Magnesium Bioresorbable Scaffold (BRS) Magmaris vs Biodegradable Polymer DES Ultimaster in NSTE-ACS Population—12-Month Clinical Outcome

Background Percutaneous coronary intervention (PCI) in the acute coronary syndrome (ACS) setting is associated with a greater probability of device failure. The currently ongoing development of new scaffold technologies has concentrated an effort on improving the PCI outcomes, including the use of new biodegradable materials. This pilot study evaluates the performance of a magnesium bioresorbable scaffold (Magmaris, Biotronik, Germany) in comparison to the sirolimus‐eluting bioresorbable polymer stents (BP-SES) (Ultimaster, Terumo, Japan) in the NSTE-ACS setting. Methods The population of this pilot comprised 362 patients assigned to one of two arms (193-Magmaris vs 169-Ultimaster). The data regarding the primary outcome comprised of death from cardiac causes, myocardial infarction, and stent thrombosis, along with target-lesion failure (TLF) and other clinical events was collected in the 1-yearfollow-up. Results There were no statistically significant differences in clinical outcomes in the short term (30 days) or in the 1-yearfollow-up between both groups. Conclusion At 12 months, there were no statistically significant differences between the Magmaris and Ultimaster for composed endpoints or the TLF.


Introduction
Te clinical outcomes of patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) have remarkably improved following the introduction of second-generationdrug-eluting stents (DES). Nevertheless, PCI in an acute coronary syndrome (ACS) setting remains associated with an increased rate of device failure [1]. Tese phenomena might be connected with the exacerbation of local infammatory response to the metallic scafold as well as the prevalence of permanent polymer coatings of a scafold bone [2]. Recently, several biodegradable materials have been proposed in order to overcome these limitations.
One of the concepts assumed replacing of permanent polymer with a biodegradable substitute, which allowed for gradual drug release and leave bare metal scafold in place facilitating local reendothelialization, reducing thus the infammatory reaction and in consequence lowering the rate of late stent-related complications [2].
Te other strategy is related to the complete resorption of scafolds (BRS) and allows for anatomical and functional restoration of the vessel without maintaining any material in the treated vessel in the long-term outcome.
Te frst generation of BRS (Absorb) was built from biodegradable poly-L-lactide (PLLA) and had initial encouraging outcomes [3]. However, longer clinical observation has raised safety-related concerns. Te data from registries suggested an increased rate of scafold thrombosis and target vessel myocardial infarction. Terefore, after publishing the results of Absorb II [4] and Absorb III [5] trials, the Absorbs have been withdrawn from commercial use in clinical practice.
Despite the initial setback of the BRS technology, a new generation of bioresorbable scafolds has recently appeared. Te Magmaris is a novel scafold with a backbone made of absorbable magnesium alloy-fully coated with biodegradable PLLA polymer BIOlute. Te initial data suggested a reasonable safety profle of this device. Nevertheless, the data regarding the head-to-head comparison between Magmaris and the novel generations of DES is still sparse [6].
Hence, this pilot study was designed to investigate the performance of a magnesium bioresorbable scafold (Magmaris) in comparison to the sirolimus-eluting bioresorbable polymer stents (BP-SES) Ultimaster in subjects with the non-ST elevation acute coronary syndrome (NSTE-ACS).

Study Population.
Te study was based on a retrospective two-center analysis of two NSTE-ACS-Registries conducted at the Clinical Departments of Cardiology. Te study population comprised 362 patients who were assigned to one out of two study arms. Te frst one consisted of 193 patients treated with Magmaris implantation. Te second arm was composed of 169 subjects treated with Ultimaster implantation. All participants were diagnosed with acute coronary syndrome according to current guidelines (with the exclusion of ST-segment elevation myocardial infarction (STEMI) cases) and had a clinical indication for PCI. All the inclusion and exclusion criteria are pooled in Figure 1.
Out of all NSTE-ACS-Ultimaster cases (541) performed between January 2015 and December 2018 at our Cardiac departments, we carefully selected 169 patients meeting the inclusion and exclusion criteria. Te BRS group was formed by the 193 NSTE-ACS subjects.

PCI Procedures.
All the PCI procedures were initiated with a predilation (using a noncompliant (NC) balloon, sized with a 1 :1 balloon to artery ratio) and followed by mandatory postdilatation with an NC balloon (at least 16 atm) sized 1 :1 balloon/scafold ratio or higher. A decision regarding the use of IVUS/OCT support during the PCI was left to the discretion of the operators. An example of the BRS implantation procedure with subsequent follow-up with additional evaluation in intravascular imaging is presented in Figure 2.

Study Devices.
Te Magmaris, initially known as a DREAMS 2G, is a metallic magnesium sirolimus-eluting scafold covered with a biodegradable polymer (BIOlute) Poly-L-Lactide (PLLA) and is available in two diameter sizes (3.0 mm and 3.5 mm). Te approximate scafold bioresorption time is 12 months.

