Vascular response and intrastent thrombus in the early phase after drug‐eluting versus bare‐metal stent implantation in patients with ST‐segment elevation myocardial infarction: An observational, single‐center study

Abstract Background and Objectives Second‐generation drug‐eluting stents (G2‐DES) are associated with a lower rate of acute and subacute stent thrombosis compared with bare‐metal stent (BMS) in the setting of ST‐segment elevation myocardial infarction (STEMI). In this study, our aim was to compare the vascular response and thrombus burden between G2‐DES and BMS in early‐phase STEMI. Methods Between May 2010 and August 2014, a total of 41 STEMI patients treated by either G2‐DES (n = 26; everolimus‐eluting stent [EES]: n = 15, zotarolimus‐eluting stent [ZES]: n = 11) or BMS (n = 15) and, with multivessel disease requiring additional percutaneous coronary intervention (PCI), were prospectively enrolled. Optical coherence tomography (OCT) imaging was performed at 1 month after stent implantation. Results Baseline clinical characteristics, except for age (61.5 ± 9.3 vs 69.3 ± 9.8, P = 0.01, t test), were comparable between patients with drug‐eluting stent (DES) and BMS. The incidence of residual thrombus after the stent implantation for STEMI was comparable between DES and BMS (7.7% vs 6.7%, P = 0.88, χ 2 test). At 1 month, thrombus burden, defined as the mean thrombus area divided by the mean lumen area, was significantly smaller with DES than with BMS (median interquartile range (IQR), 1.2 (0.0, 1.0) vs 1.2 (0.0, 2.2), P = 0.04, Mann‐Whitney U test), despite a similar percentage of malapposed (median (IQR), 6.2 (2.4, 9.0) vs 2.6 (0.0, 5.8)%, P = 0.07, Mann‐Whitney U test) or uncovered struts (median (IQR), 6.8 (1.8, 13.1) vs 6.14 (2.8, 18.5)%, P = 0.45, Mann‐Whitney U test). No significant difference in thrombus burden was observed between EES and ZES. Conclusions Thrombus burden was significantly smaller with DES than with BMS at 1‐month follow‐up in STEMI cases, although the percentage of malapposed or uncovered struts was similar between the groups. This may partly explain the lower rate of acute and subacute stent thrombosis in G2‐DES that has previously been reported in the literature.

rate of acute and subacute stent thrombosis in G2-DES that has previously been reported in the literature. KEYWORDS acute coronary syndrome, dual antiplatelet therapy, neointimal coverage, optical coherence tomography 1 | INTRODUCTION Although so-called second-generation drug-eluting stents (G2-DES) have been developed to overcome residual safety concerns from firstgeneration drug-eluting stent (DES), 1-4 delayed reendothelialization is still considered to be an inevitable safety matter in any type of DES. [5][6][7][8][9][10] In particular, the safety of DES in acute and subacute phases in cases of ST-segment elevation myocardial infarction (STEMI) was debated as a result of the activated thrombogenicity, 11,12 instability of residual plaque, 13 and higher frequency of suboptimal results in the procedure. 14,15 However, contrary to expectations, a lower rate of definite stent thrombosis with an everolimus-eluting stent (EES) compared with the bare-metal stent (BMS) was demonstrated in the EXAMINATION (clinical Evaluation of the Xience-V stent in Acute Myocardial INfArc-TION) trial. 16 Surprisingly, the difference in the rate of thrombosis between the groups was most significant in acute and subacute phases.
Although it may be favorable in all aspects of clinical practice, the mechanisms and factors underlying the fewer thrombotic events with G2-DES compared with BMS in the early phase after acute myocardial infarction (AMI) remain unclear. Thus, the aim of this study was to compare the vascular response and thrombus burden between G2-DES and BMS in early-phase STEMI, using optical coherence tomography (OCT). greater than or equal to 0.2 mV in greater than or equal to two contiguous precordial leads, greater than or equal to 0.1 mV in greater than or equal to two contiguous limb leads, or new left bundle branch block, and cardiac markers (creatine kinase MB and cardiac troponin T or I) increased to greater than the upper reference. 17 Cases with bypass graft lesions, stent thrombosis, and intolerance to antiplatelet drugs and contrast dye were excluded from the analysis. All patients provided written informed consent for all of the interventional procedures in the present study. The study protocol was approved by the ethics committee of our institution.

| PCI procedure for STEMI
All patients underwent primary PCI within 24 hours after the onset of symptoms. All patients received aspirin (loading dose 200 mg and maintenance dose of 100 mg/d), clopidogrel (loading dose 300 mg and maintenance dose of 75 mg/d), and unfractionated heparin FIGURE 1 Study flowchart. OCT, Optical coherence tomography; STEMI, ST-segment elevation myocardial infarction (5000-IU bolus injection) before PCI. To keep an activated clotting time of greater than 250 seconds during the procedure, additional unfractionated heparin was administered accordingly. Thrombus aspiration, predilatation, and stent selection were left to the operator's discretion. Intravascular ultrasound (IVUS) was conducted in all cases to confirm optimal stenting without significant malapposition, underexpansion, or residual dissection before completing the procedure.

