The Ultimaster coronary stent system: 5-year worldwide experience

Overview of the field

Percutaneous coronary intervention (PCI) for the treatment of coronary artery disease (CAD) is the most commonly performed cardiovascular procedure and one of the most frequently performed therapeutic interventions in medicine [1]. Drug-eluting stents (DES) were introduced to address the limitations of bare-metal stents (BMS) and are now considered the default therapy for patients undergoing a PCI procedure, regardless of their clinical presentation, lesion subtype or comorbidities [2–4]. Newer generation DES were aimed at improving the balance between safety and efficacy through a better stent design, polymer biocompatibility and optimized drug release. These improvements are concerning:

• Novel metallic alloys (cobalt–chromium and platinum–chromium) with thinner stent struts (50–90 μm) to enhance hemodynamic flow and drug distribution, favoring vessel healing, reducing thrombogenicity and restenosis [5,6] in comparison with first-generation DES;

• Selection of antiproliferative drugs with reduced toxicity (i.e., sirolimus or its analogues such as everolimus, zotarolimus, biolimus and novolimus that are different from each other in terms of structure, molecular weight, potency and lipophilicity) [7–10] that exhibit favorable kinetics, a wider therapeutic index and decrease the risk of delayed intimal healing compared with paclitaxel DES [6];

• The use of more biocompatible polymers with durable (DB) or biodegradable (BP) coatings that have been shown to optimize DES performance.

As a matter of fact, drug release and availability are determined not only by the properties of the drug but also by the characteristics of the polymer coating, as a drug carrier, that allows a controlled release over time. The polymer coating can be conformal, with the release of the drug over the entire surface of the stent, or abluminal, with the release only on the surface in contact with the vessel wall, resulting in a reduction of drug dose and polymer exposure [11–13]. Among these newer generation DESs, the Ultimaster coronary stent system is a cobalt–chromium, biodegradable polymer, sirolimus-eluting stent with the abluminal coating (BP-SES; Terumo, Tokyo, Japan) [14]. This coronary stent received the Conformitè Européenne (CE) mark approval in 2014 and the version with an improved delivery system, Ultimaster Tansei in 2018. The device has been the object of an intense clinical evaluation with more than 40,000 patients enrolled in controlled randomized studies and observational registries. The aim of this review was to assess the clinical performance of this device from the pivotal trials to the more recent clinical evidence (Table 1).

The Ultimaster™/Ultimaster™ Tansei™ coronary stent system

The Ultimaster™/Ultimaster™ Tansei™ coronary stent system consists of a thin strut (80 μm) cobalt–chromium (Co-Cr) BMS platform (Figure 1) coated on its abluminal side with a blend of sirolimus, at an optimized dose of 3.9 μg/mm of stent length, and bioresorbable poly(D,L-lactide-co-caprolactone) copolymer (PDLLA-PCL). Both drug and polymer are applied in a gradient and designed for simultaneous polymer resorption and drug release within 3–4 months, to match the procedure-triggered biological response and support early vascular repair.

The stent is mounted on a rapid exchange catheter with a high-pressure, semi-compliant balloon for enhanced safety and freedom from rupture in challenging lesions.

The stent platform that features open cell, two-link design with large cell opening (4.57 mm² for 3 mm stent) facilitates side-branch access and comformability to the vessel wall (Figure 3).

A thin, biocompatible, bioresorbable gradient coating was the key to the innovative design of the system. The polycaprolactone (PCL) added to PDLLA increases the elasticity of the bioresorbable polymer coating. The matrix of sirolimus and PDLLA-PCL (poly(D,L-lactide-co-caprolactone)) bioresorbable copolymer is applied only on the abluminal side of the stent for efficient and targeted drug delivery (Figure 2). The unique gradient coating technology excludes the coating on the parts of the stent that experience the most physical stress. Such design is intended to reduce the risk of polymer cracking and delamination, even when the stent is over-expanded.

