OPTIMAX-OCT is a prospective randomized study performed in 2 centers (Heart Center, Satakunta Central Hospital, Pori, Finland; Cardiovascular Center Aalst, Aalst, Belgium). The study compared neointimal healing response evaluated by OCT performed at 1- and 6-month follow-up of TiNO- stent (OPTIMAX, Hexacath, France) and EES (SYNERGY, Boston Scientific Corporation, United States) in patients presenting with ACS. The study enrolled patients with ACS and at least 1 significant (≥ 50% diameter stenosis) de novo lesion in a native coronary artery. Main exclusion criteria were cardiogenic shock, unprotected left main disease or ostial lesions, intolerance to study medications, and current participation in another study. Eligibility criteria are summarized in file 1 of the supplementary data. Eligible patients were randomly assigned in a 1:1 fashion to receive either a TiNO-stent or EES. Randomization was generated by computer-based software. Operators were by necessity not blinded to stent group allocation; however, the investigators who performed OCT analysis and data management, and patients were blinded. For follow-up purposes, patients were divided into cohort A, which underwent OCT evaluation at 30 days of follow-up, and cohort B, which underwent OCT evaluation at 6 months of follow-up. Patients underwent clinical follow-up at the assigned time point for the occurrence of major adverse cardiac events. The details of percutaneous coronary intervention, adjuvant pharmacological intervention, and the definitions of clinical endpoints are provided in file 2 of de supplementary data.

The study was initiated by the investigators and conducted according to the ethical guidelines of the 1964 Declaration of Helsinki, as revised in 2013. Informed written consent was obtained from every patient after full explanation of the study protocol. The protocol was reviewed and approved by the ethics committees of the participating centers. The OPTIMAX-OCT study is registered under ClinicalTrials.gov, with number NCT02464397.

The OPTIMAX stent is a thin-strut (81μm) balloon-expandable stent, based on a cobalt chromium platform with a twin helicoidal design. The stent platform is coated with TiNO by plasma-enhanced vapor deposition of titanium in a prespecified gas mixture of nitrogen and oxygen, in a vacuum chamber. The SYNERGY stent is a thin-strut (74-81μm) balloon-expandable stent, based on a platinum-chromium platform coated with ultrathin (4μm) biodegradable Poly (D, L lactide-co-glycolide) abluminal polymer, which elutes everolimus (100μg/cm2).

The OCT image acquisition is presented in supplementary file 3. Proprietary software (St Jude Medical, St Paul, United States) was used to analyze cross-sections at 1-mm intervals (every 5 frames) within the stented segment. Stent cross-sectional area (CSA) and lumen CSA were traced semiautomatically. The neointimal hyperplasia (NIH) area was calculated by subtracting lumen CSA from stent CSA. The percent NIH area was calculated as the ratio of NIH area to the stent CSA, multiplied by 100. In each cross-section, the total number of analysable struts was counted. Struts were classified as uncovered if any part of the strut was visibly exposed to the lumen or covered if a layer of tissue was visible all over the reflecting surfaces. The percentage of uncovered struts was calculated as the ratio of uncovered to total struts multiplied by 100. In covered struts, NIH thickness was measured from the strut marker to the endoluminal edge of tissue coverage, following a straight line connecting the marker with the center of gravity of the vessel.19 Apposition was assessed by measuring the distance between the strut marker and lumen contour following a straight line connecting the marker with the center of gravity of the vessel. A margin of 18μm was added as a correction for half the blooming. Struts with distance to lumen contour greater than the sum of strut thickness (plus polymer thickness in case of EES) + 18μm were considered malapposed. Given a coated strut thickness of 81μm, we adopted a malapposition threshold of 100μm for TiNO-stents (81μm + 18=99μm). Similarly, given a strut thickness of 81μm and a polymer thickness of 4μm, we adopted a malapposition threshold of 100μm for EES (81μm + 4μm + 18=103μm). The percentage of malapposed struts was calculated as the ratio of malapposed to total struts multiplied by 100. Struts located at the ostium of a side branch were classified as nonapposed side branch struts and were excluded from the analysis. Thrombus was defined as an irregular high- or low-backscattering (red or white thrombus) mass protruding into the lumen discontinuous from the surface. Offline OCT analysis was performed independently by 2 investigators who were blinded to patient characteristics as well as the type of the stent used.

Sample size calculations were made based on previous OCT studies comparing TiNO-stents and new-generation permanent-polymer EES in ACS patients.14,15 We assumed that an average of 150 struts per patient would be analyzed. Sample size calculation was based on the percentage of covered struts per patient at 1 month (cohort A) and at 6 months (cohort B) of follow-up. The following assumptions were made:

At the 1-month follow-up, the mean percentage of covered struts per patient with TiNO- stents would be 96%, with EES 85%. A sample size of 50 patients (1:1; TiNO-stents vs EES, 25 vs 25) would be needed to reject the null hypothesis with a power of 90% (ß=0.90) and a 2-sided α of 0.05. The total sample size accounts for 5% loss to follow-up.

At the 6-month follow-up, the mean percentage of covered struts per patient with TiNO- stents would be 99%, with EES 92%. A sample size of 30 patients (1:1; TiNO-stents vs EES, 15 vs 15) would be needed to reject the null hypothesis with a power of 80% (ß=0.80) and a 2-sided α of 0.05. The total sample size accounts for 5% loss to follow-up.

