Real-World Three-Year Clinical Outcomes of Biolimus-Eluting Stents versus Other Contemporary Drug-Eluting Stents in Patients with Acute Myocardial Infarction Patients: Data from the Korea Acute Myocardial Infarction Registry (KAMIR)

Introduction Biolimus-eluting stents (BES) are known to be superior to bare-metal stents. This study aims to evaluate the safety and efficacy of BES compared to other drug-eluting stents (DES) based on big data from the Korea Acute Myocardial Infarction Registry (KAMIR). Methods The study analyzed a total of 9,759 acute myocardial infarction (AMI) patients who underwent percutaneous coronary intervention (PCI) with DES. Total death, cardiac death, recurrent MI, revascularization, stent thrombosis, target lesion failure (TLF, composite of cardiac death, recurrent myocardial infarction (MI), and target lesion revascularization), and major adverse cardiac events (MACE, composite of total death, recurrent MI, and revascularization) were analyzed in patients with AMI up to three years. Study populations were divided into BES (n = 2,020), everolimus-eluting stents (EES, n = 5,293), and zotarolimus-eluting stents (ZES, n = 2,446) groups. Results To adjust baseline potential confounders, an inverse probability weighting (IPTW) analysis was performed. After IPTW, at three years, total death (7.2%, 8.6%, and 9.5%, P < 0.001), cardiac death (4.1%, 5.3%, and 6.6%, P < 0.001), recurrent MI (1.6%, 2.6%, and 3.2%, P < 0.001), TLF (6.5%, 8.1%, and 9.1%, P < 0.001), and MACE (15.8%, 17.5%, and 18.2%, P < 0.001) were lowest in the BES group compared with the other DES groups in AMI patients. During the 3-year clinical follow-up, the BES group showed better outcomes of MACE (hazard ratio (HR), 0.773; 95% confidence interval (CI), 0.676–0.884; P < 0.001), TLF (HR, 0.659; 95% CI, 0.538–0.808; P < 0.001), total death (HR, 0.687; 95% CI, 0.566–0.835; P < 0.001), and cardiac death (HR,0.593; 95% CI, 0.462–0.541; P < 0.001) than the EES groups. Conclusions In this study, BES was superior to EES or ZES in reducing total death, cardiac death, TLF, and MACE in AMI patients.


Introduction
Durable polymers of first-generation drug-eluting stents (DESs) have safety issues, such as very late stent thrombosis (ST), which is related to adverse clinical outcomes [1]. Recently, biodegradable polymer-coated DESs were reported to be better in reducing very late STand improving clinical outcomes than firstgeneration DES [2]. Biolimus-eluting stents (BES) are polymerfree and carrier-free drug-coated stents that transfer umirolimus (also known as biolimus A9), a highly lipophilic sirolimus analogue, into the vessel wall over a one-month period [3]. In the Prospective Randomized Comparison of the BioFreedom Biolimus A9 Drug-Coated Stent versus the Gazelle Bare-Metal Stent in Patients at High Bleeding Risk (LEADERS FREE) trial, the use of BES in patients with a high risk of bleeding who underwent percutaneous coronary intervention (PCI) reduces the incidence of target lesion revascularization (TLR) and is superior to bare-metal stents in terms of safety and efficacy [4].
In this study, we compared the three-year clinical outcomes between BES and other DESs, including everolimus-eluting stents (EES) and zotarolimus-eluting stents (ZES) in patients with acute myocardial infarction (AMI). e study was based on big data from the Korea AMI registry (KAMIR).

Study Population.
e study population is described in Figure 1. A total of 13,104 patients who underwent PCI at 15 different institutions were enrolled from 2008 to 2015. Patients treated with fibrinolysis (n � 134), plain old balloon angioplasty (POBA, n � 802), other DESs (n � 1,117), suboptimal or failed PCI (n � 1,524), and different DES (n � 24) were excluded.
A total of 9,759 patients were analyzed, and 2,020 patients were treated with BES. Of those, 2,020 patients were treated with BES. Of those, 1,488 patients were treated with Biomatrix (Biosensors international, Morges, Switzerland) and 532 patients were treated with Nobori (Terumo Corporation, Tokyo, Japan). 5,293 patients were treated with EES (Xience Prime stent, Abbott Vascular, Santa Clara, CA; Promus Element stent, Boston Scientific, Natick, MA) and 2,446 patients were treated with ZES (Resolute Integrity stent; Medtronic, Inc., Minneapolis, MN). Figure 1 shows the three main groups of BES (n � 2,020), EES (n � 5,293), and ZES (n � 2,446). In this study, data have been collected after obtaining written informed consent prior to enrolment and a three-year clinical follow-up was completed by faceto-face interviews, phone calls, or chart review.