The coating components were designed to optimize performance with minimal drug and polymer content and controlled drug release kinetics. Within 3–4 months, the polymer is either metabolized, through d,l-lactide and caprolactone, into carbon dioxide or excreted in urine and feces. Reduced drug dose was possible thanks to an abluminal coating, which is also beneficial as it leaves the luminal side of the stent free from drug and polymer, enhancing as such early vessel repair and endothelial coverage [25]. This hypothesis has been confirmed in animal studies (comparing Ultimaster to circumferentially coated stent) in which Ultimaster showed a significantly greater number of tight junctions and less fibrin deposition [26]. Furthermore, in another study, vascular endothelial (VE) cadherin, an essential component of the vascular endothelial membrane and a marker of the presence of functionally normal endothelial cells, showed greater overall expression and faster increase suggesting that the recovery of the endothelial layer in the stented region occurred at an early stage [27].

The drug release profile is adjusted to best match the biological response: initial release will suppress injury and inflammation induced by catheters manipulation and stent implantation. The remaining drug will be released along with polymer bioabsorption within 3–4 months, after which time DES is expected to become BMS.

Ultimaster/Ultimaster Tansei sirolimus-eluting coronary stent system includes sizes in the range of 2.25–4.0 mm diameter and lengths from 9 to 38 mm to enhance treatment of the broadest range of lesions and widest patient population.

The approved postdilatation limits are up to 4.5 mm for the smaller stent (Ø2.25, 2.5, 2.75, 3.0 mm) and up to 5.5 for the larger (Ø3.5, 4.0 mm) although an independent bench test confirmed overexpansion to 5.8 mm for larger stents [28].

The Ultimaster DES and its latest version Ultimaster Tansei feature identical stents and coating design, with an improved delivery system in Ultimaster Tansei. The main differences are in the introduction of a durable yet flexible tip that supports navigation through tortuous vessels; the advanced shaft technology with stainless steel tapered core wire for gradual transition from proximal stiffness to distal flexibility for enhanced pushability and a stronger hypotube to maximize kink resistance.

Pivotal studies

The CENTURY (Clinical Evaluation of New Terumo Drug-Eluting Coronary Stent System in the Treatment of Patients with CAD) was the first multicenter, single-arm, prospective study that evaluated the performance of the Ultimaster stent in a group of 105 patients with stable CAD [15]. The primary end point was in-stent late lumen loss (LLL) at 6-month follow-up angiography; secondary end points included clinical, intravascular ultrasound (IVUS) and optical coherence tomography assessments. Secondary clinical end points were assessed at 1, 6, 12 months and yearly up to 5-years and included target lesion failure (TLF), defined as the composite of cardiac death, target vessel myocardial infarction (MI) or clinically indicated target lesion revascularization (TLR). At 6 months, angiographic LLL was 0.04 ± 0.35 mm and the rate of binary restenosis was 0.9%, confirmed by IVUS assessment that documented a neointimal volume obstruction of 1.02 ± 1.62%. Moreover, IVUS analysis showed the absence of vessel remodeling with a similar peri-stent vessel volume after stent implantation and at a 6-month follow-up. At the optical coherence tomography assessment, strut coverage was complete in 96.2% of analyzed struts, with 1.66 ± 4.02 malapposed stent struts. At 12 and 24 months, the TLF rate was 3.8 and 5.7%, whereas the TLR rate was 1.9 and 2.8%, respectively. In this initial experience, the Ultimaster DES demonstrated good performance, with high procedural success and strong suppression of neointimal proliferation at 6 months. The study had some limitations: it was nonrandomized and used a historical control for the primary end point. Furthermore, it was powered only for an angiographic end point and was conducted on a low-risk population.

