Abbreviations and Acronyms

• AMI, acute myocardial infarction; 
• BMS, bare-metal stent(s); 
• DES, drug-eluting stent(s); 
• EES, everolimus-eluting stent(s); 
• GP, glycoprotein; 
• IVUS, intravascular ultrasound; 
• LAD, left anterior descending artery;
• LCX, left circumflex; 
• MACE, major adverse cardiac event(s); 
• MI, myocardial infarction; 
• PCI, percutaneous coronary intervention; 
• RCA, right coronary artery; 
• Re-MI, recurrent myocardial infarction; 
• STEMI, ST-segment elevation myocardial infarction; 
• TLF, target lesion failure; 
• TLR, target lesion revascularization;
• TVR, target vessel revascularization; 
• ZES, zotarolimus-eluting stent(s); 
• ZES-R, zotarolimus-eluting stent-Resolute

First-generation drug-eluting stents (DES), including sirolimus-eluting stents and paclitaxel-eluting stents, have been demonstrated to be superior to bare-metal stents (BMS) in reducing the need for repeat revascularization for the treatment of obstructive coronary artery disease (1). However, concerns have been raised with regard to the safety of DES, especially in the acute myocardial infarction (AMI) setting. Some studies showed that DES had a higher rate of stent thrombosis compared with BMS even long after the index procedure (2). Other studies revealed that the polymers of the first-generation DES were associated with local allergic reactions, inflammation, and delayed endothelialization, leading to early and late stent thrombosis (3). Therefore, second-generation DES with new stent platforms, polymers, and drugs have been developed with the goal to further improve upon the safety profile of first-generation DES while maintaining efficacy.

The second-generation DES use modified metal alloys that enable stent struts to be thinner and have different stent designs intended to provide better deliverability and conformability of the stent to the vessel wall. To date, the safety and efficacy of second-generation DES—such as zotarolimus-eluting stent (ZES) (Endeavor Sprint, Medtronic CardioVascular, Santa Rosa, California) and everolimus-eluting stent (EES) (Xience V, Abbott Vascular, Santa Clara, California)—has been well-established through comparisons with first-generation DES (4, 5, 6, 7 and 8). However, the role of the second-generation DES in AMI has not been fully elucidated. Furthermore, no previous study has compared EES with ZES exclusively in patients with AMI. Therefore, the aim of the present study was to evaluate the safety and efficacy of EES versus ZES in the setting of AMI in a large-scale, prospective, multicenter registry—the KAMIR registry (Korea Acute Myocardial Infarction Registry).

Methods

KAMIR

The design of the KAMIR study has been introduced before (9). In brief, it is a Korean prospective multicenter online registry designed to reflect the “real-world” practice in a series of Asian patients presenting with AMI in the DES era since November 2005. Online registry of AMI has been performed at 57 university or community hospitals, which are high-volume centers with facilities for primary percutaneous coronary intervention (PCI) and on-site cardiac surgery. Data were collected at each site by a trained study coordinator with a standardized case report form. Standardized definitions of all patient-related variables and clinical diagnoses were used. The study protocol was approved by the ethics committee at each participating institution. Patients with AMI, including both ST-segment elevation myocardial infarction (STEMI) and non–ST-segment elevation myocardial infarction (NSTEMI) were enrolled.

Study population

From January 2008 to October 2010, a total of 13,726 patients were diagnosed with AMI. In the present study, we retrospectively enrolled patients with AMI who received EES (Xience V, Abbott Vascular), or ZES (Endeavor Sprint, Medtronic CardioVascular) implantation and completed 1-year clinical follow-up. The criteria to exclude the patients were other DES or BMS implantation, balloon angioplasty alone, conservative treatment without PCI, contraindication to antithrombotic agents, known bleeding disorders, infarction related to the grafted vessel, and estimated life expectancy of <12 months.

Therefore, a total of 3,309 eligible AMI patients were finally enrolled into the present analysis. According to the DES types, patients were divided into 2 groups as follows: ZES group (n = 1,608) and EES group (n = 1,701). The use percentages of EES among the centers ranged from 7.1% to 58.6% with a median 21.8% (interquartile range: 13.3% to 33.6%). Loading doses of aspirin and clopidogrel were administered immediately after patient arrival at the hospital. The loading/maintenance doses were 200 to 300 mg/100 mg q.d. for aspirin, 300 to 600 mg/75 mg q.d. for clopidogrel. All patients were encouraged to continue dual antiplatelet therapy with aspirin and clopidogrel for at least 12 months.

PCI procedure and medical treatment

Diagnostic angiography and PCI were performed through either femoral or radial artery after administration of unfractionated heparin (70 to 100 U/kg). Patients received unfractionated heparin to maintain the activated clotting time of >250 s during the procedure. Stents were deployed after prior balloon angioplasty, and the use of cilostazol or platelet glycoprotein (GP) IIb/IIIa receptor blockers was left to the discretion of the individual operator. The successful PCI was defined as the achievement of an angiographic residual stenosis <30% in the presence of Thrombolysis In Myocardial Infarction blood flow grade 3.

During the in-hospital period, the patients received medical treatment, including beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, calcium channel blockers, and statins. After discharge, the patients were encouraged to continue the same medications they received in the hospital, except some intravenous or temporary medications.

