Comparison of First- and Second-Generation Drug-Eluting Stents in Patients with Acute Myocardial Infarction and Prediabetes Based on the Hemoglobin A1c Level

Objective To compare major clinical outcomes after successful percutaneous coronary intervention (PCI) with first-generation (1G) drug-eluting stents (DES) and second-generation (2G) DES in patients with acute myocardial infarction (AMI) and prediabetes. Background Patients with prediabetes are associated with an increased incidence of coronary artery disease. The relative superiority of 1G- and 2G-DES in these patients is not well established. Methods A total of 4997 patients with AMI and prediabetes were divided into two groups: the 1D-DES group (n = 726) and the 2G-DES group (n = 4271). The primary outcomes were the patient-oriented composite outcomes (POCOs) defined as all-cause death, recurrent myocardial infarction (Re-MI), and any disease revascularization at 2-year follow-up. The secondary outcome was probable or definite stent thrombosis (ST). Results After propensity score-matching (PSM) analysis, two PSM groups (698 pairs, n = 1396, C-statistics = 0.725) were generated. The cumulative incidence rates of POCOs (hazard ratio (HR): 1.467; 95% confidence interval (CI): 1.068–2.015; p = 0.018), any disease revascularization (HR: 2.259; 95% CI: 1.397–3.654; p = 0.001), and ST (HR: 4.361; 95% CI: 1.243–15.30; p = 0.021) in the 1G-DES group were significantly higher than those in the 2G-DES group. However, the cumulative incidence rates of all-cause death, cardiac death, and Re-MI were similar between the two groups. Conclusions In patients with AMI and prediabetes, 2G-DES implantation was more efficacious than 1G-DES implantation over a 2-year follow-up period. However, further studies are needed to confirm these results.


Introduction
In the fibrinolytic era, hyperglycemia, rather than normoglycemia, was a major independent prognostic factor of adverse clinical outcomes in patients with acute myocardial infarction (AMI) [1,2]. Similarly, in the drug-eluting stent (DES) era, hyperglycemia is an independent predictor of early and late mortality in patients with ST-segment elevation myocardial infarction (STEMI) regardless of the presence or absence of known diabetes [3,4]. e exact mechanisms by which hyperglycemia is associated with adverse major clinical outcomes in AMI have not been fully elucidated yet. With regard to diabetes mellitus (DM), many studies have shown its association with higher long-term risk of death, myocardial infarction (MI), and repeat revascularization in patients undergoing percutaneous coronary intervention (PCI) [5][6][7]. Patients with prediabetes are at an increased risk of cardiovascular disease (CVD), and prediabetes is associated with an increased incidence of coronary artery disease (CAD) [8,9]. Even though the relative superiority between the first-generation (1G) and secondgeneration (2G) DESs in patients with AMI is controversial [10][11][12], most previous studies were not performed under the circumstance of prediabetes. erefore, the comparative long-term clinical outcomes between the two DES generations were limited. Hence, we investigated and compared the major clinical outcomes after successful PCI with 1G-DES and 2G-DES in patients with AMI and prediabetes over a 2year follow-up period.

