OCT Analysis of Very Early Strut Coverage of the Synergy Stent in Non-ST Segment Elevation Acute Coronary Syndrome Patients

Abstract: Objectives. Early endothelialization of drug-eluting stent (DES) is a major challenge to reduce the risk of stent thrombosis and the duration of dual-antiplatelet therapy (DAPT) in high bleeding-risk patients. The aim of the present study is to evaluate very early strut coverage with optical coherence tomography (OCT) of the Synergy stent (Boston Scientific) at 1 month in non-ST segment elevation acute coronary syndrome (NSTE-ACS) patients. Methods. This substudy of the EARLY trial prospectively included NSTE-ACS patients treated with the Synergy DES. OCT analysis of the Synergy stent was performed during a staged PCI of additional lesions at 1 month. The primary endpoint was the percentage of covered struts assessed with OCT at 1 month. Results. Twenty-four patients were included, with a mean stent length of 35.9 ± 10.1 mm per patient. The rate of covered struts was 78.5% out of 3839 struts analyzed. Nineteen patients (79.2%) had at least 70% of their struts covered. The average neointimal thickness was 0.0508 ± 0.016 mm. Conclusions. In NSTE-ACS patients undergoing culprit percutaneous coronary intervention with the Synergy stent, the rate of covered struts at 1 month was 78.5%. This rapid coverage is in line with the results of clinical trials demonstrating the safety of short-duration DAPT in selected patients who are at high bleeding risk and treated with new-generation DES options.

J INVASIVE CARDIOL 2019;31(1):10-14 (Epub 2018 November 11).

Key words: acute coronary syndrome, drug-eluting stent, optical coherence tomography

Percutaneous coronary intervention (PCI) prevents death and myocardial infarction in patients admitted for acute coronary syndromes (ACS).^1,2 This technique has made many advances in recent decades, especially with the advent of drug-eluting stent (DES) options that have drastically reduced the rate of restenosis.³ However, the use of first-generation DES was accompanied by a higher rate of late stent thrombosis (ST) compared to bare-metal stent (BMS) implantation.⁴ This excess of late ST was mainly related to the lack of endothelialization of stent struts.^5,6

This imperfect endothelialization resulted from the local inflammation of the coronary arterial wall caused by the polymer that controls the release of the immunosuppressive eluting drug.⁶ To prevent late ST, prolonged duration of dual-antiplatelet therapy (DAPT) for at least 12 months in patients treated with first-generation DES was required. However, prolonged DAPT was associated with increased hemorrhagic events.⁷

New-generation DES options were developed to overcome these limitations. They have thinner struts, better-designed elution, and improved polymer biocompatibility. These new devices were found to be superior to BMS regarding restenosis, but were also associated with a lower rate of definite ST.⁸ The Synergy DES (Boston Scientific) has an abluminal bioabsorbable polymer that may improve its biocompatibility. In the SENIOR trial, the Synergy DES was superior to BMS regarding ischemic events in elderly patients treated with a short duration of DAPT (1 month for stable patients and 6 months for ACS patients) without excess in ST.⁹ The ZEUS and LEADERS-FREE trials randomly compared recent DES options (the Endeavor DES [Medtronic] and the BioFreedom [Biosensors], respectively) to BMS in high bleeding-risk patients treated with 1-month DAPT. In both trials, new-generation DESs were found to be superior to BMS regarding ischemic events without increased risk of ST.^10,11 These excellent clinical results suggest rapid strut endothelialization in new-generation DESs. Studies have analyzed in vivo arterial healing following stent implantation using optical coherence tomography (OCT) imaging. These studies found excellent endothelialization of new-generation DESs at different follow-up points (2-9 months).^12,13 However, we lack in vivo evaluation of the early endothelialization of these new-generation DESs at 1 month.

The aim of the present study was to evaluate the coverage of the Synergy stent with OCT imaging at 1 month post PCI in non-ST segment elevation ACS (NSTE-ACS) patients.

Methods

The OCT-EROS study was a prospective, single-center study conducted at the Hôpital Nord of Marseille. This study enrolled NSTE-ACS patients previously included in the EARLY (Early or Delayed Revascularization for Intermediate- and High-Risk Non-ST Segment Elevation Acute Coronary Syndromes?) trial (NCT02750579).¹⁴ EARLY was a prospective, randomized, controlled, open-label trial that enrolled 740 patients in order to determine the optimal timing of coronary angiography in NSTE-ACS patients (within 2 hours following admission vs 12-72 hours). The choice of the revascularization strategy and the DES used was left to each physician’s discretion. Instructions were given to follow current guidelines.¹ Culprit lesions were treated with DES if percutaneous coronary intervention (PCI) was indicated. According to current practice, patients who had additional significant coronary lesions (ie, >70%) underwent staged PCI at 1 month.