CENTURY II trial was a large-scale, prospective, multicenter, randomized, single-blind, controlled, noninferiority trial conducted in Europe, Japan and Korea in a general population of CAD patients referred for PCI [16]. This represents the pivotal trial for the Ultimaster stent system and was conducted to assess the noninferiority of Ultimaster BP-SES compared with the everolimus-eluting (EE) XIENCE stent (Abbott Vascular, CA, USA) characterized by a circumferential permanent polymer (PP-EES) coating. A total of 1.101 eligible CAD patients were included and randomly assigned in a 1:1 ratio to PCI with either BP-SES (n = 551) or PP-EES (n = 550). Randomization was balanced for diabetes mellitus (DM), acute coronary syndrome (ACS) and multivessel disease (MVD). The primary end point of the trial was TLF at 9-month follow-up. Secondary end points included target vessel failure (TVF) a composite of cardiac death, any target-vessel MI or clinically indicated target vessel revascularization (TVR); a patient-oriented composite end point including all-cause death, any MI or any coronary revascularization; the composite of cardiac death or MI; and bleeding. The trial reached the primary end point of freedom from TLF at 9 months (95.6% of patients randomized to the Ultimaster BP-SES and 95.1% of patients randomized to PP-EES; for noninferiority, p < 0.0001). Moreover, there was no significant difference between the Ultimaster BP-SES and PP-EES with respect to secondary end points. One-year clinical outcomes showed no significant difference between BP-SES and PP-EES in all-cause death, any MI, TLF, TVF and TVR. Rates of stent thrombosis (ST), bleeding and vascular complications were also similar between the two groups. However, the study was not powered to detect differences in individual end points, and the observed TLF rates were lower than anticipated (10%). The authors conclude that the Ultimaster stent was found to be as safe and as effective as PP-EES in this relatively complex patient population. Based on those results the Ultimaster stent was listed as one of the recommended DES in the ESC/EACTS 2014 guidelines published in 2014 and 2018 [29,30].

This trial gave rise to numerous sub-analyses (based on either prespecified subsets or post-hoc evaluations of available data) that evaluated the stent in different clinical scenarios.

Jiménez et al. [31] investigated clinical outcomes of PCI in high-risk ACS (ST-segment elevation and non-ST-segment elevation MI). Totally, 264 high-risk ACS patients were included in this subgroup analysis from CENTURY II trial, and the clinical outcomes including TLF, TVF, cardiac death, MI and ST were evaluated. At 24 months, TLF occurred in 6.3% of patients receiving a BP-SES versus 6.5% of patients receiving a PP-EES (p = 0.95); TVF was 6.3 versus 9.4% (p = 0.36), respectively. No significant differences were found in cardiac death, MI and ST rate.

Orvin et al. [32] evaluated the safety and efficacy of Ultimaster stent in bifurcation lesions: 194 patients treated for bifurcation lesions were randomized to either BP-SES (n = 95) or PP-EES (n = 99). The primary end point was freedom from TLF and clinically driven TLR at 1-year. Provisional or ‘crossover’ stenting was the most frequently used stent technique (93.2% BP-SES vs 92.4% PP-EES). Freedom from TLF at 1-year was 94.7% for BP-SES and 91.9% for PP-EES (for noninferiority, p = 0.031). The rate of clinically driven TLR at 1-year was 3.2% for BP-SES and 3.0% for PP-EES (p = 0.95). No significant differences were found in individual clinical end points or other secondary clinical end points between the study arms at 1-year follow up.

Lesiak et al. [33] assessed the performance of Ultimaster stent in patients with long coronary lesions. In the CENTURY II trial, 182 patients with long lesions (≥25 mm) were assigned randomly to treatment with BP-SES (n = 101) or PP-EES (n = 81). There was no difference between the baseline patient and lesion characteristics in the two study arms. At 9 months, the rates of cardiac death (2.0 vs 1.2%; p = 0.70), MI (3.0 vs 4.9%; p = 0.49), clinically driven TLR (2.0 vs 3.7%; p = 0.48) and TLF (6.9 vs 8.6%; p = 0.67) were similar for BP-SES and PP-EES, respectively. There was no ST in the BP-SES group up to 9 months; one case (1.2%) of ST occurred in the PP-EES group (p = 0.44).

Whorle et al. [34] presented a safety and efficacy prespecified analysis in a subgroup of 525 patients with small vessel CAD (reference diameter ≤2.5 mm). Patients were randomized: 277 patients received BP-SES (399 lesions) and 248 patients received PP-EES (377 lesions). The primary outcome was TLF and TLR at 12 months. Treatment groups were similar for baseline, procedural data and mean preprocedural reference diameter (BP-SES 2.30 ± 0.40 mm, PP-EES 2.31 ± 0.42 mm; p = 0.59). Stented length was 24.0 ± 11.7 mm for BP-SES and 23.5 ± 11.5 mm for PP-EES (p = 0.45). At 12 months, there was no significant difference between the BP-SES and PP-EES groups in TLF (6.9 vs 7.7%; p = 0.72), cardiac death (1.1 vs 1.2%; p = 0.90), target vessel MI (1.8 vs 3.2%; p = 0.30), TLR (4.0 vs 5.7%; p = 0.37) or definite or probable ST (0.7 vs 1.2%; p = 0.57). In conclusion, in the large-scale, randomized CENTURY II trial, patients with small-vessel CAD, treated with BP-SES and PP-EES, had similar outcomes at 12 months.