| OCT image acquisition and analysis
The OCT follow-up was performed at 3 or 6 weeks after the initial PCI greater than 100 μm for Xience Prime, Xience Xpedition, and Multi-link 8, greater than 110 μm for Integrity and Driver, and greater than 115 μm for Liberté. The well-apposed coverage was calculated as well-apposed struts with neointima divided by total struts. A thrombus was defined as an irregular protruding of signal-rich, lowbackscattering protrusions or high-backscattering protrusions beyond the stent struts into the lumen, with signal-free shadowing and a sharp intensity gap with a dimension of greater than or equal to 250 μm on the OCT image. 21,22 Percent thrombus length was calculated as the thrombus length divided by the stent length. Thrombus burden was defined as the mean thrombus area divided by the mean lumen area.
A semiquantitative assessment was also performed using the OCTthrombus score. A thrombus was classified as absent (0) or subtending 1, 2, 3, or 4 quadrants in each cross section. 23 Thrombus score was calculated as the sum of each score ( Figure 2). In the evaluation of apposition and NIH, overlapping stents and bifurcation lesions with major side branches were excluded from the analysis. Evaluation of % thrombus includes overlapping and bifurcation lesions with major side branches. Other definitions are described in the Supporting Information.

| Statistical methods
Categorical variables were reported as counts (%) and compared by the χ 2 test. The average with standard deviation was reported when the data were normally distributed, and the median with interquartile range was reported when the data were not normally distributed. Continuous variables were compared by the t test when the data were normally distributed and compared by the Mann-Whitney U test when the data were not normally distributed. All tests were two-sided, and statistical significance was defined as P < 0.05. All statistical analyses were performed using JMP 9.0 version (SAS Institute, Cary, North Carolina).

| Patient characteristics
There were no significant differences in baseline clinical characteristics between the DES group and the BMS group other than a higher age in the BMS group (Table 1). Baseline lesion and procedural characteristics including the incidence of residual thrombus evaluated by final IVUS images after the stent implantation were comparable between patients with DES and BMS (Table 2). Medications at discharge are shown in Table 3. All those medications were prescribed with the same dose and type until follow-up.

| NIH at 1 month
A total of 966 cross sections and 9871 struts were analyzed (       antithrombotic effects. [29][30][31][32] Previous studies demonstrated that polymer coating provides thromboresistance through the modification of surface properties such as electrostatic forces, hydrophilic interaction, and roughness. [33][34][35] In particular, the fluoropolymer in Xience-EES was designed to have better biocompatibility for blood and vascular tissues compared with that in older stents. [36][37][38] Another study investigating vascular responses to Xience-EES early after the implantation in STEMI also demonstrated a decreased thrombus volume, although the authors mentioned that the combination of multiple factors, including biocompatible polymer, contributed to the favorable vascular behavior. 39 These results may alleviate the safety concern for a shorter duration of dual antiplatelet therapy in patients receiving Xience-EES; this is currently being tested in a clinical trial named STOPDAPT-2 (ShorT and OPtimal Duration of Dual AntiPlatelet Therapy-2) (ClinicalTrials.gov identifier: NCT02619760).

| Thrombogenicity and stent characteristics
From findings in previous studies, strut thickness is considered to be an important factor for the thrombogenicity of coronary stents. 40 However, we think that the impact of strut thickness on the results in the present study was limited because we found a difference in thrombus burden among stents having a similar platform with thin struts. In addition to stent characteristics, vascular responses including neointimal coverage, strut malapposition, tissue protrusion, 13 and dissection may cause focal thrombus formation and subsequent clinical events, particularly in patients with acute coronary syndrome. 41 However, in the present study, the incidence of those findings on OCT images was comparable between the groups. Taken together, the presence of polymer in G2-DES might be the major contributor, among various others, to the smaller thrombus burden compared with BMS in the early phase after implantation.

| Thrombogenic properties among DES types
A significant difference in thrombus burden was not observed between EES and E-ZES in the present study, although previous  Although Orsiro-SES has a circumferential polymer in addition to the thinner strut than that in the Xience-EES, the result was worse in Orsiro compared with Xience-EES. 29 In the Orsiro stent, the polymer

| Limitations
Several limitations in this study require acknowledgment. First, this is a nonrandomized observational study conducted in a single center with a limited number of patients. Second, as an observational study, a formal sample size calculation was not performed, and thus, the study may be underpowered. Third, the residual thrombus was not volumetrically evaluated at the end of the primary procedure by OCT. Differences in residual thrombus volume among groups might have affected the results.

| CONCLUSION
Thrombus burden was significantly smaller with DES than with BMS at 1-month follow-up in STEMI cases, although the percentage of Comparisons of thrombus between EES and E-ZES. Box plots show the following: A, Thrombus length. B, Percent thrombus length was calculated as the thrombus length divided by the stent length. C, Thrombus burden was defined as the mean thrombus area divided by the mean lumen area. D, Thrombus score was the sum of each score classified as absent (0) or subtending 1, 2, 3, or 4 quadrants in each cross section. EES, everolimus-eluting stent; E-ZES, zotarolimus-eluting stent. P value was calculated by Mann-Whitney U test. The box represents the interquartile range and the line in the box, the median. Whiskers represent 1.5 IQR uncovered struts was similar between the groups. This may partly explain the lower rate of acute and subacute stent thrombosis in G2-DES that has been shown in previous studies.