Study Population.
is study was a nonrandomized, multicenter, observational, and retrospective cohort study. A total of 45863 patients from the Korea AMI Registry (KAMIR) who had AMI and underwent successful stent implantation between November 2005 and June 2015 were evaluated. KAMIR is the first nationwide and multicenter registry that included >50 community and teaching hospitals in South Korea since November 2005 [13]. Eligible patients were aged ≥18 years at the time of hospital admission. Among the patients, those with incomplete laboratory results, including unidentified blood hemoglobin (Hb) A1c and blood glucose test results (n = 27737, 60.5%), those who were lost to follow-up (n = 3275, 7.1%), those who received a bare-metal stent (n = 297, 0.6%), those with concomitant use of 1G-DES and 2G-DES (n = 174, 0.4%), those with normoglycemia (n = 3845, 8.4%), those with DM (n = 5291, 11.5%), and those with cardiogenic shock (n = 247, 0.5%) were excluded. Finally, 4997 patients with AMI and prediabetes who underwent successful DES implantation were included in the study. e patients were divided into two groups: the 1G-DES group (n = 726, 14.5%; sirolimus-eluting stent (SES; Cypher, Cordis Corp., Miami Lakes, Florida; n = 313, 43.1%) and paclitaxel-eluting stent (PES, Taxus, Boston Scientific, Natick, Massachusetts; n = 413, 56.9%)) and the 2G-DES group (n = 4271, 85.5%; zotarolimus-eluting stent (ZES; Resolute Integrity, Medtronic, Inc., Minneapolis, MN; n = 1466, 34.3%), everolimus-eluting stent (EES; Xience Prime, Abbott Vascular, Santa Clara, CA; or Promus Element, Boston Scientific, Natick, MA; n = 2132, 49.9%), biolimus-eluting stent (BES; BioMatrix Flex, Biosensors International, Morges, Switzerland; or Nobori, Terumo Corporation, Tokyo, Japan; n = 577, 13.5%), and other stents (n = 96, 2.2%); Figure 1). e study protocol was approved by the institutional review board of each participating center, and the study was conducted in accordance with the principles of the 1975 Declaration of Helsinki. In this retrospective study, we evaluated patients who had provided written informed consent prior to participation in the KAMIR study. erefore, any information concerning adverse events of these 4997 participants with AMI and prediabetes including the time intervals and the types of events after the index PCI, which occurred during a 2-year follow-up period, was monitored at the outpatient clinic, by phone calls, or by reviewing their charts at each participating center in those days.

Percutaneous Coronary Intervention and Medical
Treatment. Coronary angiography and PCI were performed in accordance with the general guideline [14]. Before PCI, all the patients received loading doses of aspirin 200-300 mg and clopidogrel 300-600 mg; alternatively, ticagrelor 180 mg or prasugrel 60 mg was administered. Dual antiplatelet therapy (DAPT; a combination of aspirin 100 mg/day with clopidogrel 75 mg/day or ticagrelor 90 mg twice daily or prasugrel 5-10 mg/day) for > 12 months was recommended for patients who underwent PCI. Administration of triple antiplatelet therapy (cilostazol (Pletal ® , Otsuka Pharmaceutical Co., Tokyo, Japan) 100 mg twice daily added to DAPT) was left to the discretion of the individual physicians.

Study Definitions and Clinical Outcomes.
Prediabetes was determined based on the medical history and glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG) levels at the index hospitalization and defined as an HbA1c level of 5.7%-6.4% and an FPG level of 100-125 mg/dL (5.6-6.9 mmol/L) [15]. ST-segment elevation myocardial infarction (STEMI) and non-STEMI were defined in accordance with the current guidelines [16,17]. In NSTEMI cases, an early invasive treatment strategy was defined as performing PCI within 24 hours after admission [17]. A successful PCI was defined as a residual stenosis of <30% and thrombolysis in myocardial infarction (TIMI) with grade III flow for the infarct-related artery (IRA) after the procedure. e primary clinical outcome of this study was the occurrence of patient-oriented composite outcomes (POCOs) defined as all-cause death, recurrent myocardial infarction (Re-MI), or any disease revascularization (ADR) at 2-year follow-up. e secondary outcome was definite or probable stent thrombosis (ST) at 2-year follow-up. Allcause death was classified as cardiac death (CD) or non-CD. ADR was composed of target lesion revascularization (TLR), target vessel revascularization (TVR), and non-TVR. e definitions of Re-MI, TLR, TVR, and non-TVR were previously published [18]. e cumulative incidence of ST was defined by current consensus as acute (0 to 24 h), subacute (24 h to 30 days), late (30 days to 1 year), and very late (>1 year) [19].

Statistical Analyses.
For continuous variables, in this study, the normality test was performed using the Kolmogorov-Smirnov normality test. According to the normality results, the independent samples t-test was applied to examine the difference of continuous variables means of the two groups, and the data were expressed as the mean ± standard deviations. For categorical variables, the differences between the two groups were analyzed using the chi-squared test or, if not applicable, Fisher's exact test, and the data were expressed as counts and percentages. To adjust for potential confounders, a propensity scorematching (PSM) analysis was performed using a logistic regression model. We tested all available variables listed in Table 1 that could be of potential relevance. e C-statistics for PSM was 0.725 in the current study. Patients in the 1G-DES group were then one-to-one matched to those in the  2G-DES group according to propensity scores with the nearest available pair-matching method. Subjects were matched with a caliper width equal to 0.01. e procedure yielded 698 matched pairs. Various clinical outcomes were estimated using the Kaplan-Meier method, and differences between the two groups were compared using the log-rank test. For all analyses, two-sided values of p < 0.05 were considered statistically significant. All statistical analyses were performed using the SPSS version 20 software (IBM; Armonk, NY, USA).