In summary, all of these subanalyses seemed to confirm the excellent results obtained in the main trial.

Long-term clinical performance

Recently, long-term clinical outcomes of the CENTURY II study were published [35]. Clinical outcomes at 5-year follow-up include the following points: freedom from TLF (the composite end point of cardiac death, MI not clearly attributable to a non-target vessel and clinically TLR); the rate of TVF (composite of cardiac death and MI not clearly attributable to a non-target vessel, and clinically driven TVR); patient-oriented composite end point (all deaths, all MI and all coronary revascularizations); rates of TLR, TVR, ST, cardiac death, MI; and composite of cardiac death and MI. At 5-year follow-up, no differences were found in TLF-free rates (90.0% for BP-SES vs 91.1% for PP-EES; p = 0.54), the composite safety end point of cardiac death and MI (5.8 and 7.1%, respectively; p = 0.39), and the patient-oriented composite end point (24.1 and 25.6%, respectively; p = 0.57) between the two treatment arms. Also, all-cause death, any MI or revascularizations, rates of ST, bleeding and vascular complication did not differ. Importantly, the very late ST was low with both stents (0.2 vs 0.2%, respectively). In the further subanalysis in patients with MVD [36], 456 patients were assigned to either BP-SES (n = 225) or PP-EES (n = 231) treatment-arm. MVD was defined as the presence of >50% diameter stenosis in two or three major epicardial coronary vessels or bypass grafts. Throughout the 5-year follow-up period, the rate of TLF composite end point was similar among the two treatment arms: 10.2 versus 13.4% in BP-SES and PP-EES arm, respectively (p = 0.29). ST, composite end point of cardiac death and MI and patient-oriented composite end point of any death, MI, and coronary revascularizations were also similar in the two groups. In conclusion, Ultimaster BP-SES showed comparable clinical outcomes to the current benchmark device. These results were maintained up to 5 years, also in high-risk patients with MVD.

Real world experience

Many controlled and observational studies were conducted since the completion of the CENTURY II trial.

• The MASTER study [17]: it is a prospective, randomized, controlled, single-blind multicenter trial conducted in Europe and Brasil. Study eligibility consisted of ST-segment elevation myocardial infarction (STEMI) patients in whom primary PCI (pPCI) was performed within 24 h of symptom onset and at least one acute infarct-related artery was identified as the target vessel with one or more stenoses in a 2.5–4.0 mm native coronary artery. Patients were randomly assigned in a 3:1 ratio to undergo pPCI with either Ultimaster BP-SES or Kaname BMS (Terumo Corporation, Tokyo, Japan). The primary end point of the trial was TVF, defined as cardiac death, not clearly attributable to a nontarget vessel or clinically driven TVR at 12 months. The primary prespecified angiographic end point was in-stent LLL at 6-month poststent implantation in the subset of patients undergoing angiographic follow-up. The major safety secondary end point was the composite of all-cause death, recurrent MI, unplanned infarct-related artery revascularization, stroke, definite ST or major bleeding at 1 month. Other secondary end points included TLF, defined as the composite of cardiac death, MI not clearly attributable to a nontarget vessel and clinically driven TLR up to 30 days, 6 months, 12 months and annually thereafter up to 3 years. Overall, 500 STEMI patients were included (375 randomized to pPCI with implantation of BP-SES and 125 of BMS). Totally, 104 randomized patients underwent angiographic follow-up at 6 months. Baseline characteristics, angiographic features and dual-antiplatelet therapy (DAPT) rate were similar in both study arms. The procedural characteristics did not differ significantly between patients receiving BP-SES versus BMS, except for the number of implanted stents (1.5 ± 0.9 vs 1.3 ± 0.6), and the mean implanted stent length (30 ± 17 vs 26 ± 12 mm), that were significantly greater in the BP-SES group. The MASTER trial proved the noninferiority at 12 months of Ultimaster BP-SES to BMS concerning the primary efficacy end point (TVF), which occurred in 6.1 versus 14.4% of patients, respectively (for noninferiority, p = 0.0004). This result was predominantly driven by a significant reduction in the rates of TLR/TVR in BP-SES versus BMS. At 1 month, the composite safety and the individual components did not differ between the two study groups. Considering the primary angiographic efficacy end point, at 6 months in-stent minimum lumen diameter was larger in BP-SES versus BMS patients, resulting in significantly lower LLL in BP-SES (0.09 ± 0.43 vs 0.79 ± 0.67 mm). Moreover, BP-SES showed a tendency towards lower definite/probable ST rates compared with BMS. The limitations of this study are represented by the single-blind design and, despite randomization, the imbalance regarding the staged procedures in favor of the BP-SES group.