Study definitions and clinical follow-up

The cardiovascular risk factors and past history records (age, sex, hypertension, dyslipidemia, smoking, diabetes mellitus, family history of coronary heart disease, prior myocardial infarction [MI], chronic heart failure and prior cerebrovascular disease, peripheral arterial disease) were mainly dependent on patient self-report, but the final records were left to physician discretion after he or she had comprehensively considered the patient self-report and in-hospital examination results. All deaths were considered cardiac in origin unless a noncardiac origin was definitely documented. Recurrent myocardial infarction (Re-MI) was defined as recurrent symptoms with new ST-segment elevation or re-elevation of cardiac markers to at least twice the upper limit of normal. Target lesion revascularization (TLR) was defined as ischemia-induced PCI of the target lesion due to restenosis or re-occlusion within the stent or in an adjacent 5 mm of the distal or proximal segment. Target vessel revascularization (TVR) was defined as clinically driven PCI of the target lesion or any segment of the coronary artery containing the target lesion. Target lesion failure (TLF) was defined as the composite of cardiac death, nonfatal Re-MI, or TLR. Total major adverse cardiac events (MACE) included total death, nonfatal Re-MI, or TVR. Stent thrombosis was defined according to the Academic Research Consortium definitions and categorized according to the timing of the event as acute (occurrence within the first 24 h after the index procedure), subacute (from 24 h to 30 days), and late (from 30 days to 1 year) (10).

Patients were required to visit the outpatient department of cardiology at the end of the first month and then every 6 months after the PCI procedure as well as whenever angina-like symptoms occurred. The cumulative incidences of various MACE during hospital stay and at 1 year were compared between the 2 groups.

Statistical analysis

Continuous variables were presented as mean ± SD and compared with the Student t test. Categorical variables were expressed as percentages and compared with the chi-square test or the Fischer exact test, where indicated. To account for the selection bias of different stents, we calculated propensity score predicting probability for receiving different DES in each patient. The covariates that were adjusted for exposure to DES included age, sex, Killip class on admission, cardiovascular risk factors (hypertension, dyslipidemia, smoking, diabetes mellitus, family history of coronary artery disease), prior MI, chronic heart failure and prior cerebrovascular disease, moderate to severe renal dysfunction, diagnosis (STEMI vs. NSTEMI), target vessel, number of diseased vessels, pre-procedure Thrombolysis In Myocardial Infarction blood flow grade, stent diameter, stent length, total stent number/patient, use of intravascular ultrasound (IVUS), and use of GP IIb/IIIa receptor blockers in procedure. The C-statistic for the logistic regression model that was used to calculate the propensity score matching for the 2 groups was 0.684.

Patients receiving EES were then 1-to-1 matched to the patients receiving ZES on the propensity scores with the nearest available pair matching method. Subjects were matched with a caliper width equal to 0.05. The procedure yielded 1,343 well-matched pairs. After propensity score matching, the baseline covariates were compared between the 2 stent groups. Continuous variables were compared with the paired t test, and categorical variables were compared with chi-square test or Fisher exact test, as appropriate. Various clinical outcomes at 1 year were estimated with the Kaplan-Meier method, and differences between groups were compared with the log-rank test in the propensity score-matched patients.

The proportional hazard models were used to assess the adjusted hazard ratio comparing the 2 stent types in both entire patients and propensity score-matched patients. The outcomes of both groups were censored at a fixed point of 1 year (365 days) to avoid any bias caused by different follow-up duration.

For all analyses, a 2-sided p < 0.05 was considered statistically significant. All data were processed with SPSS (version 13.0, SPSS-PC, Inc. Chicago, Illinois).

Results

There was considerable imbalance in baseline clinical and angiographic characteristics between the patients in the ZES group versus the EES group, including age, stent diameter, stent length, the rates of diabetes, prior heart failure, use of platelet GP IIb/IIIa receptor blockers, and use of IVUS during procedure (Table 1). However, the in-hospital medical treatments were similar between the 2 groups (Table 1).

After propensity score matching, the baseline clinical and angiographic characteristics of the 2 propensity-matched groups (1,343 pairs, n = 2,686 total) were balanced in most measured characteristics, except that patients in the EES group tended to receive longer stents compared with those in the ZES group (24.05 ± 4.56 mm vs. 23.68 ± 5.46 mm, p = 0.056) (Table 2).

Clinical outcomes are summarized in Table 3. In the entire patient cohort before propensity score matching, patients in the EES group had significantly lower incidences of in-hospital cardiac death, total death, and 1-year cardiac death than patients in the ZES group. Furthermore, the incidences of TLR, TVR, TLF, total MACE, probable or definite stent thrombosis, and subacute stent thrombosis were also significantly lower in the EES group than in the ZES group.

In the propensity score-matched cohort, the differences of in-hospital and 1-year mortality were no longer statistically significant. But patients in the EES group still showed significantly lower rates of TLF, total MACE, probable or definite stent thrombosis, and subacute stent thrombosis compared with those in the ZES group. Furthermore, there were numerically lower rates of TLR (p = 0.051) and TVR (p = 0.056) in the EES group than in the ZES group (Table 3).

Figure 1 shows Kaplan-Meier curves for various clinical outcomes up to 1 year in the propensity-matched cohort. Figure 2 presents adjusted hazard ratios for various 1-year clinical outcomes associated with EES compared with ZES in the entire patient (Fig. 2A) and propensity score-matched cohort (Fig. 2B). The use of EES was a statistically significant predictor of 1-year total death, TLR, TVR, TLF, total MACE, and probable or definite stent thrombosis in the entire patient cohort (Fig. 2A). In the propensity score-matched cohort, the use of EES was an independent protective predictor of TLR, TLF, total MACE, and probable or definite stent thrombosis (Fig. 2B). Figure 3 lists the independent predictors of TLF (Fig. 3A) and probable or definite stent thrombosis (Fig. 3B).