Baseline
Characteristics. e baseline clinical, laboratory, and procedural characteristics of the study population are summarized in Table 1. e mean age (63.8 ± 12.1 years 85.5%, p < 0.001) was significantly higher in the 2G-DES group than in the 1G-DES group. e proportion of patients with cardiopulmonary resuscitation (CPR) on admission (4.2% vs. 2.3%, p � 0.013) and the prescription rates of aspirin, ticagrelor, prasugrel, and lipid-lowering agents as discharge medications; the number of American College of Cardiology/American Heart Association (ACC/ AHA) type C lesions; the incidence of single-vessel disease; the use frequency of optical coherence tomography and fractional flow reserve; and the mean total length of the deployed stents were significantly greater in the 2G-DES group than in the 1G-DES group. By contrast, the prescription rates of clopidogrel and cilostazol as discharge medications and the incidence of ≥ 3-vessel disease were significantly higher in the 1G-DES group than in the 2G-DES group. However, these intergroup differences in baseline characteristics were well balanced after PSM adjustment.

Clinical
Outcomes. e cumulative incidences of major clinical outcomes at 2 years are listed in Table 2 and Figure 2. After PSM analysis, the cumulative incidence rates of POCOs (hazard ratio (HR): 1.467; 95% confidence interval (CI): 1.068-2.015; p � 0.018), ADR (HR: 2.259; 95% CI: 1.397-3.654; p � 0.001), and ST (HR: 4.361; 95% CI: 1.243-15.30; p � 0.021) were significantly higher in the 1G-DES group than in the 2G-DES group. However, the cumulative incidence rates of all-cause death, CD, and Re-MI were similar between the two groups. Table 3 shows the independent predictors of POCOs and ADR at 2 years. Old age (≥65 years), LVEF of <50%, CPR on admission, use of a lipid-lowering agent, and multivessel disease were significant independent predictors of POCOs. In addition, multivessel disease was a significant independent predictor of ADR in this study.