In conclusion, the MASTER study demonstrated clinical noninferiority and favorable angiographic results of BP-SES versus BMS in STEMI patients.

• The CENTURY JSV study [18]: it was designed to evaluate the safety and effectiveness of the 2.25-mm diameter Ultimaster sirolimus-eluting stent in patients with CAD due to lesions in very small vessels. It was a prospective, multicenter, single-arm study conducted in Japan. Totally, 70 patients with lesions eligible for implantation of a 2.25-mm diameter stent were enrolled in seven hospitals and then evaluated with a clinical follow-up at 1 month, 9 months, 1 year and 2 years after the PCI procedure. The primary end point was the major adverse cardiac event (MACE), a composite of cardiac death, target vessel MI and clinically driven TLR-free rate at 9-month after PCI. The MACE-free rate was 97.1%, and the lower limit of the two-sided 95% CI was 90.1% (with the performance goal set at 80%). Angiographic in-stent and in-segment late loss at 9 months were 0.22 ± 0.31 and −0.02 ± 0.34 mm, respectively. Two additional TLRs occurred between 9 months and 2 years; ST, bleeding and vascular complication did not occur throughout 2 years. Therefore, the 2.25-mm diameter Ultimaster sirolimus-eluting stent proved safety and efficacy for treating lesions in very small coronary arteries throughout the 2 years follow-up after stent implantation. The small sample size and the single-arm study design represent the main limitations of this study;

• The ULISSE registry [19]: it is a multicenter independent, single-arm, all-comers, observational, national registry conducted in nine centers in Italy. The registry retrospectively included 1660 consecutive patients (2422 lesions) undergoing Ultimaster BP-SES implantation for both elective and urgent procedures and included a large proportion of high-risk clinical profile patients (37% ACS, 29% DM, as well as complex lesions, including 65% type B2/C lesions according to the ACC/AHA classification, 17% bifurcations, 7% chronic total occlusions (CTOs) and 38% long lesions >25 mm). The primary end point was TLF at 1-year (composite of cardiac death, target-vessel MI and clinically TLR). The secondary end points were the individual components of the primary end point and ST at 1-year. The TLF evaluated in the 84% eligible patients to 1-year follow-up occurred in 5% (1.8% cardiac-deaths, 1.4% target-vessel MI, 3.2% clinically indicated TLR) and 0.9% of the patients experienced a definite ST. Multivariate logistic regression analysis identified stenting on unprotected left main (odds ratio [OR]: 4.80; 95% CI: 2.22–10.36), stenting on in-stent restenosis lesion (OR: 3.19; 95% CI: 1.60–6.40) and need for rotational atherectomy during the procedure (OR: 6.24; 95% CI: 1.84–21.09; p = 0.003) as the strongest independent predictors of TLF. Therefore, the ULISSE registry demonstrated the Ultimaster BP-SES real-world performance, that with a low rate of the primary end point and TLR was comparable with that observed in the clinical trials. Subgroup analyses were conducted for complex lesions (type B2/C lesions), bifurcations, CTOs and long lesions, DM and chronic kidney disease (CKD) patients. The TLF rate was 12.5% in patients with CKD, 8% in patients with DM, 7% in those treated for bifurcations, 6.7% in those treated for CTOs, 6.2% in those treated for long lesions and 6% in those treated for type B2/C.

