HEART (Honam EndeAvor ResoluTe) Trial is a prospective, multicenter observational study comparing the clinical benefits of ER and ES in patients with multivessel coronary artery disease in Korea. Between April 2009 and May 2011, a total of 488 patients were enrolled who underwent multivessel percutaneous coronary intervention (PCI) at 9 academic and community-based institutions in the southwestern region of Korea. The present study was conducted according to the Declaration of Helsinki. The institutional review board of all participating centers approved the study protocol. The approval number was E-2009-05-048 at Chonnam National University Hospital. Written informed consent was obtained from all participating patients.

Patients with multivessel coronary artery disease (at least 2 vessels) who underwent multivessel stent implantation with ER or ES (stent diameter: 2.5–4.0 mm, stent length: 8/9–30 mm) were deemed eligible for the trial. Inclusion criteria were patients aged ≥18 years, patients with coronary artery disease (CAD) who needed to be treated in at least 2 coronary vessels. CAD included stable angina pectoris and acute coronary syndrome [unstable angina pectoris, non-ST elevation and ST-elevation myocardial infarction (MI)]. Patients with chronic total occlusion were also deemed eligible. All patients consented to participate and authorized the collection and release of their medical information by signing the “Patient Informed Consent Form.” All lesions requiring interventions in 2 or more native coronary arteries were amendable for the implantation of 2 or more ZES. The patient or guardian was willing and able to cooperate with the study procedures and required follow-up visits. Exclusion criteria were patients with left main stem disease, patients with hypersensitivity or allergies to drugs or components in use with PCI, history of bleeding diathesis or known coagulopathy, gastrointestinal or genitourinary bleeding within the prior 3 months, major surgery within 2 months, platelet count <150,000 cells/mm³ or hemoglobin <9 g/dl, previous coronary intervention on target vessel or graft vessel disease, transplant patients, patients with left ventricular ejection fraction <30%, patients with cardiogenic shock, patients with a life expectancy <12 months, patients with kidney dysfunction (serum creatinine >2.0 mg/dl or dependence on dialysis), patients with severe hepatic dysfunction (AST and ALT >3 times upper normal reference values) and patients with known malignancy.

After PCI, aspirin at least 75 mg daily was given indefinitely. Clopidogrel 75 mg daily was given for at least 6 months. The participating centers followed the same anti-platelet regimen in terms of the duration for both study arms.

Diabetes was defined as a history of diabetes, regardless of duration of disease, need for antidiabetic agents, or a fasting blood glucose >126 mg/dl. Hypertension was defined as a history of hypertension diagnosed and treated with medication, diet and/or exercise, or blood pressure >140 mmHg systolic or 90 mmHg diastolic on at least 2 occasions, or currently being on antihypertensive pharmacologic therapy. Dyslipidemia was defined as total cholesterol >200 mg/dl, or low-density lipoprotein cholesterol ≥130 mg/dl, or high-density lipoprotein cholesterol <30 mg/dl, or admission cholesterol >200 mg/dl, or triglycerides >150 mg/dl. A family history of CAD was indicated if the patient had any direct blood relatives (parents, siblings, children) who had any of the following diagnosed at age <55 years: angina, previous coronary artery bypass graft surgery (CABG) or PCI, or MI, or sudden cardiac death without obvious cause. Chronic lung disease was defined as a history of chronic bronchitis or a diagnosis of moderate or severe obstructive (forced expiratory volume in one second <70% of predicted) or restrictive (vital capacity <70% of predicted) syndrome on spirometry.

The primary clinical endpoint was major adverse cardiac events (MACE) at 12 months. MACE were defined as the composite of death from any cause, new MI, ischemia-driven target vessel revascularization (TVR) by either PCI or CABG. Secondary end points included stent thrombosis and individual components of MACE at 12 months. TVR was considered ischemia-driven if associated with a positive functional study, a target vessel diameter stenosis ≥50% by core laboratory quantitative analysis with ischemic symptoms. The target vessel was defined as the entire major coronary vessel proximal and distal to the target lesion, which included upstream and downstream branches and the target lesion itself. MI was defined as either the development of new pathological Q waves ≥0.4 seconds in duration in ≥2 contiguous leads or an elevation of cardiac biomarkers (positive troponin-I or T, or creatine phosphokinase levels to >2.0 times normal with positive creatine phosphokinase-MB). Stent thrombosis was defined according to the Academic Research Consortium definitions.14

Clinical follow-up was done by phone or preferably by outpatient clinic visit. Follow-up coronary angiography was performed on an ischemic-driven basis. For each patient, a Case Report Form (CRF) for data recording was provided. CRFs were numbered and used in ascending numerical order. All data were recorded in a dedicated database. The investigator ensured that patient anonymity was maintained. On CRFs or other documents, patients were not identified by their names but by their CRF code. The investigator kept a separate log of patient codes, names, and addresses.