Outcomes and Endpoints. Te primary outcomes included
(i) death from cardiac causes (ii) myocardial infarction (iii) in-stent thrombosis Te secondary outcomes were device-orientated and defned as follows: (i) target-lesion failure (TLF) including death (ii) target vessel-related myocardial infarction (TV-MI) (iii) target lesion revascularization (TLR) Other clinical variables were collected, including scafold restenosis, death from any reason, cerebrovascular episodes, need for any revascularization procedure, or myocardial infarction.
All the clinical data were obtained by trained staf (physicians or/and nurses) during personal visits or telephone contact during the 30-day and 1-yearfollow-up period. Te defnition of myocardial infarction was based on the Fourth Universal Defnition of Myocardial Infarction [7].

Statistical
Analysis. Te R language was used for analyses. Continuous variables were characterized by their mean and standard deviation, or median and interquartile range, dependent on their distribution, whereas the frequencies were used for categorical variables. Te study subjects were compared between groups using a twosample Mann-Whitney's or T-Test as an appropriate test for continuous variables and Fisher's Exact Test for categorical variables. Te Bonferroni correction was applied to adjust for the multiple comparisons. Te power calculation was performed using the power.fsher.test from a statmod R package. p value <0.05 was considered statistically signifcant.

Results and Discussion
3.1. Patient Characteristics. All the data regarding patients' clinical characteristics are presented in Table 1. In both study arms majority of subjects were male (77.7% in the Magmaris and 75.7% in the Ultimaster arm, respectively). Te primary diagnosis of NSTEMI was more common in the Magmaris than in the Ultimaster group (84.5% vs 52.1%, respectively, p < 0.001) Among all comorbidities atrial fbrillation was less frequently observed in the Magmaris group (4.6% vs 14.2%, respectively, p � 0.002). Similarly, lower total cholesterol (4.6 ± 1.3 vs 4.95 ± 1.4 mM; respectively, p � 0.041) and LDL cholesterol levels were observed in the Magmaris group (2.5 ± 1.2 vs 2.92 ± 1.9 mM respectively, p � 0.025). Additionally, subjects from the Magmaris arm were characterized by higher left ventricular ejection fraction at discharge time (60.4% ± 10.9 vs 53.6% ± 13.1 respectively, p � 0.001). Te average duration of hospitalization was shorter in the Magmaris group (2.7 ± 1.8 vs 3.9 ± 2.9, respectively)

PCI Characteristics.
Subjects from the Magmaris arm maintained slightly more aggressive lesion preparation (mean pressure of 17.7 ± 0.8 vs 15.9 ± 1.9 atm., respectively, p < 0.001). Noteworthy, there were no diferences in the size of the balloon catheter used for predilatation in both arms. Similar diferences were observed regarding the postdilatation parameters size (0.25 mm greater than scafold-65.2% vs 20.7%, respectively, p < 0.001; and 0.5 mm greater than scafold 18.2% vs 8.3%, respectively, p < 0.001), as well as regarding the mean pressure used during postdilatation (   Journal of Interventional Cardiology lower radiation was used during the Magmaris implantation (1056.7 ± 697.8 vs 1244,2 ± 761.1 mGy respectively, p � 0.008). All data regarding procedural characteristics were collected in Table 2.

Clinical Outcomes.
All the data regarding clinical outcomes are summarized in Table 3. Except for the 30dayfollow-up "any other revascularization" rate (0% vs 5%, respectively, p � 0.012) there were no diferences in clinical outcomes in the 30 days follow-up between both study arms. At 1-yearfollow-up, no signifcant diferences among primary and secondary endpoints between both study groups were noticed. However, in the Magmaris cohort, a slightly lower rate of the primary endpoint (1.5% vs 5% respectively, p � 0.074) which however did not reach statistical signifcance in this pilot study. A similar trend was observed for the principal secondary outcomes (1.5% vs 5.4%, respectively, p � 0.199). Moreover, in the Magmaris arm, we reported a lower rate of other coronary revascularization (9.3% vs 14% in the Ultimaster arm, respectively, p � 0.188) again without statistical signifcance. Te power calculations revealed that for comparing 3 outcomes out of 193 vs. 9 outcomes of 169, the power of the Fisher test at 0.05 signifcance level was 0.467.