Clinical Outcomes and Study Definitions.
In this study, we compared the three-year clinical outcomes, such as total death, cardiac death, recurrent MI, coronary revascularization, ST, target lesion failure (TLF), and major adverse cardiac event (MACE), in patients treated with BES, EES, and ZES. Study definitions used in this study are as follows: all-cause death (total death) including cardiac or noncardiac death. AMI was diagnosed as the presence of clinical symptoms, electrocardiographic changes, abnormal imaging findings of MI at angiography, and an increase in troponin-T/troponin-I and CK-MB to greater than the 99th percentile of the upper normal limit. Any coronary revascularization included TLR, target vessel revascularization (TVR), and nontarget vessel revascularization (NTVR) during the 3-year follow-up period. TLR was defined as revascularization of the target lesion due to restenosis or reocclusion within the stent or 5 mm in and adjacent to the distal or proximal segment. TVR was defined as revascularization of the target vessel or any segment of the coronary artery. NTVR was defined as revascularization of any segment of the nontarget coronary artery. 2 TLF was defined as composite of cardiac death, recurrent MI, and TLR. MACE was defined as the composite of total death, recurrent MI, and any coronary revascularization. In addition, Modified American College of Cardiology/American Heart Association criteria were used to classify coronary lesion morphology [5].

PCI Procedure and Medical Treatment.
e loading doses of antiplatelet agents were as follows [6,7]: aspirin was 200 mg, clopidogrel was 300 to 6+00 mg, ticagrelor was 180 mg, and prasugrel was 60 mg. e maintenance dose antiplatelet agents were as follows: aspirin was 100 mg, clopidogrel was 75 mg, ticagrelor was 90 mg twice a day, and prasugrel was 10 mg. If the patient <60 kg, the maintenance dose of prasugrel was reduced to 5 mg per day because of the potentially increased bleeding risk as described in a previous study.
Heparin administration before the procedure is as follows. e dose of unfractionated heparin was 100 IU/kg during the procedure and the dose was reduced to 70 IU/kg when it was combined with low molecular weight heparin Enoxaparin (Clexane ® , Bristol-Myers Squibb and Sanofi-Aventis), 1 mg/Kg, and twice a day for 3-5 days.
Coronary angiography and intervention were approached with the femoral or radial artery. e administration of platelet glycoprotein IIb/IIIa receptor blockers depended on the operators' discretion. If the patient had typical angina symptoms or signs and over 70% diameter restenosis was observed in coronary angiography, the operators decided revascularization.

Statistical Analysis.
Continuous variables are expressed as means with standard deviations. Differences among the three groups, such as BES, EES, and ZES, were evaluated by analysis of variance in normally distributed data and Kruskal-Wallis H test in nonnormally distributed data. Post hoc analysis among the three groups was done using the Scheffe test or Dunnett-T3 test. Discrete variables are expressed as counts and percentages and the differences were analyzed with the χ 2 test.
To adjust for any potential confounders, an inverse probability of treatment weighting (IPTW) analysis was performed [8,9]. We utilized generalized boosted models to estimate the propensity score weight of each treatment using methods developed for the comparison of multiple treatments. e average treatment effect on the population weights was estimated using the multinomial propensity scores function in the Twang package in R Statistical Software (R Foundation for Statistical Computing, Vienna, Austria). We tested all available variables that could be of potential relevance: age, sex (male), left ventricular ejection fraction, cardiovascular risk factors (e.g., hypertension, diabetes, dyslipidemia, and stroke), comedication treatment (e.g., aspirin, other antiplatelets, RAS inhibitors, calcium channel blockers, beta blockers, and statins), angiographic and procedural characteristics (e.g., target vessel, a number of diseased vessels, and DES type). Clinical outcomes including total death, cardiac death, recurrent MI, TLR, ST, TLF, and MACE are estimated by Cox-proportional hazards models analysis. Binary logistic regression analysis is used to assess the hazard ratio (HR) of the BES group and ZES user group compared to the EES group in the IPTW population. A two-tailed P value of <0.05 was considered statistically significant. SPSS software, version 20 (SPSS Inc., Chicago, IL, USA), and R statistical software are used for statistical analysis.

Results
Baseline characteristics are listed in Table 1. e mean values of left ventricular ejection fraction were higher in the BES group than in the other two DES groups. e rates of previous diabetes mellitus (DM), stroke, PCI, and coronary artery bypass graft (CABG) were lower in the BES group than in the other two. e use of clopidogrel was lower in the EES group, while the use of ticagrelor was higher in that group compared to the other two groups. e use of aspirin, clopidogrel, prasugrel, and statin was lower in the EES group, while the use of ticagrelor was higher in that group compared to the other two groups. Aspirin and prasugrel were used more in the BES group, but ticagrelor was used less in the BES group compared to the other two DES groups. However, these intergroup differences in baseline characteristics were well balanced after IPTW adjustment, except the use of prasugrel, was used more in the BES group than the other groups.
Procedural characteristics are also listed in Table 1. e number of stents and the rates of left anterior descending (LAD) artery, right coronary artery (RCA), left main (LM), and multivessel disease as treated vessels were lower in the BES group, and the stent length was shorter in the BES group than the other group. e number of stents and the rate of LAD, LM, and MVD were higher in the BES group, and the stent length was longer in the EES group than in the other groups. However, these intergroup differences were well balanced after IPTW adjustment, but the rate of MVD and the number of stents were lower in BES than in the other groups, and stent length was longer in the EES group than the other groups.
Clinical outcomes up to three years are listed in Table 2. e rates of total death, cardiac death, TLF, and MACE were lower in the BES group than those in other DES groups. However, recurrent MI, ST, and any revascularization, such as TLR, TVL, or non-TVR were all similar in patients of all three DES groups. After IPTW adjustment, the rate of total death, cardiac death, TLF, and MACE were still lower in the BES group, and the rate of recurrent MI was also lower in the BES group than in the other DES group. However, the rate of any revascularization such as TLR, TVR, or non-TVR, and stent thrombosis were similar to the three groups.