Discussion
e main findings of this study are as follows: (1) the cumulative incidence rates of POCOs, ADR, and ST were significantly higher in the 1G-DES group than in the 2G-DES group; (2) the cumulative incidence rates of all-cause death, CD, and Re-MI were similar between the two groups; (3) Multivessel disease was a common independent predictor of both POCOs and ADR.
1G-DES is made of stainless steel with a closed-cell design and has a relatively thick inner diameter (130-150 μm), making them difficult to maneuver through significantly diseased and calcified vessels. In addition, the major serious problem of the 1G-DES was the occurrence of (very) late ST, induced by the polymer or even by the stent material itself [20]. By contrast, the 2G-DES is made of cobalt-chromium (CoCr) and has thinner stent struts (50-90 μm) and showed improved ability for deliverability while maintaining an adequate radial strength [21]. e polymers in the 2G-DES were more biocompatible and thromboresistant than those in the 1G-DES [22] One meta-analysis revealed that CoCr-EESs were associated with significantly lower rates of definite ST than PESs (odds ratio (OR): 0.34, 95% CI: 0.19-0.62) [23]. With regard to diabetes, Bavishi et al. [24] performed a meta-analysis of randomized trials to compare the efficacy and safety between the 1G-DES and the 2G-DES. In their study, the EES showed significantly decreased incidence rates of major adverse cardiac events by 18% (relative risk (RR)): 0.82, 95% CI: 0.70-0.96) and ST by 46% (RR: 0.54, 95% CI: 0.35-0.82) as compared with the 1G-DES. Moreover, the EES showed a trend toward reduced incidence rates of TLR and TVR (p � 0.05). e ZES was associated with 89% increased risk of TLR (RR: 1.89, 95% CI: 1.10-3.22) as compared with the 1G-DES in their study. e results of our study may be similar to those of their study. However, their study population was not confined to patients with AMI.
Higher blood glucose level was an important factor of increased risk of death and poor clinical outcome after AMI [25][26][27]. Kowalczyk et al. [28] reported that patients with HbA1c levels of ≤5.9% had significantly lower posthospital mortality (4.5%) than those with HbA1c levels of >5.9% (25.0%; p < 0.001) in 2146 AMI survivors. However, the evident underlying pathological mechanisms related to the adverse clinical outcomes in hyperglycemia status remain unclear. Liu et al. [29] suggested that elevated glucose level is associated with the development of endothelial dysfunction. Moreover, this endothelial dysfunction is the leading cause of platelet activation [30]. In addition, hyperglycemia plays an important role in the development of diabetic macrovascular complications, including atherosclerosis and restenosis [31]. Patients with diabetes have more diffuse disease that often rapidly progresses and tend to have exaggerated neointimal hyperplasia and increased need for repeat revascularization [32]. Moreover, glycosylation of vascular collagen and elastin is thought to lead to a more diffuse pattern of restenosis [33].
Even though the 2G-DES uses an evolved stent platform and a more biocompatible polymer than that in the 1G-DES, data concerning the outcomes between the two DESs in patients with AMI are conflicting [10,34]. With regard to diabetes, the relative superiority between the 1G-DES and the 2G-DES in patients with diabetes is controversial [35][36][37]. Furthermore, in patients with prediabetes, limited follow-up data are available regarding the comparative long-term effects of 1G-DES and 2G-DES implantation. Even though the study population, follow-up duration, and definition of prediabetes were different between in our study and that of Kok et al. [38], clinical outcomes were compared between prediabetes and diabetes (11.1% vs. 10.5%). erefore, the major clinical outcomes of our study could reflect the meta-analysis results of the study of Bavishi et al. [24].
ST is another controversial issue in the DES era. In our study, unexpectedly, the cumulative incidence of very late ST Journal of Interventional Cardiology       incidence rates of TVR, Re-MI, and ST as compared with ZES and PES. In the study of Kedhi et al. [35], the difference in the risk of ST was already observed in the early phase and was maintained during the 1-year follow-up. Similarly, in our study, the risk of ST was already determined within 1 year after the index PCI.
Although oral glucose tolerance test (OGTT) is considered more sensitive than measurement of HbA1c level for defining diabetes [15], in this study, prediabetes was determined on the basis of patients' medical history and HbA1c and FPG levels at the index hospitalization. One of the main advantages of measuring HbA1c level is that it can be performed at any time because it does not require fasting.
is is especially convenient in circumstances in which performing the test and interpreting the result may be difficult in the milieu of an acute illness such as AMI [38,40]. erefore, despite that measurement of HbA1c level may not be ideal, it can be used as an alternative diagnostic tool for making these important assessments.
In this KAMIR study, >50 high-volume university or community hospitals in South Korea participated, but the study population was insufficient to provide meaningful results. Taken together, the results of this study may provide a meaningful message to the interventional cardiologist during PCI to help select the appropriate DES, especially in patients with AMI and prediabetes.
is study has several limitations. First, some data may have been underreported and/or missing owing to the nonrandomized nature of this study. Second, a proportion of the patients with prediabetes (based on HbA1c level) may be diagnosed with overt diabetes if retested using a more sensitive diagnostic test (e.g., OGTT). is may be a source of bias in the study. ird, the study was based on discharge medications, as we could not confirm the participants' adherence or nonadherence to their antidiabetic drugs. erefore, we could not discern the degree of glycemic control of the participants during the follow-up period, which might constitute an additional bias in this study. Fourth, the 2-year follow-up period was relatively short for determining the long-term major clinical outcomes; thus, longer follow-up period data are required. Fifth, we performed a PSM analysis to strengthen our results, but variables not included in the KAMIR study may have affected the study outcomes.
In conclusion, with regard to the beneficial effects on POCOs, ADR, and ST reduction capacity, in patient with AMI and prediabetes, 2G-DES implantation was more efficacious than 1G-DES implantation during the 2-year follow-up period. However, further randomized trials are needed to more precisely confirm the superior efficacy of 2G-DES over 1G-DES.

Data Availability
e data used to support the findings of this study are included within the article and supplementary tables.

Conflicts of Interest
e authors declare that there are no conflicts of interest regarding the publication of this paper.