Furthermore, a subsequent subgroup analysis focused on acute MI (AMI) patients was done [37]. In the ULISSE registry, 23% of patients presented with AMI (54.3% NSTEMI and 45.7% STEMI). Compared with non-AMI patients, those with AMI were more frequently female and smokers, with lower left ventricular ejection fraction and CKD requiring dialysis. At 1 year, TLF rate was significantly higher in AMI than non-AMI patients (7.9 vs 4.1%; hazard ratio [HR]: 1.98; 95% CI: 1.22–3.23) driven by higher rate of cardiac death (4.0 vs 1.1%; HR: 3.59; 95% CI: 1.64–7.88) and target vessel MI (2.8 vs 0.9%; HR: 2.99; 95% CI: 1.22–7.37), without differences in TLR rate. At multivariate Cox regression analysis, the only independent predictors of TLF were eGFR <40 ml/min (HR: 2.867) and left ventricular ejection fraction <40% (HR: 2.39); thus, the higher incidence of adverse events in AMI patients was mainly driven by the unfavorable baseline risk profile.

• The JAPANESE registry [20]: it is an observational, single-center, all-comers study conducted in Japan. Ultimaster BP-SESs were used as the intentional choice during PCI for all patients requiring stent implantation over 1-year period and 1-year clinical outcomes were evaluated. The primary end points were TLR and TLF (composite of TLR, target vessel MI and cardiac death). The secondary end points were definite ST, target vessel MI, all MI, cardiac death and all-cause death. Univariate and multivariate analyses were conducted to examine the predictors of TLR and TLF on a per-patient basis. Totally, 1727 patients (2085 lesions) treated with at least one BP-SES were included. The cumulative 1-year incidences of TLR and TLF were 2.4 and 5.2%, respectively. The crude incidences of definite ST, target vessel-MI, all MI, cardiac death and all cause death were 0.12, 0.1, 0.2, 1.7 and 3.8% respectively. At multivariate analysis hemodialysis (HR: 8.40) and CTOs (HR: 4.21) were independent predictors of TLR. In conclusion, 1-year clinical outcomes after BP-SES implantation were favorable among real-world all-comer PCI cases, including patients with complex backgrounds. Hemodialysis and CTO were significantly associated with both TLR and TLF after BP-SES implantation;

• The CTO Study [21]: Azzalini et al. aimed to evaluate in a multicenter registry the outcomes of Ultimaster stent (BP-SES) in CTOs PCI, as compared with durable-polymer EES. The primary end point was the incidence of TLF (a composite of cardiac death, target-vessel MI and TLR) at 1 year. Totally, 413 patients were included. Propensity score matching was used to adjust for case mix and resulted in 131 matched pairs, which represented the subject of the main analysis. Antegrade wire escalation was the most successful crossing technique (66 vs 63% in BP-SES and EES groups, respectively; p = 0.98). No difference in procedural success rates was detected (BP-SES 96% vs EES 93%; p = 0.24). At 1-year follow-up, there were no differences in the primary end point of TLF (5.7% vs 8.3%, p = 0.44), and in cardiac death (0.9 vs 2.8%; p = 0.32), target-vessel MI (0.9 vs 1.9%; p = 0.57), TLR (3.7 vs 3.7%; p = 0.99) or ST (0.9% vs 1.9%; p = 0.57), in BP-SES versus EES, respectively. The authors concluded that patients undergoing CTO PCI with BP-SES suffer a low rate of TLF at 1-year follow-up, which is similar to that of subjects treated with durable-polymer EES;