Discussion
Tis is the frst report comparing the 1-year clinical outcome of two sirolimus-eluting magnesium bioresorbable scafolds (Magmaris), and ultrathin cobalt-chromium stent coated with a bioresorbable polymer (Ultimaster) in NSTE-ACS conditions. Since publishing the data from the frst-in-man trial [8] and receiving the CE mark, the Magmaris scafold has been proven to be a relatively safe device. However, evidence coming from small-size preclinical studies [9,10], along with initial clinical trials -mainly focused on patients with stable angina [11] and acute coronary syndrome [12] supported this statement. Although recently published midterm and long-term outcomes [13][14][15][16][17][18] are also encouraging, the data from trials comparing Magmaris with the new DES generation are still scarce. As result, we performed this pilot study to evaluate the utility of a magnesium bioresorbable scafold (Magmaris) in comparison with an ultrathin cobaltchromium stent (Ultimaster) in the acute coronary syndrome setting.
Te main fndings of this study are as follows: (1) In our relatively small, retrospective, nonrandomized study cohort Magmaris and Ultimaster showed no diferences in clinical outcomes for the Primary Endpoint (death from cardiac causes, myocardial infarction, in-stent thrombosis) as well as regarding the TLF in the 30-day and 1-year-follow-up period (2) Magmaris did not present any defnite scafoldrelated thrombosis after a 12-month observation period In recently conducted studies Ultimaster has demonstrated good overall device performance, in the ACS cohort [19]. Tese favorable ACS-related outcomes might be linked to the presence of biodegradable polymer, which intensifes the alleviation of vascular infammation and accelerates endothelial maturation, which is crucial in these high-risk patients [20]. Considering that in our study the rates of 1year composite endpoints-TLR in the Ultimaster arm were lower than previously described [21] (5.4% vs 7.9%), we might assume that the Magmaris might demonstrate the outcomes compared to the ones observed in the newgeneration DES devices.
A similar suggestion was made by Hideo-Kajita et al. [6], wherein the subpopulation of non-ACS subjects, no signifcant diferences between the Magmaris and other BP-SES (Orsiro) were observed, but again was higher than observed in our study (6% for Magmaris vs 6.4% in Orsiro group). On the other hand, a small study by Toušek et al. [22] suggests that both QCA and OCTrevealed lower efciency of Magmaris scafold when compared to the leading drugeluting metallic stent (Xience) in the 12-monthfollow-up period of patients with STEMI. However, a detailed analysis of the implantation technique used in this study reveals deviations from the recommended BRS Magmaris "4P strategy" [23], particularly in terms of lesion preparation. Tese results were partially confrmed in MAGSTEMI randomized control trial [24] which evaluated the 1-year outcome of STEMI patients treated with implantation of Magmaris or ultrathin, biodegradable polymer sirolimuseluting stent (Orsiro). Te rate of the device-oriented endpoint (TLR) was signifcantly higher in the Magmaris group (16.2% vs 5.3%), despite the use of a dedicated implantation technique [25]. However, patients after Magmaris implantation showed enhanced in-deviceendotheliumindependent and endothelium-dependent vasomotor response, compared to the Orsiro subpopulation. Also, like in our study, no thrombotic safety concerns occurred, despite the highly thrombogenic setting. We can partly attribute a relatively low rate of thrombosis to scafold backbone features-higher radial strength which reduces timedependent recoil phenomena and improves the local hemodynamic properties afecting the endothelization period [9,26,27]. In addition, magnesium used to scafold production has got favorable electrochemical properties -compare to other metals used for implants is more electronegative and may repel negatively charged platelets leading to the indirect reduction of potential thrombogenicity [27,28].
Te selection process for our study was based on the inclusion and exclusion criteria of the Magmaris registry. We qualifed patients with rather "unchallenging" anatomy of the lesions without complex calcifed cases, requiring implantation of multiple scafolds (including two stent techniques for bifurcation lesions). Tis could constitute some limitations of our study, however, what needs to be emphasized, the aim of this pilot study was focused on the clinical evaluation of Magmaris-a novel BRS that has not been widely used in clinical practice (implanted mainly in selected cardiac centers familiar with the magnesium BRS technology). Terefore, we believe that the results of our study despite some limitations may provide valuable information regarding the safety and efcacy of the magnesium BRS in the real-life NSTE-ACS setting.

Limitations
Tis study has several limitations. First, the data were collected retrospectively in the relatively short-term observation period (1-year follow-up). Second, this is a comparison between the 2 non-randomized observational registries. Tird, performed power calculation revealed that in terms of the 30-day and 1-yearfollow-up, the study is underpowered, which might be however justifed by its pilot character. Fourth, the study groups were not fully homogenous several diferences among clinical features were observed. Finally, even though we can presume that the low rate of imageguided PCI performed in this study could have afected the outcomes, the study population consisted of NSTE-ACS  patients, where the use of the OCT/IVUS procedures in an emergency setting is less frequent, which makes this study more relevant to the real-life clinical scenario.

Conclusions
In both study arms (BRS and Ultimaster), no defnite scafold-related thrombosis occurred after 12 months of follow-up. We have observed similar outcomes in terms of the two major composed endpoints-primary outcome (including death from cardiac causes, myocardial infarction, and in-stent thrombosis) and TLF. Nevertheless, the pilot character of this study and relatively low sample size point to the need for a subsequent large multicenter prospective trial in order to address precisely the efcacy and safety concerns of BRS, as well as to draw fnal conclusions and formulate precise recommendations in this matter.

Data Availability
Data are not included in the manuscript due to local laws and privacy restrictions. It can be made available from the corresponding author upon request.

Ethical Approval
Tis study was conducted according to the guidelines of the Declaration of Helsinki and was approved by Medical Lower Silesian Ethic Board (20/07/2016 approval 12.07.2016).