Additional postdilatation using noncompliant balloons after everolimus‐eluting stent implantation: Results of the PRESS trial

Abstract Background There are limited data on the clinical value of routine postdilatation using noncompliant balloons after contemporary drug‐eluting stent implantation. Hypothesis Additional postdilatation using noncompliant balloons after everolimus‐eluting stent implantation could provide better clinical outcomes. Methods We randomly assigned 1774 patients with coronary artery disease to undergo additional high‐pressure postdilatation using noncompliant balloons and moderate‐pressure dilatation using stent balloons after everolimus‐eluting stent implantation. The primary endpoint was a composite of death, myocardial infarction (MI), stent thrombosis, and target vessel revascularization (TVR) 2 years after randomization. Results The study was discontinued early owing to slow enrollment. In total, 810 patients (406 patients in the high pressure group and 404 in the moderate pressure group) were finally enrolled. At 2 years, the primary endpoint occurred in 3.6% of patients in the high pressure group and in 4.4% of those in the moderate pressure group (P = .537). In addition, no significant differences were observed between the two groups in the occurrence of an individual end point of death (0.8% in the high pressure group vs 1.5% in the moderate group, P = .304), MI (0.2% vs 0.5%, P = .554), stent thrombosis (0% vs 0.2%, P = .316), or TVR (2.8% vs 2.6%, P = .880). Conclusions The strategy of routine postdilatation using noncompliant balloons after everolimus‐eluting stent implantation did not provide incremental clinical benefits.

Results: The study was discontinued early owing to slow enrollment. In total, 810 patients (406 patients in the high pressure group and 404 in the moderate pressure group) were finally enrolled. At 2 years, the primary endpoint occurred in 3.6% of patients in the high pressure group and in 4.4% of those in the moderate pressure group (P = .537). In addition, no significant differences were observed between the two groups in the occurrence of an individual end point of death (0.8% in the high pressure group vs 1.5% in the moderate group, P = .304), MI (0.2% vs 0.5%, P = .554), stent thrombosis (0% vs 0.2%, P = .316), or TVR (2.8% vs 2.6%, P = .880).
Conclusions: The strategy of routine postdilatation using noncompliant balloons after everolimus-eluting stent implantation did not provide incremental clinical benefits.

| INTRODUCTION
Optimization of stent deployment during percutaneous coronary intervention (PCI) is a key element for improving clinical outcomes. 1 With the advent of drug-eluting stents (DESs), DESs have become the main strategy for PCI because they have significantly reduced the need for repeat revascularization. 2,3 However, suboptimal stent deployment frequently occurs during DES implantation, which may increase the risk of in-stent restenosis and stent thrombosis. [4][5][6][7][8] Therefore, even in the DES era, optimal deployment of stents remains a challenging issue.
In bare-metal stent, adjunctive postdilatation using noncompliant balloons after stent implantation provided further stent optimization to reduce the incidence of in-stent restenosis and stent thrombosis. 9,10 Even in the DES, previous studies also support the use of postdilatation with noncompliant balloons after deployment of DES. [11][12][13] In addition, a recent randomized trial showed that stent optimization with intravascular ultrasound (IVUS) and adjunct postdilatation would be helpful in patients requiring long coronary stent implantation with a discrepancy in coronary artery diameter. 14 However, there is still a lack of evidence from randomized trials to evaluate the clinical benefits of postdilatation using noncompliant balloons in patients undergoing contemporary DES implantation. Therefore, we aimed to investigate the clinical effect of postdilatation from the PRESS trial (the impact of additional high PRessure in-stEnt dilatation uSing noncompliant balloons after Xience Stent implantation). times the upper normal reference limit, history of renal dysfunction or serum creatinine level of ≥2.0 mg/dL, serious noncardiac comorbid disease with a life expectancy of <2 years, ST-elevation acute myocardial infarction (MI) within 2 weeks, planned major surgery within the next 6 months with the need to discontinue antiplatelet therapy, or inability to follow the protocol. In patients with multiple lesions who fulfilled the inclusion and exclusion criteria, the first stented lesion was considered the target lesion. The institutional review board at each participating center approved the protocol. All patients provided written informed consent.

