken in the original views after an optimal angioplasty result was obtained. In-hospital course: All patients were monitored in hospital for recurrent chest pain, heart failure, arrhythmia, electrocardiogram changes, acute or subacute closure and the need for repeat catheterization, repeat intervention and in-hospital CABG. Clinically stable patients with normal CK/CK-MB were discharged on the next day, receiving aspirin 300mg daily plus clopidogrel 75mg daily. Patients with elevated CK/ CK-MB were discharged only when values declined to normal level. Statistical analysis: Continuous variables were given as mean ± SD and categorical variables were defined as percentages. Comparisons between the two groups were carried out using an independentsamples t test and chi-square test. SPSS 15.0 software was used for basic statistical analysis (Version 15, SPSS Inc., Chicago, IL, USA). A value of p < 0.05 was accepted as statistically significant.

The 396 patients who underwent elective PCI were included in the study prospectively. The baseline characteristic properties of study patients are summarized in Table 1. There were no significant differences between the two groups with respect to sex distribution, age, frequency of major coronary risk factors (i.e., diabetes mellitus, hypertension, dyslipidemia, smoking, family history of coronary artery disease), fasting glucose, HgA1c, serum creatinine, total cholesterol, LDL-C, HDL-C or triglyceride, (p>0.05 for all). All patients had baseline CK and CK-MB values within normal limits before procedure. The patients in the SGBD group had higher CK and CK-MB levels than the patients in the SSBD group (399 ± 237 vs 361 ± 197 IU/L, 39 ± 23 vs 34 ± 18 IU/L; p=0.08 and p=0.03, respectively; see Table 1). Based on the rise in CK and CK-MB value after PCI, periprocedural myocardial necrosis (>3 time the ULN of CK and/or CK-MB value) was detected in 64 of 396 patients (16.2%). 23 out of 198 (11.6%) in the SGBD group and 41 out of 198 (20.7 %) in the SSBD group had PMI (p=0.01). There were no significant differences between the usages of acetylsalicylic acid, angiotensin converting enzyme inhibitor/ angiotensin receptor blocker, beta-blocker or statin before PCI in the two groups. The use of bare metal stent and drug-eluting stents, mean stent length and diameters were similar between the two groups (p>0.05) as were final balloon pressures. The angiographic and periprocedural characteristics of study patients in the two groups are shown in Table 2. The target vessel distribution (as LAD, CX and RCA) and lesion locations (as proximal, middle and distal) were not statistically different between the groups. The coronary dissections appearing after PCI were higher in patients belonging to the SSBD group than in patients in SGBD group (16.2% and 6.6%, respectively; p=0.002). The coronary dissection types according to type A or B (minor) and type C,D,E or F (major) were similar between the groups (p=0.4). There was little difference between the groups in the need for repeated balloon dilatation before stent implantation and for post-stent dilatation with non-compliant balloons (p>0.05). 4% of patients in the SGBD group needed a second stent owing to coronary dissection and 13.1% of patients in the SSBD group needed a second stent owing to procedure-related coronary dissection (p=0.001). We classified all the patients according to stent size (<3.0 mm and ≥3.0mm) and found that the patients with ≥ 3.0mm stent had a higher rate of coronary dissection than patients with 3.0mm stent size (7.4% vs 15%, respectively; p=0.01). In the SGBD group, the rate of coronary dissections was similar in the patients with ≥ 3.0mm stent and patients with <3.0mm stent (p=0.4). On the other hand, in the SSBD group; the rate of coronary dissections was higher in patients with ≥ 3.0mm stent than in patients with <3.0mm stent (p=0.004).