The 1-month OCT imaging performed for the OCT-EROS study was acquired in consecutive patients initially treated with a Synergy stent on the culprit lesion of their NSTE-ACS and scheduled for staged PCI at 1 month because of additional significant coronary lesions. Thus, no patients underwent additional coronary angiography or hospital admission only because of the OCT-EROS study. Exclusion criteria are summarized elsewhere.¹⁴

OCT imaging was performed with a 6 Fr guiding catheter and the Optismobile MultiSync E171M mobile console (NEC Display Solutions). An injection of 50 IU/kg unfractionated heparin was administered intravenously during the procedure. The Dragonfly OCT probe (St. Jude Medical) was brought downstream of the stent to be studied on a 0.014˝ coronary angioplasty wire (monorail system). An automatic withdrawal was performed for 2.7 seconds over a length of 54 mm. The transparent medium was obtained by the manual injection of intracoronary iodinated contrast material during the removal of the probe (10 mL for the right network and 20 mL for the left coronary network).^15-17 The thickness was 5 sections per mm (0.2 mm thickness per slice).

Very early strut analysis was performed every 5 images (1 mm) from the exit of the stent to its entrance. Strut analysis including strut coverage (yes/no), neointimal thickness, cross-sectional luminal diameter/area, stent area, stent malapposition, under-expansion, tissue protrusion, presence of thrombus, coronary dissection, stent fracture, and restenosis. The OCT analyses were carried out by two practitioners at the Hôpital Nord of Marseille (TD and ML). 

The primary endpoint was the percentage of covered Synergy stent struts at 1 month. Struts were considered covered if a tissue signal completely covered it. Struts were considered uncovered if a part was not covered by a tissue signal (Figure 1). 

Secondary endpoints analyzed included the percentage of patients with >70% covered struts; malapposition, defined by a strut-wall distance >200 µm; neointimal thickness; ST; stent under-expansion, defined by a luminal area of the stent <80% of the mean reference luminal area itself defined by (distal reference area + proximal reference area)/2); and restenosis, defined by a reduction in stent diameter >50% of mean luminal area due to neointimal proliferation. Clinical endpoints were unplanned or emergency revascularization procedure; myocardial infarction; and cardiovascular and all-cause death (these data were collected 3 months after the staged PCI). 

Statistical analysis. A descriptive analysis was performed. Categorical variables are presented as numbers (%), quantitative variables as mean ± standard deviation. Then, in order to identify the factors associated with the quantitative endpoints used, non-parametric tests were used, including Spearman’s test for correlation with other quantitative variables, Mann-Whitney and Kruskal-Wallis tests for categorical variables, binary variables, or more than two categories. For all two-sided tests, P<.05 was considered statistically significant. All analyses were done using SPSS Statistics 20.0 software (IBM).

The study protocol received ethics committee approval, and written informed consent was obtained from all patients.

Results

From December 2016 to February 2018, a total of 24 patients were prospectively included. Mean age was 67 ± 13.1 years, 25% had diabetes mellitus, and mean serum creatinine was 81.3 ± 19.9 µmol/L (Table 1). Mean SYNTAX score was 17.9 ± 6.7. During the index procedure, predilation was performed in 62.5% of PCIs, with 1.5 ± 0.8 Synergy stents implanted per patient, mean stent length of 35.9 ± 10.1 mm, and mean stent diameter of 3.0 ± 0.4 mm. Postdilation was performed in 66.7% of cases (Table 2). 

OCT analysis at 1 month. A total of 3839 struts were analyzed (159.96 ± 62.5 struts/patient). At 1 month, 78.5 ± 10% of the struts were covered (Table 3 and Figure 2). Furthermore, nineteen patients (79.2%) had 70% or more of their struts covered (Figure 3). The average neointimal thickness was 0.0508 ± 0.016 mm.

No significant restenosis was found. OCT imaging 1 month after the index PCI showed strut malapposition in 3 patients (12.5%) and stent under-expansion in 6 patients (25%); these cases were treated with postdilation during the staged PCI. Of note, these imperfect index PCI results were not seen on angiography and were visualized by OCT imaging only. Two edge dissections that were not seen on angiography were found on OCT and treated with DES implantation. Unlike creatinine clearance, diabetes mellitus, incomplete stent apposition, predilation, and postdilation, under-expansion was the only factor associated with the presence of uncovered struts (P<.001).

Clinical follow-up. No myocardial infarction or urgent revascularization was observed up to 3 months following the staged PCI. A 74-year-old patient treated with ticagrelor and aspirin died of spontaneous intracranial hemorrhage 2 months after the staged PCI (Table 4). 

Discussion

In the OCT-EROS study, the 1-month rate of strut coverage of the Synergy DES was 78.5 ± 10%. Furthermore, 79.2% of the patients had >70% of their struts covered. To our knowledge, this study is the first to analyze in vivo very early coverage of the Synergy stent at 1 month in NSTE-ACS patients. 