| Randomization and study procedures
Patients who met the inclusion and exclusion criteria were randomly assigned in a 1:1 ratio to receive additional high-pressure postdilatation using a noncompliant balloon and moderate-pressure dilatation using a stent balloon with an interactive web response system. The allocation sequence was computer generated and stratified according to participating center and blocked with block sizes of four and six varying randomly.
The procedure was performed using standard techniques. The stents were deployed at 10 to 14 atm with their stent balloon system.
If an acceptable result was achieved, randomization was performed.
An acceptable result was defined as a quantitative angiographic residual diameter stenosis of <30% with TIMI (Thrombolysis in Myocardial Infarction) grade 3 flow and absence of major stent edge dissection (type C-F) and major side branch occlusion (TIMI flow 0 or 1 in the side branches with a reference diameter of ≥2.0 mm). In the moderate pressure group, the procedure was finished. In the high pressure group, postdilatation with at least the same or larger size noncompliant balloons at 18 to 22 atm was followed ( Figure 1).
From at least 24 hours before the procedure and thereafter, all patients received aspirin (loading dose of 300 mg, followed by 100 mg/day indefinitely) and clopidogrel (loading dose of 300-600 mg, followed by 75 mg/day for at least 12 months). Heparin was administered throughout the procedure to maintain an activated clotting time of ≥250 seconds. The use of IVUS and administration of glycoprotein IIb/IIIa inhibitors were at the discretion of the operator.

| Study endpoint
The primary endpoint was defined as the occurrence of major adverse cardiac events, including all-cause death, MI, stent thrombosis, and target vessel revascularization (TVR) 2 years after the procedure. The secondary endpoints included the occurrence of an individual endpoint of death, MI, stent thrombosis, and TVR at 2 years. At 2 years, a composite of death and MI was also assessed.
Death was considered to be cardiac in etiology unless an unequivocal noncardiac cause was established. MI was diagnosed on the basis of an increase in the creatine kinase MB (myocardial band) fraction or troponin level greater than the 99th percentile of the upper normal limit with at least one of the following aspects: ischemic symptoms, electrocardiographic changes, and abnormal imaging findings of MI. 15,16 Definite, probable, and possible stent thrombosis was defined according to the Academic Research Consortium. 16 TVR was defined as any repeat revascularization of the target vessel with either of the following: (a) at least 50% of the diameter stenosis on quantitative coronary angiographic analysis with ischemic symptoms or a positive stress test finding or (b) at least 70% of the diameter stenosis on quantitative coronary angiographic analysis.

| Statistical analysis
On the basis of results from previous studies, 17,18 we assumed a primary endpoint of 7% in the additional high pressure group and 10% in the moderate pressure group at the 2-year follow-up. Using a twosided 5% significance level, we estimated that 797 patients per group were needed to detect this difference with a statistical power of 80%.
Considering a 5% follow-up loss, total sample size was estimated to 1744 patients (872 patients per group). However, because of a much slower than anticipated enrollment, enrollment was stopped in  (Table 1).

| Angiographic and procedural characteristics
The lesion type B2 or C was seen in 568 patients (71%). However, moderate to severe calcification was observed in 44 patients (5.4%). Seventy-seven patients (9.5%) were treated with overlapping stents.

T A B L E 1 Baseline characteristics of the study population
The mean stented length of the target lesions was 28.7 ± 12.6 mm.
Although the mean final balloon size was similar between the two groups, the maximal inflation pressure was higher in the high pressure group than in the moderate pressure group ( In-stent diameter stenosis, % 4.3 ± 10.7 8.9 ± 11.6 <.001 In-segment diameter stenosis, % 11.9 ± 10.6 13.3 ± 11.5 .112 In-stent acute gain, mm 1.75 ± 0.61 1.60 ± 0.54 .001 In-segment acute gain, mm 1.41 ± 0.65 1.33 ± 0.56 .066 Note: Data are expressed as n (%) or means ± SD. Note: Values are presented as n (%) as determined using the Kaplan-Meier method. *P-values were calculated using the log-rank test.