• e-ULTIMASTER Registry [22]: it is an all-comer, single-arm, prospective, multicenter registry. The study was conducted worldwide across Europe, Asia, South America and Africa to further evaluate the safety and performance of the Ultimaster DES system in an all-comer clinical setting. The registry enrolled 36,916 patients and a 1-year follow-up was completed in August 2019. At an interim analysis of 19,842 patients, a prespecified subset of left anterior descending (LAD) artery stenting has been assessed. As current guidelines recommend heart team discussion and coronary artery bypass graft consideration in patients with proximal LAD artery stenosis, this subset analysis was performed with the aim to determine clinical outcomes of patients undergoing PCI in the proximal LAD segment using Ultimaster stent. In this analysis, patients undergoing angioplasty in the proximal LAD territory were compared with those treated in nonproximal LAD locations. This analysis excluded patients with left main segment involvement and treatment and those with previous coronary artery bypass graft surgery. All other patients from the e-Ultimaster registry who had follow-up at 3 months and 1 year, or died before reaching 1 year, were included. To adjust for baseline and procedural differences among the groups, multivariate analysis and propensity score were used. The primary outcome was TLF: a composite of cardiac death, target vessel-related myocardial infarction and clinically driven TLR at 1-year follow-up. The final analysis involved 17,805 patients (mean age: 64.2 ± 11; 76% male), of which 5452 (30.6%) underwent proximal LAD and 12,353 underwent (69.4%) nonproximal LAD PCI. Patients in the proximal LAD group had MVD (48.7% vs 43.5%; p < 0.001) and more bifurcations lesions (18.8% vs 9.2%; p < 0.0001). After propensity-weighted adjustment, TLF did not differ between the proximal LAD group (3.3%) versus nonproximal LAD (2.9%), p = 0.17. In multivariate analysis, proximal LAD treatment was not an independent predictor of TLF (OR: 1.07; 95% CI: 0.88–1.31; p = 0.48). Authors concluded that at 1-year follow-up, patients had similar clinical outcomes independent of lesion location, questioning whether proximal LAD treatment should be regarded differently from stenting in any other coronary artery territory.

Final results of total population and all prespecified subsets of e-ULTIMASTER registry will be available in the course of 2020.

Future directions

Poor DES biocompatibility has been associated with chronic inflammatory response, fibrin deposition on the vessel wall and hypersensitivity reactions, resulting in delayed endothelial stent strut coverage, impaired vessel healing and stent thrombosis [5]. Recently, two studies assessed the vessel-healing pattern of Ultimaster DES:

• The DISCOVERY 1TO3 study [23]: it is a prospective, single-arm, open-label, multicenter study conducted in Europe. This was a mechanistic evaluation not powered for clinical outcomes. Patients with MVD with ≥2 de novo lesions in native coronary arteries suitable for treatment with Ultimaster BP-SES and requiring staged procedure at 1 month were included. Optical Frequency Domain Imaging (OFDI) was acquired at baseline, 1, 2 and 3 months. The primary end point was OFDI assessed percentage of stent strut coverage at 3 months postprocedure (in single implanted stents); secondary end points were: strut coverage at 1 and 2 months, percentage of acquired malapposed struts, neointimal hyperplasia thickness and obstruction at 1, 2 or 3 months, and 1-year clinical outcomes. A total of 60 patients were included and 132 lesions were treated (2.2 ± 0.5 mean number of vessels diseased, 1.4 ± 0.6 lesions per patient treated at baseline and 1.1 ± 0.4 lesions per patient treated at 1 month staged procedure). Strut coverage at 3 months of single implanted stents was 95.2 ± 5.2% and of single and overlapped stents was 95.4 ± 4.9%. Strut coverage of combined single and overlapped stents at 1 and 2 months was 85.1 ± 12.7 and 87.9 ± 10.8%, respectively. The median neointimal hyperplasia thickness over covered struts was 0.04, 0.05 and 0.06 mm; mean neointimal hyperplasia obstruction was 4.5 ± 2.4, 5.2 ± 3.4 and 6.6 ± 3.3% at 1, 2 and 3 months, respectively. Furthermore, the frequency of malapposed struts per lesion decreased over time (1.7 ± 2.6, 1.3 ± 2.2 and 0.69 ± 1.2%, respectively). At 1-year clinical follow-up, there were two additional TLR and no occurrence of death. These findings support the completion of the strut coverage process within the first month after Ultimaster BP-SES implantation, a favorable strut coverage at 3-month evaluation and a good 1-year efficacy profile in complex MVD;

• A single-center prospective study was conducted by Kobayashi et al. [24] in patients treated by staged PCI procedures. At the time of the initial PCI, patients were treated with BP-DES Ultimaster or SYNERGY (Boston Scientific Corporation, MA, USA) or PP-EES. Thereafter, staged PCI was performed for other lesions, and the initially treated lesion was observed by OFDI within 1 month after the initial procedure. Totally, 32 BP-DES and 25 PP-EES were included. Neointimal coverage was significantly superior in BP-DES in both apposed and malapposed strut (apposed: 53.9% in BP-DES vs 28.0% in PP-EES; p < 0.001 and malapposed: 22.9% in BP-DES vs 7.5% in PP-EES; p = 0.001). When the follow-up period was divided into <2 and >2 weeks, neointimal coverage in BP-DES was also significantly superior to that in PP-EES. Immediate postprocedure OFDI findings were not provided in this study limiting a more complete interpretation of results. However, the new-generation BP-DES showed excellent early neointimal coverage compared with PP-EES.