Differences between the group means were assessed with the 2-tailed Student t test. The Chi-Square test or Fisher's exact test was used to test the differences between proportions. Hazard ratios (HR) and their 95% confidence intervals (CI) were calculated for the outcome variables using Cox regression analysis. To adjust for the bias inherent to the decision of choosing ER versus ES, propensity scores were used.1516 The propensity scores were estimated for the likelihood of receiving ER using a multiple logistic regression model that contained 30 covariates shown in Tables 1 and 2: age, sex, smoking, hypertension, diabetes mellitus, dyslipidemia, prior history of MI, heart failure, family history of coronary artery disease, stroke, chronic kidney disease, chronic lung disease, clinical diagnosis, left ventricular ejection fraction, 3-vessel disease, type B2/C lesion, bifurcation lesion, pre-PCI Thrombolysis in Myocardial Infarction (TIMI) flow grade 3, transradial PCI, intravascular ultrasound-guided PCI, staged PCI, and use of aspirin, clopidogrel, glycoprotein IIb/IIIa inhibitor, unfractionated heparin, low molecular weight heparin, beta blocker, calcium channel blocker, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and statin during hospitalization. The c-statistic for the propensity model was 0.68, indicating fair ability to discriminate treatment groups. The Hosmer-Lemeshow goodness-of-fit test p-value was 0.81, confirming good calibration and fit of the multivariable model that estimated the propensity score. Matching was performed using a greedy matching protocol (1:1 nearest neighbor matching without replacement) with a caliper width of 0.2 of the standard deviation.1718 We were able to match 200 patients receiving ER to 200 patients undergoing ES implantation. We estimated standardized differences for all the covariates before and after matching to assess the balance of the covariates between the ER and ES groups. After matching, none of the covariates showed a standardized difference exceeding 10%, suggesting that all of the measured covariates were well balanced between the matched groups.1920 Differences between the matched pairs were evaluated using the paired t test or the Wilcoxon signed rank test for continuous variables and the McNemar's test for categorical variables. The risks of clinical time-to-event endpoints in the matched cohort were compared by using a Cox proportional hazards regression model stratified on matched pairs, including factors deemed significant (p-value<0.1) by univariate analysis or considered clinically important in the multivariate model. We further tested the impact of ER versus ES on 12-month clinical outcome in multiple subgroups of age, sex, diabetes, hypertension, clinical diagnosis, and 3-vessel disease. For subgroup analysis, we repeated the same propensity score matching process while matching on both the score and the subgroup variable, forcing exact matches on the subgroup characteristics. Conditional logistic regression was then used to identify treatment-subgroup interactions. Statistical significance was considered as a 2-tailed p-value<0.05. Statistical analyses were conducted using SPSS version 21 (SPSS Inc., Chicago, IL, USA) and R version 3.2.0 (R Foundation for Statistical Computing, Vienna, Austria).

In all patients, the prevalence of diabetes mellitus was higher in the ER group compared to the ES group: 42.7% vs. 31.0%, p=0.009 (Table 1). Post-PCI TIMI flow grade 3 was higher in the ER group than in the ES group: 100.0% vs. 98.0%, p=0.028 (Table 2). Medical treatment during hospitalization including dual antiplatelet therapy was not different between the groups (Table 2). In the propensity-matched cohort, there were no significant differences in baseline clinical and procedural characteristics and in-hospital medical treatment (Tables 1, 2). The rates of dual antiplatelet therapy at 12 months in ER and ES groups were 80.6% and 81.0% in all patients (p=0.903) and 79.0% and 81.0% in the propensity-matched cohort (p=0.617).

In all patients, clinical outcomes were not different between the 2 groups during hospitalization, at 1 month and 12 months (Table 3). In the propensity matched cohort, there were no differences in the in-hospital and 1-month events. Twelve-month mortality and MACE were not different between ER and ES groups: 1.0% vs. 1.0% and 5.5% vs. 2.5%, respectively (Table 3, Fig. 1). Subgroup analysis in the propensity-matched cohort showed that the treatment effects of ER and ES for 12-month MACE were similar across all the subgroups (Fig. 2).