A rapid and controlled coverage of stent struts is of the utmost importance to prevent ST and to shorten the duration of DAPT in high bleeding-risk patients. In their study, Finn et al⁵ found that a rate of uncovered struts >30% was a major risk factor for ST (odds ratio, 9.0; 95% confidence interval [CI], 3.5-22).  Their study demonstrates that a large proportion of uncovered struts remaining able to activate platelets is a potent risk factor for ST. The OCT-EROS provides important results regarding arterial healing of the Synergy DES 1 month after implantation. Furthermore, our results are reassuring regarding its low thrombotic profile. In patients presenting with high bleeding risk, discontinuation or de-escalation of DAPT is frequently proposed 1 month after stent implantation with new-generation platforms.^9-11,18 

The SENIOR trial compared the Synergy DES to BMS in elderly patients receiving a short duration of DAPT (1 month for stable patients and 6 months in ACS patients). The 1-year ST rate was 1% in the Synergy group and 1% in the BMS group (relative risk, 0.38; 95% CI, 0.00-1.48; P=.13).⁹ The 1-year ST rates in the EVOLVE II trial, which compared the Synergy DES to the Promus Element DES, were 0.4% vs 0.6%, respectively (P=.50).¹⁹ The rapid coverage of the Synergy DES in the present study provide a rationale for the results seen in these larger clinical trials.

It is also notable that the present study demonstrates rapid Synergy DES strut coverage in NSTE-ACS patients, who are at high risk of ST due to several mechanisms, including vessel-wall inflammation.²⁰ Rapid arterial healing is of the utmost importance in this population to prevent such thrombotic events. 

Our study must be interpreted in parallel to the TIMELESS study, which evaluated arterial healing at 3 months following Synergy stent implantation in 37 patients. In TIMELESS, 99% of the stent struts were covered at 3 months.¹³ Our results highlight the fact that most of the processes leading to strut coverage begin during the first month after stent implantation. 

A total of 20.8% of the patients in the present study had >30% of their struts uncovered at 1 month. This finding may be related to malapposition and under-expansion, which were not infrequent in our study. These imperfect PCI results are related to impaired endothelialization and stent failure.^21,22 The use of intravascular imaging (ultrasound or OCT) at the index PCI would probably have reduced the rate of malapposition and under-expansion, and thus would have improved endothelialization. The DOCTORS study found that OCT-guided PCI led to a change in procedural strategy in 50% of patients and was conducive to more frequent use of over-dilation, translating into less residual stenosis.²³ OCT-guided PCI may further improve very early endothelialization of new-generation DES options and reduce the rate of stent-related events in patients scheduled to receive a shortened DAPT. This hypothesis deserves to be tested in adequately designed clinical trials. 

Study limitations. This pilot study has several limitations, including its small sample size; a larger population would have strengthened the results. Also, several OCT measurements (eg, at 3-6 months) would have been interesting; however, we decided to perform OCT during a staged PCI, which is not compatible with these delays, and other studies (such as TIMELESS) have analyzed longer-term arterial healing. An association between under-expansion and uncovered struts was found in this study. Given the limited sample size, this result should be interpreted with caution. Other factors (eg, incomplete stent strut apposition) have been associated with incomplete strut coverage; however, the limited power of the present study can limit the scope of its statistical analyses and prevent other associations from being highlighted.²⁴ Another important limitation of this study lies in the fact that we analyzed strut coverage of only the Synergy DES; OCT analysis was not performed in patients treated with other DES types, which would have provided important results. Given their similar biomechanical properties, the results would probably have been similar to other thin-strut DESs; however, this hypothesis needs to be tested with properly designed studies.

Conclusion

The rate of covered struts for the Synergy stent at 1 month post implantation in NSTE-ACS patients was 78.5%. Furthermore, a total of 79.2% of patients had >70% of their struts covered at 1 month. This rapid coverage is in line with the results of recent clinical trials demonstrating the safety of short-duration DAPT in selected patients who are at high bleeding risk and treated with new-generation DES.

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From the ¹Service de Cardiologie, Hôpital Nord, Assistance Publique des Hôpitaux de Marseille, Aix Marseille Université, Marseille, France; ²Département de Cardiologie, Centre Hospitalier Universitaire Gabriel Montpied, Clermont-Ferrand, France; ³Département de Cardiologie, Hôpital Européen Georges Pompidou, Assistance Publique des Hôpitaux de Paris, Université Paris Descartes, INSERM U-970, Paris, France; ⁴Département de Santé Publique, Hôpital de la Timone, Aix-Marseille Université, Marseille, France; and ⁵USIC et Centre Hémodynamique, Institut Cœur et Poumon, CHRU de Lille, Faculté de Médecine de l’Université de Lille, Lille, France.

Funding: Research grants from St. Jude Medical, Boston Scientific, and Assistance Publique des Hôpitaux de Marseille.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Laine reports consulting fees from Boston Scientific and research grants from Boston Scientific and St. Jude Medical. The remaining authors report no conflicts of interest  regarding the content herein.

Manuscript submitted October 30, 2018, final version November 1, 2018.

Address for correspondence: Marc Laine, MD, Service de Cardiologie, Hôpital Nord Chemin des Bourrely, 13015, Marseille, France. Email: marc.laine@ap-hm.fr