Categorical variables are described as absolute and relative frequencies (percentage), whereas continuous variables are reported as median [interquartile range], or mean±standard deviation, as appropriate. The primary endpoint was the percentage of uncovered struts per patient, and the coprimary endpoint was the percentage of malapposed struts per patient, assessed at 30 days and 6 months of follow-up. To account for the nonindependence of struts in the same lesion, we adopted the method of nonparametric analysis of aggregated data for comparison of the percentage of uncovered (and malapposed) struts per patient between the 2 stent groups (patient-level analysis), in each cohort individually. In brief, the patient-level percentage was first calculated separately for each patient in a stent group, and then the median of these percentages was reported as the overall percentage estimator of the group.20 We also report the crude percentage of uncovered (and malapposed) struts for the whole stent group (strut-level analysis), in each cohort individually. The Pearson chi-square test, Fisher exact test, unpaired t test, or Mann-Whitney test were used for comparison of data between the 2 groups, as appropriate. All tests were 2-sided and a P value <.05 was considered statistically significant. Data were analyzed using SPSS v. 21 (SPSS IBM Inc, Unites States).

The current study indicates that in patients who underwent early percutaneous coronary intervention for ACS, TiNO-stent implantation was associated with a greater extent of stent coverage, compared with EES, both at the 30-day and 6-month follow-up. In addition, the percentage of strut malapposition was smaller with TiNO-stent. However, NIH was more prominent after TiNO-stent than after EES implantation. To the best of the authorś knowledge, this is the first report of the OCT-evaluated comparative healing response of TiNO-stents and EES.

Inadequate neointimal strut coverage is the most powerful predictor of early and late ST after stent implantation in histological autopsies and OCT report findings.3,21 Nevertheless, the percentage of uncovered and malapposed struts tends to decrease over time due to progressive neointimal growth and healing.22,23 Vascular healing is often delayed in patients treated with DES, especially in ACS patients.24 Stent strut coverage was adapted as a surrogate for stent safety. This is a clinically important question especially in patients with ACS patients when the risk of ST is higher in the early phase after PCI and with patients at high bleeding risk when shortened dual antiplatelet therapy is needed. Nearly one third of patients treated with PCI are considered to be at high bleeding risk.25 Few OCT studies reported early neointimal coverage after implantation of EES stent used in current study; EES showed higher portion of covered struts against permanent-polymer EES in early phase after stent implantation for ST-segment elevation myocardial infarction patients, uncovered struts were found in 57.6% at 2 weeks and in 28.4% at 4 months.26 In non–ST-elevation acute myocardial infarction patients uncovered struts occurred 21.5% at 1 month.27 Studies comparing previous-generation stainless-steel titanium-nitride-oxide-coated stents against permanent-polymer EES in ACS patients showed that uncovered struts occurred 1.2% at 2 months and 0.6% at 9 months with stainless-steel TiNO-stents compared with 11.3% and 10.8% with permanent-polymer EES.14,15 In one study with stainless-steel titanium-nitride-oxide stents (80% were ACS patients) the percentage of uncovered struts was 3.7% and NIH thickness was 71.5μm at 14 days after stent implantation.28 Furthermore, the NIH of titanium-nitride-oxide stents almost reached a plateau at 6 months, which is substantially earlier than the development of NIH with DES.29 After the healing process has finished (> 6 months), the NIH thickness of TiNO-stents falls between BMS and DES.14,16,30

There are no OCT studies comparing BMS to TiNO-stents. The results of the present study showing a low percentage of uncovered struts early after TiNO-stent implantation are in line with previous reports of neointimal healing of stainless-steel TiNO-stents.14,15,28 A recent randomized TIDES-ACS trial compared the stents used in the current study in ACS patients.13 TiNO-stents showed noninferiority to ESS for major cardiac events at 12 months and were superior to the coprimary safety endpoints of cardiac death, myocardial infarction and bleeding at 18 months with equal target lesion revascularization. There were more cardiac deaths, MI and ST at 12 months in the EES group, although the trial was underpowered to address these individual safety events. After the first year, the occurrence of cardiac death, MI and ST was low in both study groups.13 Interestingly, cardiac deaths, and MI between TiNO-stents and EES differed at an early phase after stent implantation,13 which was the period when strut coverage was lower with EES compared with TiNO-stents in the current study. This suggests that the differences in the early strut coverage and healing may at least partly explain these findings in early clinical events. The earlier and more adequate neointimal coverage of TiNO-stents comes at the expense of thicker NIH formation—which is expected—since DES are essentially designed to reduce in-stent restenosis. However, this did not result in excess target lesion revascularization in the randomized TIDES-ACS trial comparing TiNO-stents against ESS stents—the stents used in present study.13 In the current study no patients in TiNO-stent arm had ≥ 50% diameter stenosis and none underwent target lesion revascularization at 6 months. Since stent strut coverage is adopted as a surrogate for stent safety, the rapid coverage of TiNO-stents makes them safe to use in ACS patients.

The current study was based on a relatively small sample size; therefore, the results should be interpreted with caution. Moreover, the current OCT technology cannot detect neointimal coverage of less than 10-μm thickness and it is difficult to differentiate very thin layers of neointimal coverage between endothelium, thin layers of fibrin, or thrombus early after stenting (figure 1D). One limitation is that OCT was not performed before and immediately after the index procedure. Another clear limitation of the study is that 14% of the patients refused to participate in angiographic follow-up. Additionally, no independent core lab was involved in data analysis. Finally, the current study was underpowered to correlate OCT findings with clinical endpoints and larger studies are needed to address the clinical relevance of these findings.