The impact of the SGBD technique during coronary angioplasty and/or stenting has not previously been evaluated in a prospective, controlled clinical trial. The results of the current study demonstrated for the first time that among stable patients undergoing elective NSVPCI, those to whom the SGBD technique was applied had a significantly lower rate of PMI and incidence of procedure-related coronary dissection than those who underwent SSBD. This finding presumably results from the slower and more gradual balloon deflation used in SGBD technique, which may be less traumatic to the vessel wall endothelium and stent struts than SSBD during balloon deflation. The rationale behind this technique is that slower and gradual balloon deflation may protect the vessel wall and stent struts structure from a powerful, undesirable vacuum effect during sudden balloon deflation, most notably in patients who have a larger stent diameter size (≥ 3.0mm). In our study we found that the patients with larger stent diameter size (≥ 3.0mm) had a higher coronary dissection rate in the SSBD group but in the SGBD group it was decreased; this finding was statistically similar among patients who had a smaller stent diameter size (<3.0mm). During the last decades, coronary stenting either with or without predilatation has become the leading type of PCI, accounting for approximately 70% of all catheter-based procedures [24,25]. Coronary stenting is considered a well-established technique to improve outcomes of PCI and reduce the incidence of emergency coronary artery bypass grafting after PCI [26]. The worldwide use of this technique has been rapidly increasing in recent years [27]. With technological advances in PCI, procedural complications have declined and long-term outcomes have significantly improved, yet PMI remains relatively common after successful PCI. An increase of cardiac enzymes (CK and CK-MB) has been shown to occur in 5% to 30% of patients after otherwise successful PCI [15,16]. This elevation of cardiac enzymes is indicative of myocardial damage and, according to the new criteria, should be labeled as a PMI (type-4a). The most common definition of PMI is a CK elevation >3 times the ULN (16). CK and CK-MB, the most thoroughly validated biomarker for periprocedural myocardial damage, is generally regarded as the reference standard for the diagnosis of myocardial necrosis and is commonly used to monitor myocardial necrosis after PCI [28].

Multiple studies have shown a proportional relationship between the level of periprocedural CK and/or CK-MB elevation and the risk of adverse outcome during follow-up. A meta-analysis of 23 230 patients undergoing PCI in seven large prospective trials showed that long-term mortality risk increases at any level above normal periprocedural CK-MB [29]. The Evaluation of Platelet IIb/ IIIa Inhibition for Prevention of Ischemic Complication (EPIC) trial conclusively demonstrated the association between CK elevation and three-year mortality [30]. Several other studies have corroborated the relationship between PMI and short-, intermediate- and longterm outcome. In a study of 15 637 patients undergoing elective PCI, mortality at 10 years was significantly higher in those with CK elevations >3 times the ULN [31]. After excluding in-hospital and 30-day deaths, this degree of CK elevation remained an independent predictor of death. Even CK elevation 1.5 to 3.0 times the ULN is associated with higher mortality, each 100U/L increment of CK being associated with a relative risk of cardiac mortality of 1.05 [32]. Revascularization procedures resulting in direct instrumentation of the coronary arterial vasculature predispose patients to ischemic cardiac events that can lead to procedure-related coronary dissection and myocardial necrosis. A number of factors have been associated with coronary dissection and myocardial necrosis during PCI, which can broadly be categorized as (a) patient-related, (b) lesion-related, and (c) procedure-related. Procedure-related variables such as device selection, in particular, atherectomy, [1] aggressive stent expansion resulting in plaque extrusion [2], side branch occlusion [33] and side branch stenting [3] and angiographic complications including distal embolization [4], coronary dissection [5,6], no-reflow phenomenon [5,34] vasospasm [16] and unsuccessful procedures [35] are all associated with adverse cardiac events. Overcoming these challenges, a great number of studies have been conducted to prevent cardiac events, early/late thrombosis and restenosis after the arterial intervention [36-41]. Previous studies also suggest that slow, gradual and/or oscillating balloon inflation during coronary angioplasty may decrease the incidence of coronary dissection and improve clinical outcomes. Ilia et al. [20] found that the gradual inflation technique was associated with higher angiographic success, lower residual stenosis, less frequent dissection, and fewer complications than the fast inflation technique. In addition, other studies suggest that slow and/or oscillating balloon inflation techniques are safe and may be more effective than conventional fast inflation strategies [42-44].

The main limitation of the study is that the quantitative tools were not used in all of the study patients. Another limitation is that IVUS was not employed for viewing the stent struts and coronary dissections.

In conclusion, the current randomized trial of balloon deflation strategy has shown a high procedural success rate and fewer clinical and angiographic adverse events, PMI and procedure-related coronary dissection, irrespective of the initial inflation strategy used. The SGBD technique decreases the incidence of dissection or minimizes the incidence of PMI. We conclude that the SGBD technique is safer and more effective than the SSBD technique in reducing adverse coronary events. The use of this novel technique may improve early and late outcomes in patients undergoing elective NSV-PCI and may be particularly suitable in patients in whom stent size is over 3.0mm. Future studies are needed to further define the utility of this technique in a broader range of patients including those undergoing PCI.

Conflict of Interest: We declare that we have no conflict of interest.

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