Discussion
In this study, we compared the clinical outcomes up to three years among patients treated with BES, EES, or ZES. e interesting thing about this study compared to previous studies is that IPTW analysis was performed to adjust baseline potential confounders. After IPTW, at three Due to remarkable developments, next-generation DES continue to improve their clinical outcomes compared to previous generations [10]. However, in the case of AMI, there are still many challenges, and there are various opinions on the choice of DES [11]. e stent polymer of DES is a long-chain macromolecule component and plays a role in controlling drug release as a drug carrier vehicle. ese polymers, however, can lead to undesirable biological responses. In the first-generation DES, durable polymers (DP) induce hypersensitivity and eosinophilic inflammatory reactions, resulting in delayed reendothelization of the vessels, increasing the incidence of ST [11]. us, inflammation caused by residual polymer eventually causes problems such as late stent malapposition, aneurysmal formation, and restenosis. Recently, there is great interest in DES or polymer-free DES coated with a biodegradable polymer (BP) for solving this problem.
BES is a polymer-free and carrier-free drug-coated stent that transfers umirolimus, which is also known as biolimus A9. Umirolimus is a highly lipophilic sirolimus analogue that transfers into the vessel wall over a period of one month [3]. In this study, we compared the three-year clinical outcomes of unrestricted use of BES and other DES in AMI patients in real-world clinical practice from 15 Korean PCIcapable institutions. Compared to all other groups, the BES group had a similar occurrence of revascularization and ST compared with the EES and ZES groups. ese results were similar to previous studies using the KAMIR registry. Kim et al. reported that DP-DES, such as EES and ZES, and BP-DES, such as BES, showed comparable safety and efficacy during the two-year follow-up period [6]. Vlachojannis et al. have reported that BP-coated BES and DP-coated EES had similar safety and efficacy outcomes up to five years in the entire PCI population [12].
In this study, we compared three groups that showed significant differences in clinical characteristics at baseline. BES groups had higher left ventricular ejection fractions, lower rates of DM, previous MI, PCI, and CABG, and lower levels of troponin and serum creatinine than the other groups, and these differences in baseline characteristics have been associated with better outcomes of the BES group.
ere are several statistical methods for reducing the impact of confounding factors. Propensity-matched analysis is helpful in eliminating the bias in observational studies. In this study, we utilized generalized boosted models to estimate the propensity score weight of each treatment using IPTW analysis, and after IPTW, the three groups were balanced in baseline characteristics. We compared three stents to estimate the efficacy and safety of BES compared to the other stents. As a result, cardiac death, recurrent MI, TLF, and MACE were reduced in AMI patients treated with BES compared to the other DES stents. However, ST and any revascularization, such as TLR, TVL, or non-TVR, showed no differences among the patients of all three DES groups.
ere are several limitations to this study. It is a nonrandomized design. We present the results of a multicentre observational registry comparing the outcome of BES versus other contemporary DESs, such as EES or ZES, in the setting of percutaneous coronary interventions for acute myocardial infarction. erefore, each stent had a different duration of follow-up, and more missing data occurred than is typical in randomized studies. e choice of DES was dependent on the decision of each operator, which could affect the clinical outcome for that choice.
Second, the difference in vascular approaches has been reported to affect the complications and the access-site bleeding of patients in the ACS setting and impact the prevention of further cardiovascular events. However, this study produced no data relevant to the type of vascular approach used.
In conclusion, we compared the three DES groups such as BES, EES, or ZES and matched the difference of baseline characteristics using IPTW analysis. After IPTW, BES showed superior efficacy to EES in reducing total death, cardiac death, TLF, and MACE in AMI patients and similar efficacy to EES or ZES in revascularization and ST.
To get a final conclusion among the three DES groups, we assumed that a large, prospective, randomized controlled study is needed in the future.    Figure 2: Inverse probability of treatment weighting score-adjusted survival curves from Cox-proportional hazards models for total death, cardiac death, recurrent MI, TLR, TLF, and MACE according to the type of DESs in the overall population. HR, hazard ratio; CI, confidence interval; BES, biolimus-eluting stent; EES, everolimus-eluting stent; ZES, zotarolimus-eluting stent; MI, myocardial infarction; TLR, target lesion revascularization; TLF, target lesion failure; MACE, major adverse cardiac event.