Therefore, considering the evidence of very early strut coverage within the first month after the BP-SES implantation, the option of using a short DAPT duration in high-bleeding-risk (HBR) patients was explored in the subanalysis of the ULISSE registry [38]. In this real-world experience, clinical outcomes of PCI with Ultimaster BP-SES in a large unselected cohort of patients, discharged with clinical indication to short DAPT duration, were assessed. Two groups were compared: first, patients discharged with short DAPT (≤3 months) due to HBR or need for urgent major non-cardiac surgery, and second, patients discharged with recommended DAPT duration (≥6 months). The primary ischemic-safety and bleeding-safety end points were TLF (composite of cardiac-death, target vessel MI and clinically driven TLR) and Bleeding Academic Research Consortium (BARC) major bleedings (≥type 3a) at 1-year follow-up. Respectively, 82 and 1558 patients were included in a short and recommended DAPT group. No significant differences between the two groups were observed in TLF at 1-year (7.9% in short vs 4.6% recommended DAPT group; p = 0.173). Also, no differences were found in definite ST (1.3 vs 0.7%, respectively; p = 0.580). The rate of BARC major bleeding resulted significantly higher in short versus recommended DAPT group (3.9 vs 0.3%, respectively; p = 0.001), while the landmark analysis at 90 days showed no significant differences in BARC major bleedings between groups (1.4 vs 0.3%, respectively; p = 0.142).

The results of these experiences represented the basis of the MASTER DAPT trial considering that, currently, there are still no controlled data regarding the safety of short DAPT after PCI with Ultimaster BP-SES [39]. This ongoing study is an investigator-initiated, open-label, multicenter, randomized controlled trial comparing a short vs. standard duration of DAPT after Ultimaster BP-SES implantation in approximately 4300 HBR patients. After 30-day DAPT run-in phase, patients are randomized to a) a single antiplatelet regimen until study completion or up to 5 months in patients with clinically indicated oral anticoagulation (experimental 1-month DAPT group) or b) continue DAPT for at least 5 months in patients without concomitant indication to oral anticoagulation or for 2 months in patients with concomitant indication to oral anticoagulation, followed by a single antiplatelet regimen (standard antiplatelet regimen). The study is powered to assess the noninferiority of short DAPT with respect to major adverse cardiac and cerebral events composite end points and, if satisfied, for the superiority of short as compared with standard DAPT duration in terms of major or clinically relevant nonmajor bleeding.

Results from this study are expected to provide new insights into this growing field.

Conclusion

Five years from its release on the clinical field the Ultimaster coronary stent has demonstrated in controlled randomized studies and observational registries an excellent overall device performance, in terms of efficacy and safety profile during short-, medium- and long-term follow-up. The evidence from large-scale clinical trials powered for clinical primary end points enabled its unrestricted use in patients with CAD and an indication for PCI, including patients with diabetes, MVD, left main disease, AMI, saphenous vein grafts, restenotic lesions and CTOs as documented in the European Guidelines on Myocardial Revascularization [3,4]. Clinical efficacy has also been confirmed in the latest real-world studies performed worldwide. Furthermore, we are waiting for the results of the MASTER DAPT trial that is the first dedicated randomized clinical trial aiming at investigating the optimal duration of antiplatelet therapy in patients with HBR features after Ultimaster BP-SES stent implantation.

Regulatory affairs

The Ultimaster coronary stent system received the CE mark approval for clinical use in 2014, indicating that the product complies with the requirements applicable in the European Union. The CE marked indications confirm positive results achieved in clinical trials concerning the following conditions: ACS, STEMI, NSTEMI, DAPT, DM, MVD, small vessel, long lesions, elderly, in-stent restenosis, CTOs, bifurcation lesions, women, men, ostial stenosis, and left the main disease. In 2018 Ultimaster Tansei coronary stent system has received CE mark. The difference between the two is only in an improved delivery catheter of Tansei DES, while the stents design and polymer/drug coating formulation are identical.