T A B L E 3 Clinical outcomes over 2 years
angiographic analysis, the in-stent acute gain was higher and the instent diameter stenosis was smaller in the high pressure group than in the moderate pressure group. However, the incidence of edge tear or perforation and no reflow or distal embolization was low and comparable between the two groups ( Table 2). Table 3 shows the clinical outcomes. At 2 years, the primary endpoint Optimal stent deployment during PCI has an important effect on short-and long-term clinical outcomes. 1 There has been significant advances in platforms, drugs, and polymers in DESs. However, the incidence of suboptimal stent deployment was up to 30% even in the DES era. 4 In previous several reports, postdilatation of DES, improving minimal stent area and minimal stent diameter, showed improved clinical outcomes, but they analyzed limited populations in registries data and did not focus on the contemporary DES. [11][12][13] On the other hand,

| Clinical outcomes
contemporary everolimus-eluting stents demonstrated better clinical efficacy and safety compared with other DESs or bare-metal stents. 17,19,20 However, there is still a lack of evidence as to whether postdilatation using noncompliant balloons at high pressures following deployment of the contemporary DESs is associated with an improvement in clinical outcomes. Therefore, to address the clinical usefulness of high-pressure noncompliant postdilatation after contemporary everolimus-eluting stent implantation, the present study was designed.
While reducing the risk of in-stent restenosis and stent thrombosis, there are potential adverse effects from postdilatation.
Postdilatation using noncompliant balloons at high pressures could be associated with a risk of edge tear and vessel rupture. 21,22 There was also some evidence that aggressive stent expansion with postdilatation could lead to distal embolization and an increased incidence of periprocedural MI. 23,24 However, in the present study, the incidence of edge dissection or coronary perforation between the high and low pressure groups was much low and comparable. In addition, although our study included 484 patients (59.8%) with acute coronary syndrome, there were no significant differences in the occurrence of no reflow or distal embolization between the two groups. Therefore, these findings indicate that postdilatation using noncompliant balloons could be performed safely during PCI.
In the bare-metal stent era, deployment of such stents was often associated with suboptimal stent expansion. 21 Adjunctive postdilatation using noncompliant balloons improved stent expansion and reduced in-stent restenosis and stent thrombosis. 9,10,21 Even in the DES era, these suboptimal stent expansions were also reported in the literature in association with an increased risk of in-stent restenosis and repeat revascularization rates and might also predispose to stent thrombosis. [6][7][8] Similar to a previous study, 11 this study showed that postdilatation resulted in higher in-stent acute gain and smaller in-stent diameter stenosis. However, our study failed to demonstrate Since the present study has been conducted in 15 cardiac centers of South Korea between February 2012 and October 2015, our study was possible by approvals of the institutional review board at each participating center without legal restrictions. Second, the decision of enrollment of study was made by the attending operators. Unfortunately, we have no reliable data for patients screened and excluded from the current study. Third, the overall clinical event rate was lower than anticipated. Moreover, the present study was discontinued early due to slow enrollment. Therefore, the sample size could be insufficient for evaluating whether the routine postdilatation strategy benefited all subgroups. Fourth, the use of IVUS was at the discretion of operating physicians. In previous and our studies, routine use of IVUS or postdilatation during PCI did not show incremental clinical benefits. 26 However, as shown a recent randomized study, 14 selective postdilatation with specific IVUS criteria for optimal stent optimization might improve clinical outcomes in specific populations. Fifth, although postdilatation achieved higher in-stent acute gain and smaller in-stent diameter stenosis, our study did not address the longterm clinical benefits beyond the 2-year follow-up.
In conclusion, the strategy of routine application of postdilatation using noncompliant balloons after everolimus-eluting stent implantation did not improve clinical outcomes at 2 years. However, the present study did not have enough statistical power to evaluate the clinical effects of additional postdilatation. Therefore, these findings should be confirmed in further randomized clinical trials with larger populations.

ACKNOWLEDGMENTS
The Medical Information Center of Ulsan University Hospital supported this work in terms of statistical analysis. The PRESS trial was supported by Abbott Korea Co., Ltd. Abbott Korea Co., Ltd. had no role in the study design, data collection, data analysis, or data interpretation; access to the clinical trial database; or opportunity to review or comment on the report.